Immunosuppressive mechanisms for stem cell transplant survival in spinal cord injury.

Spinal cord injury (SCI) has been associated with a dismal prognosis-recovery is not expected, and the most standard interventions have been temporizing measures that do little to mitigate the extent of damage. While advances in surgical and medical techniques have certainly improved this outlook, limitations in functional recovery continue to impede clinically significant improvements. These limitations are dependent on evolving immunological mechanisms that shape the cellular environment at the site of SCI. In this review, we examine these mechanisms, identify relevant cellular components, and discuss emerging treatments in stem cell grafts and adjuvant immunosuppressants that target these pathways. As the field advances, we expect that stem cell grafts and these adjuvant treatments will significantly shift therapeutic approaches to acute SCI with the potential for more promising outcomes.

Direct pressure on a pseudomeningocele resulting in intraoperative cerebral ischemia.

PURPOSE: When positioning patients with meningocele and meningomyelocele, it is standard practice to avoid direct pressure on the lesions. That caution is intended to prevent injury to neural elements within the lesion and violation of the cerebrospinal fluid space. We herein report an additional hazard of direct intraoperative pressure on such lesions. An adult patient with a lumbosacral pseudomeningocele sustained a cerebral ischemic injury as a consequence of direct pressure on the lesion during general anesthesia. CLINICAL FEATURES: A 32-yr-old male with spina bifida and a pseudomeningocele related to recent lumbar surgery underwent a urologic procedure in the lithotomy position. Because the lesion was recognized to lie to the left of the midline, cushioning was placed under the patient's left hip and buttock. The patient was slow to awaken and has sustained significant long-term cognitive deficits. Imaging is consistent with a diffuse cerebral ischemic insult. CONCLUSION: In retrospect, the size and leftward extent of the pseudomeningocele were not appreciated preoperatively, and in spite of the care taken, intraoperative pressure was placed on the lesion. This report cautions that intraoperative pressure related to positioning patients with extra-axial lesions containing cerebrospinal fluid (CSF), e.g., meningoceles and pseudomeningoceles, can result in increases in CSF pressure and thereby a reduction in cerebral perfusion pressure sufficient to result in cerebral ischemia.

Addressing challenges for repairing adult spinal cord with insights from neonates.

Stem cell therapy has emerged as a promising area of scientific investigation, sparking considerable interest, especially in spinal cord injury (SCI). Sun et al.1 discover that the extracellular matrix (ECM) from the neonatal spinal cord transmits biochemical signals to endogenous axons, thus promoting axonal regeneration.

Characterizing the frequency, morbidity, and types of traumatic brain injuries after the Mexico-San Diego border wall extension: a retrospective cohort review.

OBJECTIVE: The aim of this study was to investigate the impact of the US-Mexico border wall height extension on traumatic brain injuries (TBIs) and related costs. METHODS: In this retrospective cohort study, patients who presented to the UC San Diego Health Trauma Center for injuries from falling at the border wall between 2016 and 2021 were considered. Patients in the pre-height extension period (January 2016-May 2018) were compared with those in the post-height extension period (January 2020-December 2021). Demographic characteristics, clinical data, and hospital charges were analyzed. RESULTS: A total of 383 patients were identified: 51 (0 TBIs, 68.6% male) in the pre-height extension cohort and 332 (14 TBIs, 77.1% male) in the post-height extension cohort, with mean ages of 33.5 and 31.5 years, respectively. There was an increase in the average number of TBIs per month (0.0 to 0.34) and operative TBIs per month (0.0 to 0.12). TBIs were associated with increased Injury Severity Score (8.8 vs 24.2, p < 0.001), median (IQR) hospital length of stay (5.0 [2-11] vs 8.5 [4-45] days, p = 0.03), and median (IQR) hospital charges ($163,490 [$86,369-$277,918] vs $243,658 [$136,769-$1,127,920], p = 0.04). TBIs were normalized for changing migration rates on the basis of Customs and Border Protection apprehensions. CONCLUSIONS: This heightened risk of intracranial injury among vulnerable immigrant populations poses ethical and economic concerns to be addressed regarding border wall infrastructure.

Derivation of Sendai-Virus-Reprogrammed Human iPSCs-Neuronal Precursors: In Vitro and In Vivo Post-grafting Safety Characterization.

The critical requirements in developing clinical-grade human-induced pluripotent stem cells-derived neural precursors (hiPSCs-NPCs) are defined by expandability, genetic stability, predictable in vivo post-grafting differentiation, and acceptable safety profile. Here, we report on the use of manual-selection protocol for generating expandable and stable human NPCs from induced pluripotent stem cells. The hiPSCs were generated by the reprogramming of peripheral blood mononuclear cells with Sendai-virus (SeV) vector encoding Yamanaka factors. After induction of neural rosettes, morphologically defined NPC colonies were manually harvested, re-plated, and expanded for up to 20 passages. Established NPCs showed normal karyotype, expression of typical NPCs markers at the proliferative stage, and ability to generate functional, calcium oscillating GABAergic or glutamatergic neurons after in vitro differentiation. Grafted NPCs into the striatum or spinal cord of immunodeficient rats showed progressive maturation and expression of early and late human-specific neuronal and glial markers at 2 or 6 months post-grafting. No tumor formation was seen in NPCs-grafted brain or spinal cord samples. These data demonstrate the effective use of in vitro manual-selection protocol to generate safe and expandable NPCs from hiPSCs cells. This protocol has the potential to be used to generate GMP (Good Manufacturing Practice)-grade NPCs from hiPSCs for future clinical use.

Novel Association of Blunt Cerebrovascular Injuries with the San Diego-Mexico Border Wall Height Extension.

BACKGROUND: The San Diego-Mexico border wall height extension is associated with increased traumatic injuries and related costs after wall falls. We report previous trends and a neurological injury type not previously associated with border falls: blunt cerebrovascular injuries (BCVIs). METHODS: In this retrospective cohort study, patients who presented to the UC San Diego Health Trauma Center for injuries from border wall falls from 2016 to 2021 were considered. Patients were included if they were admitted before (January 2016 to May 2018) or after (January 2020 to December 2021) the height extension period. Patient demographics, clinical data, and hospital stay data were compared. RESULTS: We identified 383 patients, 51 (68.6% male; mean age, 33.5 years) in the pre-height extension cohort and 332 (77.1% male; mean age, 31.5 years) in the post-height extension cohort. There were 0 and 5 BCVIs in the pre- and post-height extension groups, respectively. BCVIs were associated with increased injury severity scores (9.16 vs. 31.33; P < 0.001), longer intensive care unit lengths of stay (median, 0 days; [interquartile range (IQR), 0-3 days]; vs. median, 5 days [IQR, 2-21 days]; P = 0.022), and increased total hospital charges (median, $163,490 [IQR, $86,578-$282,036]; vs. median, $835,260 [IQR, $171,049-$1,933,996]; P = 0.048). Poisson modeling found BCVI admissions were 0.21 (95% confidence interval, 0.07-0.41; P = 0.042) per month higher after the height extension. CONCLUSIONS: We review the injuries correlating with the border wall extension and reveal an association with rare, potentially devastating BCVIs that were not seen before the border wall modifications. These BCVIs and associated morbidity shed light on the trauma increasingly found at the southern U.S. border, which could be informative for future infrastructure policy decisions.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

Expandable Sendai-Virus-Reprogrammed Human iPSC-Neuronal Precursors: In Vivo Post-Grafting Safety Characterization in Rats and Adult Pig.

One of the challenges in clinical translation of cell-replacement therapies is the definition of optimal cell generation and storage/recovery protocols which would permit a rapid preparation of cell-treatment products for patient administration. Besides, the availability of injection devices that are simple to use is critical for potential future dissemination of any spinally targeted cell-replacement therapy into general medical practice. Here, we compared the engraftment properties of established human-induced pluripotent stem cells (hiPSCs)-derived neural precursor cell (NPCs) line once cells were harvested fresh from the cell culture or previously frozen and then grafted into striata or spinal cord of the immunodeficient rat. A newly developed human spinal injection device equipped with a spinal cord pulsation-cancelation magnetic needle was also tested for its safety in an adult immunosuppressed pig. Previously frozen NPCs showed similar post-grafting survival and differentiation profile as was seen for freshly harvested cells. Testing of human injection device showed acceptable safety with no detectable surgical procedure or spinal NPCs injection-related side effects.

The impact of the Mexico-San Diego border wall extension on spine injuries: a retrospective cohort review.

BACKGROUND: The recent San Diego-Mexico border wall height extension has resulted in an increased injury risk for unauthorized immigrants falling from greater heights. However, the effects of the border wall extension on frequency and morbidity of spinal injuries and related economic costs have yet to be highlighted. METHODS: We retrospectively compared two cohorts who presented to the UC San Diego Health Trauma Center for border wall falls: pre-height extension (12 patients; January 2016-May 2018), and post-height extension (102 patients; January 2020-December 2021). Patients presented during border wall construction (June 2018-December 2019) were excluded. Demographics, clinical data and hospital costs were collected. Spinal injuries were normalized using Customs and Border Protection apprehensions. Costs were adjusted for inflation using the 2021 medical care price index. RESULTS: The increase in spine injuries per month (0.8-4.25) and operative spine injuries per month (0.3- 1.7) was statistically significant (P < 0.001). Increase in median length of stay from 6 [interquartile range (IQR) 2-7] to 9 days (IQR 6-13) was statistically significant (P = 0.006). Median total hospital charges increased from $174 660 to $294 421 and was also significant (P < 0.001). CONCLUSION: The data support that the recent San Diego-Mexico border wall extension is correlated with more frequent, severe and costly spinal injuries. This current infrastructure should be re-evaluated as border-related injuries represent a humanitarian and public health crisis.

Constructing 2D maps of human spinal cord activity and isolating the functional midline with high-density microelectrode arrays.

Intraoperative neuromonitoring (IONM) is a widely used practice in spine surgery for early detection and minimization of neurological injury. IONM is most commonly conducted by indirectly recording motor and somatosensory evoked potentials from either muscles or the scalp, which requires large-amplitude electrical stimulation and provides limited spatiotemporal information. IONM may inform of inadvertent events during neurosurgery after they occur, but it does not guide safe surgical procedures when the anatomy of the diseased spinal cord is distorted. To overcome these limitations and to increase our understanding of human spinal cord neurophysiology, we applied a microelectrode array with hundreds of channels to the exposed spinal cord during surgery and resolved spatiotemporal dynamics with high definition. We used this method to construct two-dimensional maps of responsive channels and define with submillimeter precision the electrophysiological midline of the spinal cord. The high sensitivity of our microelectrode array allowed us to record both epidural and subdural responses at stimulation currents that are well below those used clinically and to resolve postoperative evoked potentials when IONM could not. Together, these advances highlight the potential of our microelectrode arrays to capture previously unexplored spinal cord neural activity and its spatiotemporal dynamics at high resolution, offering better electrophysiological markers that can transform IONM.

Traumatic rupture of thoracic epidural capillary hemangioma resulting in acute neurologic deficit: illustrative case.

BACKGROUND: Thoracic epidural capillary hemangioma is exceedingly rare, with only a few reported cases. The typical presentation usually includes chronic, progressive symptoms of spinal cord compression in middle-aged adults. To the authors' knowledge, this case is the first report in the literature of acute traumatic capillary hemangioma rupture. OBSERVATIONS: A 22-year-old male presented with worsening lower extremity weakness and paresthesias after a fall onto his spine. Imaging showed no evidence of spinal fracture but revealed an expanding hematoma over 24 hours. Removal of the lesion demonstrated a ruptured capillary hemangioma. LESSONS: This unique case highlights a rare occurrence of traumatic rupture of a previously unknown asymptomatic thoracic capillary hemangioma in a young adult.

Review of operative considerations in spinal cord stem cell therapy.

Spinal cord injury (SCI) can permanently impair motor and sensory function and has a devastating cost to patients and the United States healthcare system. Stem cell transplantation for treatment of SCI is a new technique aimed at creating biological functional recovery. Operative techniques in stem cell transplantation for SCI are varied. We review various clinical treatment paradigms, surgical techniques and technical considerations important in SCI treatment. The NCBI PubMed database was queried for "SCI" and "stem cell" with a filter placed for "clinical trials". Thirty-nine articles resulted from the search and 29 were included and evaluated by study authors. A total of 10 articles were excluded (9 not SCI focused or transplantation focused, 1 canine model). Key considerations for stem cell transplantation include method of delivery (intravenous, intrathecal, intramedullary, or excision and engraftment), time course of treatment, number of treatments and time from injury until treatment. There are no phase III clinical trials yet, but decreased time from injury to treatment and a greater number of stem cell injections both seem to increase the chance of functional recovery.

Basal impulses: findings from the last twenty years on impulsivity and reward pathways using deep brain stimulation.

INTRODUCTION: Deep brain stimulation (DBS) is an important treatment modality for movement disorders. Its role in tasks and processes of higher cortical function continues to increase in importance and relevance. This systematic review investigates the impact of DBS on measures of impulsivity. EVIDENCE ACQUISITION: A total of 45 studies were collated from PubMed (30 prospective, 8 animal, 4 questionnaire-based, and 3 computational models), excluding case reports and review articles. Two areas extensively studied are the subthalamic nucleus (STN) and nucleus accumbens (NAc). EVIDENCE SYNTHESIS: While both are part of the basal ganglia, the STN and NAc have extensive connections to the prefrontal cortex, cingulate cortex, and limbic system. Therefore, understanding cause and treatment of impulsivity requires understanding motor pathways, learning, memory, and emotional processing. DBS of the STN and NAc shell can increase objective measures of impulsivity, as measured by reaction times or reward-based learning, independent from patient insight. The ability for DBS to treat impulse control disorders, and also cause and/or worsen impulsivity in Parkinson's disease, may be explained by the affected closely-related neuroanatomical areas with discrete and sometimes opposing functions. CONCLUSIONS: As newer, more refined DBS technology emerges, large-scale prospective studies specifically aimed at treatment of impulsivity disorders are needed.

Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Elective laminectomy and excision of the thoracic spine neoplasm: an evaluation of early outcomes.

BACKGROUND: Laminectomy with excision of spinal neoplasms is commonly performed. The current study examines risk profiles associated with elective laminectomies of benign, malignant primary, and secondary/metastatic neoplasms of the thoracic spine. METHODS: Adult patients undergoing elective thoracic laminectomy and excision of spinal neoplasm were abstracted from ACS-NSQIP years 2011-2014. Patients were classified into three cohorts: benign primary, malignant primary, secondary/metastatic. Univariate and multivariable analyses compared operation time, early complications, hospital length of stay (HLOS), and discharge destination across cohorts. RESULTS: One-hundred sixty patients were included, aged 58.0±14.8-years. Mean operation time was 209.23±101.52 minutes and cohorts did not differ significantly on multivariable analysis. Mean HLOS was 6.10±7.14 days and did not differ by cohort. Early complications were observed in 15.6% of patients; secondary/metastatic patients associated with increased odds of >1 unit of blood transfusion, but not overall complications. Failure to be discharged home occurred in 31.8% of patients (benign primary: 30.0%, malignant primary: 66.6%, secondary/metastatic: 10.5%; P<0.001). Malignant primary tumors associated with increased multivariable odds of failure to be discharged home (OR 3.63, 95% CI [1.09, 12.10], P=0.036). Tumor location (extradural, intradural/extramedullary, intramedullary) was not a significant predictor of outcomes. A higher number of concurrent fusions were observed for secondary/metastatic laminectomies (benign primary: 7.3%; malignant primary: 5.5%; secondary/metastatic: 36.8%; P<0.001). CONCLUSIONS: Comparable performance on operation time and HLOS between neoplasm cohorts suggests broad indication of resectional laminectomies for elective treatment. Primary malignant thoracic spine tumors may require higher levels of early postdischarge care. Future studies are needed to confirm these findings.

Traumatic Brain Injuries After Falls From Height vs Falls at the US-Mexico Border Wall.

This cohort study examines the incidence, severity, and mortality of fall-related injuries among migrants at the US-Mexico border in San Diego, California.

Anterior Versus Transforaminal Lumbar Interbody Fusion: Perioperative Risk Factors and 30-Day Outcomes.

BACKGROUND: Operative management of lower back pain often necessitates anterior lumbar interbody fusion (ALIF) or transforaminal lumbar interbody fusion (TLIF). Specific pathoanatomic advantages and indications exist for both approaches, and few studies to date have characterized comparative early outcomes. METHODS: Adult patients undergoing elective ALIF or TLIF operations were abstracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) years 2011-2014. Univariate analyses were performed by surgery cohort for each outcome and adjusted for demographic/clinical variables (age ≥ 65, sex, race, body mass index, American Society of Anesthesiologists physical classification score, functional status, inpatient/outpatient status, smoking, hypertension, Charlson Comorbidity Index) using multivariable regression. Means, standard errors, mean differences (B), odds ratios (ORs), and associated 95% confidence intervals (CIs) are reported. Significance was assessed at P < .05. RESULTS: Of 8263 subjects (ALIF: 4325, TLIF: 3938), ALIF subjects were younger, less obese, less physically impaired, and had significantly lower rates of hypertension, diabetes, coagulopathy, and previous cardiac surgery. On multivariable analysis, ALIF associated with shorter operative time (B = -11.80 minutes, 95% CI [-16.48, -7.12]; P < .001). Transforaminal lumbar interbody fusion was associated with increased incidence of urinary tract infections (UTIs; OR = 1.57, 95% CI [1.10, 2.26]; P = .013) and of blood transfusions (OR = 1.19, 95% CI [1.04, 1.37]; P = .012). Multivariate analysis also demonstrated TLIF associated with shorter hospital length of stay (B = -0.27 days, 95% CI [-0.54, -0.01]; P = .041), and fewer cases of pneumonia (OR = 0.55, 95% CI [0.32, 0.94]; P = .029) and prolonged ventilator dependency (OR = 0.33, 95% CI [0.12, 0.84]; P = .021). CONCLUSIONS: Comparatively, ALIF patients experienced decreased operative time and decreased incidence of postoperative UTIs and blood transfusions. Anterior lumbar interbody fusion patients were more likely to suffer postoperative pulmonary complications and longer hospital stays. Our data support the notion that both anterior and transforaminal surgical approaches perform comparably in context of 30-day perioperative outcomes.

The Current State of Rural Neurosurgical Practice: An International Perspective.

INTRODUCTION: Rural and low-resource areas have diminished capacity to care for neurosurgical patients due to lack of infrastructure, healthcare investment, and training programs. This review summarizes the range of rural neurosurgical procedures, novel mechanisms for delivering care, rapid training programs, and outcome differences across international rural neurosurgical practice. METHODS: A comprehensive literature search was performed for English language manuscripts with keywords "rural" and "neurosurgery" using the National Library of Medicine PubMed database (01/1971-06/2017). Twenty-four articles focusing on rural non-neurosurgical practice were included. RESULTS: Time to care and/or surgery and shortage of trained personnel remain the strongest risk factors for mortality and poor outcome. Telemedicine consults to regional centers with neurosurgery housestaff have potential for increased timeliness of diagnosis/triage, improved time to surgery, and reductions in unnecessary transfers in remote areas. Mobile neurosurgery teams have been deployed with success in nations with large transport distances precluding initial transfers. Common neurosurgical procedures involve trauma mechanisms; accordingly, training programs for nonneurosurgery medical personnel on basic assessment and operative techniques have been successful in resource-deficient settings where neurosurgeons are unavailable. CONCLUSIONS: Protracted transport times, lack of resources/training, and difficulty retaining specialists are barriers to successful outcomes. Advances in telemedicine, mobile neurosurgery, and training programs for urgent operative techniques have been implemented efficaciously. Development of guidelines for paired partnerships between rural centers and academic hospitals, supplying surplus technology to rural areas, and rapid training of qualified local surgical personnel can create sustainable feed-forward programs for trainees and infrastructural solutions to address challenges in rural neurosurgery.

A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury.

We tested the feasibility and safety of human-spinal-cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury (SCI). In this clinical trial, four subjects with T2-T12 SCI received treatment consisting of removal of spinal instrumentation, laminectomy, and durotomy, followed by six midline bilateral stereotactic injections of NSI-566 cells. All subjects tolerated the procedure well and there have been no serious adverse events to date (18-27 months post-grafting). In two subjects, one to two levels of neurological improvement were detected using ISNCSCI motor and sensory scores. Our results support the safety of NSI-566 transplantation into the SCI site and early signs of potential efficacy in three of the subjects warrant further exploration of NSI-566 cells in dose escalation studies. Despite these encouraging secondary data, we emphasize that this safety trial lacks statistical power or a control group needed to evaluate functional changes resulting from cell grafting.

Subacute Sclerosing Panencephalitis of the Brainstem as a Clinical Entity.

Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurological disorder of early adolescence caused by persistent infection of the measles virus, which remains prevalent worldwide despite an effective vaccine. SSPE is a devastating disease with a characteristic clinical course in subcortical white matter; however, atypical presentations of brainstem involvement may be seen in rare cases. This review summarizes reports to date on brainstem involvement in SSPE, including the clinical course of disease, neuroimaging presentations, and guidelines for treatment. A comprehensive literature search was performed for English-language publications with keywords "subacute sclerosing panencephalitis" and "brainstem" using the National Library of Medicine PubMed database (March 1981-September 2017). Eleven articles focusing on SSPE of the brainstem were included. Predominant brainstem involvement remains uncharacteristic of SSPE, which may lead to misdiagnosis and poor outcome. A number of case reports have demonstrated brainstem involvement associated with other intracranial lesions commonly presenting in later SSPE stages (III and IV). However, brainstem lesions can appear in all stages, independent of higher cortical structures. The varied clinical presentations complicate diagnosis from a neuroimaging perspective. SSPE of the brainstem is a rare but important clinical entity. It may present like canonical SSPE or with unique clinical features such as absence seizures and pronounced ataxia. While SSPE generally progresses to the brainstem, it can also begin with a primary focus of infection in the brainstem. Awareness of varied SSPE presentations can aid in early diagnosis as well as guide management and treatment.