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Background: This is a case of multifocal intracranial stenosis in a 74 year old male ultimately discovered to be due to Varicella Zoster Virus infection. Purpose: We highlight the importance of a broad differential diagnosis, even when the most likely etiology of intracranial stenosis is atherosclerosis. Our paper reviews the differential diagnosis as well as “red flags” for intracranial vasculopathy. Even though intracranial atherosclerotic disease is the most common cause of vasculopathy, infectious or inflammatory vasculitis should be considered on the differential. Conclusions: Before considering bypass surgery or other invasive neurosurgical procedures, ensure reversible causes of vasculopathy have been ruled out. The presence of cranial neuropathies, rash, and/or elevated inflammatory markers should be red flags for vasculitis in patients presenting with stroke.

Traumatic brain injury (TBI) is a risk factor for venous thromboembolism (VTE). The risk of VTE after decompressive craniectomy (DC) and its effects on the outcomes are unknown. We assessed the incidence of VTE, associated risk factors, and effects on the outcomes.Using the National Inpatient Sample database, the hospitalizations of patients aged ≥18 years with a severe TBI diagnosis from 2004 to 2014 were extracted. The outcome was discharge status without mortality. Multivariable logistic and linear regressions were used.Of the 349,165 TBI hospitalizations, 23,813 (6.82%) had undergone DC and 14,175 (4.06%) had developed VTE. The VTE incidence was higher after DC compared with no DC (6.14% vs. 3.91%; P0.0001). DC (odds ratio [OR], 1.29; P0.005) was an independent predictor for the development of VTE. Age (OR, 1.26; P0.005), chronic lung disease (OR, 1.58; P0.05), electrolyte imbalance (OR, 1.43; P0.05), liver disease (OR, 0.10; P0.05), urinary tract infection (OR, 1.56; P0.05), pneumonia (OR, 2.03; P0.0001), and sepsis (OR, 1.57; P0.05) were significantly associated with the development of VTE. Obesity (OR, 2.09; P0.05) and spine injury (OR, 2.03; P0.05) showed a trend toward significance. VTE was associated with worse discharge outcomes (OR, 1.40; P0.05), longer lengths of stay (OR, 1.01; P0.00001), and higher costs (P0.0001).Our study showed an independent association between DC and an increased risk of VTE for patients with severe TBI. The development of VTE after DC increased the proportion of poor outcomes, prolonged the length of stay, and increased the hospitalization costs. Older patients with obesity, an electrolyte imbalance, chronic lung disease, spine injury, and infections were at a greater risk of VTE after DC. These risk factors could help in considering VTE prophylaxis for these patients.

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites1. Hibernation in thirteen-lined ground squirrels (TLGS),Ictidomys tridecemlineatus, provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage2. Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cellsin vitroand in mice subjected to permanent ischemic strokein vivo. Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 μg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7 + effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1 , and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7 , and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

Introduction: Anticoagulation in patients with acute intracranial hemorrhage (ICH) and mechanical heart valves (MHV) is often held to mitigate the risk of ICH expansion or recurrence; however there exists a competing risk of acute ischemic stroke (AIS). Optimal timing to resume anticoagulation after ICH remains uncertain. Methods: We retrospectively studied ICH patients with MHV at two academic hospitals from April, 2000-August, 2018. The primary outcome was a composite endpoint of symptomatic hematoma expansion or new ICH, AIS, and intracardiac thrombus up to 30 days post-ICH. The exposure was timing of re-initiation of anticoagulation classified as early if therapeutic anticoagulation was resumed up to 7 days after ICH; late if ≥7 and up to 30 days after ICH; and never if not resumed or resumed after 30-days post-ICH. Cox proportional hazard models were built adjusted for age, sex, and covariates significantly different in univariate analysis at a pre-specified p-value threshold of 0.05. Results: We identified 184 patients with ICH and MHV (65 anticoagulated early, 100 resumed late, 19 not resumed by day 30 post-ICH). We observed 12 AIS, 16 new ICH, and 6 intracardiac thromboses. The mean time from ICH to anticoagulation in the cohort was 12.7 days. Patients resumed early versus late were more likely to have atrial fibrillation (62% versus 42%), and less likely to be reversed (75% versus 94%), to undergo hematoma evacuation (23% versus 43%), have midline shift (27% versus 52.9%), and to have intracerebral involvement (26% versus 49%). There was no significant difference in the hazard of AIS, new or symptomatic ICH expansion, or the composite outcome among those resumed early versus late. Patients not resumed within 30 days post-ICH had a significantly higher risk of AIS compared to those resumed within 30 days (HR 15.9; 95% C.I.1.9-129.7, p=0.0098). Discussion: In this study of ICH patients with MHV, there was no difference in the 30-day thrombotic and hemorrhagic brain-related outcomes in patients anticoagulated within 7 days versus 7-30 days. Withholding anticoagulation within the first 30 days was associated with a significantly higher risk of AIS. Our findings provide a discrete time window to guide resumption of anticoagulation in MHV patients with ICH.

T cells are present in early stages of the SARS-CoV-2 infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully humanized anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using RNA-sequencing and serum proteomics, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100ug/day) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab treated subjects and NGK7+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1, and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes and B cells in subjects treated with Foralumab. In addition to the downregulation of effector function, an increase in TGFb1 gene expression in cell types with known effector function was observed in Foralumab treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases and TGF-b1 signaling, was downregulated in Foralumab treated individuals. TGFb1, GIMAP7 and NKG7 transcriptomic changes observed in Foralumab treated COVID-19 subjects was also observed in healthy volunteers, MS subjects and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

BACKGROUND Growing evidence associates traumatic brain injury (TBI) with increased risk of dementia, but few studies have evaluated associations in patients younger than 55 yr using non-TBI orthopedic trauma (NTOT) patients as controls to investigate the influence of age and TBI severity, and to identify predictors of dementia after trauma. OBJECTIVE To investigate the relationship between TBI and dementia in an institutional group. METHODS Retrospective cohort study (2000-2018) of TBI patients aged 45 to 100 yr vs NTOT controls. Primary outcome was dementia after TBI (followed ≤10 yr). Cox proportional hazards models were used to assess risk of dementia; logistic regression models assessed predictors of dementia. RESULTS Among 24 846 patients, TBI patients developed dementia (7.5% vs 4.6%) at a younger age (78.6 vs 82.7 yr) and demonstrated higher 10-yr mortality than controls (27% vs 14%; P

Traumatic brain injury (TBI) results in both morbidity and mortality in which both innate and adaptive immune responses play an important role in the pathogenesis of TBI. Nonetheless, the role of gamma-delta (γδ) T cells in acute and chronic TBI is unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year after injury. TCRδ−/− mice exhibited reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We found that Vγ1 and Vγ4 γδ T cell subsets played opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation, whereas Vγ1 γδ T cells infiltrate the brain and secrete TGF-β that maintains microglial homeostasis and dampens TBI. These findings provide new insights on the role of different γδ T cell subsets after brain injury and provide novel avenues for the development of targeted γδ T-cell-based therapy for the treatment of TBI.

Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol.We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.

BackgroundIn patients with severe traumatic brain injury (TBI), coma is associated with impaired subcortical arousal mechanisms. However, it is unknown which nuclei involved in arousal (arousal nuclei) are implicated in coma pathogenesis and are compatible with coma recovery.MethodsWe mapped an atlas of arousal nuclei in the brainstem, thalamus, hypothalamus, and basal forebrain onto 3 tesla susceptibility-weighted images (SWI) in 12 patients with acute severe TBI who presented in coma and recovered consciousness within 6 months. We assessed the spatial distribution and volume of SWI microbleeds and evaluated the association of microbleed volume with the duration of unresponsiveness and functional recovery at 6 months.ResultsThere was no single arousal nucleus affected by microbleeds in all patients. Rather, multiple combinations of microbleeds in brainstem, thalamic, and hypothalamic arousal nuclei were associated with coma and were compatible with recovery of consciousness. Microbleeds were frequently detected in the midbrain (100%), thalamus (83%), and pons (75%). Within the brainstem, the microbleed incidence was largest within the mesopontine tegmentum (e.g., pedunculotegmental nucleus, mesencephalic reticular formation) and ventral midbrain (e.g., substantia nigra, ventral tegmental area). Brainstem arousal nuclei were partially affected by microbleeds, with microbleed volume not exceeding 35% of brainstem nucleus volume on average. Compared to microbleed volume within nonarousal brainstem regions, the microbleed volume within arousal brainstem nuclei accounted for a larger proportion of variance in the duration of unresponsiveness and 6-month Glasgow Outcome Scale–Extended scores.ConclusionThese results suggest resilience of arousal mechanisms in the human brain after severe TBI.

Decompressive craniectomy is recommended to reduce mortality in severe traumatic brain injury (TBI). Disparities exist in TBI treatment outcomes; however, data on disparities pertaining to decompressive craniectomy utilization is lacking. We investigated these disparities, focusing on race, insurance, sex, and age.Hospitalizations (2004-2014) were retrospectively extracted from the Nationwide Inpatient Sample. The criteria included are as follows: age ≥18 years and indicators of severe TBI diagnosis. Poor outcomes were defined as discharge to institutional care and death. Multivariable logistic regression models were used to assess the effects of race, insurance, age, and sex, on craniectomy utilization and outcomes.Of 349,164 hospitalized patients, 6.8% (n = 23,743) underwent craniectomy. White (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.44-0.57; P0.001) and Black (OR = 0.45, 95% CI = 0.32-0.64; P = 0.003) Medicare beneficiaries were less likely to undergo craniectomy. Medicare (P0.0001) and Medicaid beneficiaries (P 0.0001) of all race categories had poorer outcomes than privately insured White patients. Black (OR = 1.2, 95% CI = 1.08-2.34; P = 0.001) patients with private insurance and Black (OR = 1.39, 95% CI = 1.22-1.58; P 0.0001) Medicaid beneficiaries had poorer outcomes than privately insured White patients (P 0.0001). Older patients (OR = 0.74, 95%, CI = 0.71-0.76; P 0.001) were less likely to undergo craniectomy and were more likely to have poorer outcomes. Females (OR = 0.82, 95% CI = 0.76-0.88; P 0.001) were less likely to undergo craniectomy.There are disparities in race, insurance status, sex, and age in craniectomy utilization and outcome. This data highlights the necessity to appropriately address these disparities, especially race and sex, and actively incorporate these factors in clinical trial design and enrollment.

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead ( RIPK1D138N/D138N) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL ( Mlkl-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.

OBJECTIVETraumatic brain injury (TBI) is a leading cause of morbidity and mortality in the US, but the true incidence of TBI is unknown.METHODSThe National Trauma Data Bank National Sample Program (NTDB NSP) was queried for 2007 and 2013, and population-based weighted estimates of TBI-related emergency department (ED) visits, hospitalizations, and deaths were calculated. These data were compared to the 2017 Centers for Disease Control and Prevention (CDC) report on TBI, which used the Healthcare Cost and Utilization Project’s National (“Nationwide” before 2012) Inpatient Sample and National Emergency Department Sample.RESULTSIn the NTDB NSP the incidence of TBI-related ED visits was 59/100,000 in 2007 and 62/100,000 in 2013. However, in the CDC report there were 534/100,000 in 2007 and 787/100,000 in 2013. The CDC estimate for ED visits was 805% higher in 2007 and 1169% higher in 2013. In the NTDB NSP, the incidence of TBI-related deaths was 5/100,000 in 2007 and 4/100,000 in 2013. In the CDC report, the incidence was 18/100,000 in both years. The CDC estimate for deaths was 260% higher in 2007 and 325% higher in 2013.CONCLUSIONSThe databases disagreed widely in their weighted estimates of TBI incidence: CDC estimates were consistently higher than NTDB NSP estimates, by an average of 448%. Although such a discrepancy may be intuitive, this is the first study to quantify the magnitude of disagreement between these databases. Given that research, funding, and policy decisions are made based on these estimates, there is a need for a more accurate estimate of the true national incidence of TBI.

Traumatic brain injury is a complex and highly heterogeneous disease due to the host of concomitant injuries that may accompany the initial insult. Due to the dynamic interplay between the injuries that may arise, the management of these injuries is challenging. In a small subset of patients with traumatic brain injury, cerebral vascular injury may occur, which presents its own diagnostic and therapeutic challenges. These vascular injuries often present in a delayed fashion, thereby going unnoticed by clinicians. Early recognition and treatment of these injuries is crucial, given their high morbidity and mortality. Through a critical review of the literature, we present the spectrum of cerebrovascular injuries that may occur with traumatic brain injury and discuss classification systems that are used to stratify cerebrovascular injury. We then focus on the diagnosis of cerebral vascular injury using different neuroimaging modalities. Lastly, we explore the treatment of these injuries ranging from antiplatelet therapies to endovascular and open vascular procedures. By highlighting the pitfalls and challenges of this complex disease, we hope to provide clinicians with the framework to recognize and treat vascular injuries that are seen in patients with traumatic brain injury.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage continues to be associated with high levels of morbidity and mortality. This complication had long been thought to occur secondary to severe cerebral vasospasm, but expert opinion now favors a multi-factorial etiology, opening the possibility of new therapies. To date, no definitive treatment option for DCI has been recommended as standard of care, highlighting a need for further research into potential therapies. Milrinone has been identified as a promising therapeutic agent for DCI, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially anti-inflammatory effects to treat the underlying etiology of DCI. Intra-arterial and intravenous administration of milrinone has been evaluated for the treatment of DCI in single center case series and cohorts and appears safe and associated with improved clinical outcomes. Recent results have also brought attention to the potential outcome benefits of early, more aggressive dosing and titration of milrinone. Limitations exist within the available data, however, and questions remain about the generalizability of results across a broader spectrum of patients suffering from DCI. The development of a standardized protocol for milrinone use in DCI, specifically addressing areas requiring further clarification, is needed. Data generated from a standardized protocol may provide the impetus for a multi-center, randomized control trial. We review the current literature on milrinone for the treatment of DCI and propose a preliminary standardized protocol for further evaluation of both safety and efficacy of milrinone.

Important differences in the biology of focal and diffuse traumatic brain injury (TBI) subtypes may result in unique pathophysiological responses to shared molecular mechanisms. Interleukin-1 (IL-1) signaling has been tested as a potential therapeutic target in preclinical models of cerebral contusion and diffuse TBI, and in a phase II clinical trial, but no published studies have examined IL-1 signaling in an impact/acceleration closed head injury (CHI) model. We hypothesized that genetic deletion of IL-1 receptor-1 (IL-1R1 KO) would be beneficial in focal (contusion) and CHI in mice. Wild type and IL-1R1 KO mice were subjected to controlled cortical impact (CCI), or to CHI. CCI produced brain leukocyte infiltration, HMGB1 translocation and release, edema, cell death, and cognitive deficits. CHI induced peak rotational acceleration of 9.7 × 10(5) ± 8.1 × 10(4) rad/s(2), delayed time to righting reflex, and robust Morris water maze deficits without deficits in tests of anxiety, locomotion, sensorimotor function, or depression. CHI produced no discernable acute plasmalemma damage or cell death, blood-brain barrier permeability to IgG, or brain edema and only a modest increase in brain leukocyte infiltration at 72 h. In both models, mature (17 kDa) interleukin-1 beta (IL-1β) was induced by 24 h in CD31+ endothelial cells isolated from injured brain but was not induced in CD11b(+) cells in either model. High mobility group box protein-1 was released from injured brain cells in CCI but not CHI. Surprisingly, cognitive outcome in mice with global deletion of IL-1R1 was improved in CHI, but worse after CCI without affecting lesion size, edema, or infiltration of CD11b(+)/CD45(+) leukocytes in CCI. IL-1R1 may induce unique biological responses, beneficial or detrimental to cognitive outcome, after TBI depending on the pathoanatomical subtype. Brain endothelium is a hitherto unrecognized source of mature IL-1β in both models.

While chronic neurological effects from concussion have been studied widely, little is known about possible links between concussion and long-term medical and behavioral comorbidities. We performed a retrospective cohort study of 9205 adult patients with concussion, matched to non-concussion controls from a hospital-based electronic medical registry. Patients with comorbidities before the index visit were excluded. Behavioral and medical comorbidities were defined by International Classification of Diseases, Ninth and Tenth Revision codes. Groups were followed for up to 10 years to identify comorbidity incidence after a concussion. Cox proportional hazards models were used to calculate associations between concussion and comorbidities after multi-variable adjustment. Patients with concussion were 57% male (median age: 31; interquartile range [IQR] = 23–48 years) at enrollment with a median follow-up time of 6.1 years (IQR = 4.2–9.1) and well-matched to healthy controls. Most (83%) concussions were evaluated in outpatient settings (5% inpatient). During follow-up, we found significantly higher risks of cardiovascular risks developing including hypertension (hazard ratio [HR] = 1.7, 95% confidence interval [CI]: 1.5–1.9), obesity (HR = 1.7, 95% CI: 1.3–2.0), and diabetes mellitus (HR = 1.8, 95% CI: 1.4–2.3) in the concussion group compared with controls. Similarly, psychiatric and neurological disorders such as depression (HR = 3.0, 95% CI: 2.6–3.5), psychosis (HR = 6.0, 95% CI: 4.2–8.6), stroke (HR = 2.1 95% CI: 1.5–2.9), and epilepsy (HR = 4.4, 95% CI: 3.2–5.9) were higher in the concussion group. Most comorbidities developed less than five years post-concussion. The risks for post-concussion comorbidities were also higher in patients under 40 years old compared with controls. Patients with concussion demonstrated an increased risk of development of medical and behavioral health comorbidities. Prospective studies are warranted to better describe the burden of long-term comorbidities in patients with concussion.

BACKGROUNDPure arterial malformations (PAMs) are rare vascular anomalies that are commonly mistaken for other vascular malformations. Because of their purported benign natural history, PAMs are often conservatively managed. The authors report the case of a ruptured PAM leading to subarachnoid hemorrhage (SAH) with intraventricular extension that was treated endovascularly.OBSERVATIONSA 38-year-old man presented with a 1-day history of headaches and nausea. A computed tomography scan demonstrated diffuse SAH with intraventricular extension, and angiography revealed a right posterior inferior cerebellar artery–associated PAM. The PAM was treated with endovascular Onyx embolization.LESSONSTo the authors’ knowledge, only 2 other cases of SAH associated with PAM have been reported. In those 2 cases, surgical clipping was pursued for definitive treatment. Here, the authors report the first case of a ruptured PAM treated using an endovascular approach, showing its feasibility as a treatment option particularly in patients in whom open surgery is too high a risk.

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

Increased risk of neurological and psychiatric conditions after traumatic brain injury (TBI) is well-defined. However, cardiovascular and endocrine comorbidity risk after TBI in individuals without these comorbidities and associations with post-TBI mortality have received little attention.To assess the incidence of cardiovascular, endocrine, neurological, and psychiatric comorbidities in patients with mild TBI (mTBI) or moderate to severe TBI (msTBI) and analyze associations between post-TBI comorbidities and mortality.This prospective longitudinal cohort study used hospital-based patient registry data from a tertiary academic medical center to select patients without any prior clinical comorbidities who experienced TBI from 2000 to 2015. Using the same data registry, individuals without head injuries, the unexposed group, and without target comorbidities were selected and age-, sex-, and race-frequency-matched to TBI subgroups. Patients were followed-up for up to 10 years. Data were analyzed in 2021.Mild or moderate to severe head trauma.Cardiovascular, endocrine, neurologic, and psychiatric conditions were defined based on International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Associations between TBI and comorbidities, as well as associations between the comorbidities and mortality, were analyzed.A total of 4351 patients with mTBI (median [IQR] age, 45 [29-57] years), 4351 patients with msTBI (median [IQR] age, 47 [30-58] years), and 4351 unexposed individuals (median [IQR] age, 46 [30-58] years) were included in analyses. In each group, 45% of participants were women. mTBI and msTBI were significantly associated with higher risks of cardiovascular, endocrine, neurologic, and psychiatric disorders compared with unexposed individuals. In particular, hypertension risk was increased in both mTBI (HR, 2.5; 95% CI, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9) groups. Diabetes risk was increased in both mTBI (HR, 1.9; 95% CI, 1.4-2.7) and msTBI (HR, 1.9; 95% CI, 1.4-2.6) groups, and risk of ischemic stroke or transient ischemic attack was also increased in mTBI (HR, 2.2; 95% CI, 1.4-3.3) and msTBI (HR, 3.6; 95% CI, 2.4-5.3) groups. All comorbidities in the TBI subgroups emerged within a median (IQR) of 3.49 (1.76-5.96) years after injury. Risks for post-TBI comorbidities were also higher in patients aged 18 to 40 years compared with age-matched unexposed individuals: hypertension risk was increased in the mTBI (HR, 5.9; 95% CI, 3.9-9.1) and msTBI (HR, 3.9; 95% CI, 2.5-6.1) groups, while hyperlipidemia (HR, 2.3; 95% CI, 1.5-3.4) and diabetes (HR, 4.6; 95% CI, 2.1-9.9) were increased in the mTBI group. Individuals with msTBI, compared with unexposed patients, had higher risk of mortality (432 deaths [9.9%] vs 250 deaths [5.7%]; P .001); postinjury hypertension (HR, 1.3; 95% CI, 1.1-1.7), coronary artery disease (HR, 2.2; 95% CI, 1.6-3.0), and adrenal insufficiency (HR, 6.2; 95% CI, 2.8-13.0) were also associated with higher mortality.These findings suggest that TBI of any severity was associated with a higher risk of chronic cardiovascular, endocrine, and neurological comorbidities in patients without baseline diagnoses. Medical comorbidities were observed in relatively young patients with TBI. Comorbidities occurring after TBI were associated with higher mortality. These findings suggest the need for a targeted screening program for multisystem diseases after TBI, particularly chronic cardiometabolic diseases.

Moyamoya disease (MMD) is a rare, progressive occlusive disease characterized by bilateral internal carotid artery hypoplasia that often presents with ischemic stroke and intracerebral hemorrhage (ICH). Although MMD-related ICH is generally managed similarly to spontaneous ICH, we present a case in which standard management strategies may have led to an unprecedented devastating outcome. A 37-year-old female without any previous medical history presented with headache and right-sided weakness. A computed tomography (CT) scan revealed a large left basal ganglia ICH. Vessel imaging revealed diffuse narrowing of the entire anterior circulation with prominent leptomeningeal collaterals consistent with MMD. The patient’s systolic blood pressure was kept under 140 mmHg. During the hospitalization, she became hypocarbic while being trialed on pressure support ventilation. Several hours later, she developed fixed and dilated pupils. Repeat CT head showed new diffuse cerebral edema with tonsillar herniation. Despite hyperosmolar therapy, paralytics, pentobarbital, and cerebrospinal fluid diversion, no improvement was noted. Unfortunately, brain MRI revealed multifocal brainstem infarcts with superimposed Duret hemorrhages. Herein, we report diffuse cerebral edema as a complication of MMD-related ICH. We hypothesize that disruptions of delicate cerebral autoregulatory mechanisms led to extensive hypoxic-ischemic injury. In the setting of ICH, aggressive blood pressure management coupled with relative hypocapnia may have likely caused vasoconstriction of poorly compliant arteries leading to worsened cerebral blood flow and ischemia. Therefore, because of its complex pathophysiology, strict adherence to eucapnia should be maintained in MMD-related ICH.

Extra-axial fluid collections (EACs) frequently develop after decompressive craniectomy. Management of EACs remains poorly understood, and information on how to predict their clinical course is inadequate. We aimed to better characterize EACs, understand predictors of their resolution, and delineate the best treatment paradigm for patients.We reviewed patients who developed EACs after undergoing decompressive craniectomy for treatment of refractory intracranial pressure elevations. We excluded patients who had an ischemic stroke, as EACs in these patients have a different clinical course. We performed univariate analysis and multiple linear regression to find variables associated with earlier resolution of EACs and stratified our analyses by EAC phenotype (complicated vs. uncomplicated). We conducted a systematic review to compare our findings with the literature.Of 96 included patients, 73% were male, and median age was 42.5 years. EACs resolved after a median of 60 days. Complicated EACs were common (62.5%) and required multiple drainage methods before cranioplasty. These were not associated with a protracted course or increased risk of death (P0.05). Early bone flap restoration with simultaneous drainage was independently associated with earlier resolution of EACs (β = 0.56, P 0.001). Systematic review confirmed lack of standardized direction with respect to EAC management.Our analyses reveal 2 clinically relevant phenotypes of EAC: complicated and uncomplicated. Our proposed treatment algorithm involves replacing the bone flap as soon as it is safe to do so and draining refractory EACs aggressively. Further studies to assess long-term clinical outcomes of EACs are warranted.

Background COVID‐19 infection varies in severity from minimal symptoms to critical illness associated with a hyperinflammatory response. Data on disease progression in immunosuppressed solid organ transplant (SOT) recipients are limited. Methods We examined the electronic medical records of all SOT recipients with COVID‐19 from 12 Massachusetts hospitals between February 1, and May 6, 2020. We analyzed the demographics, clinical parameters, course, and outcomes of illness in these patients. Results Of 52 COVID‐19‐positive SOT patients, 77% were hospitalized and 35% required ICU admission. Sixty‐nine percent of hospitalized patients had immunosuppression reduced, 6% developed suspected rejection. Co‐infections occurred in 45% in ICU vs 5% in non‐ICU patients (P = .037). A biphasic pattern of evolution of laboratory tests was observed. In the first 5 days of illness, inflammatory markers were moderately increased. Subsequently, WBC, CRP, ferritin, and D Dimer increased with increasing stay in the ICU, and lymphocyte counts were similar. Five patients (16%) died. Conclusions Our data indicate that SOT is associated with high rate of hospitalization, ICU admission, and death from COVID‐19 compared to data in the general population of patients with COVID‐19. Despite reduction in immunosuppression, suspected rejection was rare. The clinical course and trend of laboratory biomarkers is biphasic with a later, pronounced peak in inflammatory markers seen in those admitted to an ICU. CRP is a useful marker to monitor disease progression in SOT.

Background: The primary aim of this study is to describe current trends in racial-, age- and sex-specific incidence, clinical characteristics and burden of cerebral venous thrombosis (CVT) in the United States (US). Methods: Validated International Classification of Disease codes were used to identify all adult new cases of CVT (n=5,567) in the State Inpatients Database of New York and Florida (2006-2016) and all cases of CVT in the entire US from the National Inpatient Sample 2005-2016 (weighted n=57,315). Incident CVT counts were combined with annual US Census data to compute age and sex-specific incidence of CVT. Joinpoint regression was used to evaluate trends in incidence over time. Results: From 2005-2016, 0.47%-0.80% of all strokes in the US were CVTs but this proportion increased by 70.4% over time. Of all CVTs over this period, 66.7% were in females but this proportion declined over time (p Conclusion: The epidemiological characteristics of CVT patients in the US is changing. Incidence increased significantly over the last decade. Further studies are needed to determine whether this increase represents a true increase from changing risk factors or artefactual increase from improved detection.

Supplemental material, sj-pdf-2-jcb-10.1177_0271678X20973609 for Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice by Sevda Lule, Limin Wu, Aliyah Sarro-Schwartz, William J Edmiston III, Saef Izzy, Tanya Songtachalert, So Hee Ahn, Neil D Fernandes, Gina Jin, Joon Yong Chung, Siddharth Balachandran, Eng H Lo, David Kaplan, Alexei Degterev and Michael J Whalen in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20973609 for Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice by Sevda Lule, Limin Wu, Aliyah Sarro-Schwartz, William J Edmiston III, Saef Izzy, Tanya Songtachalert, So Hee Ahn, Neil D Fernandes, Gina Jin, Joon Yong Chung, Siddharth Balachandran, Eng H Lo, David Kaplan, Alexei Degterev and Michael J Whalen in Journal of Cerebral Blood Flow & Metabolism

Many types of neurologic injury are known to affect the cardiovascular system. Both rhythm and pump function can be dramatically affected. In this chapter, we review the cardiovascular changes that can be seen after neurologic injury and the specific neurologic diseases most commonly associated with those changes. This chapter covers hypertension, cardiomyopathy, shock, arrhythmias, and myocardial ischemia. These neurocardiogenic changes are important to diagnose, understand, and manage in order to simultaneously optimize neurologic recovery and cardiovascular function. Recognition of these neurocardiovascular connections can help neurointensivists and cardiologists best understand the underlying driving forces behind hemodynamic instabilities that can be seen in patients after acute neurologic injury.

A 53-year-old Salvadoran woman with hyperlipidemia and no previous neurologic complaints presented to the emergency department with sudden-onset right-sided weakness and dysarthria while speaking with a friend. Two days prior to presentation, she endorsed a mild bifrontal headache but denied any constitutional symptoms.