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Abstract

Currently, there is a lack of effective therapeutic methods to restore neurological function for chronic complete spinal cord injury (SCI) by conventional treatment. Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have gotten benefits and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The aim of this consensus by 31 experts from 20 countries is to show the objective evidence of clinical neurorestoration for chronic complete SCI by the mentioned neurorestorative strategies. Complete chronic SCI patients are no longer told, “nothing can be done.” The clinical translation of more effective preclinical neurorestorative strategies should be encouraged as fast as possible in order to benefit patients with incurable CNS diseases. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Keywords

Consensus Clinical neurorestoration Complete chronic spinal cord injury Translational neuroscience Neurorestoratology

The Problem and Challenge

Restoring function for people with spinal cord injury (SCI) is one of the most challenging tasks in clinical practice, especially for chronic complete SCI. Now more than 60% of patients can be partially or fully restored by standard surgical management, medical therapy, and neurorehabilitation for acute and subacute incomplete SCI. Regretfully, facing chronic complete SCI, clinical studies often ignore previous physicians' efforts and their significant findings and state that there are no effective therapeutic methods to restore, even partially, neurological functions for intractable damage or diseases of the central nervous system (CNS) (1,19). We are glad to see that neurorestorative strategies with positive preclinical results have been translating to the clinic and have achieved some clinical neurorestoration. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis or related advanced assistive devices, neurotization or nerve bridging, neurorehabilitation, and other novel treatments. In this review, we summarize the data based on the scientific and professional information available up to April 2013. We also address questions and issues about the aforementioned experimental strategies. The aim of this consensus is to show the objective evidence to the medical community. The Beijing Declaration of the International Association of Neurorestoratology (IANR) states that “Neurorestoratology recognizes the importance of small functional gains that have significant effects on quality of life” (26). Hopefully, more people can understand new developments in this field. We should highlight the value of clinical neurorestoration for incurable CNS diseases and damage from a scientific viewpoint and encourage more clinical translational studies in neurorestoratology.

Search Strategy and Selection Criteria

We searched PubMed and ScienceDirect with a combination of search terms: “spinal cord injury,” “injured spinal cord,” “spinal cord trauma,” “treatment,” “therapy,” “transplantation,” and “human.” We also searched the reference lists of key articles and consulted experts who published important papers on neurorestoration, neural regeneration and sprouting, neuromodulation, neurostimulation, neuroprosthesis, neuroprotection, neuroplasticity, nerve bridging, controlling anti-inflammatory responses, neurogenesis, angiogenesis, remyelination or neurorepair, and neuroreplacement. Literature was excluded if it was not in English or if it was not relevant to complete chronic spinal cord injury. Abstracts and reports from meetings and articles dating prior to 1950 were excluded.

Evidence

Cell Therapy

Preclinical studies of over 30 types of cells have been confirmed to restore function of the animal CNS (20). Clinical evidence suggests that cell therapy or tissue transplantation is safe and feasible (2,5,12,21,34,43,45,48,49). Partial functional recovery and the quality of life improved for patients with chronic complete SCI following transplantation of cells into cord parenchyma (7,11,15,22,24, 25,31,32,59), administration of cells intrathecally (lesion area or lumbar subarachnoid space) (30) (Fig. 1), infusion of cells intravascularly (9,39,40), and by multiple routes of administration (14,44,47,50). Neurological function and daily life functions were assessed by one or more of the following scales: American Spinal Injury Association (ASIA), Frankel, International Association of Neurorestoratology (IANR) Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), Barthel, and Ashworth scales. Patients showed marked improvement in neurological and daily life functions (Table 1).

Figure 1.

Diagrammatic drawing of cell transplantation into spinal cord parenchyma or subarachnoid space.

Table 1.

Clinical Literature on Cell Therapy for Complete Chronic SCI up to April 2013

Group	Country	Year	Case Numbers	Damaged Level	Injured Period	Cell Type	Transplant Route	Time Between Transplant and Initial Effect	Observation Time	Result	Follow-Up Period	Outcome
Huang et al. (22)	China	2003	171	C(114) T(52) T12-L1 (5)	6 months– 18 years	Allogenic OEC	Cord parenchyma	–	2-8 weeks	Improved motor, sensation, and quality of life	–	–
Chernykh et al. (7)	Russia	2007	18	C4-6 (12) T1-9 (2) T10-12 (4)	<6 months (mean 34 months)	Autologous bone marrow stem cell	Into the cyst cavity and intravenously		2-4 months	No side effects	9.4 mo	Well tolerated, Barthel, and Ashworth scales improvement, increase in sensitivity and motor activity by ASIA score compared with historical control
Cristante et Brazil al. (9)	Brazil	2009	39		>2 years	Autologous peripheral blood stem cell	Intra-artery				2.5 years	Somatosensitive evoked potentials recovery in twenty-six (66.7%)
Deda et al. (11)	Turkey	2008	9			Autologous BM-derived hematopoietic progenitor stem cell	Cord parenchyma, spinal cord covered with stem cell storage material (gel foam), subarachnoid space, intravenous		3 weeks		1 year	All patients had ASIA grade B or C
Geffner et al. (14)	Ecuador	2008	52			Autologous bone marrow stem cells	Multiple routes: directly into the spinal cord, directly into the spinal canal, and intravenous					Improved in ASIA, Barthel (quality of life), Frankel, and Ashworth scoring
Guest et al. (15)	US	2006	1	C3	18 months	Allogenic OEC	Cord parenchyma		11 days	Improved one ASIA motor grade Descent of sensory level
Huang et al. (24)	China	2006	222	–	6 months-31 years (mean 3.1 years)	Allogenic OEC	Cord parenchyma	2-3 days	2-8 weeks	Improved motor, sensation and quality of life	–	–
Kang et al. (27)	S. Korea	2005	1			Allogenic multi-potent stem cells from human UC blood	Open procedure, subarachnoid space, intradural and extradural space		41 days	Improved sensory perception and movement
Huang et al. (25)	China	2012	108	C(51) T(42) T12-L1 (15)	0.5-30 (mean 3.48 ±4.73) years	Allogenic OEC	Cord parenchyma	–	–	–	3.47 ± 1.12 yr	Improved motor, sensation, and quality of life
Kumar et al. (30)	India	2009	297			Autologous bone marrow-derived mononuclear cell	Lumbar puncture					Sensory and motor improvements in 32.6% of patients
Lima et al. (31)	Portugal	2010	20		18 to 189 (mean 49) months	Autologous olfactory mucosal autografts	Cord parenchyma		4 months	AISA grades improved in 11, 6(A–>C),3 (B –> C), and 2(A–>B), and declined in 1 (B –> A). Improvements included new voluntary EMG responses (15 patients) and SSEPs (four patients)	–	–
Lima et al. (32)	Portugal	2006	7	C4-T6	6 months to 6.5 years	Autologous olfactory mucosa	Cord parenchyma			Two ASIA A patients became ASIA C. Every patient had improvement in ASIA motor scores.
Moviglia et al. (39)	Argentina	2006	2	T8 C3-C5		Autologous BM mesenchymal stem cells (MSCs) were cocultured with the patient's autoimmune T (AT) cells to be trans-differentiated into NSCs	Forty-eight hours prior to NSC implant patients received an IV infusion of 5×10(8) to 1×10(9) AT cells. NSCs were infused via a feeding artery of the lesion site.			Patient 1 received two AT-NSC treatments and neurore-habilitation for 6 months. His motor level corresponds to his first sacral metamere (S1) and his sensitive level to the fourth sacral metamere (S4). Patient 2 motor and sensitive levels reached her first and second thoracic metameres (T1-T2)
Moviglia et al. (40)	Argentina	2009	8 (five with jeopardized brachial plexus and three without)			(1) Autologous bone marrow mononuclear cell (2) Effector T-cell (3) Autologous neural stem cell	(1) Artery infusion (2) IV infusion (3) Feeding artery infusion			No side effects. Five patients evolved from ASIA A to D and regained the ability to stand up and, with varying effectiveness, to walk; two patients remained in the same condition, but exhibited motor and sensitive improvements; and one patient could not be evaluated.
Parketal. (44)	S.Korea	2012	10A or B			Autologous BMSCs	MSCs(8×l0⁶) were directly injected into the spinal cord, and 4×10⁷ cells were injected into the intradural space of 10 patients. After 4 and 8 weeks, an additional 5×10MSCs were injected into each patient through lumbar tapping.		30-39 months	Three patients improved in the motor power of the upper extremities and in activities of daily living, significant magnetic resonance imaging and electrophysiological changes
Rabinovich et al. (46)	Russia	2003	15	C(7) T(8)	1 month to 6 years	Allogenic hemopoietic tissues (2×10⁸) + Allogenic OEC (2×10⁵)	Subarachnoid implant	–	–	–	1.5-3.0 years	Six cases improved from ASIA A to C Five cases (ASIA A to B) Remaining four cases no improvement
Seledtsova et al. (50)	Russia	2010	43	C(22) T(12) Tll-L4(9)	<1 year (3) >1 and<5 years (37) >5 years (3)	Fetal nervous and hemopoietic cells (9:1 ratio, 2-2.5×10⁸)	Subarachnoid implant				>3 years	A decrease in neurological deficit with improvement of function in 48.9% cases
Wu et al. (59)	China	2012	11	Thoracic cervical	≥6 months	Autologous OEC	Cord parenchyma				14 months (range 1.0-1.5 years)	Sensation improved moderately, locomotion recovery was minimal

OEC, olfactory ensheathing cell.

Neurostimulation/Neuromodulation and Neuroprosthesis and/or Related Advanced Assistive Devices

Task-specific training with epidural stimulation might reactivate previously silent spared neural circuits or promote plasticity. These interventions could be a viable clinical approach for functional recovery for patients with complete chronic SCI (16,37,56). Transcranial direct current stimulation and visual illusion can be effective in the management of neuropathic pain following chronic SCI, with minimal side effects and can be well tolerated (13,52). Functional electrical stimulation of permanently deinnervated muscle in patients with complete chronic lower motor neuron lesions is an effective therapy, which results in rescue of muscle mass, function, and perfusion. Additional benefits are improved leg cosmetic appearance and enhanced cushioning effect for seating (28,29).

Brain–machine interfaces with neuroprosthetic limbs can help patients with long-term paralysis to recover the natural and intuitive command signals for hand placement, orientation, and reaching, allowing them to perform several of the required activities of daily living (8,18,42,51). Sensory afferentation, feedback input, and related cerebral voluntary motor commands—the latter by electroencephalography-brain–computer interface (EEG-BCI)—may thus contribute to wireless informational powering of the respective robotic suit engine for bionic standing and gait assistance. In this respect, the first conceptual and practical related insights/contributions of this are available (42).

Neurotization or Nerve Bridging

Neurotization or nerve bridging can restore some function for complete chronic SCI in patients, especially if associated with physical rehabilitation after transferring axons to a deinnervated target. Three forms of neurotization are currently being practiced in China (33,60,62,63) and Italy (4,55) and are successful in generating some functional recovery. The first involves taking a peripheral nerve from above the injury site, such as the accessory nerve or intercostal nerve, and bridging it to nerve roots or peripheral nerves for paralyzed muscles below the injury site (62,63). The second involves taking the ventral root from lumbar 5 or the sacral 1 segment above or below the injury site and connecting it to the ventral root of sacral 2 or 3 segments that normally innervate the bladder (6,33,60). The third involves taking a peripheral nerve and inserting the central stumps 4–5 mm into the ventral–lateral bundles of the thoracic cord (the corticospinal tract) just above the complete cord lesion and the distal stump of the grafts connecting to the muscle nerve of the lower limb (4,55).

Neurorehabilitation

A phenomenon called “learned nonuse” occurs after CNS injuries, and intensive, repetitive exercise can reverse atrophy of muscle and nervous tissues. Substantial recovery of function (two ASIA grades) is possible in a patient with severe C-2 ASIA Grade A injury by “activity-based recovery” (36). Multimodal intensive exercise can significantly improve motor function in subjects with chronic complete SCI, which might have therapeutic value for these patients as an adjunct to other restorative therapies (17). An individual with chronic SCI ASIA Grade A improved in overground walking ability following intensive physical therapy and robotic locomotor training (35). Yet these studies were all performed with small sample sizes, so more studies are necessary.

Combination Therapies

The degree of clinical neurorestoration by a single neurorestorative therapy is limited. Preliminary results of combination therapies for complete chronic SCI are promising for more functional neurorestoration, which include identical cell transplantation by two or more routes (14,39,40), two kinds of cells being transplanted in combination (40,46,50), cell therapy with neurorehabilitation (25), cell therapy with laser puncture, and neurorehabilitation (3). Therefore, combination therapy studies pose major challenges in terms of logistics and design in the future.

Mechanisms of Neurorestorative Therapies

The mechanisms of neurorestorative therapies for SCI include neuromodulation, neuroprotection, remyelination or neurorepair, neuroplasticity, axonal regeneration and sprouting, nerve bridging, controlling anti-inflammatory responses, neurogenesis, angiogenesis, and neuroreplacement (Fig. 2). Science is unraveling the mechanisms of neurorestoration; however, clinically, we can only provide supportive care for patients with SCI. Generally, the patient's functional neurorestoration originated from some or all of the complex mechanisms mentioned above. In fact, current neurorestoration or functional recovery most likely originates from neuromodulation or unmasking, neuroprotection, neuroplasticity, axonal sprouting and remyelination, nerve bridging and neural circuit reconstruction by neurotrophins, immune or inflammatory modulation, and local microenvironment change (20,41). Neurogenesis or axonal regeneration likely plays a smaller role in recovery (54,61). So the term neurorestoration is more accurate in describing functional recovery than neuroregeneration.

Figure 2.

Neurorestorative strategies and mechanisms for chronic complete SCI. The first vertical column lists neurorestorative strategies; the second one lists neurorestorative mechanisms; the third one shows functional neurorestoration. One strategy may restore functions through some different mechanisms, and different strategies may share the same mechanisms.

Questions

Study Design

Many would criticize many of the clinical trials for complete SCI for failing to be a randomized, double-blind control study. As we know, randomized, doubleblind control studies are not suitable for some clinical trials or studies, for example, organ (heart, liver, and kidney) transplantation, because of ethical, lawful, and scientific considerations. On the contrary, self-comparison is likely a better assessment method for clinical studies of those diseases. This is why cardiology, liver, and urology studies are not often criticized for their failure to conduct randomized, double-blind control studies. In clinical practice, patients with complete chronic SCI are always informed that there is no way of restoring their motor function, much like patients with heart failure, liver failure, and kidney failure. Furthermore, patients with chronic complete SCI vary in structural damage, level of injury, and age (even those with clinical ASIA Grade A). Results of randomized, double-blind control studies may be influenced by such diversity. However, the results of self-comparison studies are only influenced by the intervention itself. Rama's clinical study used the self-comparison design (47). Results were encouraging and support the idea of applying this design to more clinical studies of intractable diseases, such as chronic complete SCI, heart failure, liver failure, and kidney failure.

Ethics

Some ethical issues have arisen with regards to potential treatments, such as methods being immature and their mechanisms of action being unclear. The Declaration of Helsinki offers a cogent response to such concerns: “In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures if in the physician's judgement it offers hope of saving a life, re-establishing health or alleviating suffering” (58). Obviously, one of the most important objectives for physicians is to try their best to help patients. The need of clinical neurorestoration for complete chronic SCI is known, though a cure has not yet been elucidated. Many promising therapeutic techniques have been, or are being, explored. To deliberate or question is simple; however, helping patients with complete chronic SCI to improve their neurological function and quality of life presents many challenges. The medical community should encourage any efforts to discover effective therapeutic strategies and should favor, not fear, the initial clinical endeavors and pioneering strategies for patients with complete chronic SCI according to the Beijing Declaration of the International Association of Neurorestoratology (IANR) (26). We therefore encourage that the integration and combination of current confirmed effective therapies for complete chronic SCI be carried out as soon as possible so that patients can be correctly informed, enabling them to make their own decisions on receiving the maximal benefits from the achievements and advancement of neurorestoratology.

Reliability of Results

Huang et al. (20) have previously reviewed the fact that thousands of years ago (about 2500 BC), SCIs were described as “crushed vertebra,” as well as symptoms of neurological deterioration without treatment in the ancient Egyptian medical papyrus known as the Edwin Smith Surgical Papyrus by the physician and architect of the Sakkara pyramids, Imhotep. Nearly 100 years ago, in 1926, Ramon y Cajal stated with certainty that there were not any ways for CNS regeneration to occur in adults. Until now, the medical mainstream community still persists that there are not any ways to restore neurological functions for patients with SCI (1,38,53). According to the assessment standards by the Center for Evidence-based Medicine at the University of Oxford, England (http://www.cebm.net/index.aspx?o=1025), a series of clinical studies or trials with over 6 months follow-up for complete chronic SCI by cell therapy (7,9,25,30,31), neurotization, or nerve bridge (63) showed strong evidence of neurorestoration with grades A-1c. Indeed, the current neurorestoration is only partial without full recovery, but evidence is reliable and is more than enough to answer “yes” or “no” for the question of whether clinical neurorestoration is able to be attained in patients with complete chronic SCI.

Safety

Many have expressed concerns about the safety of neurorestorative strategies as new methods for patients with complete chronic SCI, but fortunately, all studies or trials including cell therapy, neuromodulation and neuroprosthesis, neurotization, or nerve bridging were well tolerated and showed good results with regard to safety and feasibility (2,5,7,9,11,12,14,15,21,22,24,25,27,30–32, 34,39,40,43–50,59).

Comprehension Difference From Medical Community and Patients

Current considerations in medical communities are if clinical neurorestoration is attainable for patients with complete chronic SCI. However, many patients with complete chronic SCI want to be cured. They often misunderstand academic language, such as that pertaining to function that may or may not cure diseases or damages. Currently, patients do not reach the whole clinical neurorestoration or total recovery that they expect, but most patients are satisfied with some degree of improving functions and quality of life (10,57). Thus, when patients intend to get any kind of neurorestorative therapies, they should know the methods, potential results, limitations, and risks, which should be clearly explained by physicians.

Implementing Translational Medicine

The key issue for implementing translational medicine is to do, not only to say. By comparing Huang et al. (20) and current publishing papers (2,3,7,11,12,15, 21,22,24,25,27,31,32,34,43,45,48,49,59), we can see that only a few kinds of cells have so far been translated from the bench to the bedside, but we would expect more to follow as our understanding of the benefits and potential pitfalls of each cell type is identified. The time is right for doing more clinical trials as patients with a severe medical status are looking forward to garnering more positive results. With the current advances in clinical progresses in the field of neurorestoratology (23), more translational studies can really make patients benefit more.

Conclusion

Translating neurorestorative strategies with positive preclinical results for complete chronic SCI to the clinic has shown that patients are able to get some degree of clinical neurorestoration. These strategies include cell therapy, neurostimulation/neuromodulation, neuroprosthesis, neurotization or nerve bridging, neurorehabilitation, and combined therapies. Now it is time to change the traditional concept that there are not any effective therapeutic methods to restore neurological function for lesions of the CNS (including complete chronic SCI). From now on, complete chronic SCI patients may no longer be told that nothing can be done. In the future, more effective preclinical neurorestorative strategies should be encouraged to be translated to the clinic as soon as possible in order to benefit patients with incurable CNS disorders.

Footnotes

Acknowledgments

Dr. Huang wrote the manuscript draft, and then all authors added more data and revised the manuscript. Dr. Huang overall revised it according to all authors' revised suggestions; at last, all authors approved the final manuscript. This article has support from the International Association of Neurorestoratology. The authors declare no conflict of interests.

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Consensus of Clinical Neurorestorative Progress in Patients with Complete Chronic Spinal Cord Injury

Abstract

Keywords

The Problem and Challenge

Search Strategy and Selection Criteria

Evidence

Cell Therapy

Neurostimulation/Neuromodulation and Neuroprosthesis and/or Related Advanced Assistive Devices

Neurotization or Nerve Bridging

Neurorehabilitation

Combination Therapies

Mechanisms of Neurorestorative Therapies

Questions

Study Design

Ethics

Reliability of Results

Safety

Comprehension Difference From Medical Community and Patients

Implementing Translational Medicine

Conclusion

Footnotes

Acknowledgments

References