Stems cells have the ability to self-renew (blue arrow), and turn into different cell types such as muscle cells, skin cells, and nerve cells (pictured).¹

All tissues and organs in the body originate from stem cells. Stem cells are unspecialized, blank cells that have the ability to turn into specialized cells (e.g., neural cells, muscle cells, etc) through chemical signals in the body. These cells are responsible for maintaining and repairing the tissue they are found in. Stem cells are defined by two characteristic features: 1) their ability to self-renew (i.e., make copies of themselves) and 2) their ability to differentiate into functioning cell types (i.e., they can turn into specialized cells). Some stem cells are only found in certain parts of the body or at certain stages of life. There are four main types of stem cells that are currently used in stem cell therapy or research.

Neurons extending from a group of embryonic stem cells.²

Embryonic stem cells

Embryonic stem cells are sourced from embryos that are about a week old. In Canada, embryos cannot be specifically created for research purposes. Instead, these stem cells originate from unused embryos from fertility clinics. Their use in research raises ethical controversies as the embryos are destroyed during the harvesting process. These cells are pluripotent which means that they can turn into any cell in the body except for the umbilical cord and placenta.

Adult stem cells

Adult stem cells (also known as somatic stem cells or tissue-specific stem cells) are sourced from organ tissues (e.g., the heart, bone marrow, fat) found in the bodies of infants, children, and adults. They can also be produced from discarded placentas and umbilical cords. They have less capability to self-divide and specialize into different cell types compared to embryonic stem cells. Rather, adult stem cells more commonly produce tissue types in which they are found, so are multipotent. For instance, blood stem cells only have the potential to generate red blood cells, white blood cells, and platelets.

Induced pluripotent stem cells

Advancements in technology have allowed researchers to reprogram specialized adult cells back into their pluripotent state to resemble embryonic stem cells. These cells are known as induced pluripotent stem cells. These cells are often obtained from taking a small sample from adult tissue, such as the skin. Because this process does not harm the donor nor does it involve embryos, the same ethical issues facing above-discussed cells are not encountered with induced pluripotent stem cells. Induced pluripotent stem cells can also reduce the risk of rejection by the body because the adult cells are derived from the person’s own body. Despite this exciting discovery, there are lots of obstacles to overcome before they are used in human studies.

Stem cell therapy is the use of stem cells to help replace or repair damaged tissue in the human body. In this type of therapy, stem cells are either differentiated into the cell of interest outside of the body prior to transplantation (exogenous), or directly transplanted into the site of injury (endogenous). In exogenous repair, scientists differentiate specific stem cell types in a laboratory and then implant the cells into the body. On the other hand, endogenous repair consists of directly transplanting stem cells into the body, and depends on the body’s ability to transform the cells into the specific type required for repair. These cells can be sourced from various places: autologous transplantation involves the use of stem cells from the person who is receiving the transplant, whereas allogenic transplantation involves receiving stem cells from a donor.

Currently, only a small number of conditions are approved to be treated with stem cell therapy. Bone marrow transplants for leukemia have been performed for many years. Epithelial stem cell transplants are also done to regenerate cells in those who have suffered burns or disorders of the cornea. Stem cell therapy for other purposes, including SCI, is still relatively new and much of the research is still in its early stages. The figure below highlights important landmarks in the history of stem cells research.

Healthcare professionals preparing for a stem cell transplant.¹⁸

With SCI, stem cells could theoretically be used to replace injured or destroyed nerve cells or protect further attack by the immune system around the injury site. The main goal of stem cell therapy for SCI is to improve the conduction of information past the injury. As of yet, there are no stem cell treatments that can reverse or repair a SCI. While there is some thought that stem cells may be used to help recovery, researchers are still currently unsure of exactly how stem cells/cell transplantation can help recovery from a spinal cord injury. However, many hypotheses have been made:

• Neuroprotection: Stem cells may help prevent further damage to the tissue in the area surrounding a spinal cord injury. By limiting the amount of damage, more function may be saved.
• Supporting the host cell: Stem cells may help enhance the survival of nearby cells by secreting molecules that control inflammation and/or improve the regeneration of blood cells
• Creating new blood vessels: Stem cells may help promote faster regrowth of new blood vessels and protection of the existing ones. Having more blood vessels may increase the amount of oxygen and nutrients available for surviving cells.
• Regrowth of axons: Stem cells may help axons regrow through developing bridges across the site of the lesion and decreasing scars. However, it is important to note that the regeneration of axons may not always lead to functional benefits and could even lead to adverse effects such as increased pain.
  
  

  The anatomy of a neuron.¹⁹

• Regeneration of myelin: Myelin forms insulation around nerves, allowing electrical signals to transmit efficiently to other nerve cells. Stem ce­lls may also be used to replace the support cells that wrap myelin around nerves.

Refer to our article on Neuroprotection for more information

SCI research on stem cells has largely focused on laboratory and animal experiments. Human studies are in their initial phase.²⁰

There are a number of ongoing and completed studies of weak to moderate evidence that evaluates the safety and efficacy of stem cells in people with SCI. Given that stem cells are still experimental, there is no specific stem cell type that is proven to be more effective over another. In research, studies have tested a large variation of stem cell sources, including blood, bone marrow, the nose, umbilical cords, and other nerves. While some of these stem cell sources come from fetuses, most studies have used stem cells from the person’s own body.

Care should be taken when interpreting these findings as they are derived from small trials with flaws in study design and documentation. Many more large-scale studies are required to determine whether stem cells have a role in treating people with SCI and if so, how transplantation should be done to minimize the health risks and maximize the potential of stem cell-based therapy.

Improved AIS score

In research, a common way to determine the success of any treatment is through comparing ASIA Impairment Scale (AIS) scores before and after transplantation. An individual’s AIS score consists of their muscle strength and sensation below their level of injury, in addition to anal sensation and contraction. Two weak evidence studies with a small number of participants (less than 10) found that stem cell treatments improved the AIS score of all participants. Conversely, two weak evidence studies found that only a portion (29-66.7%) of their participants saw an improvement in AIS scores.

Refer to our article on Spinal Cord Injury Basics for more information on AIS scores.

Improved sensation

There have been some mixed findings on the efficacy of stem cells on sensation. Some weak evidence research studies have seen improvements in sensation for some individuals, but no large-scale study has found improvements for their entire sample. A moderate evidence study found significant changes in sensation when compared to individuals who did not receive stem cell therapy. However, a second moderate evidence study found that sensation improved over a year, but the amount of improvement was not significantly different than individuals who did not receive stem cell therapy. Currently, it is hard to conclude whether the use of stem cells is effective for the restoration of sensation.

Improved motor function

There is some weak to moderate evidence showing that stem cells may help the recovery of motor function. The type of recovery in these studies has been quite diverse, ranging from a tetraplegic individual regaining the ability to hold their head up and move their upper limb, to the ability to walk with crutches and braces. However, the percentage of people who re-develop the ability to walk again in studies is low (i.e., 1-2 people out of 10-20 total participants). Moderate evidence suggests that stem cells may be more beneficial for movement in the arms and hands than the legs compared to people who did not receive stem cell therapy. Similar to sensation, no large-scale study has shown a high success rate in the recovery of motor functioning in response to stem cell therapy. In fact, there have been several studies that have found no improvements in motor function amongst their participants.

Improved neural connectivity

The signals relayed from the brain to the muscles are disrupted when a spinal cord injury occurs. To observe what connection remains, researchers apply stimulation to the brain and observe whether or not a signal is received at the arms/legs. If there is a signal present, researchers then note of how long it takes for the signal to get to the arms/legs, and the strength of the signal. As stem cells are supposed to theoretically help repair the spinal cord, it is thought that these signals would start to reappear/improve with stem cell therapy.

Motor evoked potentials

Motor evoked potentials are used to evaluate the connections between the brain and the muscles. Four low to moderate evidence studies have seen a reappearance of motor evoked potentials in individuals who were lacking them before, although the proportion of individuals who see a return is quite low (i.e., a range of 3-10 participants out of 20). Weak-moderate evidence research has also found improvements in the time it takes for signals to go through after stem cell therapy. It is important to note that these improvements are not always associated with improvements in AIS grades. Contrary to the previous findings, one research group found that the time taken for signals to travel from the brain to the muscle did not change, despite increases in AIS grade. This means that while functional improvements were seen, the connections between the brain and the muscle did not improve.

Somatosensory evoked potentials

The brain normally interprets sensation through a pathway (in green) of nerves that travel from the limb, to the spinal cord, to the brain.²⁴

are used to evaluate the sensory connections between the brain and the rest of the body. Several studies have found a reappearance of sensory signals in the wrist and/or ankles in a portion of their participants. For participants with sensory signals present prior to receiving stem cells, evidence shows that these signals may be strengthened, and that these signals may travel faster. Although these findings appear promising, the longevity of the strengthening effect is brought to light by one group of researchers who showed that the newly obtained sensory signals disappeared after one year. More research is required to determine how to consistently obtain these results, and to determine whether these effects are truly non-lasting.

Refer to our article on Understanding Research Evidence for more information on spontaneous recovery.

Bladder & Bowel

Individuals with spinal cord injury often experience a lack of sensation and control of their bowel and bladder. Some research suggests that stem cell therapy may restore some sensation of bladder fullness and anal sensation. There are also some positive reports on the restoration of voluntary bladder contractions and anal control. Moreover, one study (moderate evidence) indicates that stem cell therapy may further improve bladder function by allowing individuals to hold more urine in their bladder, to increase the rate of urine passage, and to empty urine with less effort from by the bladder. However, the proportion of people in these studies who receive these bladder benefits are low.

Functional Independence and Quality of Life

There is limited evidence that stem cell therapy has a positive impact on functional independence and quality of life. Participants from three studies (weak evidence) reported that their self-care ability has improved in areas including bowel/bladder management, grooming, feeding, transferring, dressing, and mobility.

Sexual functioning

Most of the research on the effects of stem cell therapy and sexual functioning has been conducted with men. One weak study found that 31% of the men had improved erections while another found that sexual functioning improved as a result of increased sensitivity in the genital area. More research is required to determine the consistency of the effects in addition to the impact on sexual functioning of women.

Evidence for no improvement

While there have been some successful findings from stem cell therapy use in SCI, there are trials that have found no effects. Three studies found that none of their participants experienced any changes in their sensory or motor function. Meanwhile, other studies with a small number of participants (e.g., 5-20) have found that stem cell therapy may have an effect for some individuals, but not others. The number of people who do not experience any positive benefits from stem cell therapy is unpredictable, and has ranged from 40-87%.

Even though Health Canada and USA Food and Drug Administration (FDA) have not yet approved of any stem cell therapies for SCI in Canada, some private clinics around the world are already selling these treatments before establishing safety and effectiveness. In Canada, offering stem cell therapies is illegal unless it is for research purposes. Before you decide, consider the following points below with a health care provider. Use these points to think critically about what is being advertised.

There is no consensus on whether stem cell therapy is effective.

As described in this article, there is a lack of evidence supporting the use of stem cell therapy for spinal cord injury. Stem cell therapy is being explored as a treatment for many types of medical conditions; however, there is only strong evidence that supports its use with blood or immune system disorders that are often experienced after cancer. Currently, scientists are unsure how to repeatedly produce positive effects with the use of stem cell therapy for individuals with SCI. In addition, there remain many uncertain aspects of stem cell therapy such as knowing which type of stem cell is most effective for replacing different tissues, how these stem cells should be manipulated to produce the required cells, and what is the best way to deliver stem cells to the target area.

There are a variety of risks associated with stem cell therapy

Safety

There are many safety risks associated with stem cell treatments, and these risks may be higher for individuals with spinal cord injuries. Some stem cell marketers may emphasize that a treatment is safer if the cells are coming from your own body; however, this does not guarantee safety. If the stem cells are grown and multiplied before being injected into your spinal cord, the cells may lose some important properties and traits in the process, such as the ability to control growth. This may lead to the development of various tumors and/or cancers. In addition, when the cells are removed from your body, it is possible that they be exposed to bacteria or viruses prior to being re-transplanted into your spine. There is also a chance that complications may arise which may lead to short- or long-term health problems. This may lead to your injury or symptoms becoming more difficult to manage.

In clinical trials with people with SCI, there have been multiple adverse events resulting from stem cell therapy. The majority of stem cell studies conclude that transplantation is relatively safe due to the lack of serious safety problems or complications observed. Mild adverse events are infrequently reported in studies, but some have been documented. Some examples that have been reported include urinary tract infections, pain, hypothermia, headaches, increased spasticity, pressure sores, and depression. Serious adverse events that have been noted in research studies include:

• • the worsening of motor functioning
  • development of a cyst on the spine (which causes a concern for cancer)
  • collection of fluid along the surgical site
  • meningitis, resulting in a decrease in AIS score
  • worsening of sensation (e.g., worsened symptoms of tingling, decrease in sensation)

However, it is important to note that these adverse effects were only monitored over the period of the study. Currently, long term effects and side effects of stem cell therapy is unknown. Further longitudinal research is required.

Financial

As the use of stem cell therapy is not currently approved by the government, most often government health programs and insurance companies will not cover the costs. The costs of receiving stem cell therapy can be very high. On top of the cost for the treatment (being in the tens of thousands of dollars itself), there is the cost of travel, accommodations, and other fees. In addition, travelling for stem cell therapy may require you to go through a medical procedure without the support of all your family and friends.

Research

Receiving an experimental treatment is not the same as participating in a clinical trial. If you choose to receive stem cell therapy from a private clinic, you may be ineligible to participate in future clinical trials. Participating in a clinical trial is advised over receiving stem cell therapy from an unregulated private clinic, as:

• • Clinical trials are overseen by an independent medical ethics committee. This group of people is there to protect your rights and safety as a participant.
  • Clinical trials require some safety and efficacy testing before trying it in humans. This ensures that the treatment is relatively safe and effective.
  • By participating in a clinical trial (research), you are contributing back to the pool of knowledge. When you partake in a research study, you help scientists learn more about stem cell therapy and the safety or effectiveness of it.
  • There is no cost for the treatment in a clinical trial, as participants are not required to pay to partake in research studies.

Stem cell marketing sites are likely misleading

Private stem cell clinics often use overly positive/ optimistic advertisements that may be misleading.³¹

Unapproved stem cell marking websites often feature many patient testimonials in addition to references to research studies. The use of testimonials may be very persuasive, but may be misleading. Some of the positive benefits that these individuals may be feeling may be the result of the placebo effect. Given that many people who go in for stem cell therapy treatment have a strong belief that it will work, they may perceive less pain or greater sensation after their treatment. Patient anecdotes should not be held equal to research evidence supporting the use of stem cell therapy.

Additionally, many private stem cell therapy clinics will try to sell the treatment by citing multiple research studies to build credibility. In reality, these research articles often have no direct association with stem cell therapy specific to spinal cord injuries. Currently, there is a lack of high-quality research studies on stem cell therapy. As a result, many of the human-based studies cited are low quality and are not specific to spinal cord injury, and some reports are based on animal trials.

Before taking part in a research trial, it is important to seek medical advice from your healthcare team. Your healthcare providers can direct you to SCI studies that are available, assess whether you are a suitable candidate, and provide you with educational resources. There are also online databases containing registered clinical trials such as SciTrialsFinder.net, ClinicalTrials.gov, ISRCTN Registry, and the International Clinical Trials Registry Platform (ICTRP).

Refer to our article on Understanding Research Evidence for more information about different types of research studies.

Ensure that the trial you wish to partake in is approved by:

• An independent review committee such as an Institutional Review Board (IRB) or Ethics Review Board (ERB) to protect your rights as a participant
• A regulatory agency such as Health Canada, USA Food and Drug Administration (FDA), or European Medicines Agency (EMEA) to make sure the treatment will be conducted in a safe manner

Experimental Treatments for Spinal Cord Injury: What you should know is a guide that outlines other important considerations to think about before agreeing to participate in a clinical trial for an experimental treatment.

Stem cells continue to be a hot topic in SCI research. Their therapeutic potential in preventing further damage to the spinal cord and promoting regrowth of nerve cells has inspired a vast number of studies. However, it is important to note that there is a lack of consistency in the research in regards to the effectiveness and reported benefits of stem cell therapy for individuals with SCI. While there has been some positive evidence for stem cell therapy in these studies, it remains unclear whether this treatment is safe and effective for people with SCI.

There are currently no approved stem cell treatments for SCI. Stem cell treatments have not been proven to be safe and effective in clinical trials. Even so, many clinics around the world offer stem cell therapies that do not have proper evidence to back up their claims. Although stem cells therapy is taking a long time to get approved as a regulated treatment, remember that the process by which research is translated into medical practice is in place to minimize harms and to maximize benefits and effectiveness. If you wish to undergo a stem cell treatment, the risks should be weighed against the benefits. It is best to discuss all treatment options with your health providers to find out which treatments are suitable for you.

For a review of how we assess evidence at SCIRE Community and advice on making decisions, please see SCIRE Community Evidence.

Understanding research evidence: https://community.scireproject.com/topic/understanding-research-evidence/

The International Society for Stem Cell Research (ISSCR): https://closerlookatstemcells.org/about-isscr/

Experimental Treatments for Spinal Cord Injury: What you should know: https://asia-spinalinjury.org/wp-content/uploads/2016/02/Experimental_Treatments_for_SCI.pdf

European Spinal Cord Injury Federation: Unproven therapies – a list of unproven stem cell clinics around the world: www.escif.org/unproven-therapies/

Evidence for “What are stem cells” is based on:

Canadian Stem Cell Foundation (2016). About Spinal Cord Injury. 1–4.

Evidence for “What are stem cells used for” is based on:

Insoo, H. (2010). The bioethics of stem cell research and therapy. Journal of Clinical Investigation. https://doi.org/10.1172/jci40435

International Society for Stem Cell Research. (2008). Patient Handbook on Stem Cell Therapies. 8.

Science learning hub. (2016). Stem cell research – timeline. Retreived from: https://sciencelearn.org.nz/resources/1967-stem-cell-research-timeline

What is biotechnology? (n.d.). Stem cells. Retrieved from: https://whatisbiotechnology.org/index.php/science/summary/stem/stem-cells-repair-tissues-and-regenerate-cells

New Scientist. (2014). Stem cell timeline: the history of a medical sensation. Retreived from: https://newscientist.com/article/dn24970-stem-cell-timeline-the-history-of-a-medical-sensation/

Evidence for “How can stem cells be used for SCI” is based on:

Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R., & Tetzlaff, W. (2017). Cell transplantation therapy for spinal cord injury. Nature Neuroscience, 20(5), 637–647. https://doi.org/10.1038/nn.4541

Evidence for “What stem cell research has been done in SCI” is based on:

Al-Zoubi, A., Jafar, E., Jamous, M., Al-Twal, F., Al-Bakheet, S., Zalloum, M., … Al-Zoubi, Z. (2014).  Transplantation of Purified Autologous Leukapheresis-Derived CD34 + and CD133 + Stem Cells for Patients with Chronic Spinal Cord Injuries: Long-Term Evaluation of Safety and Efficacy . Cell Transplantation, 23(1_suppl), 25–34. https://doi.org/10.3727/096368914×684899

Cheng, H., Liu, X., Hua, R., Dai, G., Wang, X., Gao, J., & An, Y. (2014). Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury.https://doi.org/10.1186/s12967-014-0253-7

Chotivichit, A., Ruangchainikom, M., Chiewvit, P., Wongkajornsilp, A., & Sujirattanawimol, K. (2015). Chronic spinal cord injury treated with transplanted autologous bone marrow-derived mesenchymal stem cells tracked by magnetic resonance imaging: a case report. https://doi.org/10.1186/s13256-015-0535-6

Cristante, A. F., Barros-Filho, T., Tatsui, N., Mendrone, A., Caldas, J. G., Camargo, A., … Marcon, R. M. (2009). Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord, 47, 733–738. https://doi.org/10.1038/sc.2009.24

Dai, G., Liu, X., Zhang, Z., Wang, X., Li, M., Cheng, H., … An, Y. (2013). Comparative analysis of curative effect of CT-guided stem cell transplantation and open surgical transplantation for sequelae of spinal cord injury. Retrieved from http://www.translational-medicine.com/content/11/1/315

Deda, H., Kürekçi, A. E., Kayıhan, K., Zgün, E. O. ¨, Stünsoy, U. ¨, & Kocabay, S. (2008). Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy, 10(6), 565–574. https://doi.org/10.1080/14653240802241797

Fawcett, J.W., Curt, A., Steeves, J.D., Coleman, W.P.,Tuszynski, M.H., Lammertse, D…& Short, D. (2007). Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal cord, 45(3), 190-205. doi:10.1038/sj.sc.3102007

Frolov, A. A., & Bryukhovetskiy, A. S. (2012). Effects of Hematopoietic Autologous Stem Cell Transplantation to the Chronically Injured Human Spinal Cord Evaluated by Motor and Somatosensory Evoked Potentials Methods. Cell Transplantation, 21, 49–55. https://doi.org/10.3727/096368912X633761

Jarocha, D., Milczarek, O., Kawecki, Z., Wendrychowicz, A., Kwiatkowski, S., & Majka, M. (2014). Preliminary study of autologous bone marrow nucleated cells transplantation in children with spinal cord injury. Stem Cells Translational Medicine, 3(3), 395–404. https://doi.org/10.5966/sctm.2013-0141

Jarocha, D., Milczarek, O., Wedrychowicz, A., Kwiatkowski, S., & Majka, M. (2015). Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury. Cell Transplantation, 24(4), 661–672. https://doi.org/10.3727/096368915X687796

Kang, K.-S., Kim, S. W., Oh, Y. H., Yu, J. W., Kim, K.-Y., Park, H. K., … Han, H. (2005). A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study. International Society for Cellular Therapy, 7(4), 368–373. https://doi.org/10.1080/14653240500238160

Liu, J., Han, D., Wang, Z., Xue, M., Zhu, L., Yan, H., … Wang, & H. (2013). Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy, 15, 185–191. https://doi.org/10.1016/j.jcyt.2012.09.005

Moviglia, G. A., Fernandez Viña, R., Brizuela, J. A., Saslavsky, J., Vrsalovic, F., Varela, G., … Shuster, G. S. (2006). Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy. https://doi.org/10.1080/14653240600736048

Oh, S. K., Choi, K. H., Yoo, J. Y., Kim, D. Y., Kim, S. J., & Jeon, S. R. (2016). A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury. Neurosurgery, 78(3), 436–447. https://doi.org/10.1227/NEU.0000000000001056

Oraee-Yazdani, S., Hafizi, M., Atashi, A., Ashrafi, F., Seddighi, A.-S., Hashemi, S. M., … Zali, A. (2016). Co-transplantation of autologous bone marrow mesenchymal stem cells and Schwann cells through cerebral spinal fluid for the treatment of patients with chronic spinal cord injury: safety and possible outcome. https://doi.org/10.1038/sc.2015.142

Park, H. C., Shim, Y. S., Ha, Y., Yoon, S. H., Park, S. R., Choi, B. H., & Park, H. S. (2005). Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Engineering, 11(5–6), 913–922. https://doi.org/10.1089/ten.2005.11.913

Park, J. H., Kim, D. Y., Sung, I. Y., Choi, G. H., Jeon, M. H., Kim, K. K., & Jeon, S. R. (2012). Long-term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery, 70(5), 1238–1247. https://doi.org/10.1227/NEU.0b013e31824387f9

Shin, J. C., Kim, K. N., Yoo, J., Kim, I. S., Yun, S., Lee, H., … Park, K. I. (2015). Clinical Trial of Human Fetal Brain-Derived Neural Stem/Progenitor Cell Transplantation in Patients with Traumatic Cervical Spinal Cord Injury. Neural Plasticity, 2015. https://doi.org/10.1155/2015/630932

Vaquero, J., Zurita, M., Rico, M. A., Bonilla, C., Aguayo, C., Montilla, J., … Reina, L. De. (2016). An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy, 18(8), 1025–1036. https://doi.org/10.1016/j.jcyt.2016.05.003

Vaquero, J., Zurita, M., Rico, M. A., Bonilla, C., Aguayo, C., Fernández, C., … Fernández, M. V. (2017). Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. Cytotherapy, 19, 349–359. https://doi.org/10.1016/j.jcyt.2016.12.002

Yazdani, S. O., Hafizi, M., Zali, A. R., Atashi, A., Ashrafi, F., Seddighi, A. S., & Soleimani, M. (2013). Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury. Cytotherapy. https://doi.org/10.1016/j.jcyt.2013.03.012

Evidence for “What are the risks and considerations of using stem cells” is based on:

A Closer Look at Stem Cells. (2019). Nine things to know about stem cell treatments. Retreived from: https://closerlookatstemcells.org/stem-cells-medicine/nine-things-to-know-about-stem-cell-treatments/

Al-Zoubi, A., Jafar, E., Jamous, M., Al-Twal, F., Al-Bakheet, S., Zalloum, M., … Al-Zoubi, Z. (2014).  Transplantation of Purified Autologous Leukapheresis-Derived CD34 + and CD133 + Stem Cells for Patients with Chronic Spinal Cord Injuries: Long-Term Evaluation of Safety and Efficacy . Cell Transplantation, 23(1_suppl), 25–34. https://doi.org/10.3727/096368914×684899

Anderson, K. D., Guest, J. D., Dietrich, W. D., Bunge, M. B., Curiel, R., Dididze, M., … Levi, A. D. (2017). Safety of Autologous Human Schwann Cell Transplantation in Subacute Thoracic Spinal Cord Injury. Journal of Neurotrauma, 34, 2950–2963. https://doi.org/10.1089/neu.2016.4895

Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R., & Tetzlaff, W. (2017). Cell transplantation therapy for spinal cord injury. Nature Neuroscience, 20(5), 637–647. https://doi.org/10.1038/nn.4541

Blight, A., Curt, A., Ditunno, J. F., Dobkin, B., Ellaway, P., Fawcett, J., … Guest, J. D. (2009). Position statement on the sale of unproven cellular therapies for spinal cord injury: The international campaign for cures of spinal cord injury paralysis. Spinal Cord, 47(9), 713–714. https://doi.org/10.1038/sc.2008.179

Cheng, H., Liu, X., Hua, R., Dai, G., Wang, X., Gao, J., & An, Y. (2014). Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. https://doi.org/10.1186/s12967-014-0253-7

Chotivichit, A., Ruangchainikom, M., Chiewvit, P., Wongkajornsilp, A., & Sujirattanawimol, K. (2015). Chronic spinal cord injury treated with transplanted autologous bone marrow-derived mesenchymal stem cells tracked by magnetic resonance imaging: a case report. ??? https://doi.org/10.1186/s13256-015-0535-6

Cristante, A. F., Barros-Filho, T., Tatsui, N., Mendrone, A., Caldas, J. G., Camargo, A., … Marcon, R. M. (2009). Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord, 47, 733–738. https://doi.org/10.1038/sc.2009.24

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Dai, G., Liu, X., Zhang, Z., Wang, X., Li, M., Cheng, H., … An, Y. (2013). Comparative analysis of curative effect of CT-guided stem cell transplantation and open surgical transplantation for sequelae of spinal cord injury. Retrieved from http://www.translational-medicine.com/content/11/1/315

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Neuroprotection is the use of medical treatments to protect the spinal cord from further injury in the hours to weeks after a spinal cord injury first happens. The term neuroprotection is used to describe a wide range of mainly experimental treatments that aim to reduce damage known as secondary injury.

Secondary injury

There are two main phases of damage that happen after a spinal cord injury, primary injury and secondary injury. The damage that is directly caused by the initial injury is called primary injury. Primary injury happens when the spinal cord is bruised, compressed, pulled or torn, which directly injures the nerve cells and spinal cord tissues.

As the body responds to the initial injury, several bodily processes can happen, which further damage the spinal cord. This is known as secondary injury. Secondary injury is caused by several processes, such as inflammation, lack of blood flow (ischemia), and build-up of damaging chemicals, which can worsen the original injury.

Secondary injury can worsen the spinal cord injury, expanding the size of the injury and leading to further loss of function.¹

Secondary injury processes are responsible for expanding the size of the injury in the days to weeks afterwards and causing further loss of function. They can also make it harder for the body to heal.

Neuroprotection is also used to help protect against further nerve damage in other neurological conditions, such as brain injuries and degenerative diseases like amyotrophic lateral sclerosis (ALS).

During inflammation, special immune cells help get rid of foreign substances. This can lead to localized swelling.²

Inflammation and swelling

Inflammation is a natural bodily process where cells from the immune system (such as white blood cells) are brought to the site of an injury or illness. These cells remove harmful bacteria and dead cells from the area to help with healing.

Some inflammation is needed for healing. However, when it is excessive or continues for a long time, it can be damaging. Inflammation can end up breaking down healthy nerve cells (neurons), which makes the injury worse. Inflammation and other factors can also contribute to swelling of the spinal cord near the injury. Swelling can compress the spinal cord even more, damaging nerve cells and impairing blood flow.

Lack of blood flow

When the spinal cord is injured, the small blood vessels that provide oxygen and nutrients to the cord are also injured. If the blood vessels are torn, they may bleed within the spinal cord causing a bruise (called haemorrhage), which can increase the pressure on the spinal tissues and cause damage.

If the blood vessels are compressed or if there is not enough whole body blood pressure (which happens as a part of neurogenic shock), they are also unable to maintain adequate blood flow to the cord. This is called ischemia (pronounced ‘iss-kee-mee-ah’). A lack of blood flow means that oxygen or nutrients cannot reach the tissues, which can damage or kill healthy cells. Ischemia can become severe within hours after the injury and can damage nerve cells and surrounding tissues, causing the injury to get bigger.

Build-up of damaging chemicals

Damaged nerve cells can cause the release of chemical compounds like glutamate. Glutamate is a neurotransmitter that stimulates nerve cells to fire. However, too much glutamate can overstimulate the cells, causing calcium to build up inside them, which damages and kills healthy cells. This is called excitotoxicity. Excitotoxicity is a major cause of secondary damage after SCI.

Inflammation, excitotoxicity and cell damage can release by-products called free radicals. Free radicals are molecules that are unstable and highly reactive. Free radicals can damage DNA, the fragile outer membranes, and other parts of cells.

‘Neuroprotection’ refers to a wide range of different treatments, including medications and other treatments like cooling the body that aim to reduce secondary injury. It is sometimes used to describe surgical decompression and blood pressure control after SCI, although these treatments are not discussed on this page.

While there are many different neuroprotective treatment options being explored, below we briefly outline the most promising treatments currently being studied.

Steroids (Methylprednisolone)

The steroid medication Methylprednisolone is the most well-known neuroprotective treatment. It is also the only treatment that is currently used outside of research studies. High doses of methylprednisolone may affect many different aspects of secondary injury, including reducing inflammation and damage from free radicals that are thought to help prevent cells from dying after injury.

Three large-scale clinical trials were completed during 1980’s and 1990’s, which established methylprednisolone as a standard treatment that all patients with SCI should receive. However, later debate among experts criticized conclusions made in these studies and questioned the value of methylprednisolone as a treatment. It has been argued that methylprednisolone has shown only limited benefits for recovery, but well-established risk of side effects like infections.

At this time, methylprednisolone continues to be a controversial treatment among experts. It may be used in some clinical settings in certain groups of people with SCI.

Riluzole

Riluzole is a drug that blocks sodium from entering into nerve cells, which may help to reduce excitotoxicity. Riluzole is currently used to treat the degenerative neurological condition amyotrophic lateral sclerosis (ALS).

Animal studies have shown that Riluzole is effective as a neuroprotection treatment in rats with SCI. One preliminary study supported that Riluzole is safe and has potential to provide neuroprotection after SCI in humans. Currently, a large-scale clinical trial is in progress to determine whether Riluzole is effective as neuroprotection after SCI.

Minocycline

Minocycline is an antibiotic medication that is most commonly used to treat bacterial infections. Minocycline may also have neuroprotective effects after SCI. Animal studies have shown that minocycline may suppress immune cells involved in inflammation, cell death and the release of damaging chemicals. An early clinical trial has shown that IV minocycline is safe for use after acute SCI, and has potential as neuroprotection in people with incomplete SCI. Currently, a large-scale study is ongoing to investigate whether minocycline is effective as neuroprotection after SCI.

Cooling the body (therapeutic hypothermia)

Cooling the body, known as therapeutic hypothermia, is a treatment that involves reducing the temperature of the body to help protect against further damage. The body is cooled by inserting a cooling catheter into a blood vessel, which cools blood moving through circulation by a few degrees. Reducing body temperature slows metabolism, which can reduce inflammation and minimize further damage. This procedure is currently used to help prevent neurological damage after cardiac arrest.

A small preliminary study has shown that therapeutic hypothermia is safe and has potential as neuroprotection after SCl. Currently, a clinical trial is underway to determine whether spinal cord cooling is effective as neuroprotection for SCI in humans.

Cerebrospinal fluid drainage

Cerebrospinal fluid (CSF) drainage is a technique that involves inserting a small catheter through the coverings of the spinal cord to drain a small amount of the fluid that surrounds the spinal cord and brain (called cerebrospinal fluid). Draining the cerebrospinal fluid is thought to help relieve pressure and reduce further injury to the spinal cord.

Animal studies have shown that cerebrospinal fluid drainage may help improve spinal cord blood flow when combined with careful blood pressure management. One small research study has shown that cerebrospinal fluid drainage was safe for use in people with acute SCI. A larger study has been completed to determine whether cerebrospinal fluid drainage is effective as neuroprotection after SCI. However, the results have not yet been published.

Magnesium

Magnesium has been proposed as a neuroprotective treatment because it can help to reduce excitotoxicity and inflammation. Animal studies have shown benefits for magnesium as neuroprotection.

Cethrin (VX-210)

Cethrin (VX-210) is a medication that reduces the effects of Rho, a protein that is present in inflammation. Rho causes damage to nerve cells and prevents nerve cell regrowth. Cethrin reverses the action of Rho, which may help protect nerve cells and allow neurons to regrow. An early study has shown that Cethrin is safe. A clinical trial testing whether it is effective has been completed with the results pending publication.

Other treatments being studied

A wide range of other treatments have been or are currently being studied. These include:

• Fibroblast growth factor
• Hepatocyte growth factor
• Erythropoetin (EPO)
• GM-1 Ganglioside (Sygen)
• Granulocyte-colony stimulating factor (G-CSF)
• Thyrotropin-releasing hormone (TRH)
• Glibenclamide or glyburide
• Special diets such as intermittent fasting

Neuroprotective treatments that are not effective

Research evidence on the following treatments has suggested that they are not effective for use as neuroprotection after SCI. These include:

• Naloxone
• Tirilazad mesylate (was not more effective than methylprednisolone, but had more side effects)
• Nimodipine
• Gacyclidine

Secondary injury is a complicated process that scientists are still working to understand. While there are many promising treatments currently being studied, there are no widely accepted treatments so far. Neuroprotection is a relatively new area of study compared to other aspects of medicine and there are a number of other factors that makes neuroprotection difficult to study.

Testing experimental treatments is lengthy and expensive

Most neuroprotective treatments are experimental and have not been tested in humans. This means that each treatment must undergo vigorous testing to determine if it is safe and effective. There are several phases of study that must be done. Usually, research studies are tested on animals first, and then typically go through at least three phases of human studies (Phase I, II, and III clinical trials) before a treatment can be determined to be safe and effective for real world use. These trials can cost millions of dollars and take several years to complete.

Designing and conducting high quality studies is very difficult

It is also very difficult to design and carry out high quality studies. There are many factors relevant to the design and how the study findings are analyzed that can affect the study’s findings. This is why many previous research studies (such as those done on methylprednisolone), are controversial even amongst experts.

In addition, neuroprotection treatments are usually given immediately after the injury during a highly stressful and confusing period. It can be challenging for patients and their families to determine whether they want to take part in a study and give their consent to participate.

Promising experimental treatments often do not translate into effective treatments

Unfortunately, many treatments that are shown to be effective in animal studies do not go on to show the same effects in the real world scenarios involved in clinical trials. Translating research into effective treatments is a complex process with many steps that are undertaken to ensure that treatments are safe and effective.

Because secondary injury is so complex, some researchers believe that it is unlikely that one single treatment will be discovered that will completely “protect” the spinal cord from further damage. Research may lead clinicians to several different treatment options that may be used together or in different situations to help protect the spinal cord from further damage.

Neuroprotection is the use of medical treatments early after the initial injury to help protect the spinal cord from further damage caused by secondary injury.

There are many different treatments being studied for use as neuroprotection. The steroid methylprednisolone is the most well known treatment, but its use is controversial among experts. Most neuroprotective treatments are currently being investigated in research studies.

Neuroprotection after SCI is an emerging area of research and clinical care that we will learn more about as research findings arise in the next few years.

Search for studies on ClinicalTrials.gov

Evidence for “Steroids (Methylprednisolone)”

Alibai E, Zand F, Rahimi A, Rezaianzadeh A. Erythropoietin plus methylprednisolone or methylprednisolone in the treatment of acute spinal cord injury: a preliminary report. Acta Med Iran 2014; 52(4):275-279.

Amar AP, Levy ML. Surgical controversies in the management of spinal cord injury. J Am Coll Surgeons 1999; 188(5):550-566.

Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: results of the second national acute spinal cord injury study. New Engl J Med 1990; 322(20):1405-1411.

Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277(20):1597-1604.

Bracken MB, Shepard MJ, Holford TR, et al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up: results of the third national acute spinal cord injury randomized controlled trial. J Neurosurg 1998; 89(5):699-706.

Chikuda H, Yasunaga H, Takeshita K, et al. Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database. Emerg Med J 2014; 31(3):201-206.

Christie SD, Comeau B, Myers T, Sadi D, Purdy M, Mendez I. Duration of lipid peroxidation after acute spinal cord injury in rats and the effect of methylprednisolone: laboratory investigation. Neurosurg Focus 2008; 25(5).

George ER, Scholten DJ, Buechler CM, et al. Failure of methylprednisolone to improve the outcome of spinal cord injuries. Am Surgeon 1995; 61(8):659-664.

Gerhart KA, Johnson RL, Menconi J, Hoffman RE, Lammertse DP. Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons. Paraplegia 1995; 33(6):316-321.

Gerndt SJ, Rodriguez JL, Pawlik JW, et al. Consequences of high-dose steroid therapy for acute spinal cord injury. J Trauma 1997; 42(2):279-284.

Hall ED. The neuroprotective pharmacology of methylprednisolone. J Neurosurg 1992; 76(1):13-22.

Ito Y, Sugimoto Y, Tomioka M, Kai N, Tanaka M. Does high dose methylprednisolone sodium succinate really improve neurological status in patient with acute cervical cord injury?: a prospective study about neurological recovery and early complications. Spine 2009; 34(20):2121-2124.

Lee BH, Lee KH, Yoon DH, et al. Effects of methylprednisolone on the neural conduction of the motor evoked potentials in spinal cord injured rats. J Korean Med Sci 2005; 20(1):132-138.

Matsumoto T, Tamaki T, Kawakami M, Yoshida M, Ando M, Yamada H. Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine 2001; 26(4):426-430.

Prendergast MR, Saxe JM, Ledgerwood AM, et al. Massive steroids do not reduce the zone of injury after penetrating spinal cord injury. J Traum 1994; 37(4):576-580.

Rasool T, Wani MA, Kirmani AR, et al. Role of methylprednisolone in acute cervical cord injuries. Indian J Surg 2004; 66(3):156-159.

Suberviola B, González-Castro A, Llorca J, Ortiz-Melón F, Miñambres E. Early complications of high-dose methylprednisolone in acute spinal cord injury patients. Injury 2008; 39(7):748-752.

Vaquero J, Zurita M, Oya S, Aguayo C, Bonilla C. Early administration of methylprednisolone decreases apoptotic cell death after spinal cord injury. Histol Histopathol 2006; 21(10-12):1091-1102.

Xiong M, Chen S, Yu H, Liu Z, Zeng Y, Li F. Neuroprotection of erythropoietin and methylprednisolone against spinal cord ischemia-reperfusion injury. J Huazhong Univ Sci 2011; 31(5):652-656.

Zhuang C, Wang L, Xu Y. Early methylprednisolone impact treatment for sensory and motor function recovery in patients with acute spinal cord injury: a self-control study. Neural Regen Res 2008; 3(5):577-580.

Evidence for “Riluzole”

Fehlings MG, Nakashima H, Nagoshi N, Chow DS, Grossman RG, Kopjar B. Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord. 2016 Jan;54(1):8-15.

Grossman RG, Fehlings MG, Frankowski RF, et al. A prospective, multicenter, Phase i matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotraum 2014; 31(3):239-255.

Satkunendrarajah K, Nassiri F, Karadimas SK, Lip A, Yao G, Fehlings MG. Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Exp Neurol. 2016 Feb;276:59-71.

Schwartz G, Fehlings MG. Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg 2001; 94(2 Suppl):245-256.

Wilson JR, Fehlings MG. Riluzole for acute traumatic spinal cord injury: a promising neuroprotective treatment strategy. World Neurosurg 2014; 81(5-6):825-829.

Evidence for “Minocycline”

Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain 2012; 135(Pt 4):1224-1236.

Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004; 3(12):744-751.

Evidence for “Cooling the body (therapeutic hypothermia)”

Kwon BK, Mann C, Sohn HM et al. , Hypothermia for spinal cord injury. Spine J. 2008, 8, 6:859–874.

Lo TP Jr, Cho KS, Garg MSet al.  , Systemic hypothermia improves histological and functional outcome after cervical spinal cord contusion in rats. J Comp Neurol . 2009, 514, 5:433–448.

Levi AD, Green BA, Wang MYet al.  , Clinical application of modest hypothermia after spinal cord injury. J Neurotrauma . 2009, 26, 3:407–415.

Evidence for “Cerebrospinal fluid drainage”

Kwon BK, Curt A, Belanger LMet al.  , Intrathecal pressure monitoring and cerebrospinal fluid drainage in acute spinal cord injury: a prospective randomized trial. Journal Neurosurg Spine . 2009, 10, 3:181–193.

Martirosyan NL, Kalani MY, Bichard WD, et al. Cerebrospinal fluid drainage and induced hypertension improve spinal cord perfusion after acute spinal cord injury in pigs. Neurosurgery 2015;76(4):461-469

Evidence for “Magnesium”

Kaptanoglu E, Beskonakli E, Okutan O, Selcuk Surucu H, Taskin Y. Effect of magnesium sulphate in experimental spinal cord injury: evaluation with ultrastructural findings and early clinical results. J Clin Neurosci 2003a;10(3): 329-334.

Kaptanoglu E, Beskonakli E, Solaroglu I, Kilinc A, Taskin Y. Magnesium sulfate treatment in experimental spinal cord injury: emphasis on vascular changes and early clinical results. Neurosurg Rev 2003b;26(4):283-287.

Evidence for “Cethrin (VX-210)”

Fehlings MG, Theodore N, Harrop J, et al. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotraum 2011; 28(5):787-796.

McKerracher L, Guertin P. Rho as a target to promote repair: translation to clinical studies with cethrin. Curr Pharm Design 2013; 19(24):4400-4410.

Evidence for “Other treatments”

Geisler FH, Coleman WP, Grieco G, Poonian D. The Sygen® multicenter acute spinal cord injury study. Spine 2001c; 26(24 Suppl):S87-S100.

Geisler FH, Dorsey FC, Coleman WP. GM-1 ganglioside in human spinal cord injury. J Neurotraum 1992; (9 Suppl 2):S517-530.

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Image credits:

1. ‘Figure 3 – There are two phases of injury after damage to the spinal cord’ from: O’Higgins M, Badner A and Fehlings M (2017) What Is Spinal Cord Injury? Front Young Minds. 5:17. doi: 10.3389/frym.2017.00017. (CC BY 3.0)
2. Immune response ©Nason vassiliev, CC BY-SA 4.0
3. Expensive watch ©Vectors Point, CC BY 3.0 US
4. Overworked ©Luis Prado, CC BY 3.0 US
5. Explosion in lab ©Gan Khoon Lay, CC BY 3.0 US