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Background This study proposes a modification to the traditional Hunt and Hess (tHH) grading scale for prognostication in aneurysmal subarachnoid hemorrhage (aSAH), which differentiates the most severe‐grade patients based on the presence or absence of brainstem dysfunction [determined by Glasgow Coma Scale (GCS) scores 3‐5]. Methods Weighted aSAH hospitalizations were retrospectively identified in the National Inpatient Sample from 2015 to 2019 and were stratified by tHH and modified HH (mHH) grades. mHH grade 5 was defined as tHH grade 5 with GCS score 3–5, while mHH grade 4 comprised tHH grade 5 with GCS score 6–8 and tHH grade 4. HH grades 1–3 do not differ between the traditional and modified scales. Measures of diagnostic performance were compared for the primary study end point [poor outcome as determined by the previously validated NIS‐SAH Outcome Measure (NIS‐SOM), shown to have high concordance with modified Rankin Scale scores > 2]. External validation of the mHH was performed using data from a prospectively maintained aSAH registry. Results Among 6130 aSAH hospitalizations, 2245 (36%) were tHH grade 5. Seven hundred and eighty‐five (35%) of these had a GCS 3–5 and were designated as mHH grade 5. Poor outcomes were identified in 78% and 77% of grade 4 tHH and mHH, respectively, and in 83% and 95% of grade 5 tHH and mHH, respectively. In comparison with the tHH, the mHH achieved superior discrimination [c‐statistic 0.793 (95% CI 0.768, 0.818) versus 0.780 (95% CI 0.750, 0.807); DeLong p < 0.001] for poor outcome, as well as improved specificity (0.929 versus 0.304) and positive predictive value (PPV) (0.949 versus 0.827). External registry validation of the mHH demonstrated excellent discrimination [c‐statistic 0.835 (95% CI 0.801, 0.870)], with a specificity of 0.950 and PPV of 0.905. Conclusion The mHH achieved a favorable diagnostic performance profile using retrospective data and may aid in the prognostication of high‐severity patients with aSAH.

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation- induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration., Introduction Inflammation-induced neurodegeneration is the principal driver of disease progression and the accumulation of neurological disabilities in people with multiple sclerosis (pwMS) (1, 2), the most prevalent inflammatory disease of [...]

Background Anticoagulation in patients with intracranial hemorrhage (ICH) and mechanical heart valves is often held for risk of ICH expansion; however, there exists a competing risk of acute ischemic stroke (AIS). Optimal timing to resume anticoagulation remains uncertain. Methods and Results We retrospectively studied patients with ICH and mechanical heart valves from 2000 to 2018. The primary outcome was a composite end point of symptomatic hematoma expansion or new ICH, AIS, and intracardiac thrombus up to 30 days post‐ICH. The exposure was timing of reinitiation of anticoagulation classified as early (resumed up to 7 days after ICH), late (≥7 and up to 30 days after ICH), and never if not resumed or resumed after 30 days post‐ICH. We included 184 patients with ICH and mechanical heart valves (65 anticoagulated early, 100 late, 19 not resumed by day 30 post‐ICH). Twelve patients had AIS, 16 new ICH, and 6 intracardiac thromboses. The mean time from ICH to anticoagulation was 12.7 days. Composite outcomes occurred in 12 patients resumed early (18.5%), 14 resumed late (14.0%), and 4 never resumed (21.1%). There was no increased hazard of the composite outcome (hazard ratio [HR], 1.1 [95% CI, 0.2–6.0]), AIS, or worsening or new ICH among patients resumed early versus late. There was no difference in the composite among patients never resumed versus resumed. Patients who never resumed anticoagulation had significantly more severe ICH (median Glasgow Coma Scale: 10.6, 13.9, and 13.9 among those who resumed never, early, and late, respectively; P=0.0001), higher in‐hospital mortality (56.5%, 0%, and 0%, respectively; P30 days was associated with severe baseline ICH, higher in‐hospital case fatality, and elevated AIS risk.

Abstract Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8+ T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8+ T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8+ T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8+ T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8+ T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8+ T cell entry into the CNS and triggers CD8+ T cell-mediated focal BBB breakdown.

Abstract Objective Patients with posterior reversible encephalopathy syndrome (PRES) can develop seizures during the acute phase. We sought to determine the long‐term risk of seizure after PRES. Methods We performed a retrospective cohort study using statewide all‐payer claims data from 2016–2018 from nonfederal hospitals in 11 US states. Adults admitted with PRES were compared to adults admitted with stroke, an acute cerebrovascular disorder associated with long‐term risk of seizure. The primary outcome was seizure diagnosed during an emergency room visit or hospital admission after the index hospitalization. The secondary outcome was status epilepticus. Diagnoses were determined using previously validated ICD‐10‐CM codes. Patients with seizure diagnoses before or during the index admission were excluded. We used Cox regression to evaluate the association of PRES with seizure, adjusting for demographics and potential confounders. Results We identified 2095 patients hospitalized with PRES and 341,809 with stroke. Median follow‐up was 0.9 years (IQR, 0.3–1.7) in the PRES group and 1.0 years (IQR, 0.4–1.8) in the stroke group. Crude seizure incidence per 100 person‐years was 9.5 after PRES and 2.5 after stroke. After adjustment for demographics and comorbidities, patients with PRES had a higher risk of seizure than patients with stroke (HR, 2.9; 95% CI, 2.6–3.4). Results were unchanged in a sensitivity analysis that applied a two‐week washout period to mitigate detection bias. A similar relationship was observed for the secondary outcome of status epilepticus. Interpretation PRES was associated with an increased long‐term risk of subsequent acute care utilization for seizure compared to stroke.

Introduction Infectious intracranial aneurysms (IIA) represent one of several cerebrovascular pathologies associated with infective endocarditis (IE). Neuroimaging in patients with IE, especially in those undergoing cardiac procedures, have scarcely been examined in the literature. Digital subtraction angiography (DSA), or cerebral angiogram, remains the gold standard for the detection of IIA, yet the utility of this invasive imaging modality is uncertain. Herein, we aim to better understand current national trends in the use of neuroimaging in this group of patients, and its impact on patient outcomes. Methods Hospitalizations for IE with concurrent procedures for left‐sided cardiac valve surgery (VS) were identified in the National Inpatient Sample (NIS) registry during the period of 2015‐2020 using weighted approximations and validated International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) diagnosis and procedural coding. The primary exposure was DSA and the trend of its use was evaluated during the study period. Multivariable logistic regression analysis was performed to evaluate the adjusted association of angiography with in‐hospital mortality, the primary study endpoint, while accounting for age and illness severity [quantified by All Patient Refined Diagnostic Related Groups (APR‐DRG) illness severity subclass]. Effect size was reported as adjusted odds ratio (aOR) with 95% confidence interval (CI) and a stringent statistical significance threshold of p < 0.001. Results This analysis identified 31,550 hospitalizations for IE treated with VS, of which 1,160 (3.7%) underwent DSA. Utilization of angiography significantly increased during the study period (trend p < 0.001; Kendall’s tau‐b = 0.002), with the rate of the final year of the study nearly doubling that of the first (2020 4.9% vs. 2015 2.5%, p < 0.001). IE VS patients undergoing angiography experienced significantly decreased mortality rates in comparison to those not receiving an angiogram (4.3% vs. 7.5%; p < 0.001). Following multivariable logistic regression analysis, angiography was significantly associated with decreased mortality, independent of age and illness severity (aOR 0.49, 95% CI 0.37, 0.66; p < 0.001). Conclusion The current literature on neurological complications of IE includes limited data on the defined role of neuroimaging in dictating management. The theoretical risk in IE patients undergoing cardiac procedures involving heparinization includes the risk of intracerebral hemorrhage, especially in those with IIA. While less invasive neuroimaging is thought to suffice in detecting bleeds, DSAs remain more sensitive for IIA detection. In our study, not only did the number of IE patients undergoing DSA increase over time, but they had better mortality rates. Future directions should focus on understanding the appropriate timing of imaging in relation to the patient’s disease course to optimize inpatient care.

Introduction The rapid growth of the elderly population, an increase in cardiac disease, and notable use of intracardiac prosthetic devices has led to an increased prevalence of infective endocarditis (IE). Among the sequelae observed with an IE diagnosis, acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), vasculitis, septic emboli, cerebral abscess, and infectious intracranial aneurysms (IIA) continue to complicate overall management of this disease. Current literature on neurological complications of IE includes limited data on the defined role of neuroimaging in dictating inpatient management. Transcranial doppler (TCD) emboli monitoring with high intensity signals (HITS) offers a real time, radiation‐free, relatively low cost, non‐invasive imaging option to potentially risk stratify and identify candidates for earlier intervention to prevent further cerebrovascular (CV) complications. Methods We conducted an observational study of infective endocarditis cases admitted to our institution from April 2022 to May 2023 who had TCD with HITS completed. Baseline clinical characteristics (age, sex, date and timing of TCD with HITS study, date of last positive blood culture, organism of infection, other neuroimaging utilized) were recorded. Observations recorded included the results of the TCD with HITS studies, the overall incidence and timing of neurological complications (AIS, SAH, ICH, IIA, septic emboli, cerebral abscess), timing of valve surgery, and inpatient mortality rates. A positive HITS was defined as detection of cerebral microembolism during ultrasound monitoring of bilateral middle cerebral arteries (MCA) for 30 minutes using a TCD machine (VIASONIX Dolphin IQ). Results Between April 2022 to July 2023, we identified 22 patients with confirmed left‐sided infective endocarditis who underwent TCD with HITS. Mean age was 66 years (SD, 10), and 82% were men. Leading pathogen types were Enterococcus Faecalis (27%) and Staphylococcus Epidermidis (18%). CV complications were noted in 19/22 patients (86%), the most common being AIS (82%) and IPH (18%). Two patients (9%) were found to have a positive HITS study, both of which developed septic emboli that caused ischemic stroke in one case, and hemorrhagic stroke in the other case. Average days from admission to timing of TCD with HITS study was 8.5 days. 14/22 patients underwent valve surgery (64%) during the admission on average 9.2 days after TCD with HITS study in the negative HITS group versus 5 days in the positive HITS group. Of the positive HITS cases, one of them died inpatient. Conclusion The association between neurological complications in patients with IE and cerebral microemboli detected with TCD monitoring has yet to be elucidated. While our observational study was limited by our sample size, both of our IE patients who had positive TCD with HITS studies developed more severe CV complications, and aggressive care was sought out more urgently to further minimize complications. Future directions include pursuing a prospective study incorporating TCD with HITS monitoring for patients with IE in order to risk‐stratify neurological complications and safety of valve surgery.

Background Cerebrovascular dysregulation syndromes, posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), are challenging to diagnose because they are rare and require advanced neuroimaging for confirmation. We sought to estimate PRES/RCVS misdiagnosis in the emergency department and its associated factors. Methods and Results We conducted a retrospective cohort study of PRES/RCVS patients using administrative claims data from 11 states (2016–2018). We defined patients with a probable PRES/RCVS misdiagnosis as those with an emergency department visit for a neurological symptom resulting in discharge to home that occurred ≤14 days before PRES/RCVS hospitalization. Proportions of patients with probable misdiagnosis were calculated, characteristics of patients with and without probable misdiagnosis were compared, and regression analyses adjusted for demographics and comorbidities were performed to identify factors affecting probable misdiagnosis. We identified 4633 patients with PRES/RCVS. A total of 210 patients (4.53% [95% CI, 3.97–5.17]) had a probable preceding emergency department misdiagnosis; these patients were younger (mean age, 48 versus 54 years; P

Sindrom multiple endokrine neoplazije 2B (MEN2B) rijetka je autosomno dominatno nasljedna bolest uzrokovana mutacijama protoonkogena RET. Karakteriziran je pojavom medularnog karcinoma štitnjače već od rane, nerijetko dojenačke dobi, feokromocitoma koji je najčešće obostran, sluzničkim neuromima te drugim ekstraendokrinim manifestacijama i specifičnim fenotipskim značajkama koje mogu pomoći u prepoznavanju ovih bolesnika. Prikazujemo pacijenta sa sindromom MEN2B, dijabetesom melitusom tipa 1, inverznim položajem organa te prirođenim malformacijama bubrega i mokraćnog sustava. Pregledom literature uočeno je da se malformacije mokraćnog sustava opisuju i u drugih bolesnika sa sindromom MEN2B. Prepoznata uloga gena RET u razvoju anomalija mokraćnog sustava čini moguću etiološku poveznicu sa sindromom MEN2B. Predlažemo da se malformacije bubrega razmotre kao jedno od obilježja sindroma MEN2B. Budući da se osobine bolesnika sa sindromom MEN2B postupno razvijaju s dobi, prepoznavanje prirođene mane, uz prve znakove ostalih fenotipskih značajki, moglo bi pomoći ranom postavljanju dijagnoze i liječenju ovih bolesnika.

Cistična fibroza najčešća je nasljedna bolest, koja skraćuje životni vijek, a uzrokuje je defekt u genu za transmembranski regulator provodljivosti cistične fibroze (eng. cystic fibrosis transmembrane regulator – CFTR). Poremećena je homeostaza elektrolita, što se očituje simptomima u više organskih sustava. Plućne manifestacije, s kroničnim infekcijama, upalom i, na kraju, respiratornim zatajenjem, ostaju i dalje najvažnija prijetnja životnom vijeku bolesnika. Do prije jednog desetljeća bilo je dostupno samo simptomatsko liječenje. Od 2012. g. dostupno je liječenje tzv. modulatorima CFTR-proteina i njihovim kombinacijama za osobe s cističnom fibrozom koje nose različite varijante CFTR-gena. Pojavom tih lijekova uvelike se promijenila perspektiva i kvaliteta života ljudi s cističnom fibrozom, ali postavljeni i novi izazovi u vezi s dugoročnim komplikacijama, pitanje eventualnog smanjenja konvencionalnog liječenja, ali i financiranja terapije, koja je mnogim bolesnicima nedostupna. Iznesene su bazične spoznaje o cističnoj fibrozi i funkciji CFTR-proteina, klasifikaciji varijanata CFTR-gena, mogućnostima liječenja CFTR-modulatorima te osnovni ishodi liječenja bolesnika s cističnom fibrozom u Hrvatskoj, gdje se ta terapija primjenjuje od jeseni 2021. godine.

We describe a case of a 61-year-old man who was found dead at home. He was not known for any illness and no symptoms were described before death. At autopsy, signs of pneumonia were detected. The macroscopically examination of the brain revealed no pathological findings. The microscopically evaluation of the brain showed small groups of inflammatory cells in the brainstem. The detailed analyze of MR images of the brain, showed an hypo-intensity on T1-weighted images and an hyper-intensity on T2-weighted images of the frontal and temporal lobes with damage of the cingulate cortex, the limbic lobe and the left insular cortex. These images raised the suspicion of an herpes simplex virus encephalitis. Neuropathological and immunohistochemical investigations, which thus were carried out, showed various infiltrates of CD3+ and CD8+ T-cells in the brainstem. Additionally to these infiltrations, we found CD68+ macrophages and activated microglia. Furthermore we could, immunohistochemically, show a HSV-1 and HSV-2 positivity of the hippocampi. With this case report we would like to show the difficulty to diagnose the herpes simplex encephalitis in postmortem and how easy a diagnosis can be missed, especially if the person doesn’t show any symptoms before death. In order to detect this kind of encephalitis several examinations must be performed; but for initiating these examinations the clinical history must be known and the suspicion of an encephalitis must be evocated. Moreover, this case underlines the importance of MRI for the correct evaluation of the brain and the value of interdisciplinary work for medico-legal cases.