Spinal cord injury (SCI) can lead to paraplegia or quadriplegia. Although there are no fully restorative treatments for SCI, various rehabilitative, cellular and molecular therapies have been tested in animal models. Many of these have reached, or are approaching, clinical trials. Here, we review these potential therapies, with an emphasis on the need for reproducible evidence of safety and efficacy. Individual therapies are unlikely to provide a panacea. Rather, we predict that combinations of strategies will lead to improvements in outcome after SCI. Basic scientific research should provide a rational basis for tailoring specific combinations of clinical therapies to different types of SCI.

/pdf/therapeutic-interventions-after-spinal-cord-injury-319za83fnv.pdf

Therapeutic interventions after spinal cord injury.

Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and ...

/pdf/efns-guidelines-on-the-clinical-management-of-amyotrophic-23ryvnse4m.pdf

EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) : revised report of an EFNS task force

From basics to clinical: a comprehensive review on spinal cord injury.

Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.

http://www.kumc.edu/Documents/msctc/Mackay-Sim%20A,%20Brain.%202008%20.pdf

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial.

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.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2006-0807

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.

Objective To evaluate the restoration of function after spinal cord injury (SCI) in patients of different ages who have underwent intraspinal transplantation of olfactory ensheathing cells ( OECs). Methods One hundred andseventy-one SCI patients were included in this study. Of them, 139 were male and 32 were female, with age ranging from 2 to 64 years ( mean, 34. 9 years). In all SCI patients the lesions were injected at the time of operation with OECs. According to their ages, the patients were divided into 5 groups: ≤20 years group (n =9), 21 -30 years group (n = 54), 31 -40 years group (n=60), 41 -50 years group (n=34) and >51 years group (n = 14). The spinal cord function was assessed based on the American Spinal Injury Association (ASIA) Classification System before and 2 - 8 weeks after OECs transplantation. One-way ANOVA and q test were used for statistical analysis, and the data were expressed as mean ′ SD. Results After surgery, the motor scores increased by 5. 2 ′ 4.8, 8.6 ′ 8.0, 8. 3 ′ 8.8, 5.7 ′ 7.3 and 8. 2 ′7. 6 in 5 age groups respectively (F=1.009, P = 0. 404); light touch scores increased by 13.9 ′ 8.1, 15.5 ′ 14.3, 12.0 ′ 14.4, 14. 1 ′ 18.5 and 24.8 ′ 25.3 respectively (F=1.837, P= 0. 124); and pin prick scores increased by 11.1 ′ 7.9, 17. 2 ′ 14.3, 13. 2 ′ 11., 13. 6 ′ 13.9 and 25.4 ′ 24.3 respectively (F=2.651, P =0.035). Restoration of pin prick in >51 years group was better than other age groups except 21 -30 years group. Conclusion OECs transplantation can improve the neurological function of spinal cord of SCI patients regardless of their ages. Further research into the long-term outcomes of the treatment will be required.

Influence of patients' age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.

This study was designed to clarify whether transplantation of fetal olfactory ensheathing cells (OECs) would affect the clinical course of patients with amyotrophic lateral sclerosis (ALS). Thirty-five patients with probable or definite ALS were enrolled from December 2004 to September 2006; 15 patients received OECs transplantation and 20 patients did not receive OECs transplantation. OECs were cultured and injected into the bilateral corona radiata involving the pyramidal tracts of the frontal lobes. The primary end point used to indicate effectiveness was the rate of change according to the ALS Functional Rating Scale (ALS-FRS) total score. All patients were tested five times at baseline and monthly intervals during a four-month follow-up period using assessment of ALS-FRS. Thirty-one patients (14 in the OECs treated group and 17 in the controls) completed the four-month study; the remaining four patients were lost to follow-up. Patients' data were analyzed four months after OECs transplantation and at the end of the controlled period. There was no significant difference in the rate of progression as measured by the ALS-FRS total score during the first two months (p > 0.05). The functional deterioration, however, was significantly slower in the treated group than in the control group during the last two months (p < 0.05). The mean (+/-SD) change for the ALS-FRS total score was 0.07 +/- 4.18 for the treated group and 6.12 +/- 5.49 for the control group (p = 0.002) during the four months. Of the 14 patients in the treatment group, seven experienced neurological functional improvements, two were stable compared with their clinical status at entry, and the ALS-FRS scores in the other five decreased by a mean of 4.4. Of the 17 patients in the control group, only one patient's condition remained stable while the ALS-FRS scores in the other 16 decreased by a mean of 6.5. The result indicates OECs transplantation appears to be able to slow the rate of clinical progression of ALS in the first four months posttransplantation.

Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study.

Objective To determine the safety of the fetal olfactory ensheathing cell (OEC) transplantation in patients with chronic spinal cord injury (SCI) by examination of the magnetic resonance imaging (MRI) Methods A prospective clinical study involving 16 patients with chronic SCI was designed to investigate the feasibility and biological safety of the fetal OEC transplantation in treatment of SCI The olfactory bulbs from the 3-4-month-old aborted human fetuses following the strict ethical guidelines were harvested and trypsinized down to single fetal OEC These cells were then cultured for 12-17 days and were prepared for a clinical use From November 2001 to December 2002, 16 patients with chronic SCI were randomly enrolled The patients suffered from SCI for 15-8 years (average 43 years) after the injury The suspension (50 microl) containing about 1 x 10(6) fetal OECs was transplanted by an injection into the patients' spinal cords above and below the injury site All the patients were assessed before the transplantation and were followed up with MRI for 29-42 months (average 38 mon) after the transplantation Results No cell-related adverse effects were observed in any patient during the follow-up period The follow-up with MRI did not reveal any development of optic glial tumor, tumor-like mass, new hemorrhage, edema, expanding cyst, new cyst formation, infection or disruption of the neural structure in the transplant site of all the patients Conclusion This is the first clinical study demonstrating the long-term safety of the OEC therapy for SCI The results indicate that our protocol is feasible and safe in treatment of patients with chronic SCI within 38 months after the injury Although the size of the samples for our study was not big enough, the positive results of the study have encouraged us to make a further research in this field

Safety of fetal olfactory ensheathing cell transplantation in patients with chronic spinal cord injury. A 38-month follow-up with MRI.

Objective To analyze the therapeutic effect of olfactory ensheathing cells (OECs) transplantation for central nervous system diseases. Methods Between November 2001 and January 2008, 1 255 participants with central nervous system diseases were enrolled in this clinical study for fetal OECs transplantation. There were 928 males and 327 females aged 1.2-87 (mean 40) years. The course of disease was (4.52 ± 4.67) years. Among them, 656 participants su ered from chronic spinal cord injury (SCI), 457 amyotrophic lateral sclerosis (ALS), 68 cerebral palsy (CP), 20 multiple sclerosis (MS), 11 the sequelae of stoke, 10 ataxia, and 33 residual diseases. The participants came from 71 countries or regions. Accidentally abortional fetal olfactory bulbs were donated voluntarily and were cultured for 2 weeks, then were transplanted. Results One thousand one hundred and twenty-eight cases were followed up for 2-8 weeks (mean 4 weeks) to obtain integrated data. Among them, the neurological functional amelioration was noticed in 994 participants with the overall short-term improvement rate of 88.12%. Seventy-six patients experienced the various perioperative complications with the incidence rate of 6.74%. One hundred and twenty patients with SCI received over 1 year follow-up. And according to ASIA assessment, motor scores increased from (39.82 ± 20.25) to (44.55 ± 18.99) points, light touch scores from (51.56 ± 25.89) to (59.81 ± 27.72) points, pain scores from (50.36 ± 27.44) to (57.09 ± 28.51) points for foreign patients (P 0.05); motor scores increased from (40.52 ± 20.80) to (46.45 ± 20.35) points, light touch scores from (55.64 ± 26.32) to (68.64 ± 25.89) points, pain scores from (57.05 ± 26.00) to (66.13 ± 24.29) points for good rehabilitation Chinese patients (overall P 0.05); motor scores from (37.03 ± 18.52) to (38.03 ± 18.50 points (P 0.05), light touch scores from (45.88 ± 22.56) to (46.63 ± 23.09) points (P 0.05), pain scores from (45.25 ± 23.68) to (45.28 ±23.63) points (P 0.05) for poor rehabilitation Chinese patients. Compared foreign patients and good rehabilitation Chinese patients with poor rehabilitation Chinese patients, di erence in score change was remarkable (P 0.05). One hundred and six cases of ALS, 32 CP, 8 MS, 7 ataxia, and 2 stroke sequelae were followed up for 3-48, 3-36, 2-20, 7-17, 6 and 24 months, One hundred and six cases of respectively. Majority of them (113/155, 72.9%)were bene ted from OECs transplantation. Conclusion OECs transplantation into brain and spinal cord is feasible and safe . The therapeutic strategy is valuable treatment for such central nervous system diseases such as chronic SCI, ALS, CP and stroke sequelae and can improve the patients’ neurological functions and/or decrease the progressive deterioration.

[Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255 patients].

OBJECTIVE To explore the influence factors for the functional improvement after the fetal olfactory ensheathing cell (OEC) transplantation for chronic spinal cord injury(SCI). METHODS The olfactory bulbs were harvested and trypsinized down to single fetal OEC. They were cultured for 12-17 days prepared for use. From November 2001 to December 2003, a total of 300 patients volunteered for the fetal OEC transplantation, among whom 222 suffered from complete chronic SCI and 78 suffered from incomplete chronic SCI. The procedures were performed on the patients with a disease course ranging from 6 months to 31 years (average 3.1 years) after their injuries. The fetal OEC was transplanted by the form of injections into the spinal cord at the upper and lower ends of the injury site. All the patients were assessed by the ASIA standard before the transplantation and 2-8 weeks after the transplantation. The influence factors including age, sex, duration after the injury, and injury degrees and levels were compared with those in the functional improvement after fetal OEC transplantation. RESULTS The partially-improved neurological functions assessed by the ASIA standard were indicated by the motor scores increasing from 39.1 +/- 20.6 to 45.9 +/- 20.3 (P < 0.001), the light touch scores from 51.7 +/- 24.9 to 63.4 +/- 23.0 (P < 0.001), and the pin prick scores from 53.0 +/- 24.2 to 65.3 +/- 22.7 (P < 0.001). There was no significant difference in the functional improvement of the motor, light touch, and pin brick when compared with the age, sex, duration after the injury, and the injury degrees and levels. The motor scores and light touch scores at the cervical level were higher than the scores at the thoracic level. CONCLUSION The fetal OEC transplantation can partially improve the neurological functions quickly in treatment of the chronic spinal cord injury. All the influence factors except the motor scores and light touch scores, which were higher at the cervical level than at thoracic level, have no impact on the functional improvement after the fetal OEC transplantation.

Lin Chen

Papers

Influence of patients' age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.

Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study.

Safety of fetal olfactory ensheathing cell transplantation in patients with chronic spinal cord injury. A 38-month follow-up with MRI.

[Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255 patients].

Influence factors for functional improvement after olfactory ensheathing cell transplantation for chronic spinal cord injury.