Spinal Cord Disorders Research Articles

Utilising International Statistical Classification of Diseases and Related Health Conditions (ICD)-10 Australian Modification Classifications of “Health Conditions” to Achieve Population Health Surveillance in an Australian Spinal Cord Injury Cohort

Study designRetrospective, non-randomised, registry controlled.ObjectiveTo develop a conceptual ICD-10 taxonomic framework for population health surveillance across all-phases of spinal cord injury and disorders (SCI/D).SettingPublic Hospital Admitted Patient Care (APC) collection, South Australian Dept. Health, South Australia, Australia.MethodsA core ICD-10-Australian Modification (AM) coded dataset was retrieved from the APC hospital patient admission collection (2012–2017). Search filters and key words referenced to the National Library of Medicine thesaurus identified and quantified incident SCI/D cases. Incident SCI/D case data held in the Australian Spinal Cord Injury Registry (ASCIR) of South Australia (2012–2017) tested fidelity. Data linkage to the South Australian Death Registry controlled for cohort attrition. Both unadjusted and case-mix adjusted core data set yields were evaluated. Outcomes were assessed in terms of APC frequency difference (Δ%) versus ASCIR.Results3,504 APC cases were extracted, of which 504 (mean, SD age 55 ± 20 yrs; 348 [69%] male, 202 [39%] traumatic; 135 [32%]) cervical; 51 [10.1%] thoracic and (16 [3.2%]) lumbar met criteria. Comparator data were 385 ASCIR new index cases mean, SD age 56 ± 19 yrs, 229 [75%] male, 162 [42%] traumatic. Case-mix adjusted analysis yielded 336 (APC Δ33%) all-cause incident cases (vs. ASCIR −13 Δ%) and 131 incident cases of traumatic aetiologies (vs. ASCIR −19 Δ%).ConclusionsThe ICD-10 core “Health Condition” data-set assembled extends our understanding of SCI/D epidemiology and with further development may create a cost-efficient and sustainable framework that will improve health system performance and equity within and between countries.SponsorshipThe Lifetime Support Authority of South Australia sponsored the study.

Multidrug-resistant bacteria in urine culture among patients with spinal cord injury and disorder: Time to first detection and analysis of risk factors.

Retrospective cohort study. The aim of this study was to assess the time to first detection of multidrug-resistant bacteria (MDRB) in urine culture and identify risk factors associated with the first detection of MDRB (1st MDRB). Spinal Care Ward and Department of Microbiology, Regional HospitalLiberec a.s., Liberec, Czech Republic. We cultured urine samples from patients in the acute phase of spinal cord injury or disorder (SCI/D). Multidrug resistance (MDR) was defined as acquired nonsusceptibility to at least one agent from three or more antimicrobial categories. Multivariate logistic regression was used to assess the association of bladder management, broad-spectrum antibiotic exposure, mechanical ventilation, pressure ulcers, positive urine culture on admission, and other risk factors with 1st MDRB. We used only the first urine culture with MDRB for evaluation. A total of 655 urine cultures from 246 individuals were evaluated, and 829 isolates were obtained. The MDRB prevalence among all isolates was 40.2%. MDRB was detected in 146 (59.3%) patients for the first time, and 76.0% of these isolates were from patients with asymptomatic bacteriuria. The median time to 1st MDRB was 37 days (95% CI, 33-41). According to multivariate logistic regression, 1st MDRB was associated with bladder management with urethral or suprapubic catheterization (OR: 2.8, 95% CI, 1.1-7.2). The prevalence of infections caused by MDRB was high among the SCI/D population, with three-quarters from patients with asymptomatic bacteriuria. Bladder management with an indwelling catheter is associated with an increased risk of 1st MDRB.

Dual utilization of Medicare and VA outpatient care among Veterans with spinal cord injuries and disorders

Objective Veterans with spinal cord injuries and disorders (SCI/D) utilizing Veterans Affairs healthcare facilities are also Medicare eligible. Use of multiple health care systems potentially duplicates or fragments care in this population; yet little is known about those using multiple systems. This study describes dual use of services paid for by VA and Medicare among Veterans with SCI/D. Design Retrospective, cross-sectional, observational study. Participants Veterans with SCI/D (n = 13,902) who received healthcare services within the VA SCI System of Care and were eligible for or enrolled in Medicare in 2011. Interventions N/A. Outcome Measures Patient characteristics, average number of visits and patient level frequencies of reasons for visits were determined for individuals within healthcare utilization (VA only, Medicare only, or dual VA/Medicare) groups. Multinomial logistic regression analyses were used to investigate associations of patient variables on dual use. Results 65.3% of Veterans with SCI/D were VA only users for outpatient encounters, 4.4% had encounters paid for by Medicare only, and 30.3% were dual users. Veterans were less likely to be VA only users if they were older than 69 and if they had been injured for greater than ten years. African American Veterans with SCI (compared to white) were more likely to be VA only users. Conclusion A substantial number (∼30%) of Veterans with SCI/D are dual users. These numbers highlight the importance of improved strategies to coordinate care and increase health information sharing across systems.

Blood GFAP as an emerging biomarker in brain and spinal cord disorders.

Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine.

A New Framework for Investigating the Biological Basis of Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 5]: Mechanical Stress, Vulnerability and Time.

Study DesignLiterature Review (Narrative)ObjectiveTo propose a new framework, to support the investigation and understanding of the pathobiology of DCM, AO Spine RECODE-DCM research priority number 5.MethodsDegenerative cervical myelopathy is a common and disabling spinal cord disorder. In this perspective, we review key knowledge gaps between the clinical phenotype and our biological models. We then propose a reappraisal of the key driving forces behind DCM and an individual’s susceptibility, including the proposal of a new framework.ResultsPresent pathobiological and mechanistic knowledge does not adequately explain the disease phenotype; why only a subset of patients with visualized cord compression show clinical myelopathy, and the amount of cord compression only weakly correlates with disability. We propose that DCM is better represented as a function of several interacting mechanical forces, such as shear, tension and compression, alongside an individual’s vulnerability to spinal cord injury, influenced by factors such as age, genetics, their cardiovascular, gastrointestinal and nervous system status, and time.ConclusionUnderstanding the disease pathobiology is a fundamental research priority. We believe a framework of mechanical stress, vulnerability, and time may better represent the disease as a whole. Whilst this remains theoretical, we hope that at the very least it will inspire new avenues of research that better encapsulate the full spectrum of disease.

Data Checkers: A Grid-Based UI for Managing Patient-Generated Data Sharing to Support Collaborative Self-Care

Chronic health conditions are becoming increasingly prevalent. As part of chronic care, sharing patient-generated health data (PGHD) is likely to play a prominent role. Sharing PGHD is increasingly recognized as potentially useful for not only monitoring health conditions but for informing and supporting collaboration with caregivers and healthcare providers. In this paper, we describe a new design for the fine-grained control over sharing one's PGHD to support collaborative self-care, one that centers on giving people with health conditions control over their own data. The system, Data Checkers (DC), uses a grid-based interface and a preview feature to provide users with the ability to control data access and dissemination. DC is of particular use in the case of severe chronic conditions, such as spinal cord injuries and disorders (SCI/D), that require not just intermittent involvement of healthcare providers but daily support and assistance from caregivers. In this paper, after providing relevant background information, we articulate our steps for developing this innovative system for sharing PGHD including (a) use of a co-design process; (b) identification of design requirements; and (c) creation of the DC System. We then present a qualitative evaluation of DC to show how DC satisfied these design requirements in a way that provided advantages for care. Our work extends existing research in the areas of Human-Computer Interaction (HCI), Computer-Supported Cooperative Work (CSCW), Ubiquitous Computing (Ubicomp), and Health Informatics about sharing data and PGHD.

Risk Factors and Consequences of Lower Extremity Fracture Nonunions in Veterans With Spinal Cord Injury

ABSTRACTWe used Veterans Health Administration (VHA) national administrative data files to identify a cohort (fiscal years 2005–2014) of veterans with spinal cord injuries and disorders (SCID) to determine risk factors for and consequences of lower extremity fracture nonunions. Odds ratios (OR) for fracture nonunion were computed using multivariable‐adjusted logistic regression models. We identified three risk factors for nonunion: (i) older age (OR = 2.29; 95% confidence interval [CI] 1.21–4.33), (ii) longer duration of SCID (OR = 1.02; 95% CI 1.00–1.04), and (iii) fracture site (distal femur), with OR (comparison distal femur) including distal tibia/fibula (OR = 0.14; 95% CI 0.09–0.24), proximal tibia/fibula (OR = 0.19; 95% CI 0.09–0.38), proximal femur (OR = 0.10; 95% CI 0.04–0.21), and hip (OR = 0.13; 95% CI 0.07–0.26). Nonunions resulted in multiple complications, with upwards of 1/3 developing a pressure injury, 13% osteomyelitis, and almost 25% requiring a subsequent amputation. Our data have identified a high‐risk population for fracture nonunion of older veterans with a long duration of SCID who sustain a distal femur fracture. In view of the serious complications of these nonunions, targeted interventions in these high‐risk individuals who have any signs of delayed union should be considered. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Development of nose-to-brain nano-DDS and its application to the treatment of brain and spinal cord disorders

Development of nose-to-brain nano-DDS and its application to the treatment of brain and spinal cord disorders

Clinical and electrical diagnosis of spinal cord and root disorders

Clinical and electrical diagnosis of spinal cord and root disorders

Clinical outcomes associated with guideline-discordant management of asymptomatic bacteriuria and urinary tract infection in hospitalized patients with neurogenic bladder.

To compare clinical outcomes associated with appropriate and inappropriate management of asymptomatic bacteriuria (ASB) and urinary tract infection (UTI) among inpatients with neurogenic bladder (NB). Multicenter, retrospective cohort. The study was conducted across 4 Veterans' Affairs hospitals. The study included veterans with NB due to spinal cord injury or disorder (SCI/D), multiple sclerosis (MS), or Parkinson's disease (PD) hospitalized between January 1, 2017, and December 31, 2018, with diagnosis of ASB or UTI. In a medical record review, we classified ASB and UTI diagnoses and treatments as appropriate or inappropriate based on national guidelines. Frequencies of Clostridioides difficile infection, acute kidney injury, 90-day hospital readmission, postculture length-of-stay (LOS), and multidrug-resistant organisms in subsequent urine cultures were compared between those who received appropriate and inappropriate management. We included 170 encounters with ASB (30%) or UTI (70%) diagnoses occurring for 166 patients. Overall, 86.1% patients were male, 47.6% had SCI/D and 77.6% used bladder catheters. All ASB encounters had appropriate diagnoses, and 96.1% had appropriate treatment. In contrast, 37 UTI encounters (31.1%) had inappropriate diagnoses and 61 (51.3%) had inappropriate treatment, including 30 encounters with true ASB. Among patients with SCI/D or MS, appropriate ASB or UTI diagnosis was associated with a longer postculture LOS (median, 14 vs 7.5 days; P = .02). We did not detect any significant associations between appropriate versus inappropriate diagnosis and treatment and other outcomes. Almost one-third of UTI diagnoses and half of treatments in hospitalized patients with NB are inappropriate. Opportunities exist to improve ASB and UTI management in patients with NB to minimize inappropriate antibiotic use.

Prevalence of Spinal and Bony Structural Disorders in Saudi Adult Using MRI in Different Genders

Background: Magnetic resonance imaging is the primary imaging modality for the evaluation of spinal cord and spinal column disorder. Aims: to assess the prevalence of bony structure and spinal disorders in the Saudi population and to find a correlation between patient age and gender. Material and Methods: A retrospective study was conducted using magnetic resonance imaging in Al-Taif city from November 2020 to February 2021 at King Abdul-Aziz Specialist Hospital and King Faisal Hospital in Taif City, Kingdom of Saudi Arabia, to assess the prevalence of bony structure and spinal disorders in the Saudi population. The data was collected after gaining ethical approval from the directorate of health affairs in Taif’s administration of research and studies, and then analyzed using SPSS version 25 to determine the frequency and percentage of disorder. To check if there was a significant difference between the two groups, the Pearson’s chi square test was utilized. Results: One hundred young adults underwent MR examination of the spine. The results show that the most common age group affected by spinal disorders is over 50 years (53%), the most common bony structural spinal disorders are straightening 59%, followed by lordosis (20%), and the most common disc disorders are disc bulges (15%), and the most common degenerative changes are spondylo-degenerative changes (21%), and there is no significant correlation between genders and MRI findings (p-value). Conclusion: The study found that straightening is the most prevalent MRI-diagnosed spine disorder, followed by degenerative illnesses and that there is no significant association between gender and the type of MRI-diagnosed spinal disorders.

198. Comparison of Antibiotic Treatment Durations for Symptomatic Bacteriuria in Veterans with Spinal Cord Injuries or Disorders (SCI/D)

BackgroundIt is unclear based on published literature whether shorter courses of antibiotic treatment may be appropriate for urinary tract infections (UTI) in patients with SCI/D given their complex baseline clinical status. MethodsThis retrospective cohort study was conducted at the VA San Diego Healthcare System (VASDHS), which has a dedicated SCI/D unit. Adults with SCI/D were identified for inclusion if they had received antibiotics for a positive urine culture in conjunction with UTI symptoms from 1/2018-12/2020. Individual UTI events were excluded if associated with potential sources of harbored infection, anatomic abnormalities increasing risk of bacteriuria, non-bacterial pathogens, concurrent infections prolonging antibiotic treatment, or antibiotic courses managed outside of VASDHS. Treatment groups comprised UTI events treated with no more than 7 days of antibiotics (group 1) versus more than 7 days (group 2). Study endpoints were recurrence or new incidence of UTI within 30 and 90 days after completion of antibiotic treatment and onset of C. difficile infection or death within 30 or 90 days, respectively, after treatment completion. Statistical tests included Chi-square, Mann-Whitney U, and logistic regression. ResultsOne-hundred and seven patients with 241 unique UTI events were included in this study, with 79 events in group 1 and 162 events in group 2. Baseline characteristics were similar across both groups, aside from a higher incidence of hospital admission and more severe SCI/D based on the American Spinal Cord Injury Association (ASIA) impairment scale in group 2. Efficacy outcomes are described in Table 1. No deaths occurred within 90 days of treatment completion, and C. difficile infection occurred in 1 patient in group 2 after 3 days of antibiotic therapy. Duration of antibiotic therapy was not predictive of treatment failure within 30 days of antibiotic completion. Factors predictive of treatment with longer courses of antibiotic therapy included hospital admission and more severe ASIA impairment scale score. Table 1. Incidence of UTI after antibiotic completion ConclusionThe findings of this study suggest that for some patients with SCI/D, UTI treatment lasting 7 days or fewer may be effective compared to longer courses of antibiotics and could be beneficial in reducing collateral damage from antibiotic use. Disclosures All Authors: No reported disclosures

Pragmatic Approach to Neuraxial Anesthesia in Obstetric Patients With Disorders of the Vertebral Column, Spinal Cord, and Neuromuscular System

(Reg Anesth Pain Med. 2021;46:258–267) Approximately 40% of women of childbearing age are affected by vertebral column, spinal cord, and neuromuscular system disorders and conditions, raising questions about neuraxial anesthesia safety and efficacy for labor analgesia and obstetric surgical anesthesia. As research regarding how to approach neuraxial anesthesia during care is limited, the aim of this review is to familiarize anesthesiologists with anatomy, present available data, and empower physicians to use a pragmatic approach to neuraxial anesthesia.

The value of quantitative diffusion tensor imaging indices of spinal cord disorders

BackgroundDifferent lesions affecting the spinal cord can lead to myelopathy. Diffusion tensor imaging (DTI) is widely used to predict the degree of spinal cord microstructure affection and to assess axonal integrity and diffusion directionality. We hypothesized that not all DTI parameters have the same affection with different spinal cord pathologies. The purpose of this study is to assess the value of the quantitative diffusion tensor imaging indices in different spinal cord lesions.ResultsThere is highly statistically significant difference of the fractional anisotropy (FA), relative anisotropy (RA), volume ratio (VR) and secondary eigenvector values (E2 and E3) between various studied cord lesions and control levels. There is no statistically significant difference of the apparent diffusion coefficient (ADC) and the primary eigenvector value (E1) (ANOVA test). The ROC curve analysis showed the higher sensitivity and accuracy were ‘88% and 62.5%, respectively,’ with FA cutoff value about 0.380.ConclusionThe resulted quantitative DTI indices ‘fractional anisotropy, relative anisotropy, volume ratio and secondary eigenvalues’ work as a numerical in vivo marker of overall tissue injury in different pathologies affecting the spinal cord.

Detection of locomotion deficit in a post-traumatic syringomyelia rat model using automated gait analysis technique.

Syringomyelia (SM) is a spinal cord disorder in which a cyst (syrinx) filled with fluid forms in the spinal cord post-injury/disease, in patients syrinx symptoms include loss of pain and temperature sensation or locomotion deficit. Currently, there are no small animal models and connected tools to help study the functional impacts of SM. The objective of this study was to determine the detectability of subtle locomotion deficits due to syrinx formation/expansion in post-traumatic syringomyelia (PTSM) rat model using the recently reported method of Gait Analysis Instrumentation, and Technology Optimized for Rodents (GAITOR) with Automated Gait Analysis Through Hues and Areas (AGATHA) technique. First videos of the rats were collected while walking in an arena (using GAITOR) followed by extracting meaningful locomotion information from collected videos using AGATHA protocol. PTSM injured rats demonstrated detectable locomotion deficits in terms of duty factor imbalance, paw placement accuracy, step contact width, stride length, and phase dispersion parameters compared to uninjured rats due to SM. We concluded that this technique could detect mild and subtle locomotion deficits associated with PTSM injury, which also in future work could be used further to monitor locomotion responses after different treatment strategies for SM.

Supine arm cycling during the post-flap recovery period for persons with spinal cord injuries: The multi-purpose arm cycle ergometer (M-PACE) safety and pilot testing

Objective: To describe how using a supine arm cycle ergometer can safely reduce deconditioning experienced by patients with spinal cord injury or disorder (SCI/D) during their four to six weeks of complete bed rest after surgery to close a stage 4 pressure injury. Design: This pilot project used a newly designed arm cycle ergometer (known as the M-PACE) that extends over the bed, allowing a patient to lie completely supine while exercising. Setting: The M-PACE was designed and built at the Minneapolis Veterans Affairs Health Care System (MVAHCS) and pilot tested at the MVAHCS SCI/D Center. Participants: Patients with SCI/D, recovering from flap surgery and deemed appropriate to use the arm cycle ergometer were enrolled in the pilot study (n = 47). Outcome Measures: A pre–post six-minute arm test (6MAT), a proxy for conditioning, was conducted on a subset (n = 15) of participants before and after the supine cycling exercise training program. Participants’ rating of perceived exertion (RPE) scores were collected at cessation of each 6MAT. Participants gave feedback on their perception of using the M-PACE. Results/Conclusions: The 6MAT RPE was significantly reduced after training with the M-PACE while on bed rest (P = 0.003). Also, significantly more rotations were performed after completing the training program (P = 0.02). Further, study participants who accessed the M-PACE found using it helped offset the tedium of laying supine during flap surgery recovery. The differences in the 6MAT pre- to post measures indicate the M-PACE should be further studied for offsetting the normal deconditioning that occurs with extended bedrest.

Using Deep Learning to Detect Spinal Cord Diseases on Thoracolumbar Magnetic Resonance Images of Dogs.

Deep Learning based Convolutional Neural Networks (CNNs) are the state-of-the-art machine learning technique with medical image data. They have the ability to process large amounts of data and learn image features directly from the raw data. Based on their training, these networks are ultimately able to classify unknown data and make predictions. Magnetic resonance imaging (MRI) is the imaging modality of choice for many spinal cord disorders. Proper interpretation requires time and expertise from radiologists, so there is great interest in using artificial intelligence to more quickly interpret and diagnose medical imaging data. In this study, a CNN was trained and tested using thoracolumbar MR images from 500 dogs. T1- and T2-weighted MR images in sagittal and transverse planes were used. The network was trained with unremarkable images as well as with images showing the following spinal cord pathologies: intervertebral disc extrusion (IVDE), intervertebral disc protrusion (IVDP), fibrocartilaginous embolism (FCE)/acute non-compressive nucleus pulposus extrusion (ANNPE), syringomyelia and neoplasia. 2,693 MR images from 375 dogs were used for network training. The network was tested using 7,695 MR images from 125 dogs. The network performed best in detecting IVDPs on sagittal T1-weighted images, with a sensitivity of 100% and specificity of 95.1%. The network also performed very well in detecting IVDEs, especially on sagittal T2-weighted images, with a sensitivity of 90.8% and specificity of 98.98%. The network detected FCEs and ANNPEs with a sensitivity of 62.22% and a specificity of 97.90% on sagittal T2-weighted images and with a sensitivity of 91% and a specificity of 90% on transverse T2-weighted images. In detecting neoplasms and syringomyelia, the CNN did not perform well because of insufficient training data or because the network had problems differentiating different hyperintensities on T2-weighted images and thus made incorrect predictions. This study has shown that it is possible to train a CNN in terms of recognizing and differentiating various spinal cord pathologies on canine MR images. CNNs therefore have great potential to act as a “second eye” for imagers in the future, providing a faster focus on the altered image area and thus increasing workflow in radiology.

Assessment of safety of self-controlled repetitive trans-vertebral magnetic stimulation

ObjectiveThe aim of this study was to assess safety issues of self-controlled repetitive trans-vertebral magnetic stimulation (rTVMS) in humans. MethodsWe investigated effects of self-controlled rTVMS (≤20 Hz, ≤90% intensity) on vital signs and subjective sensations in 1690 trials of 30 healthy volunteers and 12 patients with spinal cord disorders. ResultsHealthy volunteers and the patients received 4595 ± 2345, and 4450 ± 2304 pulses in one day, respectively. No serious adverse events were observed in any participants, and only minor events were seen as follows. While blood pressure was unaffected in the patients, the diastolic blood pressure increased slightly after rTVMS in healthy volunteers. The peripheral capillary oxygen saturation increased after rTVMS in healthy volunteers. “Pain” or “Discomfort” was reported in approximately 10% of trials in both participants groups. Degree of the evoked sensation positively correlated with stimulus intensity and was affected by the site of stimulation. ConclusionSelf-controlled rTVMS (≤20 Hz and ≤90% intensity) did not induce any serious adverse effects in healthy volunteers and patients with spinal cord disorders. SignificanceOur results indicate that rTVMS can be used safely in physiological investigations in healthy volunteers and also as treatment for neurological disorders.

Therapeutic Effects of Risperidone against Spinal Cord Injury in a Rat Model of Asphyxial Cardiac Arrest: A Focus on Body Temperature, Paraplegia, Motor Neuron Damage, and Neuroinflammation.

Cardiac arrest (CA) causes severe spinal cord injury and evokes spinal cord disorders including paraplegia. It has been reported that risperidone, an antipsychotic drug, effectively protects neuronal cell death from transient ischemia injury in gerbil brains. However, until now, studies on the effects of risperidone on spinal cord injury after asphyxial CA (ACA) and cardiopulmonary resuscitation (CPR) are not sufficient. Therefore, this study investigated the effect of risperidone on hind limb motor deficits and neuronal damage/death in the lumbar part of the spinal cord following ACA in rats. Mortality, severe motor deficits in the hind limbs, and the damage/death (loss) of motor neurons located in the anterior horn were observed two days after ACA/CPR. These symptoms were significantly alleviated by risperidone (an atypical antipsychotic) treatment after ACA. In vehicle-treated rats, the immunoreactivities of tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β), as pro-inflammatory cytokines, were increased, and the immunoreactivities of IL-4 and IL-13, as anti-inflammatory cytokines, were reduced with time after ACA/CPR. In contrast, in risperidone-treated rats, the immunoreactivity of the pro-inflammatory cytokines was significantly decreased, and the anti-inflammatory cytokines were enhanced compared to vehicle-treated rats. In brief, risperidone treatment after ACA/CPR in rats significantly improved the survival rate and attenuated paralysis, the damage/death (loss) of motor neurons, and inflammation in the lumbar anterior horn. Thus, risperidone might be a therapeutic agent for paraplegia by attenuation of the damage/death (loss) of spinal motor neurons and neuroinflammation after ACA/CPR.

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord.

In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.