Subsequent Neurological Deterioration Research Articles

Perinatal and Neonatal Chikungunya Virus Transmission: A Case Series.

Large-scale epidemics in countries with high birth rates can create a concerning scenario where pregnant people are more likely to transmit the virus. In addition, increased international mobility has made arboviruses a growing problem for travelers. The increased risk of vertical transmission has been related to maternal viremia near delivery. Such transmission leads to severe infection of newborns and may be associated with subsequent neurological impairment including cerebral palsy. This case series provides an overview of clinical and laboratory findings in pregnant individuals with confirmed chikungunya virus (CHIKV) infection as well as the clinical effects on their newborn emphasizing the severity of neonatal chikungunya. An ambispective case series enrolled newborns with confirmed exposure to CHIKV in utero or in the neonatal period. During the delivery period, the transmission rate among viremic individuals was approximately 62% (18/29). Fever, irritability, rash, and poor feeding in the first week of life were critical signs of neonatal chikungunya, highlighting its severity. Close monitoring of healthy newborns during the first week of life is essential in areas affected by CHIKV epidemics, and in offspring of pregnant travelers who visited the outbreaks zones. This case series is intended to increase neonatologists' awareness of the possibility of mother-to-child transmission of CHIKV among newborns with a sepsis-like presentation. Prioritizing CHIKV vaccination for women of childbearing age should also be considered.

ISMRM Clinical Focus Meeting 2023: "Imaging the Fire in the Brain".

Set during the Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), the "Clinical Focus Meeting" (CFM) aims to bridge the gap between innovative magnetic resonance imaging (MRI) scientific research and daily patient care. This initiative is dedicated to maximizing the impact of MRI technology on healthcare outcomes for patients. At the 2023 Annual Meeting, clinicians and scientists from across the globe were invited to discuss neuroinflammation from various angles (entitled "Imaging the Fire in the Brain"). Topics ranged from fundamental mechanisms and biomarkers of neuroinflammation to the role of different contrast mechanisms, including both proton and non-proton techniques, in brain tumors, autoimmune disorders, and pediatric neuroinflammatory diseases. Discussions also delved into how systemic inflammation can trigger neuroinflammation and the role of the gut-brain axis in causing brain inflammation. Neuroinflammation arises from various external and internal factors and serves as a vital mechanism to mitigate tissue damage and provide neuroprotection. Nonetheless, excessive neuroinflammatory responses can lead to significant tissue injury and subsequent neurological impairments. Prolonged neuroinflammation can result in cellular apoptosis and neurodegeneration, posing severe consequences. MRI can be used to visualize these consequences, by detecting blood-brain barrier damage, characterizing brain lesions, quantifying edema, and identifying specific metabolites. It also facilitates monitoring of chronic changes in both the brain and spinal cord over time, potentially leading to better patient outcomes. This paper represents a summary of the 2023 CFM, and is intended to guide the enthusiastic MR user to several key and novel sequences that MRI offers to image pathophysiologic processes underlying acute and chronic neuroinflammation. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

Predictive factors for intracranial hemorrhage in patients with traumatic brain injury

Background: Intracranial hemorrhage (ICH) is a critical neurological condition that occurs due to the rupture of cerebral blood vessels, leading to blood infiltration into brain parenchyma. It is a leading cause of morbidity and mortality, with a greater impact on disability-adjusted life years (DALYs) compared to ischemic stroke. The primary causes of non-traumatic ICH are small-vessel disease (SVD) and cerebral amyloid angiopathy (CAA), which are affected by aging, hypertension, and other risk factors. Timely diagnosis and management of ICH are crucial due to the potential for hematoma expansion and subsequent neurological impairment. Aim: This study aims to identify predictive factors associated with ICH in patients with traumatic brain injury (TBI) and provide insights into improving patient outcomes through early diagnosis and intervention. Methods: A cohort study design was utilized to assess the predictive factors influencing ICH development in patients diagnosed with TBI. Clinical, radiological, and demographic data were collected, including age, sex, blood pressure, and medical history. Statistical analyses were performed to identify key predictors of ICH, such as the presence of hypertension, anticoagulant use, and delayed imaging. Results: The findings indicated that older age, high blood pressure, and the use of antithrombotic medications were significant predictors of ICH.

Decreased human leukocyte antigen-D–related expression on CD14+ monocytes in patients with out-of-hospital cardiac arrest provided target temperature management therapy: a prospective observational study

Abstract Background Post–cardiac arrest syndrome involves systemic inflammation, which causes subsequent neurological impairments. We investigated the influence of targeted temperature management (TTM) therapy in patients with out-of-hospital cardiac arrest (OHCA) after return of spontaneous circulation (ROSC) by observing the changes in circulating CD14+ monocytes and the expression of human leukocyte antigen D–related (HLA-DR) and programmed cell death ligand 1 (PD-L1) in CD14+ monocytes. Methods Adult patients admitted to the emergency department of Beijing Chao-Yang Hospital after OHCA between January 2017 and March 2018 were included in this study. Thirty control subjects, 10 patients with OHCA, and 37 patients with OHCA who received 72 hours of TTM therapy were enrolled. Peripheral blood samples of patients in the OHCA and TTM groups were collected on Days 1 and 3 (D1 and D3) after ROSC and evaluated for HLA-DR and PD-L1 expression on CD14+ monocytes using flow cytometry. Results Compared with control subjects, the percentage of circulating CD14+ monocytes, HLA-DR+/CD14+ monocyte ratios, and mean fluorescence intensity were significantly decreased in patients with OHCA. After ROSC, HLA-DR expression in CD14 + monocytes in the TTM group was lower than that in patients with OHCA. However, there were no significant differences in the percentage of PD-L1+/CD14+ monocytes or the mean fluorescence intensity between patients with OHCA and healthy volunteers. Conclusion After ROSC, circulating CD14+ monocytes and HLA-DR+/CD14+ monocyte ratios decreased significantly in patients with OHCA. Human leukocyte antigen D–related expression in CD14+ monocytes was lower in patients treated with TTM.

Risk factors and management of intraprocedural rupture during coil embolization of unruptured intracranial aneurysms: role of balloon guiding catheter.

Intraprocedural rupture (IPR) is a serious complication of endovascular coil embolization of unruptured intracranial aneurysms (UIAs). Although outcomes after IPR are poor, methods to prevent subsequent neurological deterioration have not yet been investigated. We evaluated the risk factors and management strategies for IPR, particularly the role of balloon guiding catheters (BGCs) in rapid hemostasis. We retrospectively reviewed all UIA cases treated with coil embolization at three institutions between 2003 and 2021, focusing on preoperative radiological data, operative details, and outcomes. In total, 2,172 aneurysms were treated in 2026 patients. Of these, 19 aneurysms in 19 patients (0.8%) ruptured during the procedure. Multivariate analysis revealed that aneurysms with a bleb (OR: 3.03, 95% CI: 1.21 to 7.57, p = 0.017), small neck size (OR: 0.56, 95% CI: 0.37 to 0.85, p = 0.007), and aneurysms in the posterior communicating artery (PcomA) (OR: 4.92, 95% CI: 1.19 to 20.18, p = 0.027) and anterior communicating artery (AcomA) (OR: 12.08, 95% CI: 2.99 to 48.79, p < 0.001) compared with the internal carotid artery without PcomA were significantly associated with IPR. The incidence of IPR was similar between the non-BGC and BGC groups (0.9% vs. 0.8%, p = 0.822); however, leveraging BGC was significantly associated with lower morbidity and mortality rates after IPR (0% vs. 44%, p = 0.033). The incidence of IPR was relatively low. A bleb, small aneurysm neck, and location on PcomA and AcomA are independent risk factors for IPR. The use of BGC may prevent fatal clinical deterioration and achieve better clinical outcomes in patients with IPR.

Cenicriviroc prevents dysregulation of astrocyte/endothelial cross talk induced by ischemia and HIV-1 via inhibiting the NLRP3 inflammasome and pyroptosis.

Blood-brain barrier (BBB) breakdown is one of the pathophysiological characteristics of ischemic stroke, which may contribute to the progression of brain tissue damage and subsequent neurological impairment. Human immunodeficiency virus (HIV)-infected individuals are at greater risk for ischemic stroke due to diminished immune function and HIV-associated vasculopathy. Studies have shown that astrocytes are involved in maintaining BBB integrity and facilitating HIV-1 infection in the brain. The present study investigated whether targeting astrocyte-endothelial cell signaling with cenicriviroc (CVC), a dual chemokine receptor (CCR)2 and CCR5 antagonist, may protect against dysregulation of cross talk between these cells after oxygen-glucose deprivation/reoxygenation (OGD/R) combined with HIV-1 infection. Permeability assay with 10 kDa fluorescein isothiocyanate (FITC)-dextran demonstrated that CVC alleviated endothelial barrier disruption in noncontact coculture of human brain microvascular endothelial cells (HBMECs) with HIV-1-infected human astrocytes, and reversed downregulation of tight junction protein claudin-5 induced by OGD/R- and HIV-1. Moreover, CVC attenuated OGD/R- and HIV-1-triggered upregulation of the NOD-like receptor protein-3 (NLRP3) inflammasome and IL-1β secretion. Treatment with CVC also suppressed astrocyte pyroptosis by attenuating cleaved caspase-1 levels and the formation of cleaved N-terminal GSDMD (N-GSDMD). Secretome profiling revealed that CVC ameliorated secretion levels of chemokine CC chemokine ligand 17 (CCL17), adhesion molecule intercellular adhesion molecule-1 (ICAM-1), and T cell activation modulator T cell immunoglobulin and mucin domain 3 (TIM-3) by astrocytes synergistically induced by OGD/R and HIV-1. Overall, these results suggest that CVC contributes to restoring astrocyte-endothelial cross interactions in an astrocyte-dependent manner via protection against NLRP3 activation and pyroptosis.NEW & NOTEWORTHY The present study reveals the role of astrocytic NOD-like receptor protein-3 (NLRP3) inflammasome in dysfunctional astrocyte-endothelial cross interactions triggered in response to oxygen/glucose deprivation injury associated with human immunodeficiency virus type 1 (HIV-1) infection. Our results suggest that blocking NLRP3 inflammasome activation and pyroptosis-mediated inflammation with cenicriviroc (CVC) may constitute a potentially effective therapeutic strategy for blood-brain barrier (BBB) protection during HIV-1-associated ischemic stroke.

Post-Traumatic Vasospasm after Mild Brain Trauma, a Lesson Learned.

Background: Post-traumatic vasospasm is a frequent secondary injury in patients with traumatic brain injury, occurring in up to 63% of patients and with associated deleterious consequences. Most studies have reported post-traumatic vasospasm in patients with severe or moderate brain trauma; however, there are documented cases of post-traumatic vasospasm in patients with mild traumatic brain injury that support a more aggressive search to prevent deleterious neurological outcomes. Observation(s): The pertinent literature has been reviewed, and an exemplary case has been reported (post-traumatic vasospasm associated with mild brain trauma in an adult patient that subsequently transformed into cerebral ischemia that was managed with endovascular therapy and oral nimodipine without subsequent neurological deterioration). To date, only 4 cases have been described, to our knowledge this is the first literature review so far. Lessons: Given the possibility of post-traumatic vasospasm associated with mild brain trauma, the authors believe that GCS score alone may be an inadequate risk predictor of symptomatic cerebral vasospasm and a more aggressive search should be performed in patients with mild trauma who present with neurological deterioration without apparent cause.

Plate-only open-door laminoplasty is associated with durable, significantly improved clinical outcomes and a very low reoperation rate for progressive spondylosis or adjacent segment disease: average 8-year follow-up

Background ContextMultilevel cervical myelopathy is a common cause of spinal cord dysfunction in adults. Surgical intervention via laminoplasty can provide satisfactory clinical outcomes by expansive decompression of the spinal cord. Traditional suture or bone graft techniques have been associated with insufficient fixation, leading to premature closure and subsequent neurological deterioration. In contrast, plated laminoplasty has been shown to provide stable fixation to maintain canal enlargement, but longer-term outcomes are lacking. PurposeTo evaluate longer-term clinical outcomes and reoperations associated with plate-only open-door laminoplasty. Study designRetrospective review of prospectively collected data. Patient SamplePostoperative patients who underwent plate-only open door laminoplasty with minimum 5-year follow up. Outcome Measuresmodified Japanese Orthopaedic Association (mJOA) score, Neck Disability Index (NDI), and 12-item Short Form Health Survey (SF-12). MethodsAll patients at a single academic institution who underwent plate-only open-door cervical laminoplasty from 9/1/2006 to 9/1/2016 were identified to ensure minimum 5 year follow up. Clinical outcomes included the modified Japanese Orthopaedic Association (mJOA) score, the Neck Disability Index (NDI), and the 12-item Short Form Health Survey (SF-12). The occurrence of any repeat operations on the cervical spine was evaluated, as well as its cause. The study team attempted to contact all eligible patients to achieve at least 5 years postoperative follow-up. Pairwise t tests were performed to compare clinical outcomes at preoperative, 6 months, 1-year, and final postoperative follow-up with an α level of 0.05. ResultsA total of 774 met the initial inclusion criteria, of which 157 were included in the study (20.3%). Most common reasons for exclusion included inability to reach after 3 attempts (49.48%), inactive phone numbers (20.28%), and patient declining (3.49%). Included patients had an average age of 60.66±10.63 and an average follow-up time of 8.37±2.57 years (minimum 5 years). mJOA scores (preoperative 11.59±2.16) improved significantly at 6-months (14.57±2.07, p<.001), 1-year (15.19±1.95, p<.001), and final follow-up (14.59±2.63, p<.001). NDI (preoperative 33.89±18.54) improved significantly at 6 months (27.89±19.72, p=.03), 1-year (25.96±19.79, p=.01) and final follow-up (17.88±17.17, p<.001). SF-12 MCS (preoperative 44.73) improved significantly at 6 months (52.01, p=.001), 1-year (51.62, p=.008), and final follow-up (52.32, p<.001). No patient underwent reoperations for plate failure or canal closure with recurrent stenosis. Reoperations for progressive spondylosis during the follow up period were rare and occurred in only three patients for new onset radiculopathy (1.9%) and two patients for myelopathy (1.3%) at an average of 3.2 years postoperative. There were no reoperations performed for adjacent segment disease. ConclusionsAt a minimum of 5 years and an average of more than 8 years postoperative, laminoplasty was associated with significant and sustained improvements in mJOA, NDI, and SF-12 MCS. Importantly, no patients underwent revision surgery for plate failure or recurrent canal closure. Reoperations for new onset radiculopathy and myelopathy were also very rare over the 8-year average follow-up period, with no reoperations for adjacent segment disease. Plate-only laminoplasty is a durable means of treating multilevel myelopathy with excellent longer-term outcomes and a very low risk of reoperation, either for premature closure or the inevitable spondylotic changes that occur over time in patients with similar baseline characteristics to the study population.

Severe Hemolytic Anemia and Metabolic Acidosis at Birth with Glutathione Synthetase Deficiency and Progressive Neurological Symptoms on Follow-Up.

BACKGROUND Glutathione synthetase deficiency (GSD) is a rare autosomal recessive disorder caused by glutathione synthetase (GSS) gene variants that occur in 1 in 1 million individuals. The severe form of GSD is characterized by hemolytic anemia, metabolic acidosis with 5-oxoprolinuria, progressive neurological symptoms, and recurrent bacterial infections. This case report presents a male Japanese infant with severe hemolytic anemia and metabolic acidosis at birth caused by GSD, who developed progressive neurological symptoms on follow-up. CASE REPORT A Japanese male term infant developed severe hemolytic anemia and metabolic acidosis in the early neonatal period. We suspected GSD based on his symptoms and a high 5-oxoproline urine concentration. We began correcting his metabolic acidosis and administering vitamins C and E supplements. The patient required blood transfusion twice during the acute phase for hemolytic anemia. After age 1 month, he maintained good control of metabolic acidosis and hemolytic anemia. A definitive diagnosis of GSD was made based on high concentrations of 5-oxoproline in urine, low concentrations of glutathione and GSS activity in erythrocytes, and genetic testing. Several episodes of febrile convulsions were started at age 11 months, but none occurred after 2 years. At the last follow-up at age 25 months, metabolic acidosis and hemolytic anemia were well controlled, but he had mild neurodevelopmental delay. CONCLUSIONS This case report shows that GSD can present with severe hemolytic anemia and metabolic acidosis at birth, and manifest with subsequent neurological impairment despite early diagnosis and treatment. Therefore, a careful long-term follow-up that includes neurological evaluation is essential for patients with GSD.

Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway

Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer’s disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.

Cerebrospinal Fluid Lactate and Glucose Levels as Predictors of Symptomatic Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a complex neurovascular syndrome with profound systemic effects associated with high rates of disability and mortality. Delayed cerebral ischemia (DCI), which encompasses all neurobiological events occurring in the subacute-late stage after aSAH, has a complex pathogenesis and can occur in the absence of instrumental vasospasm. Our aim was to assess the correlation between cerebrospinal fluid (CSF) lactate and glucose levels measured on the second or third day after aSAH with clinical deterioration caused by DCI and with 3-month functional outcome. This prospective study included all aSAH patients admitted between January 2020 and December 2021 who underwent external ventricular drain placement and CSF lactate and glucose measurement. Among 133 aSAH patients, 48 had an external ventricular drain placed and early CSF lactate and glucose assessment. Independent predictors of symptomatic DCI were World Federation of Neurosurgical Societies grade IV-V (adjusted odds ratio [aOR] 25.8, 95% confidence interval [CI] 2.9-649.2, P= 0.012), elevated CSF glucose (aOR 28.8, 95% CI 3.3-775.2, P= 0.010), and elevated CSF lactate (aOR 14.7, 95% CI 1.9-205.7, P= 0.018). The only independent predictor of 3-month functional outcome was occurrence of symptomatic DCI (aOR 0.02, 95% CI 0.0-0.2, P= 0.01). Elevated CSF lactate and glucose levels in the first 3 days following aSAH were independent predictors of subsequent DCI-related neurological impairment; the presence of instrumental vasospasm was not significantly correlated with DCI after multivariate adjustment. CSF lactate and glucose monitoring may represent a point-of-care test, which could potentially improve prediction of subacute neurological worsening and guide therapeutic choices. Further research with larger prospective cohorts is warranted.

Abstract WP142: T Cells Aggravate Intracerebral Hemorrhage Injury

Intracerebral hemorrhage (ICH), a devastating form of stroke, has a mortality of 40% and no available treatment. Inflammation contributes to the genesis and expansion of perihematomal edema (PHE) in ICH, thus driving secondary injury and subsequent neurological deterioration. This study was carried out to elucidate contributions of lymphocytes, specifically CD4 + cells in the formation of PHE and ICH-induced neural injury. Upon examination of brain sections of ICH patients, we observed abundant CD4 + T cells among the PHE-infiltrating immune cells as early as 24 hours post-ictus. Analogous findings in ICH mouse model induced with autologous blood or collagenase injection confirmed the phenomenon. Using anti-CD4 antibody to deplete CD4 + T cells, we find that brain-infiltrating CD4 + T cells exacerbates acute ICH injury in mice by reducing BBB integrity and promoting leukocytes recruitment with early and time-dependent CD4 + T cells activation. Brain infiltrating CD4 + T cells exhibit activated transcriptome signatures, promoting local inflammation via IL-17. In the hemorrhagic brain, CD4 + T cells induces CD31 + endothelial cell apoptosis via death receptor-ligands TRAIL-DR5 pathway; specific ablation of CD4 + T cells with depleting antibody results in reduced PHE volume and improved long-term neurological outcome. In all, these data sheds new lights on T cell-mediated immune responses contributing to PHE and brain injury in ICH.

Oxytocin: a new target for neuroprotection?

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante-/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders affecting more than 9 million children each year. Most pharmacological candidates to prevent perinatal brain damage have failed to demonstrate substantial benefits. In contrast, environment enrichment based on developmental care, skin-to-skin contact and vocal/music exposure appear to exert positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the neonatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. In particular, excessive cortisol release in response to perinatal stress associated with prematurity or IUGR is recognized to induce brain-programming effects and neuroinflammation, a key predictor of subsequent neurological impairments. These deleterious effects are known to be balanced by oxytocin (OT), a neuropeptide released by the hypothalamus, which plays a role during the perinatal period and in social behavior. In addition, preclinical studies suggest that OT is able to regulate the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with developing white matter damage, we recently reported that carbetocin, a brain permeable OT receptor (OTR) agonist, induced a significant reduction of activated microglia, the primary immune cells of the brain. Moreover, this reduced microglia reactivity was associated with long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the mechanisms linking endogenous OT and central inflammation response to injury have not yet been established. Further studies are needed to assess the protective role of OT in the developing brain through modulation of microglial activation, a key feature of brain injury observed in infants born preterm or growth-restricted. They are expected to have several impacts in the near future not only for improving knowledge of microglial cell physiology and reactivity during brain development, but also to design clinical trials testing interventions associated with endogenous OT release as a relevant strategy to alleviate neuroinflammation in neonates.

Impact of chronic smoking on traumatic brain microvascular injury: An in vitro study.

Traumatic brain injury (TBI) is a major reason of cerebrovascular and neurological damage. Premorbid conditions such as tobacco smoking (TS) can worsen post‐TBI injuries by promoting vascular endothelial impairments. Indeed, TS‐induced oxidative stress (OS) and inflammation can hamper the blood‐brain barrier (BBB) endothelium. This study evaluated the subsequence of chronic TS exposure on BBB endothelial cells in an established in vitro model of traumatic cell injury. Experiments were conducted on confluent TS‐exposed mouse brain microvascular endothelial cells (mBMEC‐P5) following scratch injury. The expression of BBB integrity–associated tight junction (TJ) proteins was assessed by immunofluorescence imaging (IF), Western blotting (WB) and quantitative RT‐PCR. We evaluated reactive oxygen species (ROS) generation, the nuclear factor 2–related (Nrf2) with its downstream effectors and several inflammatory markers. Thrombomodulin expression was used to assess the endothelial haemostatic response to injury and TS exposure. Our results show that TS significantly decreased Nrf2, thrombomodulin and TJ expression in the BBB endothelium injury models while increased OS and inflammation compared to parallel TS‐free cultures. These data suggest that chronic TS exposure exacerbates traumatic endothelial injury and abrogates the protective antioxidative cell responses. The downstream effect was a more significant decline of BBB endothelial viability, which could aggravate subsequent neurological impairments.

Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination – A report of two UK cases

Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache,with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. Arapid vaccinationprogramme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens.However, some cases have proved fatal. Itis critical that clinicians arealerted to the emergence of such eventstofacilitate appropriate management.Patients presenting with CVST features and thrombocytopenia post-vaccination should undergoPF4 antibody testing and be managed in a similar fashion to HIT,in particular avoiding heparin and platelet transfusions.

USP30 protects against oxygen-glucose deprivation/reperfusion induced mitochondrial fragmentation and ubiquitination and degradation of MFN2.

Cerebral ischemia-reperfusion induces mitochondrial fragmentation and dysfunction, which plays a critical role in the subsequent neuronal death and neurological impairment. Protection of mitochondria is an effective strategy to prevent neuronal damage after cerebral ischemia-reperfusion injury. USP30 is a deubiquitinating enzyme that localizes to the outer mitochondrial membrane. USP30 participates in the regulation of mitophagy and maintenance of mitochondrial morphology. In this study, the neuroprotective effect of USP30 and the underlying mechanisms were assessed in an ischemia-reperfusion injury model. SK-N-BE (2) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. Ubiquitination of mitochondrial proteins is increased during the early stage of reperfusion after oxygen-glucose deprivation (OGD), but the ubiquitination of cytoplasmic proteins exhibits no obvious changes. OGDR insult also induces rapid ubiquitination and degradation of the mitochondrial fusion protein mitofusin 2 (MFN2) in the early stage of reperfusion after OGD. Overexpression of MFN2 attenuates OGDR induced mitochondrial fragmentation. USP30 overexpression suppresses OGDR-induced ubiquitination and degradation of MFN2, and protects against mitochondrial fragmentation. Therefore, precisely targeting USP30 may provide a novel therapeutic strategy for cerebral ischemia-reperfusion related disorders.

Steroids for delayed cerebral edema after traumatic brain injury.

Background: Brain edema is a common phenomenon after traumatic brain injury (TBI) resulting in increased intracranial pressure and subsequent neurological deterioration. Experimental studies have proven that brain edema is biphasic (cytotoxic followed by vasogenic). Till date, all studies, including the corticosteroid randomization after significant head injury (HI) trial, have used high-dose steroids in the acute period during which the edema is essentially cytotoxic in nature. No clinical data exist pertaining to delayed cerebral edema (vasogenic) and steroids.Methods: Patients who had received steroids for delayed cerebral edema after TBI were retrospectively analyzed over a 2-year period. Steroid dose, timing of steroid prescription, time to improvement of symptoms, and complications were noted.Results: There were six males and three females. Mean age was 41.1 years. There were no severe HI cases. All subjects had cerebral contusions on imaging. Dexamethasone was the preferred steroid starting with 12 mg/day and tapered in 5–7 days. The mean interval to steroid administration after trauma was 7 days. The mean duration of steroid prescription was 6.3 days. All patients had complete symptomatic improvement. The mean time to symptom resolution was 3.8 days. No patients experienced any complications pertinent to steroid usage.Conclusion: This is the first study to document efficacy of steroids for delayed cerebral edema after TBI, at least in mild/moderate head injuries. The timing of steroid usage and dose of steroids is key aspects that might determine its efficacy in TBI which was the drawbacks of the previous studies. Future prospective trials with the above factors in consideration may confirm/refute above findings.

Risk factors for delayed diagnosis of spinal fracture associated with diffuse idiopathic skeletal hyperostosis: A nationwide multiinstitution survey

BackgroundPatients with DISH are susceptible to spinal fractures and subsequent neurological impairment, including after minor trauma. However, DISH is often asymptomatic and fractures may have minimal symptoms, which may lead to delayed diagnosis. The purpose of this study was to identify risk factors for delayed diagnosis of spinal fractures in patients with diffuse idiopathic skeletal hyperostosis (DISH). MethodsThe subjects were 285 patients with DISH surgically treated at 18 medical centers from 2005 to 2015. Cause of injury, imaging findings, neurological status at the times of injury and first hospital examination, and the time from injury to diagnosis were recorded. A delayed diagnosis was defined as that made >24 h after injury. ResultsMain causes of injury were minor trauma due to a fall from a standing or sitting position (51%) and high-energy trauma due to a fall from a high place (29%) or a traffic accident (12%). Delayed diagnosis occurred in 115 patients (40%; 35 females, 80 males; mean age 76.0 ± 10.4 years), while 170 (60%; 29 females, 141 males; mean age 74.6 ± 12.8 years) had early diagnosis. Delayed group had a significantly higher rate of minor trauma (n = 73, 63% vs. n = 73, 43%), significantly more Frankel grade E (intact neurological status) cases at the time of injury (n = 79, 69% vs. n = 73, 43%), and greater deterioration of Frankel grade from injury to diagnosis (34% vs. 8%, p < 0.01). In multivariate analysis, a minor trauma fall (OR 2.08; P < 0.05) and Frankel grade E at the time of injury (OR 2.29; P < 0.01) were significantly associated with delayed diagnosis. ConclusionIn patients with DISH, it is important to keep in mind the possibility of spinal fracture, even in a situation in which patient sustained only minor trauma and shows no neurological deficit. This is because delayed diagnosis of spinal fracture can cause subsequent neurological deterioration.

Lipidomic UPLC-MS/MS Profiles of Normal-Appearing White Matter Differentiate Primary and Secondary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative inflammatory disease where an autoimmune response to components of the central nervous system leads to a loss of myelin and subsequent neurological deterioration. People with MS can develop primary or secondary progressive disease (PPMS, SPMS) and differentiation of the specific differences in the pathogenesis of these two courses, at the molecular level, is currently unclear. Recently, lipidomics studies using human biofluids, mainly plasma and cerebrospinal fluid, have highlighted a possible role for lipids in the initiation and progression of MS. However, there is a lack of lipidomics studies in MS on CNS tissues, such as normal-appearing white matter (NAWM), where local inflammation initially occurs. Herein, we developed an untargeted reverse phase ultra-performance liquid chromatography time of flight tandem mass spectrometry (RP-UPLC-TOF MSE)-based workflow, in combination with multivariate and univariate statistical analysis, to assess significant differences in lipid profiles in brain NAWM from post-mortem cases of PPMS, SPMS and controls. Groups of eight control, nine PPMS and seven SPMS NAWM samples were used. Correlation analysis of the identified lipids by RP-UPLC-TOF MSE was undertaken to remove those lipids that correlated with age, gender and post-mortem interval as confounding factors. We demonstrate that there is a significantly altered lipid profile of control cases compared with MS cases and that progressive disease, PPMS and SPMS, can be differentiated on the basis of the lipidome of NAWM with good sensitivity, specificity and prediction accuracy based on receiver operating characteristic (ROC) curve analysis. Metabolic pathway analysis revealed that the most altered lipid pathways between PPMS and SPMS were glycerophospholipid metabolism, glycerophosphatidyl inositol (GPI) anchor synthesis and linoleic acid metabolism. Further understanding of the impact of these lipid alterations described herein associated with progression will provide an increased understanding of the mechanisms underpinning progression and highlight possible new therapeutic targets.

Abstract 75: Hemorrhagic Transformation After Acute Ischemic Stroke Due to a Large Vessel Occlusion is Associated With Less Treatment Benefit

Introduction: Intracranial hemorrhage after acute ischemic stroke patients manifests as natural progression or as a complication of treatment with potential subsequent neurological deterioration. Currently it is unclear whether these hemorrhagic transformations (HT) contribute to the poorer functional outcomes observed in patients with large infarcts. The purpose of this study is to assess the association of HT with follow-up infarct volume (FIV) and functional outcome at 90 days after AIS. Additionally, we determined whether the development of HT was associated with a diminished endovascular therapy (EVT) effect. Methods: All patients from the HERMES collaboration with follow-up imaging were included. HERMES is pooled data from seven randomized controlled trials that assessed the efficacy and safety of EVT compared to usual care. Patients with HT were identified according to the ECASS classification and FIV was assessed on CT or MRI. Infarct and hemorrhage were included in the FIV. We assessed functional outcome using the modified Rankin Scale 90 days after stroke onset. Ordinal logistic regression with adjustment for potential confounders was used to determine the association of HT and FIV with functional outcome. Results: Of all included patients with follow-up imaging (n=1665), 42% had HT (n=698). Before and after adjustment for confounders HT and FIV were associated with a shift in the direction of poorer functional outcome (aOR:0.71,95%CI:0.58-0.86 and aOR:0.99,95%CI:0.99-0.99). EVT was beneficial in patients with and without HT, but effect was greater in patients without (aOR:1.70,95%CI:1.27-2.28 vs. aOR:2.51,95%CI:1.97-3.20)(figure 1.) Conclusions: In this analysis, patients with HT after AIS were less likely to have good functional outcome compared to those without HT, independent of the FIV. While the EVT effect was slightly diminished in patients who developed HT, EVT was always of significant benefit.