Caroline Cristofaro investigates olfactory ensheathing transplantation in the treatment of paraplegic patients who have suffered from complete severing of the spinal nerves.
pFor many years now, patients who suffered a spinal cord injury, with complete severing of the spinal nerves leading to paraplegia, had very limited treatment options. These were typically limited to physiotherapy or the more novel treatment of nerve cell stimulation, which hopes to stimulate nerves responsible for muscle contraction (mostly used in patients with incomplete severing of the spinal nerves) (MedGadget, 2014). Both of these treatments led to patients having more independence and enabled them to better cope with their disability. In other words, these treatments helped with the management of the disability, but they did not help repair the injury (Féron et al, 2005). Thus patients had very little hope of ever being able to walk again. That is, until neurosurgeons and neurologists focused their attention on stem cell-like therapies. After about a decade, we now have published papers detailing human trials of olfactory ensheathing cell transplantation actually improving both motor and sensory functions (Tabakow et al, 2013) (Lima et al, 2005). With incredible results like these reproduced in several different countries, for patients with complete severing of the spinal nerves, walking again may eventually become a reality.
- CFS (Cerebrospinal Fluid)
- CNS (Central Nervous System)
- OEC (Olfactory Ensheathing Cells)
- ONF (Olfactory Nerve Fibroblasts)
Stem cell-like therapy itself seems like a logical treatment option in patients who are looking to regenerate nerve cells within the spinal cord, but why are specifically olfactory ensheathing cells (OECs) used? Firstly, these cells are the only part of the nervous system that are capable of lifelong regeneration and can develop into supporting cells or mature neurons (Lima et al, 2005).
Secondly, OECs won’t activate the body’s immune defences as the CNS is already constantly in contact with these cells (Lima et al, 2005) (Féron et al, 2005). CSF bathes the olfactory mucosa via the olfactory route of CSF drainage cells (Lima et al, 2005). These cells are classified as stem-like progenitor cells, not stem cells, due to their stem cell-like properties (Lima et al, 2005). In order to transplant these cells, there are two main methods that are used. The first is an olfactory mucosa autograft in the spinal cord (Lima et al, 2005), and the second is OEC and olfactory nerve fibroblast (ONF) transplantation (see footnotes) (Féron et al, 2005) (MacKay-Sim et al, 2008) (Tabakow et al, 2013).
During olfactory mucosa autograft transplantation, the scar tissue surrounding the damaged area is removed to uncover the viable nervous tissue (Lima et al, 2005). During the scar tissue removal, vasoconstrictors are administered into the olfactory mucosa before the mucosa is harvested transnasally with an endoscope (Lima et al, 2005). Lastly, the olfactory mucosa is cut into small pieces and transplanted to close the gap between the two ends of the severed spinal cord (Lima et al, 2005).
During OEC/ONF transplantation, instead of grafting the olfactory mucosa in the spinal cord gap, OECs and ONFs are isolated from the olfactory mucosa and then injected via over one hundred microinjections (Tabakow et al, 2013). These are done at various injection sites in the damaged portion of the spinal cord with extremely complex technology designed for impeccable precision with the utmost sterility (Tabakow et al, 2013).
Both the injection of OEC/ONF and autologous olfactory mucosa grafts have been found to be safe procedures, with risks similar to any major surgery (i.e. post-op infection) (Lima et al, 2005). It must be noted that the studies currently published have been more focused on assessing the safety of these procedures in humans as opposed to the benefit that could possibly be accrued from the transplants (Féron et al, 2005) (MacKay-Sim et al, 2008) (Tabakow et al, 2013) (Lima et al, 2005). With that being said, studies have, at the same time, published the improvements seen in sensory and motor functions of patients.
Darek Fidyka, a 38-year-old man who was stabbed in the back in 2010, received the OEC injections and after just 6 months, he is now able to walk with the help of a frame (cbc.ca, 2014). Fidyka has been the most successful transplant patient by far and his case has led to the recent publicity on this innovative treatment. Although Fidyka’s outcome was due to the OEC/ONF treatment, other patients receiving that same treatment did not show as significant an improvement (Tabakow et al, 2013). Most importantly, although Fidyka was classified as a patient with completely severed spinal nerves, there were a very small number of nerves still connected that had not been severed at the time of his trauma, thus greatly influencing his outcome after treatment (cbc.ca, 2014). As this is a very new treatment, the trials investigating the treatments have published conflicting results (Ekberg et al, 2014).
With the information published so far, OEC/ONF transplantations seem to be a safer treatment option compared with olfactory mucosa autografts. A paper by Ekberg et al. found that around 15% of patients undergoing an olfactory mucosa autograft developed Myelomalacia or Syringomyelia (see footnotes), but there are a minimal number of studies addressing this method compared with OEC transplantation (Ekberg et al, 2014). Millions of patients have received OEC transplantations and such large numbers are due to papers analysing the different types of injections available for patients; injections varying in the purity of OECs/ONFs and types of cells transplanted from the nasal mucosa (Ekberg et al, 2014). Results published by Tabakow et al. stated that patients who had received the OEC transplant showed regained continuity in some white matter tracts in the injured spinal cord segment and restored afferent and efferent long white matter tracts (Tabakow et al, 2013). Other papers published have also said that olfactory cell transplants may specifically be able to promote axonal regeneration (Ekberg et al., 2014). These benefits, alongside intensive neurorehabilitation, lead to “modest” functional improvement (Tabakow et al, 2013). However, compared with the very minimal improvement expected with just neurorehabilitation, olfactory cell transplantation is the first method of treatment tried with such significant and positive results, especially in patients with complete severing of the spinal nerves.
Although Fidyka’s case has perhaps led the public to believe that a cure to paraplegia in patients with completely severed spinal nerves has been found, this is still only the very beginning. Most studies investigating these treatments are, as was previously mentioned, focused on the aspect of safety and accordingly have strict inclusion and exclusion criterion leading to less than 10 patients in studies (Féron et al, 2005) (MacKay-Sim et al, 2008) (Tabakow et al, 2013) (Lima et al, 2005). Thus it will be several years before OEC/ONF injections are used as a mainstream treatment. In the future, neurologists and neurosurgeons will focus on developing this treatment to enable more patients to enter the study and leading to more concrete results being published. In addition to this, the role of neurorehabilitation must be closely examined to maximise the benefits and functional improvements in patients, as rigorous physiotherapy after the treatment is vital (Tabakow et al, 2013). Therefore, even though the practice of transplanting olfactory ensheathing cells has been found to be safe and produced some promising results so far (Féron et al, 2005) (MacKay-Sim et al, 2008) (Tabakow et al, 2013) (Lima et al, 2005), much research and treatment refinement must be done before paraplegic patients with complete severing of the spinal nerves are able to walk again.
- ONFs and OECs are the two main cell types found in the olfactory basement membrane (Tabakow et al, 2013)
- Myelomalacia: the softening of the spinal cord primarily caused by bleeding (Ekberg et al, 2014)
- Syringomyelia: cyst, called a syrinx, forms in the spinal cord which elongates over time and leads to the destruction of the spinal cord (Ekberg et al, 2014)
cbc.ca, (2014). Paralyzed man Darek Fidyka walks after cell transplant, rehab. [online] Available at: http://www.cbc.ca/news/health/paralyzed-man-darek-fidyka-walks-after-cell-transplant-rehab-1.2807316 [Accessed 8 Jan. 2015].
Ekberg, Jenney A.K. et al. (2014). Crucial roles for olfactory ensheathing cells and olfactory mucosal cells in the repair of damaged neural tracts. The Anatomical Record, Vol. 297(1), pp.121-128.
Feron, F. et al. (2005). Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain, 128(12), pp.2951-2960.
Lima, C. et al. (2005). Olfactory Mucosa Autografts in Human Spinal Cord Injury: A Pilot Clinical Study. The Journal Of Spinal Cord Medicine, 29(3), pp.191-203.
Mackay-Sim, A. et al. (2008). Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain, 131(9), pp.2376-2386.
Medgadget.com, (2015). Spinal Cord Electrical Stimulation Device Raising Hope for Paraplegics to Walk Again. [online] Available at: http://www.medgadget.com/2014/05/spinal-cord-electrical-stimulation-device-raising-hope-for-paraplegics-to-walk-again.html [Accessed 8 Jan. 2015].
Tabakow, P. et al. (2013). Transplantation of Autologous Olfactory Ensheathing Cells in Complete Human Spinal Cord Injury. cell transplant, [online] 22(9), pp.1591-1612. Available at: http://www.ingentaconnect.com/content/cog/ct/2013/00000022/00000009/art00008?token=004d14259a6b437a63736a6f3547465d7e7634775c2e3e6f644a467c79675d7c4e72477038fb6 [Accessed 8 Jan. 2015].