Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

Nitric Oxide in Selective Cerebral Perfusion Could Enhance Neuroprotection During Aortic Arch Surgery

BackgroundHypothermic circulatory arrest (HCA) in aortic arch surgery has a significant risk of neurological injury despite the newest protective techniques and strategies. Nitric oxide (NO) could exert a protective role, reduce infarct area and increase cerebral perfusion. This study aims to investigate the possible neuroprotective effects of NO administered in the oxygenator of selective antegrade cerebral perfusion (SCP) during HCA.MethodsThirty male SD adult rats (450–550 g) underwent cardiopulmonary bypass (CPB), cooling to 22°C body core temperature followed by 30 min of HCA. Rats were randomized to receive SCP or SCP added with NO (20 ppm) administered through the oxygenator (SCP-NO). All animals underwent CPB-assisted rewarming to a target temperature of 35°C in 60 min. At the end of the experiment, rats were sacrificed, and brain collected. Immunofluorescence analysis was performed in blind conditions.ResultsNeuroinflammation assessed by allograft inflammatory factor 1 or ionized calcium-binding adapter molecule 1 expression, a microglia activation marker was lower in SCP-NO compared to SCP (4.11 ± 0.59 vs. 6.02 ± 0.18%; p < 0.05). Oxidative stress measured by 8oxodG, was reduced in SCP-NO (0.37 ± 0.01 vs. 1.03 ± 0.16%; p < 0.05). Brain hypoxic area extent, analyzed by thiols oxidation was attenuated in SCP-NO (1.85 ± 0.10 vs. 2.74 ± 0.19%; p < 0.05). Furthermore, the apoptotic marker caspases 3 was significantly reduced in SCP-NO (10.64 ± 0.37 vs. 12.61 ± 0.88%; p < 0.05).ConclusionsNitric oxide administration in the oxygenator during SCP and HCA improves neuroprotection by decreasing neuroinflammation, optimizing oxygen delivery by reducing oxidative stress and hypoxic areas, finally decreasing apoptosis.

Effect of Neoadjuvant Iodine-125 Brachytherapy Upon Resection of Glioma

Background: A more extensive surgical resection of glioma contributes to improved overall survival (OS) and progression-free survival (PFS). However, some of the patients lost the chance of surgical resection when the tumor involves critical structures. Purpose: The present study aimed to assess the feasibility of neoadjuvant 125I brachytherapy followed by total gross resection for initially inoperable glioma.Methods:Six patients diagnosed with inoperable glioma due to invasion of eloquent areas, bi-hemispheric diffusion, or large tumor volume received 125I brachytherapy. Surgical resection was performed when the tumor shrank, allowing a safe resection, assessed by the neurosurgeons. Patients were followed up after surgery.Results:Tumor shrinkage after adjuvant 125I brachytherapy enabled a total gross resection of all six patients. Four patients were still alive at the last follow-up, with the longest survival time of more than 50 months, two of which returned to a normal life with the KPS of 100. Another two patients got a neurological injury with the KPS of 80 and 50, respectively. One patient with grade Ⅱ glioma died 34 months, and another patient with grade Ⅳ glioma died 40 months later after the combined therapy.Conclusions: In the present study, the results demonstrated that 125I brachytherapy enabled a complete resection of patients with initially unresectable gliomas. 125I brachytherapy may offer a proper neoadjuvant therapy method for glioma.

Contiguous-Level Unilateral Cervical Spine Facet Dislocation—A Report of a Less Discussed Subtype

Unilateral facet dislocation of subaxial cervical spine trauma is characterized by dislocation of inferior facet of superior vertebra over the superior facet of inferior vertebra. The injury is due to high-velocity trauma and associated with instability of spinal column. Such unilateral facet dislocations occurring at multiple adjacent levels for some reason are not reported or studied frequently. We have reported two cases of multiple-level dislocation of unilateral facets managed in our hospital with a review of available literature. The injury occurs as one side of the motion segment translates and rotates around an intact facet on the contralateral side. The major mechanism of injury is distractive flexion injury with axial rotation component. The injury is associated with instability secondary to loss of the discoligamentous complex. In cases with multiple-level dislocations of unilateral cervical facets, there are multiple mechanisms associated with significant neurological injury and most of them succumb at the site of injury. Only three other cases are available in English language literature. The neurological outcome is invariably poor. Multiple-level facet dislocations of subaxial cervical spine are reported sparsely in literature. We suspect that due to high-velocity nature of these injuries, most of them succumb soon after injury and not often reported. This article reports two cases of contiguous-level unilateral facet dislocation of subaxial cervical spine with associated injuries and the outcomes with review of literature.

Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.

Nickels and tines: the myth of nickel allergy in intracranial stents

BackgroundMost intracranial stents contain nickel alloy, and nickel allergy or hypersensitivity is common. Neurological injury following endovascular treatment with a nickel containing intracranial stent has been reported in patients with purported nickel allergy, but it is unclear whether these reactions represent true nickel hypersensitivity. We quantified nickel release from commonly used intracranial stents to investigate whether such stents should be avoided in patients with nickel allergy.MethodsWe examined nickel release from seven commonly used intracranial stents: Enterprise, LVIS Jr, Neuroform, Wingspan, Zilver, Pipeline Flex Embolization Device, and Surpass Evolve. We incubated each stent in human plasma-like media for 30 days. Dimethylglyoxime (DMG) spot testing was performed on each stent to detect released nickel at 0 and 30 days. Inductively coupled plasma–optical emission spectroscopy (ICP-OES) was then used to quantify the nickel concentration of the media at 30 days. Nickel currency and nickel standard for atomic absorption spectrometry were used as positive controls.ResultsDMG spot tests indicated nickel release only from nickel currency at 0 and 30 days of incubation. No nickel release was detected from any stent at 30 days using ICP-OES.ConclusionsNickel release from commonly used intracranial stents is negligible. These results suggest that previously reported hypersensitivity to these stents may be misattributed to nickel allergy, and that patients with nickel allergy may be safely treated with select nickel-containing stents.

The Relationship Between and Correlates of Problematic Sexual Behavior and Major Mental Illness

While research has consistently found that general distress and psychopathology are not predictive of sexual recidivism, examination of specific syndromes and their relationship to offending has revealed a potentially more complicated relationship. One proposed mechanism for the mixed findings with respect to major mental illness and sexual offending may be the confound of neurological injury. As identified in Mann et al. (2010) work on psychologically meaningful risk factors, mental illness represents an area in need of more study given the indirect influence it may exert on risk. To this end, the current paper summarizes the study of the relationship between neurological injury, psychosis and problematic sexual behavior among two Canadian samples of forensic and civil psychiatric patients. In the first study we observed higher than expected rates of sexually-themed psychotic symptoms (45%) and problematic sexual behavior (PSB; 40%) among a combined group of forensic and civil psychiatric patients (n = 109). Indeed 70 percent of those individuals who engaged in PSB endorsed sexually-themed psychotic symptoms. While comorbidity is common amongst this group, brain injury appeared to represent a specific liability. Compared to those who did not engage in PSB, those who did were almost 4x (OR = 3.83) more likely to have a documented history of brain injury (e.g., traumatic and acquired brain injury, including fetal alcohol syndrome). In the second study we sought to replicate this finding in a larger forensic sample of 1,240. However, the recorded rates of brain injury were significantly less, such that no relationship to PSB was observed. Based on the mixed findings to date, including our own data, questions remain about the nature of a potential shared vulnerability for psychosis and PSB previously postulated. Among psychiatrically complex individuals who engage in PSB, understanding etiology and links to risk are helpful, but perhaps more importantly is attention to the mechanisms through which symptoms confer risk (e.g., problem solving, sexual disinhibition, social/intimacy deficits) and how best to treat and manage them.

Biomarkers to aid the return to play decision following sports-related concussion: a systematic review

Premature return to play (RTP) following sports-related concussion (SRC) is associated with significant morbidity including risk of neurological and non-neurological injury, persistent post-concussion symptoms and chronic neurological deficits. Assessing athletes for RTP is critical but these decisions are currently based on clinical assessments that are subject to bias and symptomatic reporting that rely on compliance. An objective and easily obtained biomarker that can indicate recovery following SRC would aid clinicians to make safer RTP decisions. We performed a systematic review to identify potential biomarkers from saliva, urine and blood sources that could inform the clinical RTP decision. The MEDLINE database was searched. Inclusion criteria were studies focusing on adults diagnosed with SRC, fluid biomarkers from blood, saliva or urine and clinical recovery from SRC or at RTP. We assessed each biomarker for their time course post SRC and relationship to clinical recovery. Secondary outcomes included correlation with symptom scores and predictive value for prolonged RTP. We identified 8 studies all investigating blood-based markers of diffuse axonal injury (tau, NFL, SNTF), neuroglial injury (NSE, VLP-1, UCH-L1, S100B, GFAP), inflammation and hormonal disturbances. Tau, SNTF, UCH-1, GFAP, S100B and the inflammatory cytokine MCP-4 are raised post SRC and return to baseline by RTP. Changes in tau, NFL, SNTF, GFAP and MCP-4 post SRC correlate with severity of concussion as measured by symptom severity or RTP duration. There is only preliminary case-reporting for hormonal biomarkers. The evidence is limited by a lack of highly powered studies, variation in use of athletic and Contact sport controls (CSC) and a lack of consistent sampling and assessment protocols. There is promise for biomarkers to aid RTP decisions following SRC, most notably in use alongside clinical assessment in RTP criteria to allow greater precision in identifying mild and severe concussion.