Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra.

INTRODUCTION: Stroke represents an attractive target for cell therapy. Although different types of cells have been employed in animal models with variable results, the human adipose-derived stem cells (hASCs) have demonstrated favorable characteristics in the treatment of diseases with inflammatory substrate, but experience in their intracerebral administration is lacking. The purpose of this study is to evaluate the effect and safety of the intracerebral application of hASCs in a stroke model. METHODS: A first group of Athymic Nude mice after stroke received a stereotactic injection of hASCs at a concentration of 4 × 104/µL at the penumbra area, a second group without stroke received the same cell concentration, and a third group had only stroke and no cells. After 7, 15, and 30 days, the animals underwent fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging; subsequently, they were sacrificed for histological evaluation (HuNu, GFAP, IBA-1, Ki67, DCX) of the penumbra area and ipsilateral subventricular zone (iSVZ). RESULTS: The in vitro studies found no alterations in the molecular karyotype, clonogenic capacity, and expression of 62 kDa transcription factor and telomerase. Animals implanted with cells showed no adverse events. The implanted cells showed no evidence of proliferation or differentiation. However, there was an increase of capillaries, less astrocytes and microglia, and increased bromodeoxyuridine and doublecortin-positive cells in the iSVZ and in the vicinity of ischemic injury. CONCLUSIONS: These results suggest that hASCs in the implanted dose modulate inflammation, promote endogenous neurogenesis, and do not proliferate or migrate in the brain. These data confirm the safety of cell therapy with hASCs.

Tractographical model of the cortico-basal ganglia and corticothalamic connections: Improving Our Understanding of Deep Brain Stimulation.

The cortico-basal ganglia and corticothalamic projections have been extensively studied in the context of neurological and psychiatric disorders. Deep brain stimulation (DBS) is known to modulate many of these pathways to produce the desired clinical effect. The aim of this work is to describe the anatomy of the main circuits of the basal ganglia using tractography in a surgical planning station. We used imaging studies of 20 patients who underwent DBS for movement and psychiatric disorders. We segmented the putamen, caudate nucleus (CN), thalamus, and subthalamic nucleus (STN), and we also segmented the cortical areas connected with these subcortical areas. We used tractography to define the subdivisions of the basal ganglia and thalamus through the generation of fibers from the cortical areas to the subcortical structures. We were able to generate the corticostriatal and corticothalamic connections involved in the motor, associative and limbic circuits. Furthermore, we were able to reconstruct the hyperdirect pathway through the corticosubthalamic connections and we found subregions in the STN. Finally, we reconstructed the cortico-subcortical connections of the ventral intermediate nucleus, the nucleus accumbens and the CN. We identified a feasible delineation of the basal ganglia and thalamus connections using tractography. These results could be potentially useful in DBS if the parcellations are used as targets during surgery.

[Erdheim-Chester disease, an incredible simulator. Cases reports and review of literature]. / Enfermedad de Erdheim-Chester, una gran imitadora. Presentación de casos y revisión de la literatura.

Erdheim-Chester disease is a non-Langerhans histiocytosis. Until 2014 at least 550 cases have been reported. According to European Rare Disease Organization and National Organization for Rare Disorders it is a rare disease. The most common symptom is bone pain in the lower extremities and it usually appears between the 5th and 7th decades of life. The diagnostic is based on immunohistochemical results: S100(+/-), CD68(+), and CD1a(-), the latter 2 are mandatory. The best treatment nowadays is alpha-interferon or pegylated alpha-2. The overall survival is 96% at one year and 68% at 5 years. Central nervous system involvement is associated with a worse outcome. Two cases are presentedwith central nervous system lesions in the absence of lesions in other organs on their onset. Very few cases have been reported with this kind of presentation. We also noted that these patients had recurrences or new lesions at 8 months. A follow-up is proposed with brain MRI and thoraco-abdominal PET every 3-4 months.

Cavernous hemangioma of the peripherical nerve: A case report.

Cavernous hemangiomas, also known as deep hemangiomas are benign tumors of blood vessels, including normal and abnormal vascular structures, that develop in skin tissue and sometimes even in deep tissues. Its intraneural development in the peripheral nerve is very rare with less than 50 cases reported in the literature. We present a case of a cavernous hemangioma of the medial sural nerve in a patient with symptoms of severe pain and allodynia with complete resolution of symptoms with microsurgery.

Real-world outcomes of single-stage spinal cord stimulation in chronic pain patients: A multicentre, European case series.

Background: Spinal cord stimulation (SCS) is effective in treating chronic neuropathic pain. A screening trial is typically conducted prior to implantation to evaluate whether a patient is a good candidate for SCS. However, the need for a screening trial has been debated. We evaluated real-world clinical outcomes in patients who underwent a single-stage procedure to receive SCS therapy (i.e., no screening trial period) (SS-SCS). Methods: This observational, multicentre, real-world consecutive case series evaluated SS-SCS chronic pain patients. Pain and other functional outcomes were collected as part of standard care by site personnel with no sponsor involvement. Assessments included Numerical rating scale (NRS), Percent Pain Relief (PPR) and EQ-5D-5L (EuroQol 5 Dimensions-5L), recorded prior to SCS and following implantation. Results: A total of 171 chronic pain patients (mean age: 59.4; 53.2% females) underwent a single-stage procedure (mean last follow-up, 408 days) and were included in the analysis. A 5.0 â€‹± â€‹2.1-point improvement in overall pain was reported at 3 months and sustained until the last follow-up post-implantation (p â€‹< â€‹0.0001). At last follow-up, 50.3% (86/171) of patients reported an NRS pain score ≤3. Additionally, quality of life also improved (46.1-point change, from 70.2 to 25) at the last follow-up, based on EQ-5D-5L scores. Conclusions: In routine clinical practice, SS-SCS can provide significant long-term pain relief and improve quality of life in chronic pain patients. Our results suggest that effective long-term outcomes and success may be achieved without a trial period prior to permanent implantation of an SCS system.

Spinal cord stimulation and cauda equina syndrome: Could it be a valid option? A report of two cases.

Spinal cord stimulation (SCS) consists of the application of electrical stimuli to the dorsal columns of the spinal cord or to the posterior nerve roots in order to modulate the pain signals carried by the ascending pain pathways to the brain. Two cases of SCS in patients with cauda equina syndrome after lumbar surgery are presented. They were treated for persistent neuropathic pain but also experienced improvement in their motor and urinary symptoms after this treatment. Although the primary indication for SCS is neuropathic pain control, its application can also lead to improvement of motor deficits, sensory disorders, and urinary incontinence, as shown in these two cases. SCS will likely play a fundamental role in rehabilitative therapies in different neurological diseases. Further investigation in the field is needed.

Spinal cord stimulation to treat meralgia paresthetica. Is it feasible? A case report.

Meralgia paresthetica is a neurological disorder caused by a neuropathy of the lateral femoral cutaneous nerve. Its aetiology can be spontaneous or iatrogenic. It is characterized by pain, paresthesia, and numbness in the anterolateral aspect of the thigh. Diagnosis is based on clinical examination, although image and neurophysiological tests can be useful as well. Despite conservative measures use to be effective in most of patients, refractory cases can benefit from alternative treatments. Available surgical procedures are: nerve decompression (neurolysis) or section (neurectomy) and radiofrequency ablation. We present a case of refractory meralgia paresthetica where spinal cord stimulation was used as a possible effective technique in pain relief and to avoid the neurectomy of the lateral femoral cutaneous nerve.

[Lipomatous ependymomas of the posterior fossa. An infrequent and little-known subtype. A case report and review of the literature]. / Ependimomas lipomatosos de la fosa posterior. Un subtipo muy infrecuente y poco conocido. Presentación de caso y revisión de la literatura.

Ependymomas are well defined glial tumours composed of uniform small cells with round nuclei in a fibrillar matrix. They have characteristic perivascular acellular areas (pseudorosettes) and, in some cases, ependymal rosettes. The three most well-known histological phenotypes are papillary, clear-cell and tanycytic. The WHO classification includes rare cases of ependymoma with lipomatous metaplasia. Lipomatous ependymomas of the posterior fossa are extremely rare; we only found 7reports of cases in adults. They usually arise in the fourth ventricle and may extend into the cerebellum, when they often show extensive vacuolization, pushing the nucleus to the periphery and giving rise to a signet-ring cell appearance. Radiologically, there are few findings characteristic of these tumours. Immunohistochemistry is essential to differentiate this subtype from other more common lesions, such as metastatic adenocarcinoma, especially from breast, intestine and kidney.

Spinal cord stimulation and cauda equina syndrome: Could it be a valid option? A report of two cases.

Spinal cord stimulation (SCS) consists of the application of electrical stimuli to the dorsal columns of the spinal cord or to the posterior nerve roots in order to modulate the pain signals carried by the ascending pain pathways to the brain. Two cases of SCS in patients with cauda equina syndrome after lumbar surgery are presented. They were treated for persistent neuropathic pain but also experienced improvement in their motor and urinary symptoms after this treatment. Although the primary indication for SCS is neuropathic pain control, its application can also lead to improvement of motor deficits, sensory disorders, and urinary incontinence, as shown in these two cases. SCS will likely play a fundamental role in rehabilitative therapies in different neurological diseases. Further investigation in the field is needed.

Foot drop after percutaneous treatment with radiopaque gelified ethanol (Discogel®).

Sciatica due to a lumbar disc herniation is a frequent symptom, between 13% and 40% of the general population will experience an episode of sciatica during their lives. Different techniques exist to treat this condition. Among them the percutaneous intradiscal Discogel®. In all the series of patients reviewed treated with Discogel®, so far, there is not any case reported with disc extrusion and significant neurological damage. We present a case of a foot drop, caused by a disc herniation after percutaneous treatment with Discogel®. We hypothesize that the pathogenic mechanism would be the increased intradiscal volume and pressure post-puncture and annulus fibrosus damage, which could produce the disc extrusion. The extrusion of Discogel® material is possible. To the best of our knowledge, this is the first reported case of this complication with this product.

Are We Ready for Cell Therapy to Treat Stroke?

Clinical trials of cell therapies that target stroke started at the beginning of this century and they have experienced a significant boost in recent years as a result of promising data from basic research studies. The increase in the information available has paved the way to carry out more innovative and varied human studies. Efforts have focused on the search for a safe and effective treatment to stimulate neuro-regeneration in the brain and to reduce the sequelae of stroke in patients. Therefore, this review aims to evaluate the clinical trials using cell therapy to treat stroke published to date and assess their limitations. From 2000 to date, most of the published clinical trials have focused on phases I or II, and the vast majority of them demonstrate that stem cells are essentially safe to use when administered by different routes, with transient and mild adverse events that do not generally have severe consequences for health. In general, there is considerable variation in the trials in terms of statistical design, sample size, the cells used, the routes of administration, and the functional assessments (both at baseline and follow-up), making it difficult to compare the studies. From this general description, possibly the experimental protocol is the main element to improve in future studies. Establishing an adequate experimental and statistical design will be essential to obtain favorable and reliable results when conducting phase III clinical trials. Thus, it is necessary to standardize the criteria used in these clinical trials in order to aid comparison. Shortly, cell therapy will be a key approach in the treatment of stroke if adequate and comprehensive levels of recovery are to be achieved.

Decompressive craniectomy in traumatic brain injury: The intensivist's point of view.

OBJETIVE: To perform a score with early clinical and radiological findings after a TBI that identifies the patients who in their subsequent evolution are going to undergo DC. METHOD: Observational study of a retrospective cohort of patients who, after a TBI, enter the Neurocritical Section of the Intensive Care Unit of our hospital for a period of 5 years (2014-2018). Detection of clinical and radiological criteria and generation of all possible models with significant, clinically relevant and easy to detect early variables. Selection of the one with the lowest Bayesian Information Criterion and Akaike Information Criterion values for the creation of the score. Calibration and internal validation of the score using the Hosmer-Lemeshow and a bootstrapping analysis with 1000 re-samples respectively. RESULTS: 37 DC were performed in 153 patients who were admitted after a TBI. The resulting final model included Cerebral Midline Deviation, GCS and Ventricular Collapse with an Area under ROC Curve: 0.84 (95% IC 0.78-0.91) and Hosmer-Lemeshow p=0.71. The developed score detected well those patients who were going to need an early DC (first 24h) after a TBI (2.5±0.5) but not those who would need it in a later stage of their disease (1.7±0.8). However, it seems to advice us about the patients who, although not requiring an early DC are likely to need it later in their evolution (DC after 24h vs. do not require DC, 1.7±0.8 vs. 1±0.7; p=0.002). CONCLUSION: We have developed a prognostic score using early clinical-radiological criteria that, in our environment, detects with good sensitivity and specificity those patients who, after a TBI, will require a DC.

Supra and infratentorial massive strokes in previously healthy young patients with SARS-CoV-2. The role of neurosurgery.

The coronavirus disease 2019 (COVID-19) has amazed by its distinct forms of presentation and severity. COVID-19 patients can develop large-scale ischemic strokes in previously healthy patients without risk factors, especially in patients who develop an acute respiratory distress syndrome (SARS-CoV-2). We hypothesize that ischemic events are usually the result of the combined process of a pro-inflammatory and pro-coagulant state plus vascular endothelial dysfunction probably potentiated by hypoxia, hemodynamic instability, and immobilization, as reported in other cases. To the best of our knowledge, we report the first case of partial obstruction of a vertebral artery in a patient with COVID-19. Decompressive surgery remains a life-saving maneuver in these patients (as in other non-COVID-19 strokes) and requires further investigation.

Neurorestoration Approach by Biomaterials in Ischemic Stroke.

Ischemic stroke (IS) is the leading cause of disability in the western world, assuming a high socio-economic cost. One of the most used strategies in the last decade has been biomaterials, which have been initially used with a structural support function. They have been perfected, different compounds have been combined, and they have been used together with cell therapy or controlled release chemical compounds. This double function has driven them as potential candidates for the chronic treatment of IS. In fact, the most developed are in different phases of clinical trial. In this review, we will show the ischemic scenario and address the most important criteria to achieve a successful neuroreparation from the point of view of biomaterials. The spontaneous processes that are activated and how to enhance them is one of the keys that contribute to the success of the therapeutic approach. In addition, the different routes of administration and how they affect the design of biomaterials are analyzed. Future perspectives show where this broad scientific field is heading, which advances every day with the help of technology and advanced therapies.

Decompressive craniectomy in traumatic brain injury: the intensivist's point of view. / Craniectomías descompresivas en el traumatismo craneoencefálico: la visión del intensivista.

OBJETIVE: To perform a score with early clinical and radiological findings after a TBI that identifies the patients who in their subsequent evolution are going to undergo DC. METHOD: Observational study of a retrospective cohort of patients who, after a TBI, enter the Neurocritical Section of the Intensive Care Unit of our hospital for a period of 5 years (2014-2018). Detection of clinical and radiological criteria and generation of all possible models with significant, clinically relevant and easy to detect early variables. Selection of the one with the lowest Bayesian Information Criterion and Akaike Information Criterion values for the creation of the score. Calibration and internal validation of the score using the Hosmer-Lemeshow and a bootstrapping analysis with 1,000 re-samples respectively. RESULTS: 37 DC were performed in 153 patients who were admitted after a TBI. The resulting final model included Cerebral Midline Deviation, GCS and Ventricular Collapse with an Area under ROC Curve: 0.84 (95% IC 0.78-0.91) and Hosmer-Lemeshow p=0.71. The developed score detected well those patients who were going to need an early DC (first 24hours) after a TBI (2.5±0.5) but not those who would need it in a later stage of their disease (1.7±0.8). However, it seems to advice us about the patients who, although not requiring an early DC are likely to need it later in their evolution (DC after 24hours vs do not require DC, 1.7±0.8 vs 1±0.7; p=0.002). CONCLUSION: We have developed a prognostic score using early clinical-radiological criteria that, in our environment, detects with good sensitivity and specificity those patients who, after a TBI, will require a DC.

Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke.

Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl3 . After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1598-1606, 2019.

Brown-Séquard syndrome and cervical post-traumatic subarachnoid hematoma.

Cervical Traumatic SSH are very rare in literature. They are usually caused by cardiopulmonary diseases that increase vascular pressure causing spinal vessels rupture. In thoracolumbar spine, the spinal puncture is the most common cause. The ventrolateral position is even more unusual. In traumatic brain injury (TBI), an abrupt extension-flexion movement could have caused the rupture of subarachnoid vessels. This, accompanied by the slowed blood "wash out" (probably due to the previous osteoarthrosis and spinal canal stenosis), led to the formation of an organized clot, which caused an acute spinal cord compression syndrome. Cervical subarachnoid spinal hematoma can present as Brown-Séquard syndrome. The treatment is prompt surgical removal and decompression. The posterior approach (partial hemilaminectomy with or without laminoplasty) with microsurgical technique is feasible, fast and simple to evacuate the hematoma with good results. Surgical nuances in posterior approach are: small spinal canal, difficulty in mobilizing the cervical cord, these haematomas are wrapped and attached to the spinal cord or nerve roots by multiple arachnoid bands, requiring techniques of Microdissection for its evacuation unlike the epidural and subdural haematomas that are easily aspirated. Here, we report a unique case of a ventrolateral SSH due to TBI.

Ependimomas lipomatosos de la fosa posterior. Un subtipo muy infrecuente y poco conocido. Presentación de caso y revisión de la literatura / Lipomatous ependymomas of the posterior fossa. An infrequent and little-known subtype. A case report and review of the literature

Los ependimomas son tumores gliales bien circunscritos compuestos de células pequeñas uniformes con un núcleo redondo en una matriz fibrilar. Se caracterizan por zonas anucleadas perivasculares (pseudorrosetas) y, en algunos casos, rosetas ependimarias. Tres fenotipos histológicos son los más reconocidos: papilar, de células claras y tanicítico. La OMS reconoce casos raros de ependimomas con metaplasia lipomatosa. Los ependimomas lipomatosos de fosa posterior son extremadamente infrecuentes, y en nuestra búsqueda hemos encontrado 7casos reportados en la literatura (excluyendo niños). Se originan habitualmente del 4.° ventrículo y podrían presentar extensión cerebelosa. Estos suelen presentar extensa vacuolización empujando el núcleo a la periferia y simulando la apariencia de «signet-ring cells» (células en anillo de sello). Radiológicamente hay pocos hallazgos que sean característicos de este tipo de tumores. La inmunohistoquímica es decisiva para no confundir esta variante con lesiones más comunes, como el adenocarcinoma metastásico, especialmente los de mama, intestino y renal.(AU)

Ependymomas are well defined glial tumours composed of uniform small cells with round nuclei in a fibrillar matrix. They have characteristic perivascular acellular areas (pseudorosettes) and, in some cases, ependymal rosettes. The three most well-known histological phenotypes are papillary, clear-cell and tanycytic. The WHO classification includes rare cases of ependymoma with lipomatous metaplasia. Lipomatous ependymomas of the posterior fossa are extremely rare; we only found 7reports of cases in adults. They usually arise in the fourth ventricle and may extend into the cerebellum, when they often show extensive vacuolization, pushing the nucleus to the periphery and giving rise to a signet-ring cell appearance. Radiologically, there are few findings characteristic of these tumours. Immunohistochemistry is essential to differentiate this subtype from other more common lesions, such as metastatic adenocarcinoma, especially from breast, intestine and kidney.(AU)

Foot drop after percutaneous treatment with radiopaque gelified ethanol (Discogel®) / Pie caído posterior al tratamiento percutáneo con etanol gelificado radiopaco (Discogel®)

Sciatica due to a lumbar disc herniation is a frequent symptom, between 13% and 40% of the general population will experience an episode of sciatica during their lives. Different techniques exist to treat this condition. Among them the percutaneous intradiscal Discogel®. In all the series of patients reviewed treated with Discogel®, so far, there is not any case reported with disc extrusion and significant neurological damage. We present a case of a foot drop, caused by a disc herniation after percutaneous treatment with Discogel®. We hypothesize that the pathogenic mechanism would be the increased intradiscal volume and pressure post-puncture and annulus fibrosus damage, which could produce the disc extrusion. The extrusion of Discogel® material is possible. To the best of our knowledge, this is the first reported case of this complication with this product (AU)

La ciática secundaria a una hernia discal lumbar es un síntoma frecuente; entre el 13% y el 40% de la población general experimentará un episodio de ciática durante sus vidas. Se han desarrollado diferentes técnicas para tratar esta dolencia. Entre ellas, el Discogel® intradiscal percutáneo. En todas las series revisadas de pacientes tratados con Discogel®, hasta el momento, no se ha informado ningún caso de extrusión discal ni daño neurológico importante. Presentamos un caso de pie caído, causado por una hernia de disco posterior al tratamiento percutáneo con Discogel®. Nuestro mecanismo teórico es el aumento del volumen y la presión intradiscal más el daño del anillo fibroso pospunción que podría producir una extrusión discal. La extrusión del material Discogel® es posible. Hasta donde sabemos, este es el primer caso reportado de esta complicación con este producto (AU)