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Thread: Spinal Cord Injury Site "Scar Tissue"

  1. #21
    "• The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going."

    Dr.Wise, concerning this point ,it was a good suggestion made by Antiquity("Perhaps a mandatory, one time membership fee could be considered")(http://sci.rutgers.edu/forum/showthr...72#post1207372 post#193) .Implementation of it would considerably enhance the membership status and at the same time probably will bring closer the "club" dissolution what is a desire of this club unintentional members.

  2. #22
    Quote Originally Posted by Wise Young View Post
    There is no rational or evidential basis for removing scar tissue from the spinal cord. It is not rational to remove "scar" because the act of removing scar will simply create more scar. There is no evidence that a majority of people with spinal cord injury have a "scar". This is where the discussion usually breaks down. What people are calling "scar" is simply accumulation of glial cells, i.e. astrocytes that grow at injury sites. This is properly called gliosis.
    .
    Wise,

    I have watched lectures of yours where you mention necrotic material being removed during intradural decompression. Is this necrotic matter gliosis related, and why would you suggest that removal of it seemed to provide such benefit to the patients?

    Thanks

  3. #23
    Quote Originally Posted by Wise Young View Post

    • The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going.

    Finally, let's work together to make all of this happen.

    Wise.
    Thank you for the reminder. You prompted me to make my 2011 $365 donation to JustADollar.

  4. #24
    Quote Originally Posted by kivi66 View Post
    "• The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going."

    Dr.Wise, concerning this point ,it was a good suggestion made by Antiquity("Perhaps a mandatory, one time membership fee could be considered")(http://sci.rutgers.edu/forum/showthr...72#post1207372 post#193) .Implementation of it would considerably enhance the membership status and at the same time probably will bring closer the "club" dissolution what is a desire of this club unintentional members.
    kivi66, as I have pointed out many times, CareCure is not for fundraising. It is a free information service for the community.

    Even if we were to decide to impose a membership fee of some kind, I suspect that less than 10% of the members of this site would be interested in contributing. It will only end up harming CareCure and will not help the cause.

    wise.

  5. #25
    Quote Originally Posted by KofQ View Post
    Wise,

    I have watched lectures of yours where you mention necrotic material being removed during intradural decompression. Is this necrotic matter gliosis related, and why would you suggest that removal of it seemed to provide such benefit to the patients?

    Thanks
    Necrotic tissue eventually is removed by macrophages. The macrophages are slowly replaced by glial cells. It is likely that all the dead and dying tissues are releasing toxins that are killing cells in the surrounding cord.

    Wise.

  6. #26
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    Wise, thanks for making a very complicated issue better understood. While I am hopeful for the future "cure" for spinal cord trauma, I wanted to know if any of these interventions (CABC) would have applications in chronic spinal cord central pain. Would these same glial cells be responsible for severe neuralgia, or paresthesia w/pain?
    My apologies if this is not the correct forum, but I am fairly new to this site and trying to research as much information on chronic neuropathic pain.
    Thanks again.

  7. #27
    Quote Originally Posted by BobG603 View Post
    Wise, thanks for making a very complicated issue better understood. While I am hopeful for the future "cure" for spinal cord trauma, I wanted to know if any of these interventions (CABC) would have applications in chronic spinal cord central pain. Would these same glial cells be responsible for severe neuralgia, or paresthesia w/pain?
    My apologies if this is not the correct forum, but I am fairly new to this site and trying to research as much information on chronic neuropathic pain.
    Thanks again.
    Bob,

    Until recently, there was no credible rationale for stem cell therapies or regenerative therapies to have any beneficial effects on neuropathic pain. In fact, the worry that may scientists and clinicians had was that the therapies may make neuropathic pain worse [1]. Of course, some people thought that transplantation of neural stem cells that can make inhibitory GABAergic neurons may inhibit neuropathic pain [2]. Davies, et al. [3] reported that certain types of transplanted astrocyte can make pain worse. Karimi-Abdolrezaee, et al. [4] reported that the combination of transplanted neural progenitor cells, growth factors, and CABC did not increase neuropathic pain in animals.

    Stem cells are now recognized to be anti-inflammatory and even anti-immune. While the mechanisms of these anti-immune/inflammatory effects are not well understood, the FDA recently approved the use of mesenchymal stem cells to treat graft-versus-host disease (GVHD) which occurs when transplanted bone marrow cells attack the body of the person receiving the cells. Umbilical cord blood has also been recognized to have these effects, possibly explaining why umbilical cord blood does not have to have perfect 6:6 HLA matching in order to engraft. One possibility is that stem cells, when transplanted to the spinal cord or even given intravenously or intrathecally, may release cytokines and other factors that inhibit inflammation in the spinal cord. Inflammation is believed to be one of the mechanisms by which neuropathic pain develops. Of course, inflammation is associated with neurotrophin production and these, in turn, stimulate sprouting that may aggravate neuropathic pain. However, all these theories don't amount to a pile of beans without evidence that stem cells reduce neuropathic pain. The proof is in the pudding.

    Clinical trial experience suggest that increased pain may be a consequence of stem cell transplants. For example, in 2007, Yoon, et al. [5] reported that patients treated with bone marrow cell transplants during the subacute phase after injury may have increased neuropathic pain. Kishk, et al. [6] recently reported that 24 or 43 subjects that received intrathecal administration of autologous bone marrow cells developed neuropathic pain. Note that these are in chronic patients that are an average of 3.6 years after injury. Recently, we incidentally observed that lithium reduced neuropathic pain in patients with chronic spinal cord injury [in preparation].

    So, evidence that stem cells or other regenerative therapies will reduce neuropathic pain is not yet available. There is some evidence suggesting that stem cell therapies may increase neuropathic pain but more evidence is required to document this.

    Wise.

    Cited References

    1. Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR and Kurpad SN (2006). Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol 201: 335-48. Department of Neurosurgery, Neuroscience Research Laboratories, Medical College of Wisconsin and Clement J Zablocki VA Medical Center, Milwaukee, WI 53226, USA. Transplantation of neural stem cells (NSCs) in the injured spinal cord has been shown to improve functional outcome; however, recent evidence has demonstrated forelimb allodynia following transplantation of embryonic NSCs. The aim of this study was to investigate whether transplantation of murine C17.2 NSCs alone or transfected with glial-derived neurotrophic factor (C17.2/GDNF) would induce allodynia in transplanted spinal cord-injured animals. One week after a T8-level spinal cord injury (SCI), C17.2, C17.2/GDNF or normal saline was injected at the injury site. Locomotor function and sensory recovery to thermal and mechanical stimuli were then measured. Spinal cords were processed immunohistochemically at the injury/transplantation site for characterization of NSC survival and differentiation; and at the cervicothoracic level for calcitonin gene-related peptide (CGRP), a neuropeptide expressed in dorsal horn nocioceptive neurons, and growth-associated protein-43 (GAP43), a marker of neuronal sprouting. Locomotor function was not significantly improved following NSC transplantation at any time (P >0.05). Significant forelimb thermal and mechanical allodynia were observed following transplantation with both NSC populations (P <0.05). The C17.2 and C17.2/GDNF NSCs survived and differentiated into a predominately astrocytic population. Calcitonin gene-related peptide and GAP43 immunoreactivity significantly increased and co-localized in cervicothoracic dorsal horn laminae I-III following C17.2 and C17.2/GDNF transplantation. This study demonstrated that murine C17.2 NSCs differentiated primarily into astrocytes when transplanted into the injured spinal cord, and resulted in thermal and mechanical forelimb allodynia. Sprouting of nocioceptive afferents occurred rostral to the injury/transplantation site only in allodynic animals, suggesting a principal role in this aberrant pain state. Further, a difference in the degree of allodynia was noted between C17.2- and C17.2/GDNF transplant-treated groups; this difference correlated with the level of CGRP/GAP43 immunoreactivity and sprouting observed in the cervicothoracic dorsal horns. Both allodynia- and CGRP/GAP43-positive afferent sprouting were less in the C17.2/GDNF group compared to the C17.2 group, suggesting a possible protective or analgesic effect of GDNF on post-injury neuropathic pain.

    2. Mukhida K, Mendez I, McLeod M, Kobayashi N, Haughn C, Milne B, Baghbaderani B, Sen A, Behie LA and Hong M (2007). Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. Stem Cells 25: 2874-85. Cell Restoration Laboratory, Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada. Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5- 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post-transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and beta-III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell-based therapies to treat chronic pain syndromes.

    3. Davies JE, Proschel C, Zhang N, Noble M, Mayer-Proschel M and Davies SJ (2008). Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol 7: 24. Department of Neurosurgery, Anschutz Medical Campus, University of Colorado Denver, 12800 East 19th Ave, Aurora, CO 80045, USA. Stephen.Davies@UCHSC.edu. ABSTRACT: BACKGROUND: Two critical challenges in developing cell-transplantation therapies for injured or diseased tissues are to identify optimal cells and harmful side effects. This is of particular concern in the case of spinal cord injury, where recent studies have shown that transplanted neuroepithelial stem cells can generate pain syndromes. RESULTS: We have previously shown that astrocytes derived from glial-restricted precursor cells (GRPs) treated with bone morphogenetic protein-4 (BMP-4) can promote robust axon regeneration and functional recovery when transplanted into rat spinal cord injuries. In contrast, we now show that transplantation of GRP-derived astrocytes (GDAs) generated by exposure to the gp130 agonist ciliary neurotrophic factor (GDAsCNTF), the other major signaling pathway involved in astrogenesis, results in failure of axon regeneration and functional recovery. Moreover, transplantation of GDACNTF cells promoted the onset of mechanical allodynia and thermal hyperalgesia at 2 weeks after injury, an effect that persisted through 5 weeks post-injury. Delayed onset of similar neuropathic pain was also caused by transplantation of undifferentiated GRPs. In contrast, rats transplanted with GDAsBMP did not exhibit pain syndromes. CONCLUSION: Our results show that not all astrocytes derived from embryonic precursors are equally beneficial for spinal cord repair and they provide the first identification of a differentiated neural cell type that can cause pain syndromes on transplantation into the damaged spinal cord, emphasizing the importance of evaluating the capacity of candidate cells to cause allodynia before initiating clinical trials. They also confirm the particular promise of GDAs treated with bone morphogenetic protein for spinal cord injury repair.

    4. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D and Fehlings MG (2010). Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 30: 1657-76. Division of Genetics and Development, Toronto Western Research Institute and Krembil Neuroscience Center, University Health Network, Toronto, Ontario M5T 2S8, Canada. karimis@cc.umanitoba.ca. The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.

    5. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, Park HC, Park SR, Min BH, Kim EY, Choi BH, Park H and Ha Y (2007). Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells 25: 2066-73. Inha Neural Repair Center, Department of Neurosurgery, Inha University College of Medicine, 7-206, Sinheung-dong 3-ga, Jung-Gu, Incheon, Korea. To assess the safety and therapeutic efficacy of autologous human bone marrow cell (BMC) transplantation and the administration of granulocyte macrophage-colony stimulating factor (GM-CSF), a phase I/II open-label and nonrandomized study was conducted on 35 complete spinal cord injury patients. The BMCs were transplanted by injection into the surrounding area of the spinal cord injury site within 14 injury days (n = 17), between 14 days and 8 weeks (n = 6), and at more than 8 weeks (n = 12) after injury. In the control group, all patients (n = 13) were treated only with conventional decompression and fusion surgery without BMC transplantation. The patients underwent preoperative and follow-up neurological assessment using the American Spinal Injury Association Impairment Scale (AIS), electrophysiological monitoring, and magnetic resonance imaging (MRI). The mean follow-up period was 10.4 months after injury. At 4 months, the MRI analysis showed the enlargement of spinal cords and the small enhancement of the cell implantation sites, which were not any adverse lesions such as malignant transformation, hemorrhage, new cysts, or infections. Furthermore, the BMC transplantation and GM-CSF administration were not associated with any serious adverse clinical events increasing morbidities. The AIS grade increased in 30.4% of the acute and subacute treated patients (AIS A to B or C), whereas no significant improvement was observed in the chronic treatment group. Increasing neuropathic pain during the treatment and tumor formation at the site of transplantation are still remaining to be investigated. Long-term and large scale multicenter clinical study is required to determine its precise therapeutic effect. Disclosure of potential conflicts of interest is found at the end of this article.

    6. Kishk NA, Gabr H, Hamdy S, Afifi L, Abokresha N, Mahmoud H, Wafaie A and Bilal D (2010). Case Control Series of Intrathecal Autologous Bone Marrow Mesenchymal Stem Cell Therapy for Chronic Spinal Cord Injury. Neurorehabil Neural Repair BACKGROUND: Autologous bone marrow mesenchymal cells that include stem cells (MSCs) are a clinically attractive cellular therapy option to try to treat severe spinal cord injury (SCI). OBJECTIVE: To study the possible value of MSCs injected intrathecally to enhance rehabilitation. METHODS: This case control, convenience sample included 64 patients, at a mean of 3.6 years after SCI. Forty-four subjects received monthly intrathecal autologous MSCs for 6 months and 20 subjects, who would not agree to the procedures, served as controls. All subjects received rehabilitation therapies 3 times weekly. Subjects were evaluated at entry and at 12 months after completing the 6-months intervention. By the ASIA Impairment Scale, ASIA grading of completeness of injury, Ashworth Spasticity Scale, Functional Ambulation Classification, and bladder and bowel control questionnaire. RESULTS: No differences were found in baseline measures and descriptors between the MSC group and control group. Although a higher percentage of the MSC group increased motor scores by 1-2 points and changed from ASIA A to B, no significant between-group improvements were found in clinical measures. Adverse effects of cells included spasticity and, in 24 out of the 43 patients developed neuropathic pain. One subject with a history of post-infectious myelitis developed encephalomyelitis after her third injection. CONCLUSION: Autologus MSCs may have side effects and may be contraindicated in patients with a history of myelitis. Their utility in treating chronic traumatic SCI needs further study in pre-clinical models and in randomized controlled trials before they should be offered to patients.

  8. #28
    Senior Member alan's Avatar
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    I remember from my spinal cord stimulator days (1986) that the doctor said he was unable to push the stimulator above my C-5 injury level because the area was blocked by scar tissue. He could barely get to C-6.

    Would a doctor today encountering the same problem in someone else still call the problem "scar tissue?"
    Alan

    Proofread carefully to see if you any words out.

  9. #29
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    I'm trying to understand what happens to the nerves after a spinal cord ischemia...is it possible that nerve cells might never rengenerate. I have a friend who has regained motor skills, but no sensory ( he can't feel anything). Could the myelin be destroyed? His SC stroke was C2-C8 but he was also given heavy dose of steroids within 12 hours. I'm just not really understanding how he can have motor without sensory? Are they different parts of the nerve ending? Could it be possible that sensory would never come back? I found the below info, but can't really tell if this is relevant more for spinal cord injuries from an accident or trauma. Also, he had an MRA and blood vessels looked normal and according to one doc his spinal cord actually showed shrinkage after the two doses of steroids ( the 2nd MRI he had about 5 days after stroke).

    This is what I pulled from NINDS site, but not sure if this happens during spinal cord stroke too. That's my main ? I guess. "When nerve cells die, they release excessive amounts of a neurotransmitter called glutamate. Since surviving nerve cells also release glutamate as part of their normal communication process, excess glutamate floods the cellular environment, which pushes cells into overdrive and self-destruction. Researchers are investigating compounds that could keep nerve cells from responding to glutamate, potentially minimizing the extent of secondary damage."

  10. #30
    Quote Originally Posted by Sarahale View Post
    I'm trying to understand what happens to the nerves after a spinal cord ischemia...is it possible that nerve cells might never rengenerate. I have a friend who has regained motor skills, but no sensory ( he can't feel anything). Could the myelin be destroyed? His SC stroke was C2-C8 but he was also given heavy dose of steroids within 12 hours. I'm just not really understanding how he can have motor without sensory? Are they different parts of the nerve ending? Could it be possible that sensory would never come back? I found the below info, but can't really tell if this is relevant more for spinal cord injuries from an accident or trauma. Also, he had an MRA and blood vessels looked normal and according to one doc his spinal cord actually showed shrinkage after the two doses of steroids ( the 2nd MRI he had about 5 days after stroke).

    This is what I pulled from NINDS site, but not sure if this happens during spinal cord stroke too. That's my main ? I guess. "When nerve cells die, they release excessive amounts of a neurotransmitter called glutamate. Since surviving nerve cells also release glutamate as part of their normal communication process, excess glutamate floods the cellular environment, which pushes cells into overdrive and self-destruction. Researchers are investigating compounds that could keep nerve cells from responding to glutamate, potentially minimizing the extent of secondary damage."
    Sarahale,

    Thank you very much for your post and questions. The answer to your questions will take some time to formulate because the reasons for your confusion are legitimate and are based on long-established misunderstandings of the spinal cord both by the public and scientists. Give me a few days to answer your question. I will do so in another thread since the discussion will include much more than whether there is "scar" in the spinal cord. It would require an explanation of what a "stroke" does to the spinal cord, what structures are responsible for motor and sensory function, the difference between neuronal and axonal regeneration, and what recovery of motor function entails.

    Wise.

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