Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wildtype mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe.

Segmentation of infarcts is clinically important in ischemic stroke management and prognostication. It is unclear what role the combination of DWI, ADC, and FLAIR MRI sequences provide for deep learning in infarct segmentation. Recent technologies in model self-configuration have promised greater performance and generalizability through automated optimization. We assessed the utility of DWI, ADC, and FLAIR sequences on ischemic stroke segmentation, compared self-configuring nnU-Net models to conventional U-Net models without manual optimization, and evaluated the generalizability of results on an external clinical dataset. 3D self-configuring nnU-Net models and standard 3D U-Net models with MONAI were trained on 200 infarcts using DWI, ADC, and FLAIR sequences separately and in all combinations. Segmentation results were compared between models using paired t-test comparison on a hold-out test set of 50 cases. The highest performing model was externally validated on a clinical dataset of 50 MRIs. nnU-Net with DWI sequences attained a Dice score of 0.810 ± 0.155. There was no statistically significant difference when DWI sequences were supplemented with ADC and FLAIR images (Dice score of 0.813 ± 0.150; p = 0.15). nnU-Net models significantly outperformed standard U-Net models for all sequence combinations (p < 0.001). On the external dataset, Dice scores measured 0.704 ± 0.199 for positive cases with false positives with intracranial hemorrhage. Highly optimized neural networks such as nnU-Net provide excellent stroke segmentation even when only provided DWI images, without significant improvement from other sequences. This differs from-and significantly outperforms-standard U-Net architectures. Results translated well to the external clinical environment and provide the groundwork for optimized acute stroke segmentation on MRI.

OBJECTIVE: The few voxel-wise lesion-symptom mapping (VLSM) studies aimed at identifying the anatomy of executive function are limited by the absence of a model and by small populations. Using Trail Making Test (TMT) and verbal fluency and a model of their architectures, our objective was to identify the key structures underlying two major executive processes, set-shifting and strategic word search.
METHODS: We applied a validated VLSM analysis to harmonized cognitive and imaging data from 2009 ischemic stroke patients as a part of the Meta VCI Map consortium. All contrast analyses used an adjusted threshold with 2000 Freedman-Lane permutations (p ≤ 0.05).
RESULTS: The TMT parts A and B were associated with structures involved in visual-spatial processing, the motor system, the frontal lobes, and their subcortical connections. Set-shifting depended on the left dorsomedial frontal region. Both semantic and phonemic fluency tests depended on verbal output abilities and processing speed with similar slopes in different languages. The strategic search process depended on Broca\'s area, F2 and related tracts, temporal and deep regions. Lastly, the lesion map of set-shifting did not overlap with those of strategic word search processes.
CONCLUSIONS: Our results identify the anatomical substrates of two main executive processes, revealing that they represent only a specific subpart of previously reported structures. Finally, our results indicate that executive functions depend on several specific, anatomically separable executive processes mainly operating in various parts of the frontal lobes.

OBJECTIVE: The association between white matter abnormalities (WMA) and cognitive decline previously reported in poststroke patients has been mainly documented using visual scales. However, automated segmentation of WMA provides a precise determination of the volume of WMA. Nonetheless, it is rarely used in the stroke population and its potential advantage over visual scales is still unsettled. The objective of this study was to examine whether automated segmentation of WMA provides a better account than the visual Fazekas and Wahlund scales of the decline in executive functions and processing speed in stroke patients.
METHODS: The analyses were conducted on the 358 patients of the GRECogVASC cohort with an MRI performed at six months poststroke in the Amiens center. WMA were visually analyzed using the Fazekas (subcortical abnormalities) and Wahlund scales. Segmentation was performed using LST (3.0.3). Following preliminary studies to determine the optimal segmentation threshold, we examined the relationship between cognitive status and WMA volume computed at each threshold using receiver operating characteristic (ROC) curves. Finally, we assessed the ability of both Fazekas and Wahlund visual scores and WMA volume to account for cognitive scores by using a bivariate Pearson correlation analysis, comparing correlation coefficients with the Fisher transformation and repeating correlation analysis after adjustment for the lesion volume.
RESULTS: Increasing the threshold led to an underestimation of WMA (P=0.0001) (significant for a threshold ≥0.2) and an improvement in correct rejection of signal changes in the stroke cavity (P=0.02) (significant for a threshold ≤0.5), susceptibility artifacts (P=0.002) (significant for a threshold ≤0.6), and corticospinal degeneration (P=0.03) (significant for a threshold ≤0.5). WMA volume decreased with increasing threshold (P=0.0001). Areas under the curve (AUC) did not differ according to the threshold (processing speed: P=0.85, executive cognitive functions: P=0.7). Correlation coefficients between cognitive scores and WMA were higher for WMA volume than the Fazekas (processing speed: Z=-3.442, P=0.001; executive functions: Z=-2.751, P=0.006) and Wahlund scores (processing speed: Z=-3.615, P=0.0001; executive functions: Z=-2.769, P=0.006). Adjustment for lesion volume did not alter the correlations with WMA volume (processing speed: r=-0.327 [95%CI: -0.416; -0.223], P=0.0001; executive functions: r=-0.262 [95%CI: -0.363; -0.150], P=0.0001).
CONCLUSIONS: This study shows that WMA volume assessed by automated segmentation provides a better account of cognitive disorders than visual analysis. This should favor its wider use to refine imaging determinants of poststroke cognitive disorders.

BACKGROUND: This multicenter study examines the contemporary management of penetrating carotid artery injury (PCAI) to identify trends in management, outcomes, and to determine prognostic factors for stroke and death.
METHODS: Data from three large urban trauma centers in South Africa were retrospectively reviewed for patients who presented with PCAI from 2012 to 2020.
RESULTS: Of 149 identified patients, 137 actively managed patients were included. Twenty-four patients (17.9%) presented in coma and 12 (9.0%) with localizing signs (LS). CT angiography was performed on admission for 120 (87.6%) patients. Thirty patients (21.9%) underwent nonoperative management, 87 (63.5%) open surgery, and 20 (14.6%) endovascular stenting. Eighteen patients (13.1%) died, and 15 (12.6%) surviving patients had strokes. Ligation was significantly related to death and reperfusion to survival. A mechanism of gunshot wound, occlusive injuries, a threatened airway, a systolic blood pressure <90 mmHg, hard signs of vascular injury, a low GCS, coma, a CT brain demonstrating infarct, a high injury severity score and shock index, a low pH or HCO3, and an elevated lactate were significant independent prognostic factors for death. Ligation was unsurvivable in all patients with severe neurological deficits, whereas reperfusion procedures resulted in survival in 63% (12/19) patients with coma and 78% (7/9) with LS although with high stroke rates (coma: 25.0%, LS: 85.7%).
CONCLUSIONS: Outcomes in PCAI, including patients with severe neurological deficit and stroke, are better when reperfused. Reperfusion holds the best promise of survival and ligation should be reserved for technically inaccessible bleeding injuries.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon genetic disorder that affects small blood vessels in the brain. It leads to neurological symptoms, disability-adjusted life years, and difficult emotional and physical situations for patients and their families. As unusual brain symptoms appear, it becomes important to understand the different clinical manifestations of CADASIL. Our case report and review examine several cases to demonstrate different presentations and management strategies of CADASIL. A 52-year-old male with a family history of strokes at a young age from his father and paternal grandfather presented to a neurology clinic for left facial droop and drooling. Brain magnetic resonance imaging showed extensive periventricular and subcortical white matter disease, including the external capsule and subcortical white matter of the temporal lobe. Findings were suggestive of small vessel vasculopathy. A cerebral angiogram showed that all large extra- and intracranial vessels were patent without evidence of aneurysm formation. There was no obvious evidence of beading of the distal intracranial vessels. Cerebrospinal fluid studies were normal. The NOTCH3 mutation was sent to test for CADASIL, which came back positive. The patient was started on aspirin (81 mg) and atorvastatin (20 mg) daily. The patient was counseled on the possibility of having an ischemic or hemorrhagic stroke. Aspirin and atorvastatin were continued, a neuropsychological evaluation was ordered, and CADASIL genetic counseling and testing were offered to him and his children. Over several years, patients developed several strokes and seizures due to infarcts. He also developed intraparenchymal hemorrhage complicated by dysphagia, requiring a feeding tube. Due to his severe physical debility, he was discharged to a nursing home for rehabilitation, where he did not improve with therapy and remained bedbound. He was discharged and sent home with his family. CADASIL can present as a diagnostic challenge due to its common presentation with migraines, transient ischemic attacks, and strokes, with or without risk factors. This unique presentation of CADASIL with facial palsy highlights the importance of emerging atypical presentations and the need for a detailed history of neuroimaging, family history, and personal history of neurovascular events. By accurately diagnosing the condition, patients and families can be counseled on the disease course and genetics. Management requires a multidisciplinary approach with neurology, genetic counseling, physical therapy, psychology, and psychiatry if depression or anxiety is present, with the aim of improving the patient\'s quality of life.

Vertebral artery dissections (VAD) pose a significant risk for strokes, particularly in young adults. This case report details the presentation and management of a 48-year-old patient who was diagnosed with an extracranial VAD following cervical spine manipulation (CSM). The patient\'s symptoms included acute right-sided ataxia, giddiness, vertigo, nausea, vomiting, and persistent pain behind the right ear, prompting immediate evaluation. After ruling out acute intracerebral hemorrhages, a computed tomography angiogram (CTA) of the head and neck identified a severe narrowing of the right distal vertebral artery with a string sign at the level of the right C1 loop (V3 segment), indicating an extracranial VAD. This finding was further supported when ultrasound (US) imaging revealed a high resistance flow pattern in the right distal vertebral artery. Furthermore, T2 and diffusion-weighted magnetic resonance imaging (MRI) confirmed a 1.8 cm VAD/hematoma and a 1.4 cm acute/subacute infarct in the right posterior inferior cerebellar artery (PICA) territory. This research accentuates the importance of recognizing and addressing that neck pain can be a symptom of musculoskeletal dysfunction or could have neurovascular origins. In this case, the patient\'s neck pain may have been musculoskeletal or could have been due to a previous dissection. Thus, differentiation should be considered before cervical spine manipulation.

BACKGROUND: Several neurovascular procedures require temporary occlusion of cerebral arteries, leading to ischemia of unpredictable length, occasionally causing brain infarction. Experimental models of cerebral ischemia-reperfusion injury have established that platelet adhesion and coagulation play detrimental roles in reperfusion injury following transient cerebral ischemia. Therefore, in a model of cerebral ischemia-reperfusion injury (IRI), we investigated the therapeutic potential of a dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic which is able to bind to vascular injury sites.
METHODS: Brain ischemia was induced in mice by transient occlusion of the right middle cerebral artery for 60 min. APAC, unfractionated heparin (UFH) (both at heparin equivalent doses of 0.5 mg/kg), or vehicle was intravenously administered 10 min before or 60 min after the start of ischemia. At 24 h later, mice were scored for their neurological and motor behavior, and brain damage was quantified.
RESULTS: Both APAC and UFH administered before the onset of ischemia reduced brain injury. APAC and UFH pretreated mice had better neurological and motor functions (p < 0.05 and p < 0.01, respectively) and had significantly reduced cerebral infarct sizes (p < 0.01 and p < 0.001, respectively) at 24 h after transient occlusion compared with vehicle-treated mice. Importantly, no macroscopic bleeding complications were observed in either APAC- or UFH-treated animals. However, when APAC or UFH was administered 60 min after the start of ischemia, the therapeutic effect was lost, but without hemorrhaging either.
CONCLUSIONS: Pretreatment with APAC or UFH was safe and effective in reducing brain injury in a model of cerebral ischemia induced by transient middle cerebral artery occlusion. Further studies on the use of APAC to limit ischemic injury during temporary occlusion in neurovascular procedures are indicated.

OBJECTIVE: To investigate an association between pancreatitis and chronic kidney disease (CKD) in cats.
METHODS: 154 client-owned cats: 77 cats with pancreatitis and 77 control cats with no evidence of pancreatitis.
METHODS: Retrospective record review from October 1, 2017, to October 1, 2022, including cats with gastrointestinal clinical signs, pancreatic lipase immunoreactivity (PLI) ≥ 8.8 μg/L or PLI 4.5 to 8.7 μg/L with sonographic evidence of pancreatitis. Control cats had a PLI ≤ 4.4 μg/L with no sonographic evidence of pancreatitis.
RESULTS: Cats with pancreatitis had significantly higher International Renal Interest Society CKD stages than controls (P < .001; OR, 13 [95% CI, 6.3 to 31]), and mean creatinine was on average 0.79 mg/dL (95% CI, 0.56 to 1.0) higher than controls (P < .001; age covariate ANCOVA, P = .003). Odds of CKD in cats with pancreatitis compared to controls increased significantly with age (P = .002). Cats aged 10 to < 15 years and 15 to 20 years with pancreatitis had significantly higher prevalence of CKD stage 2 to 4 compared to controls (P < .001; OR, 10.9 [95% CI, 3.4 to 44]; and P = .001; OR, 66 [95% CI, 4.6 to > 1,000], respectively). Cats with pancreatitis had significantly more sonographic renal infarcts (P = .004; OR, 6.9 [95% CI, 1.8 to 46]) and concurrent diabetes mellitus (P = .002; OR, 6 [95% CI, 1.9 to 27]). Cats with pancreatitis were fed more exclusively dry-food diets compared to controls (P = .014).
CONCLUSIONS: Pancreatitis is associated with CKD in cats. Investigating and treating these diseases concurrently early in the disease process may reduce morbidity and mortality due to progressive disease and expensive hospitalizations. Renal infarcts may be associated with pancreatitis in cats without overt cardiac disease.

BACKGROUND: Cerebrovascular accidents (CVAs) in dogs are diagnosed using magnetic resonance imaging (MRI). This modality is sometimes unavailable, and CVAs can resemble other lesions on MRI. D-dimer concentration and thromboelastography (TEG) are utilized in human medicine in addition to diagnostic imaging to support diagnosis of CVAs, but their use in veterinary patients has not been assessed.
OBJECTIVE: Assess utility of blood D-dimer concentration and TEG in supporting the imaging diagnosis of CVAs in dogs.
METHODS: Sixty-eight client-owned dogs with neurologic signs that had brain MRI and D-dimer concentration or TEG performed.
METHODS: Multicenter, retrospective study. The incidence of abnormal D-dimer concentration or TEG was compared between patients with MRI evidence of CVA and a control population. Analysis methods included Fisher\'s exact test or Chi-squared test for association and comparison of independent proportions.
RESULTS: Neither D-dimer concentration nor TEG was significantly associated with a CVA (P = .38 and .2, respectively). D-dimer testing was performed in a low-risk population and showed low sensitivity (30.8%; 95% confidence interval [CI], 10%-61%) and high specificity (86.4%; 95% CI, 64%-96%) for CVA diagnosis. Thromboelastography was performed in a high-risk population and showed moderate sensitivity (64.3%; 95% CI, 44%-81%) and specificity (66.7%; 95% CI, 24%-94%) for CVA diagnosis. Abnormal D-dimer concentration or TEG were not helpful in differentiating hemorrhagic from ischemic stroke (P = .43 and .41, respectively).
CONCLUSIONS: Although blood D-dimer concentration or TEG alone are not diagnostic of CVAs in dogs, a positive D-dimer result supports additional testing for CVA.