Comparison Of Spinal Decompression Surgery And Stem Cell Therapy For Treating Spinal Cord Injuries

1. Defined as a systematic review that uses quantitative statistical methods to synthesize and summarize the results.

2. Just as in other systematic reviews a meta-analysis has other studies as “subjects”, and identification of the studies must be done comprehensively

3. Goals are to minimize bias and random error while potentially increasing study power by considering a wide range of studies on a particular question

What would you need in order to perform a meta-analysis? Are you likely to be able to complete one?

Framing the Research question

Spinal cord injuries (SCIs) referred to damages to the spinal cord that are found responsible for alteration for changes in the function of the spinal cord that can be either permanent or temporary (McDonald, Becker and Huettner 2013). SCIs are also found to create significant effects on the autonomic functions of the body in regions that are served by the spinal cord, below the location where the lesion or injury has occurred. Hence, spinal cord injuries are considered as an emergency situation that can lead to weakness or complete loss of muscular function and sensation (Shah and Tisherman 2014). Depending on the severity of damage occurred along the spinal cord, and the location where the injury has been experienced by the individual, there are a wide variety of symptoms that range from numbness to pain and also lead to paralysis of the body. According to the National Spinal Cord Injury Association, approximately 450,000 individuals living in the United States are found to suffer from spinal cord injury (American Association of Neurological Surgeons 2018). The body systems that are primarily affected due to spinal cord injury are responsible for controlling the motor sensory and autonomic functions, found below the level of lesion.

Research evidences have identified physical trauma as the major risk factors that causes damage to the spinal cord (White and Black 2016.). However, some non-traumatic cases that involve insufficient blood flow to different parts of the body, growth of tumor and carcinoma, and infection are also considered as risk factors for such injuries (Singh et al. 2014). Forces that significantly contribute to development of these injuries encompass hyperflexion that is associated with forward movement of head, and hyperextension that involves backward movement of the head. In addition lateral stress, rotation and compression also result in traumatic injuries thereby increasing the likelihood of the person from suffering from vertebral fracture (Silva et al. 2014). Upon diagnosing these injuries with the help of CT scan or X-ray, prevention techniques are generally applied. Spinal decompression surgery encompasses various procedures implemented with the aim of relieving symptoms, caused due to compression or pressure on the spinal cord and the nerve roots (Minamide et al. 2013). This procedure generally involves removal of the bony roof that covers the spinal cord, with the aim of creating more space for the vertebrate to move freely.  It is performed the anyway all along the spine from the lumbar region to the cervical region, with a surgical incision made in the back. Three common types of spinal decompression used for treating SCIs are laminectomy, laminotomy, laminoplasty and foraminotomy (Patil et al. 2013). On the other hand, stem cell therapy involves administration of umbilical cord tissue derived stem cells that are mesenchymal in origin, in the spinal cord region that helps in regeneration of the damaged portions (Nakamura and Okano 2013). This systematic review will involve a comparison of two such prevention techniques namely, spinal decompression surgery and stem cell therapy. 

Search terms

Framing the Research question

The Research question is the integral part of a systematic review, since it focuses on this study and helps in determining the methodology. This question guides all the stages of enquiry, evaluation and reporting of relevant findings from the systematic review (Costantino, Montano and Casazza 2015). The PICO framework of questioning was used for the same. This framework is divided into four elements namely, problem/patient, intervention, comparison and outcome. The research question formulated for the systematic review was given below:

Is stem cell therapy more effective than spinal decompression surgery for treating patients with spinal cord injuries?

The question given above included all the PICO elements as follows:

Table 1- PICO elements

Search terms

The search terms used for retrieving relevant literature to be included in the systematic review were comprehensive and specific, in addition to being relevant to the research question. Focusing the search terms on the question helped in capturing all relevant data and narrowed down articles, thereby minimising capture of extraneous hits, which might result in unnecessary effort and time in assessing them (McGowan et al. 2016). The search terms used for the systematic review were ‘spinal’, ‘injuries’, ‘cord’, ‘SCI’, ‘laminectomy’, ‘laminotomy’, ‘foraminotomy’, ‘laminaplasty’, ‘decompression’, ‘surgery’, ‘stem cell’, ‘therapy’, ‘mesenchymal’, ‘umbilical’, ‘regeneration’, ‘motor’, ‘function’, ‘improvement’ and ‘treatment’. Use of several boolean operators, in combination with the aforementioned search terms helped in either broadening or narrowing down the search results.  The operator ‘AND’ narrowed down the retrieved articles by presenting all keywords in the retrieved hits.  The operator ‘NOT’ excluded irrelevant terms from the hits.  On the other hand, the ‘OR’ operator broadened the hits by connecting between synonyms that were used as search terms.

Use of wildcard searches and truncation helped in retrieving plural or singular forms of different words and also facilitated extraction of articles that contained the key terms with both British and American spelling.

Table 2- Search terms

Inclusion and exclusion criteria

Inclusion criteria refer to the characteristics that the prospective articles must have had if they were to be included in the systematic review.  The inclusion criteria were as follows:

• The articles should primarily focus on spinal cord injuries
• The intervention must be applied on adolescents and adults
• Accepted manuscripts
• The articles must be published in English
• The articles must be published not prior to 2011
• They should contain data that will allow a feasible comparison of the two preventive measures.

Exclusion criteria helped in disqualifying the prospective articles from inclusion in the systematic review and are given below:

• Systematic review based articles
• Interventions that were administered on patients eat read less than 15 years
• Articles published in foreign languages
• Articles published prior to 2011

The articles were retrieved by using the PRISMA framework that stands for ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’. It refers to an evidence-based practice or checklist that should be met while reporting systematic reviews. The PRISMA Framework most often focuses on reporting the review that is used for evaluation of randomised control trials. However, they can also be used as the foundation for reporting systematic reviews particularly that involve evaluation of certain interventions (Fleming, Koletsi and Pandis 2014). The primary purpose of using PRISMA was to improve reporting of the different types of articles, in relation to decompression surgery and stem cell therapy, for spinal cord injury treatment.  This helps in improving the overall quality of research, and will also facilitate in future clinical decision making.

Inclusion and exclusion criteria

Following search of the PubMed database, where the search terms were entered individually, with the use of truncations wildcards and boolean operators, duplicate articles were removed from the retrieved hits. This was followed by adding the number of articles that were screened, which was similar to the number of articles that were found after removal of duplicates. The articles were also screened for their abstracts and titles, the relevance of which was evaluated with regards to the research question. All articles that appeared to provide a suitable answer to the research question were included. Subtracting the total number of excluded articles, followed by the screening phase gave certain hits that were assessed for their full text eligibility. The final list comprised of six articles that were focused on either spinal decompression surgery or stem cell therapy for treating SCIs (refer to appendix).

A total of six articles were analysed for the same of which three articles were focused on exhaustive research studies that aimed to investigate the effectiveness of early versus late decompression surgery in cases of traumatic spinal cord injuries, among patients. While one of these three articles was based on a cohort study, the other was a cost-utility analysis. On the other hand, the other three articles illustrated the significance of stem cell therapy in the treatment of spinal cord injuries. The effects of intrathecal transplantation of adipose tissue derived stem cells, human induced pluripotent cells and mesenchymal stem cell graft were evaluated in these articles. The research helped in identifying the fact that there exists a wide range of options by which decompression surgery and stem cell therapy can be implemented upon patients to facilitate their survival. The review also helped to recognize the inherent property of stem cells that make them suitable for functional recovery of the spinal cord, following a traumatic or non-traumatic injury. The differences between early and late decompression surgery was also elucidated by the articles included in the review. A thematic approach has been adopted for this review, where the information presented below will be organized around a particular attribute or topic, rather than a chronological progression (Liñán and Fayolle 2015).

Feature of stem cells

The study conducted by Hur et al. (2016) illustrated the role of methylprednisolone, as the only effective agent for reducing axonal damage in SCI. This statement was supported by previous findings that determined the effectiveness of the aforementioned compound. Following an identification of the need for administering a safer treatment, in the form of a therapeutic strategy, the authors elaborated on the use of regenerated damaged cells by stem cell transplantation. The authors provided enough evidence for the use of adult stem cells owing to the fact that these cells have fewer moral and ethical issues, upon comparison to fetal-origin or embryonic stem cells. Furthermore, the basis of this research was established by previous findings presented by the authors that suggested the lack of adequate literature to investigate the effectiveness of adipose-tissue derived stem cells that are mesenchymal in origin, in treating SCI and other spinal cord injuries. Similar findings were presented by Fujimoto et al. (2012) who focused on reconstructing the damaged CNS, in cases of spinal nerve injuries. Showing consistency with the previous article, these authors also considered neural stem cell transplantation to be of extreme importance in treating SCIs, due to their inherent capability of differentiating into oligodendrocytes and neurons, with the secretion of neurotropic factors.

Evaluation of Studies

Furthermore, the feasible generation of human iPSCs from adult tissue cells led the authors conclude that these can be used to treat SCI patients. This was further facilitated by development of a protocol that focused on long-term self-renewing neuroepithelial-like stem cell generation (lt-NES). Consistency was shown with the study conducted by Quertainmont et al. (2012) in the fact that they also identified the differentiation and self-renewing capabilities of adult mesenchymal stem cells (MSCs) that made them consider these cells as potential targets for autologous transplantation. The fact that less ethical concerns are faced while working with MSCs, in comparison to foetal/embryonic stem cells made the authors select them as the intervention.

Fehlings et al. (2012) was able to identify the fact that the primary aim of intervention should be directed towards reducing extent of tissue damage and improving the neurological outcomes of all patients, having suffered from SCIs. The authors cited the fact that spinal decompression surgery has been found effective in attenuating mechanisms of SCIs and also improve neurological outcomes, which was validated by previous findings. Furthermore, the fact that previous findings correlated the neuroprotective effect strength with time elapsed, in an inverse manner helped them in forming the clinical hypothesis that timely decompression surgery would lead to less destruction of neural tissue. Consistent statements were presented by Furlan et al. (2015) who focused on the fact that early conduction of decompression surgeries after a traumatic SCI is beneficial for reducing length of hospitalization and ICU stays. Furthermore, the fact that appropriate surgical timing within 24 hours of a traumatic SCI could reduce impairment to a certain extent formed the basis of this research. The cohort study conducted by Wilson et al. (2012) also emphasized on the fact that persistent compression of the spinal cord exacerbates the secondary injury process and a timely surgery results in an improvement in the neurological functional outcomes of the patients.

Hur et al. (2016) conducted the clinical trial on candidates suffering from SCI related neurological impairment, aged 16-69 years. They sample was selected from a group of participants who were subjected to SCI treatments for a minimum period of 3 months, before the trial. Fehlings et al. (2012) conducted the multicentred trial on adults with cervical SCI, aged 16-80 years. Furlan et al. (2015) recruited patients, who were grouped into patients suffering from motor complete and incomplete SCI. The cohort study conducted by Wilson et al. (2012) enlisted participants with presenting complaints related to traumatic SCI, with neurological deficits and supporting spinal cord compression radiological evidence. However, the study conducted by Fujimoto et al. (2012) and Quertainmont et al. (2012) used mice models for the investigation.

ASIA and BMS scores

Hur et al. (2016) showed that 5 of the recruited participants demonstrated an improvement in motor functions in terms of the ASIA motor scores. Furthermore, improvement in sensory scores was also observed among 10 participants. According to Fujimoto et al. (2012) mice having subjected to hsp-NSCs were able to touch the ground with their paws, and provide support to the body with hindlimbs, thereby indicating an improvement in the BMS scores, when compared to control mice not subjected to the intervention. Functional recovery was also observed in the sample mice. An ablation of the transplanted cells reduced the scores to levels that were observed in the control mice. Similar findings were also reported by Quertainmont et al. (2012) where the MSC grafted mice demonstrated a statistically significant improvement in their mean scores, compared to control group. The MSC grafted animals were also able to reach the score that corresponded to their weight support, and also realised fine motor movements. Fehlings et al. (2012) demonstrated at least a grade 1 improvement in the AIS scores in 74 patients (56.5%) of the early decompression group and 45 patients (49.5%) in the late surgery group. Moreover, significant grade 2 improvement in AIS scores was observed among 26 patients (19.8%) in the early surgery group.

Baseline data comparison in the study conducted by Furlan et al. (2015) showed the presence of higher severity of AIS scores in the delayed compression surgery group, compared to the early intervention, for both motor complete and incomplete SCIs. Similar findings were reported by Wilson et al. (2012) where grade 1 AIS improvements were manifested by seven patients in early group (21.2%) and nine in the late surgery group (18.4%), respectively. The mean AIS score improvement was 6.2 and 9.7 points for the early and late groups, respectively.

Adverse effects

No serious adverse effects related to administration of ADMSC during the intervention and follow-up period was demonstrated by any patients (Hur et al. 2016). Minor post-operative complications were associated with headache, nausea, vomiting and urinary tract infection. Fehlings et al. (2012) suggested that 97 cases of major health complications occurred, of which 48 belonged to the early surgery group (24.2%), and 49 to the late surgery group (30.5%). Furthermore, one case of mortality in each of the two groups was encountered. However, the study conducted by Furlan et al. (2015) failed to demonstrate any significant differences in post-operative complications between the early and late decompression surgery groups. Common adverse effects were associated with wound infection, respiratory distress, neurological deterioration, and pulmonary embolism.

Cost effectiveness

There was lack of information on the cost effectiveness of the two kinds of intervention namely, decompression surgery and stem cell therapy that had been utilized as novel treatments for SCI in human subjects or mice models. The study conducted by Furlan et al. (2015) showed that early decompression surgery accounted for lower costs (US$ 524,483.81 per QALY gained), when compared to delayed spinal decompression (US$ 544,851.76 per QALY gained), thereby signifying the greater cost-effectiveness of the early surgery, in addition to the neurological benefits it exerts.

An analysis of the aforementioned systematic review suggests that on comparing adult stem cells and MSC with fetal/embryonic stem cells that have ethical complications associated with their use, the former can be considered as a potential source for therapy that aims to restore the motor condition of SCI patients. Adult stem cells generated from the umbilical cord, bone marrow, and adipose tissue can be used for SCI treatment due to their inherent characteristic differentiating into a range of mesenchymal cells (Yang et al. 2013). Furthermore, a close observation of the results presented by the aforementioned articles help to draw the conclusion that transplantation of stem cells in damaged spinal cord significantly contribute to an improvement in the neurological outcomes, with an enhanced sensory and motor capabilities. Thus, this feature significantly contributes to the fact that stem cell transplantation replaces the lost cells of the compressed or herniated spinal cord and facilitates a reconnection between the damaged neural circuits, by triggering axonal regrowth (Jin et al. 2013).

On the other hand, the timing of decompression surgery plays an important role in bringing about an improvement in neurological outcomes. Conduction of a decompression surgery, within 24 hours of SCI results in fewer complications and an increased improvement in ASI motor and sensory scores (Zhong et al. 2014). Furthermore, the decompression surgeries might also fail for patients having suffered from spinal cord injuries, who have previous histories of spinal fusion, in combination with instrumentation. Furthermore, early and late decompression might also have potential disadvantages that encompass persistent pain, nerve damage and migration of the bone graft (Fushimi et al. 2013). On the other hand, potential advantages of stem cell transplantation can be correlated with the fact that the umbilical tissues produce an abundant supply of stem cells. Furthermore, it also eliminates the need of administering drugs for production of granulocytes (Bakar et al. 2016).

Conclusion and Recommendations

Thus, it can be concluded that grafting of umbilical cord derived mesenchymal stem cells in patients suffering from SCI brings about significant improvements in neurological function and also results in regeneration of the damaged cell tissues. Grafting or injection of stem cells at the region of the spinal cord where the lesion has occurred will help to regenerate injured or damaged spinal cord. The two primary features of stem cells that confirms its selection as the appropriate intervention includes the capability of adult stem cells to differentiate to different types of cells and the ability to renew into new cells.

Furthermore, the feasibility of adoption of this technique attributes to its potential mechanism that results in a replacement of the damaged neuronal cells and also helps in remyelination of axons. Moreover, potential disadvantages related to wound infection, blood clots, CSF leakage, nerve injury, dural tear and pain symptoms result in negating out the administration of decompression surgery. The consistent feature of the ability of stem cells to differentiate and proliferate facilitates the process of neuronal recovery. Thus, the cost-effective stem cell therapy is recommended as the best procedure for treating spinal cord injuries.

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