Adapting international clinical practice guidelines for rehabilitation management of acute spinal cord injury in Iran.

Purpose The main purpose of this study was to investigate the socio-cultural considerations for home modifications among individuals with spinal cord injury (SCI) in Iran. Materials and methods A descriptive qualitative design was employed, involving semi-structured interviews with 18 participants. Data were analyzed using reflexive thematic analysis to identify key themes and subthemes. Results Three main themes were identified: (1) Holding out hope for recovery from SCI, (2) Absence of home modifications led to unique solutions but potential risks, and (3) Occupational therapy recommendations regarding home modifications need to be culturally safe. Participants often received misinformation about their prognosis, leading to delayed or avoided home modifications. Conclusion The findings underscore the importance of providing accurate information regarding SCI prognosis to facilitate the implementation of needed home modifications. Occupational therapists and other health care professionals are advised to consider cultural factors, including practices related to values such as privacy, to ensure that recommendations are client-centered, effective, and culturally adaptable. This study highlights the necessity of developing culturally sensitive guidelines for home modifications and emphasize the critical role of involving in decision-making process, and improving access to appropriate assistive technology.

This was a qualitative study conducted using an interpretative phenomenological approach. This study investigated the experience of pregnancy and childbirth in women with spinal cord injury (SCI). Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran. The data were collected using telecommunication and face-to-face semi-structured interviews with eight women with SCI. The study employed the interpretative phenomenological approach suggested by Van Manen in 2016 and thematic analysis to provide a comprehensive understanding of the childbearing experience of women with SCI. MAXQDA 10 software was used to manage the collected data. Five main themes have emerged from data analysis: "revivification", "fear and concern of motherhood with SCI", "flawed health care system", "maternal experience under a supportive umbrella", and "strengthening spirituality and religious belief". Childbearing had a positive effect on the family relationship, continuity of marriage, and quality of life following SCI. There are potential benefits in establishing a center that provides consultation on childbearing and childcare for women with SCI. Moreover, training for the medical team, which includes nurses, midwives, and specialists is highly recommended. Further research is needed to expand our understanding of childbearing from the perspectives of healthcare providers.

The main objective of this study was to determine the percentage of families experiencing catastrophic costs as a result of spinal cord injury. Patients with spinal cord injuries often encounter significant expenses related to treatment, rehabilitation, and caregiving. Catastrophic expenditures are the direct consequence of the lack of effective health insurance. This financial burden, along with the potential for catastrophic costs, presents a serious challenge for these individuals. Data were obtained from the International Spinal Cord Injury Survey in Iran (InSCI-IR), which included 291 patients from Guilan Province. The study collected detailed information on direct and indirect costs, changes in household income after spinal cord injury, coping strategy earnings, and the household wealth index. Catastrophic costs were calculated using multiple approaches, including the household budget share method, disease-specific cost calculations, analyses excluding coping earnings, income estimation based on asset ownership, and Xu’s method based on capacity to pay. In addition, regression models and sensitivity analyses were conducted. The prevalence of households experiencing catastrophic costs due to spinal cord injury (SCICC) was 45.0%, ranging from 22.0% to 49.4% depending on the calculation method. Factors associated with catastrophic costs included gender (female patients were less likely to experience catastrophic costs, β = -0.75), presence of complete SCI (β = 1.53) or incomplete SCI (β = 1.46), household size (larger households were less likely to experience catastrophic costs, β = -0.27), higher activity participation levels (β = 0.29), greater independence scores (associated with a lower likelihood of catastrophic costs, β = -0.16), and the occurrence of pressure ulcers (β = 0.90). Health insurance strategies that enhance cost-sharing arrangements and broaden coverage for underrepresented services, along with preventive measures aimed at managing pressure ulcers and pain, can significantly mitigate the incidence of catastrophic financial burdens faced by patients with spinal cord injuries.

Objectives:To explore individuals’ perception of the personal, family and societal educational needs following a spinal cord injury (SCI).Methods:Sixty-one patients who sustained a traumatic SCI between March 2015 and June 2016 referred to Brain and Spinal Cord Injury Research Center (BASIR) were included in a cross sectional study and completed an online survey containing open-and closed-ended questions, in Iran. Participants’ responses were analyzed i using a qualitative approach with a thematic analysis.Results:Following a thematic analysis of the patient’s perceived educational needs, 3 themes and 14 subthemes were identified. The 3 themes included personal, family, and societal educational perceived needs. Within personal educational needs, there were 7 subthemes which included personal independence and transportation, financial independence, life skills modification, knowledge about SCI, prevention of SCI complications, relationships and sexual function, and psychological adjustments. Among family educational needs, the 3 subthemes were caregiver skills and communication, first aid and emergency skills, and emotional and psychological support. For societal educational needs, the 4 subthemes described were social integration, interpersonal communication skills, SCI awareness and injury prevention, sympathize while avoiding pity.Conclusion:According to our findings, people with SCI have various needs that need to be addressed. Educational support should be a part of a comprehensive rehabilitation program and geared towards addressing the patients’ personal and family needs, while educating the community about SCI in order to allow for reintegration into society.

Objective/backgroundIn patients with spinal cord injury (SCI), SCI causes psychosocial complications that vary based on culture, conditions, and the amenities of each community. Health planners and social services should have full knowledge of these issues in order to plan schedules that address them. In this study, we aimed to understand the psychosocial problems of persons with SCI in Iran and to explore the requirements for minimizing these difficulties.DesignThis was a descriptive cross-sectional study.SettingBrain and Spinal Cord Injury Research (BASIR) Center, Tehran University of Medical Sciences, Tehran, Iran.ParticipantsOne hundred nineteen persons with SCI referred to BASIR clinic to receive outpatient rehabilitation.MethodsIn this study, trained interviewers administered a questionnaire to the participants. The questionnaire consisted of socio-demographic variables and psychosocial questions about finances, employment, housing, education, and social communication problems.ResultsPsychosocial problems for persons with SCI are mainly associated with financial hardship due to unemployment and the high cost of living, followed by difficulties with transportation, house modification, education, marriage, social communication, sports, and entertainment. Psychological problems include sadness, depression, irritability/anger, suicidal thoughts, and a lack of self-confidence. The levels of the aforementioned problems differ with respect to sex.ConclusionPersons suffering from SCI can face some serious psychosocial problems that may vary according to sex. For example, transportation difficulties can lead to problems such as unsociability. After recognizing these problems, the next step would be providing services to facilitate a productive lifestyle, enhancing social communication and psychological health, and ultimately creating a higher quality of life.

Background: Spinal cord injury (SCI) causes multiple complications, which can be prevented or minimized, through patient education (PE). Individuals with SCI are different, according to culture, socioeconomic status, level of education, access to educational facilities, and geographic region. Therefore, different teaching strategies should be used to increase effectiveness of education. Objectives: The aim of this study is to evaluate the perspectives of individuals with SCI, about their preferred methods of PE. Patients and Methods: This was a descriptive cross-sectional study undertaken at the brain and spinal cord injury research center (BASIR), Tehran university of medical sciences, Tehran, Iran. The participants comprised of 119 SCI persons (81 men and 38 women), with mean age of 32 ± 10.5 years, referred to BASIR clinic to receive outpatient rehabilitation, in 2012. The patients were asked about their views, concerning preferred methods of PE. Results: Most participants (94%) appreciated to be informed concerning their illness. The two most preferred education methods were educational movies by CD or DVD (44%) and lectures or face classes (36%), followed by educational TV programs (30%), brochures (24%), education via internet or computer-aided (14.3%), and, finally, educational books (2%). Conclusions: Health care providers should take into account the differences between individuals with SCI, to use effective teaching strategies. Also, they should apply appropriate teaching methods and more than one teaching strategy, in relation to the different time and situation. Effective PE, in individuals with SCI, can increase their knowledge and motivation in self-care, improve satisfaction, prevent complications and make the PE more effective.

Spinal cord injury (SCI) is a severe medical condition that affects millions of people worldwide each year. In Iran, an estimated 9 out of every 100,000 individuals experience traumatic SCI occurrences. Long-term disabilities and comorbidities stemming from SCI often necessitate multiple therapeutic interventions. The aim of this study is to evaluate the morbidity in Iranian SCI patients. In this study, a four-step process was used to select, extract, analyze, and synthesize relevant literature. The search covered 750 records from five databases, resulting in 25 articles included in the review. These articles, published between 2000 and 2023, utilized cross-sectional, qualitative, or cohort designs. The findings explored the prevalence, risk factors, and consequences of comorbidities associated with SCI, categorized into four themes: physical, sexual, psychological, and metabolic morbidity. Physical morbidity refers to medical conditions or complications affecting body functions or structures in SCI patients. The most frequently reported cases include pressure ulcers, pain, osteoporosis, fractures, impaired pulmonary function, renal failure, and obesity. Metabolic morbidity includes conditions such as vitamin D deficiency and cardiometabolic risk factors. Psychological morbidity encompasses depression, anxiety, and adjustment disorders. Sexual morbidity refers to conditions or complications affecting the sexual function or satisfaction of SCI patients. This narrative literature review offers a comprehensive examination of various aspects of SCI in Iranian patients. The review identifies numerous challenges and difficulties faced by SCI patients while also highlighting protective factors that can improve their well-being. Additionally, the review acknowledges gaps and limitations within the current literature and suggests possible avenues for future research.

Context: One of the changes that occur in a person and lead to a change in the patient’s sexual desire is chronic diseases, including spinal cord injury (SCI). Objectives: This study aimed to evaluate the epidemiology of sexual dysfunction (SD) in patients with SCI in Iran by a systematic review and meta-analysis. Methods: In the present systematic review and meta-analysis, using the keywords “spinal cord injury”, “sexual dysfunction”, and “Iran” a list of related articles were extracted from national and international databases. The search was conducted by two researchers in the national databases (SID, Magiran, and Irandoc) and international databases (Web of Science, PubMed, and Scopus). The necessary data were collected using a specialized checklist and analyzed using CMA v.2.0 software. Results: The result showed 183 articles were extracted in the initial search, and after reviewing the articles, six articles were included in the systematic review and meta-analysis stage. The prevalence of SD in patients with SCI was equal to 45.9%, 95% (CI: 30.2 - 62.4). Conclusions: The prevalence of SD and sexual dissatisfaction in patients with SCI was reported to be high. For this reason, it is suggested to do necessary interventions to improve the sexual satisfaction of these patients.

BackgroundSpinal cord injury (SCI) is one of the most serious types of physical trauma and has become a major life-threatening condition in the recent decade. It is essential that the life perception and experiences of patients with SCI be studied and evaluated in different cultural contexts so that their needs and the challenges they face can be properly determined. The present study aims to explore the how patients with SCI in the south of Iran perceive facing life's challenges.MethodsThe present study is a qualitative research with a descriptive phenomenological design. Participants were identified through purposive sampling of patients with spinal cord injury admitted to two state hospitals affiliated with a university of medical sciences in western Iran. The researchers collected data using semi-structured, in-depth interviews with 25 SCI patients conducted between August and October 2021. Data was analyzed according to Colaizzi's method using MAXQDA v. 2007.ResultsAnalysis of the data led to the emergence of three themes and nine sub-themes. The three main themes were emotional shock (crisis making and mental rumination, persistent depressive disorder, pitying behaviors, fear of the future), loss of dignity (poor self- care, sexual dysfunction, loss of job and educational status), and lack of effective support (lack of financial institutions and sponsors, lack of social support).ConclusionPatients with spinal cord injuries face various issues in their care and social lives. Attention to their psycho-emotional needs along with comprehensive health support play key roles in generating a sense of self efficacy and promoting the mental well-being and dignity of patients with spinal cord injuries. Accordingly, healthcare administrators and caregivers are recommended to provide more comprehensive health support to SCI patients to meet their needs more effectively.

Descriptive cross-sectional study. Pain is a prevalent complication of individuals with spinal cord injury (SCI). Our objective was to examine the association between social support, socioeconomic factors and psychosocial factors and pain to develop more effective management strategies. Brain and Spinal Cord Injury Research (BASIR) Center, Tehran University of Medical Sciences, Tehran, Iran. The Persian version of the Brief Pain Inventory was used to measure the pain, and the Multidimensional Scale of Perceived Social Support was used to measure social support through structured face-to-face interviews in SCI individuals. The overall prevalence of pain was 50.7%; 79.3% of individuals had bilateral pain, with lower limbs and back being the most common location. The quality of pain was described as aching (41.4%), tingling (32.9%), pressure (15.7%), coldness (5.7%) and feeling electric shock sensations (4.3%). The frequency of pain in individuals with paraplegia (60.9% vs 45.7%) and incomplete (53.5% vs 52.5%) SCI was higher than with other types of neurological injuries. Patients with a medium level of education had the least pain and those with good economic situation reported higher frequency of having pain (P=0.034). There was no significant relationship between pain and social support. There was a positive correlation between pain and impairment of mood, normal work, relations with other people and lack of sleep (P<0.001). These novel findings will inform the development of strategies to manage pain by improving access to health-care facilities and supplies.

ObjectivesWe described the associations between demographic and injury-related factors on bone mineral density (BMD) of the spine and the hip among adult patients with chronic spinal cord injury (SCI).DesignBMD in spinal and femoral bone sites were assessed. Multivariate analysis was performed to evaluate the relationship between anthropometric and injury-related factors with BMD. Serum level and amount of dietary intake of calcium, phosphor, and 25-hydroxy vitamin D were measured.SettingA referral tertiary rehabilitation center in Iran.ParticipantsPatients with SCI who had no previous history of endocrine disorders and were not on specific medications entered the investigation. Those with non-traumatic SCI, pregnant, or with substance dependency were excluded as well.InterventionsNo interventions were applied.Main study outcome measuresDual X-ray absorptiometry was performed to estimate BMD. Body mass index was positively associated with higher femoral (P < 0.01, r = 0.56) and hip (P < 0.0001, r = 0.82) BMD only in female participants. The high prevalence of vitamin D deficiency (60%) was noticeable.ResultsOlder male patients revealed lower BMD only in spinal vertebrae (P < 0.02, r = −0.21). A significant higher BMD loss in lumbar vertebras in male patients with complete spinal cord lesion (P < 0.009) was detected. Spinal reduction of BMD was more severe when the level of injury was above T6 (P < 0.02).ConclusionAlong with the clarification of age, gender, post injury duration, and the other factors' effect on the BMD in the SCI patients, here we have also shown the noticeable prevalence of the 25-hydoxy vitamin D deficiency in these patients which needs attention.

Context: Spinal cord injury (SCI) is a disorder that causes several adverse effects on all aspects of the individual’s life and disrupts the normal routine of life. Objectives: The present study aimed at evaluating the prevalence of depression and pain among patients with SCI. Methods: The present systematic review was conducted using the Iranian literature. The study population included all articles available in Iranian and international databases as well as Google Scholar search engine. For this purpose, databases including SID, Magiran, IranMedex, IranDoc, Scopus, PubMed, ScienceDirect, Web of Science, and ProQuest were searched. The quality of published articles was assessed by two highly qualified researchers; the primary search was also performed separately. The data were analyzed with comprehensive meta-analyses (CMA) statistical package. Results: According to the findings, the prevalence of mild depression in the studied patients was 22.6% (95% confidence interval (CI): 17.50 - 28.8), moderate depression 19.6% (95% CI: 14.7% - 25.7%), and severe depression was 12.1% (95% CI: 8.3% - 17.3%); in addition, 46.5% of the patients had no depression (95% CI: 26.7% - 67.6%), and 65.9% of the subjects complained of pain (95% CI: 53.9% - 76.1%). Conclusions: Because of high prevalence of pain and depression among patients with SCI, it is essential to take appropriate measures to prevent depression and pain in such patients in order to improve their health status and quality of life.

Descriptive cross-sectional study. To investigate the relationship between perceived social support and depression and to evaluate the role of family, friends and other caregivers in the perception of social support in Iranian individuals with spinal cord injury (SCI). Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran. Social support was evaluated using the Multidimensional Scale of Perceived Social Support questionnaire, which gauges perceptions of support from family, friends and 'important persons'. The presence and severity of depression were assessed with the Beck Depression Inventory (BDI-II-PERSIAN)-a 21-item multiple-choice questionnaire. A total of 140 individuals with SCI were enrolled in the study. The average age of the participants was 29.4±7.9 years; the mean duration of injury was 46.3±46.5 months and most patients were male (72%). Social support and all subscales of social support were numerically greater in males; however, this difference was not statistically significant. The subcategory of friends' support in men was 17.9±7.9 compared to 14.6±8.0 in women (P=0.04). The self-reported social support score (r=-0.387, P<0.001) and subscales of social support, including family (r=-0.174, P=0.045), friends (r=-0.356, P<0.001) and important persons (r=-0.373, P<0.001), were all negatively correlated with depression. Higher self-reported perception of social support appears to be associated with lower levels of depression in individuals with SCI. SCI care providers should consider the relationship between social support and depression in their continuing care.

A descriptive cross-sectional study. The burden of care among primary caregivers of individuals with spinal cord injury (SCI) is affected by different factors. We aimed to evaluate the level of burden among caregivers and the association between the caregiver burden and sociodemographic factors of SCI individuals and their caregivers. Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran. The Zarit caregiver burden interview was used to evaluate the level of burden in caregivers through structured face-to-face interviews with 163 individuals with SCI, who were referred to receive outpatient rehabilitation, and their caregivers. The mean of caregivers' burden score was 38.9±15.2 and 11.7% reported no or little burden, 43.6% reported 'mild-to-moderate' burden, 33.1% reported 'moderate-to-severe' burden and 11.7% reported 'severe' burden of care. There was relationship between the level of injury (P=0.010) and occupational status (P=0.041) in SCI individuals and caregiver burden score. There was also a positive relationship between the caregiver burden score and duration of injury (r=0.176, P=0.025), the caregivers' age (r=0.350, P<0.001), and length of time that the current caregiver providing care (r=0.253, P=0.001). There was a negative relationship between the burden and caregiver's educational level (r=-0.235, P=0.002). The burden of care among the caregivers of SCI individuals is a multidimensional issue. The sociodemographic characteristics of individuals with SCI and their caregivers can affect the caregiver's burden. Many of these factors can be modified to reduce the burden of care.

AANS: American Association of Neurological Surgeons AIS: Abbreviated Injury Scale ASIA: American Spinal Injury Association CNS: Congress of Neurological Surgeons CSFD: cerebrospinal fluid drainage FDA: Food and Drug Administration FGF: fibroblast growth factor G-CSF: granulocyte colony-stimulating factor HGF: hepatocyte growth factor IL: interleukin iPSC: induced pluripotent stem cell MAP: mean arterial blood pressure MPSS: methylprednisolone sodium succinate MSC: mesenchymal stem cell NASCIS: National Acute Spinal Cord Injury Studies Nogo: neurite outgrowth inhibitor NgR: Nogo receptor NPC: neural precursor cell NSS: Neuro-Spinal Scaffold OEC: olfactory ensheathing cell OPC: oligodendrocyte progenitor cell PEG: polyethylene glycol PLGA: poly(lactic-co-glycolic acid) SCI: spinal cord injury TH: therapeutic hypothermia TNF: tumor necrosis factor Traumatic spinal cord injury (SCI) is a devastating event caused by trauma to the spine which leads to mechanical disruption of the spinal cord. The incidence of SCI varies worldwide. Focusing on developed regions, North America (39 per million) has a higher annual incidence than Australia (16 per million) or Western Europe (15 per million).1 Direct costs for lifetime patient care reach $1.1 to 4.6 million per patient, which further underscores the need for the development of effective SCI treatments.2 Substantial research effort has been dedicated to uncovering the pathophysiology of SCI. This has led to the development of pharmacologic and cell-based therapies, which are now demonstrating functional motor recovery in animal models. Among these, several promising therapeutic agents are already being investigated in clinical trials for SCI. This review will summarize the pathophysiology and current evidence-based clinical strategies to manage an acute spinal cord injury followed by a discussion of key emerging treatments including pharmacological approaches, cell-based therapies, biomaterials and physiological approaches. PATHOPHYSIOLOGY Phases of SCI Tissue damage after SCI has been divided into primary and secondary injury phases.3,4 The physical forces of the initial trauma cause the primary injury and this is the main determinant of the severity of SCI. The axons, blood vessels, and cell membranes are disrupted by physical forces such as compression, shearing, laceration, and acute stretch. Secondary injury refers to delayed, progressive damage which continues after the primary injury and represents an additional important determinant of neurological deficits (Figure).5,6 Due to the disruption of the blood–spinal cord barrier following the primary injury, infiltration of inflammatory cells such as macrophages, microglia, T-cells, and neutrophils can be observed. Inflammatory cytokines such as tumor necrosis factor (TNF) α, interleukin (IL)-1α, IL-1β, and IL-6 are released by these cells, with levels of these cytokines peaking 6 to 12 h after injury and remaining elevated up to 4 d after injury.7 Increases in intracellular calcium are caused by the disruption of ionic homeostasis after SCI and activates calcium-dependent proteases (eg, phospholipases, calpain, caspase, and nitric oxide synthase). These proteases trigger dysfunction of mitochondria which leads to cell death.8 Oligodendrocytes are highly susceptible to apoptotic loss and apoptosis has been observed, not only at the lesion epicenter, but also distant from the epicenter leading to demyelination of preserved axons.9-11 Furthermore, delayed necrosis and apoptosis are induced by reactive oxygen species which are released by phagocytic inflammatory cells.12-14 Moreover, the disrupted cells release excitatory amino acids (eg, glutamate and asparate) after SCI15,16 and the excessive activation of excitatory amino acid receptors causes further loss of neurons and glia by both necrotic and apoptotic cell death.17 To achieve repair and regeneration of the injured spinal cord, researchers have attempted to disrupt elements of the secondary injury pathway with the aim of neural preservation, inhibition of the barriers to axonal regeneration, and replacement of the damaged cells by cell transplantation therapy. From a pathophysiological perspective, it is likely that the optimal therapy will be a combinatorial one consisting of administration of drugs to reduce secondary injury at the acute phase, followed by cell transplantation or other regenerative therapies to regenerate the damaged spinal cord tissue in the subacute to chronic phases.18,19 These therapies are discussed in greater detail below.FIGURE: Three pathophysiological phases after SCI including acute (eg, hemorrhage, edema, and inflammation), subacute (eg, demyelination and axonal dieback), and chronic (eg, cavity formation) phases. Primary injury is caused by the physical forces of the initial traumatic event. Secondary injury refers to delayed, progressive damage which includes inflammation, loss of ionic homeostasis, oxidative damage, excitotoxicity, apoptosis, and necrosis. Oligodendrocytes are highly susceptible to apoptotic loss resulting in axonal demyelination. Cystic cavitation forms in the center of the spinal cord, with surrounding glial scar in the subacute and chronic phases. Nonastrocyte cells mainly form a chemical barrier by secreting growth inhibitory CSPGs.Barriers to Regeneration The adult mammalian Congress of Neurological Surgeons (CNS), including the spinal cord, has generally been considered to have limited regenerative capacity due to the finite number of available regenerative cells and the restricted plasticity of the adult CNS.20 While recent research has shown that the spinal cord has more regenerative capacity than was previously thought,21,22 compared with the peripheral nervous system, the regenerative capacity of the CNS is lower and it gradually decreases with increasing age.23 Schwab et al24 reported the inhibitory nature of CNS myelin in 1985. Myelin-associated proteins, such as neurite outgrowth inhibitor A (Nogo A),25,26 oligodendrocyte-myelin glycoprotein,27 and myelin-associated glycoprotein28,29 function through Nogo receptors (NgR). The NgRs lack an intracellular signaling domain and transduce inhibitory signals by forming coreceptor complexes with TNF receptor family proteins (eg, p75, TROY, and LIGO-1) to activate the GTPase Rho A. The downstream effector of Rho A is Rho-associated protein kinase which affects changes in the actin cytoskeleton and leads to growth cone collapse of regenerating axons, neurite retraction, and increasing apoptosis. SCI is accompanied by mechanically induced and excitotoxic cell death, with associated demyelination. The lost parenchyma is replaced by cystic cavitation and regeneration is often hindered by the presence of this cystic cavity which lacks the substrate to support axonal growth and cell migration.30 Furthermore, at the site of injury, glial and fibrotic scarring is also present (Figure). Glial and fibrotic scarring results when pericytes, hypertrophied astrocytes, fibroblast lineage cells, and inflammatory cells form a physical barrier, walling off injured tissue from healthy tissue.31,32 Recent research has shown that both astrocytes and nonastrocyte cells can form a physical and chemical barrier by secreting growth inhibitory chondroitin sulfate proteoglycans (CSPGs) such as neurocan, versican, brevican, phosphacan, and NG2.33 A fibroblast-derived scar can also be located in the perilesional region and is associated with the deposition of inhibitory extracellular matrix molecules. Similar to myelin-associated inhibitors, these molecules act as chemical barriers to the regeneration of axons. CURRENT CLINICAL STRATEGIES Early Surgical Intervention To reduce the effects of cord compression and resultant ischemia, early bony and ligamentous surgical decompression is performed to provide relief from the mechanical pressure. To elucidate the effectiveness of early decompression, a prospective cohort study, The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) was conducted with 313 cervical SCI patients.34 After adjusting for confounders, the early decompression group (<24 h after SCI) was 2.8 times as likely to demonstrate an Abbreviated Injury Scale (AIS) improvement of 2 or more grades at 6 mo after SCI compared with the late decompression group (≥24 h after SCI). A subsequent prospective Canadian cohort study (including cervical, thoracic, and lumbar SCI, n = 84) also revealed that early decompression was associated with a 2 or more grade AIS improvement at the time of rehabilitation facility discharge.35 The findings of these studies support the concept of "Time is Spine" which emphasizes the importance of early diagnosis and intervention to improve long-term outcomes. Central Cord Syndrome Central cord injury is characterized by greater weakness in the upper extremities than the lower extremities, variable sensory loss, variable bowel/bladder dysfunction, and, usually, early rapid improvements in neurological function. Early decompression has traditionally been avoided in cases of central cord injury with patients being allowed to plateau in their recovery over a number of weeks before any intervention.36 However, for patients with pre-existing canal stenosis, recent evidence suggests that early surgery may improve long-term outcomes. A systematic review demonstrated that patients undergoing early decompression (<24 h after SCI) had American Spinal Injury Association (ASIA) motor scores that were 6.31 points higher, and a greater chance of improvement in ASIA grade (odds ratio of 2.81) at 12-mo follow-up than those undergoing late decompression (≥24 h after SCI).37 Although the prospective randomized controlled Comparing Surgical Decompression Versus Conservative Treatment in Incomplete Spinal Cord Injury (COSMIC, NCT01367405) trial was initiated in 2013, it was terminated in 2016 due to difficulties in enrolling patients. Blood Pressure Augmentation The neuroprotective effects of blood pressure augmentation act through enhancing systemic perfusion. Several studies have shown that high-normal mean arterial blood pressures (MAPs) of 85 to 90 mm Hg may improve outcomes in SCI patients.38-40 The guidelines of the American Association of Neurological Surgeons (AANS) and (CNS) recommend MAP targets of 85 to 90 mm Hg as an option in SCI to be initiated as early as possible and maintained for 7 d after injury.41 This MAP elevation requires invasive blood pressure monitoring, maintenance of slightly hypervolemic state, and central venous access for continuous infusion of vasopressors. A noninferiority trial named Mean Arterial Blood Pressure Treatment for Acute Spinal Cord Injury (MAPS; NCT02232165) comparing MAP ≥ 85 mm Hg and MAP ≥ 65 mm Hg has been developed to assess the efficacy of lower targets. ASIA motor scores at 1 yr postinjury will be evaluated, and this trial is expected to complete in March 2017. Steroids for SCI Methylprednisolone sodium succinate (MPSS) is the only agent from completed clinical trials that has entered clinical use. It acts by reducing oxidative stress to enhance neural cell survival in animal models of traumatic SCI. Three landmark National Acute Spinal Cord Injury Studies (NASCIS) examined the use of MPSS for acute SCI.42-47 Although no neurological benefit in the MPSS-treated group was observed in the overall analyses of these studies, a subgroup analysis in the NASCIS II and III trials demonstrated that use of the drug in a higher dosing regimen than that used in NASCIS I within 8 h of injury resulted in neurological improvement, and that MPSS bolus 3 to 8 h after injury improved neurological function when it was administered for 48 h rather than 24 h.44-47 Recent evidence further supports the use of MPSS for SCI. A 2012 Cochrane meta-analysis and review demonstrated a 4 point greater ASIA motor score improvement in the group that received MPSS for acute SCI and that its administration was not associated with a significant increase in the risk of complications.48 Nevertheless, the 2013 AANS/CNS Section on Disorders of the Spine and Peripheral Nerves guideline provided a level I recommendation against the administration of MPSS which represents a marked change from the previous version despite little change in the evidence considered. Accordingly, an updated AOSpine guideline suggests that 24 h of MPSS IV be administered within 8 h of SCI to patients without medical contraindication.49 Emerging Therapies for SCI Key emerging technologies for SCI treatment include pharmacological approaches, cell-based therapies, biomaterials, and physiological approaches. A summary of these technologies is provided in Table.TABLE: Key Emerging Technologies for Acute SCIPharmacological Approaches Riluzole Riluzole is a benzothiazole antiepileptic which acts via sodium channel blockade. It is approved by the US Food and Drug Administration (FDA), European Medicines Agency, and Health Canada for the treatment of amyotrophic lateral sclerosis.50,51 Its role in neuroprotection stems from its ability to mitigate excitotoxicity and block sodium influx to neurons in addition to restricting the presynaptic release of glutamate.52 In animal studies, Riluzole has been shown to reduce neuronal loss and cavity size which led to improvements in motor function and electrophysiology.53-55 In the phase I trial for acute SCI was recently completed, and 36 patients were enrolled.56 Although elevations of liver enzyme levels were observed temporarily, no serious adverse events were attributed to the drug. Regarding the neurological outcomes, cervical SCI patients treated with riluzole showed the better improvement in ASIA motor score compared with non-riluzole treated patients matched from an historical registry cohort. The phase II/III RCT entitled riluzole in Spinal Cord Injury Study (RISCIS; NCT01597518) is recruiting patients with acute C4-8 injuries with ASIA grade A, B, or C and will compare riluzole versus placebo and assess AIS, Spinal Cord Independence Measure, and brief pain inventory. This study which was initiated in 2014 has to date recruited 70 patients and is expected to conclude in 2020. Minocycline Minocycline is a second-generation semisynthetic tetracycline antibiotic that has the ability to cross the blood–brain barrier. It also has potent anti-inflammatory properties and inhibits microglial activation, TNF-α, IL-1β, cyclooxygenase-2, and matrix metalloproteinases.57-60 In animal studies, minocycline treatment after acute SCI has been shown to protect against neuron loss and reduce the lesion size.61,62 A phase II study showed that patients with incomplete cervical SCI (n = 25) demonstrated an ASIA score improvement of 14 points with minocycline treatment compared to placebo (P = .05).63 The follow-up Phase III Minocycline in Acute Spinal Cord Injury (MASC; NCT01828203) study will compare IV minocycline for 7 d and is expected to conclude in 2018. VX-210 (Cethrin) The Rho pathway is known to negatively impact axonal and neurite growth.64 A toxin produced by Clostridium botulinum, C3 transferase (cethrin), has been shown to inhibit Rho-mediated inhibition of axonal growth which promoted neural regeneration and motor function recovery in rodent SCI models.65 Cethrin is a permeable material intended for application to the dura mater at the site of SCI during decompressive surgery in the acute phase. A phase I/IIa multicenter, dose-escalation human trial evaluating this drug in a human population was published in 201166; no serious adverse events were attributed to the drug.66 Cervical patients treated with 3 mg of cethrin showed improvement in ASIA motor score at 12 mo and this was shown to be superior to historical recovery rates. A phase IIb/III study of cethrin has commenced in cervical SCI patients in 2016 and is expected to conclude in 2018. Anti-Nogo-A antibody (ATI-355) A monoclonal antibody of major inhibitory fractions within CNS myelin, IN-1, has been shown to promote axonal sprouting and functional recovery following SCI in animal models.67 The humanized anti-Nogo antibody, ATI-355, has been shown to promote axonal sprouting and functional recovery following SCI in numerous animal models and is a rare therapeutic in that it has been demonstrated to improve functional outcomes in a primate model.26 A phase I human trial of humanized anti-Nogo antibody (ATI-355) was completed in Europe, rather than the US, as the FDA expressed concerns with the infusion pump. Although this trial has been completed, it has not been published. A phase II study of ATI-355 is about to commence in Europe. Granulocyte Colony Stimulating Factor Granulocyte colony-stimulating factor (G-CSF) has been shown to increase the mobilization of bone marrow stromal cells from the bone marrow and to increase their presence at the site of SCI. In a rodent model, G-CSF enhances neurogenesis, reduces apoptosis, and decreases expression of TNF-α and IL-1β. These positive effects are associated with white matter sparing and improved hind-limb function.68 The phase I/IIa trials, which were nonrandomized, showed no increase in serious adverse events with G-CSF administration alongside AIS grade improvement.69,70 G-CSF is currently in a phases III clinical trial in Japan with results expected in 2018. Hepatocyte Growth Factor Hepatocyte growth factor (HGF) is mainly secreted by mesenchymal cells and promotes cellular growth and motility. HGF enhances neuron survival, decreases lesion size, and reduces oligodendrocyte apoptosis to improve behavioral outcomes in rodent models.71 Moreover, in a primate model of cervical SCI, HGF improved hand dexterity which is one of the most important key functions of the upper limb.72 A phase I/II clinical trial (NCT02193334) comparing intrathecal HGF (KP100IT) versus placebo is now underway with results expected in 2017. Magnesium (AC105) Magnesium is a physiological antagonist of NMDA receptors which decreases excitotoxicity and also functions as an anti-inflammatory agent. Magnesium with polyethylene glycol (PEG) improves cerebrospinal fluid levels without requiring large magnesium doses.73-75 The use of magnesium with PEG in the treatment of animal models of SCI has been shown to enhance tissue sparing and improve motor functional recovery.76,77 However, a phase I/II clinical trial (NCT01750684) of magnesium with PEG (AC105) was terminated in 2015 due to difficulties in enrolling patients. Fibroblast Growth Factor Fibroblast growth factor (FGF) plays a key role in preserving motor neurons adjacent to the SCI site and reduces acute respiratory deficits resulting from the loss of ventral horn neurons by reducing glutamate-mediated excitotoxicity in animal models.78,79 Although a phase I/II trial (NCT01502631) of the FGF-analog (SUN13837) has been completed, the results have not been published to date. Cell-Based Therapies Regenerative therapies based on transplanted multipotent and differentiated cells are an exciting therapeutic approach showing promising results in translational studies. Initial research focused on embryonic stem cell lines derived from aborted early-stage embryos, however, ethical considerations and limited numbers of donor cells created challenges. More recently, the discovery of induced pluripotent stem cells (iPSCs), which can be derived within weeks from any somatic cell source, has revolutionized the field by providing a nearly limitless source of pluripotent cells for research and therapeutic purposes.80 Furthermore, iPSCs can potentially be derived from autologous tissue reducing or eliminating the risk of graft rejection.80 While unforeseen challenges in iPSC technology, such as epigenetic memory and early senescence, have been found, they continue to be a substantial technological advance in spinal cord regeneration.81 The most translationally relevant cell therapies derived from pluripotent stem cells or harvested from adult tissue are discussed cells are known to peripheral regeneration by providing a and support to axons. In rodent models of SCI, have been shown to reduce lesion size, axons, and provide motor The to has a phase trial (n = to assess for patients with chronic AIS grade injuries in the cervical or The study is expected to conclude in 2018. additional phase I trial (n = of derived for AIS grade A injuries has with results expected in ensheathing cells olfactory neurons and provide from and the In animal models of SCI, they have been to enhance neurite outgrowth and resulting in significant functional the are now and for chronic While a meta-analysis of several of these trials (n = no increase in serious adverse efficacy has to be due to concerns within the A previous study showed the of transplanted on from the into the spinal clinical trials of for chronic SCI have been completed and in a meta-analysis which no significant increase in to the stem cells are multipotent tissue cells of into and to repair ability to the and systemic inflammatory led to their application in SCI they were to promote tissue sparing through signaling and of is now a Phase II/III randomized trial of autologous via and intrathecal for patients with AIS grade cervical SCI within 12 mo of The study is expected to conclude in precursor cells are multipotent CNS cells of to astrocytes, and to lost cells and provide are most the central canal of the spinal cord and after however, their numbers are limited of or stem a promising In animal models of cervical and SCI, transplanted have been shown to reduce cystic axons, and improve behavioral outcomes over In 2 phase II trials led by were terminated early due to The studies were the effects of human CNS stem cell for and cervical The results of these trials have not been however, provide evidence that cell are in on emerging it is likely that further to the transplanted cells their will be to enhance motor outcomes. progenitor cells have multipotent to but they to to axons. Several studies have and functional recovery after A phase I/II trial (n = is now underway by to assess with results expected by have the of several of biomaterials with to SCI. These can be with stem cells, to growth and can be to over Moreover, they are being to cavitation with a that the extracellular In rodent biomaterials such as and have been shown to improve and behavioral to clinical Neuro-Spinal Scaffold is a and poly(lactic-co-glycolic currently in phase III trial by n = The trial will the effects of in with AIS grade A injuries and no as a was provided by the FDA this a The study is expected to conclude by Approaches to to via a of has been shown to reduce CNS injury after and These reduce the of the CNS and the systemic inflammatory to SCI, is tissue sparing and improvements in behavioral recovery in the In patients with AIS grade A a study (n = early therapeutic hypothermia to be associated with better neurological A phase II/III trial by the to entitled for Traumatic of the currently The study will assess of initiated within 6 h of injury to both efficacy and treatment is known to be a of the secondary injury Similar to MAP cerebrospinal fluid drainage to improve early spinal cord pressure to reduce the While an initial trial (n = to recent studies have that drainage and MAP augmentation can act to enhance spinal cord blood A phase (n = randomized trial and MAP elevation is now underway to the treatment can improve neurological outcomes for patients with acute AIS grade A, B, or C injuries from The study is expected to conclude in The of SCI research is and findings are being with from SCI clinical To achieve in clinical trials in SCI, the of and to In with to level of injury as as ASIA grade have been in of the clinical trials including the cethrin and riluzole The of SCI is likely to the administration of drugs to mitigate the secondary injury at the acute phase, followed by cell transplantation therapy to regenerate damaged spinal cord tissue from subacute to chronic that the therapeutic discussed in this review and the continuous in and clinical research are a to regenerative for SCI. 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