Exploring the impact of the interthalamic adhesion on human cognition: insights from healthy subjects and thalamic stroke patients.

The interthalamic adhesion (IA) is a structure that connects the median borders of both thalami. Its anatomical variants and functions remain poorly studied. The main objective of this study was to explore the role of the IA on cognition. 42 healthy subjects and 40 patients with chronic isolated thalamic strokes underwent a neuroimaging and a neuropsychological assessment. The presence, absence, or lesion of the IA and its anatomical variants were evaluated. 76% of participants had an IA, with a higher prevalence among women (92%) than men (61%). The presence or absence of an IA did not affect the neuropsychological performance of healthy subjects nor did the type of IA variant. Across all the tests and when compared to healthy subjects using a Bayesian rmANOVA, patients exhibiting more cognitive impairments were those without an IA (n = 10, BF10 = 10,648), while those with an IA were more preserved (n = 18, BF10 = 157). More specifically, patients without an IA performed more poorly in verbal memory or the Stroop task versus healthy subjects. This was not explained by age, laterality of the infarct, volume or localization of the lesion. Patients with a lesioned IA (n = 12) presented a similar trend to patients without an IA, which could however be explained by a greater volume of lesions. The IA does not appear to play a major role in cognition in healthy subjects, but could play a compensatory role in patients with thalamic lesions.

Prevalence and characteristics of vascular cognitive impairment in a European cohort of adult patients with Moyamoya angiopathy.

INTRODUCTION: Moyamoya angiopathy (MMA) is associated with a high risk of stroke, but it is also increasingly recognized as leading to cognitive impairment. The aim of this study was to determine the prevalence, nature, and severity of vascular cognitive impairment no dementia (VCIND) in adults with MMA and to identify clinical and imaging factors associated with VCIND. METHODS: We conducted a retrospective study of consecutive adult patients with MMA followed in two tertiary hospitals (Toulouse and Paris Lariboisiere). All patients underwent neuropsychological assessment and brain magnetic resonance imaging (MRI). VCIND was defined as at least two variables of the same cognitive process with z-scores of < 2 standard deviations, regardless of the cognitive domain, that do not interfere in everyday life. Baseline demographic, clinical, and imaging data were compared between patients with and without VCIND. RESULTS: A total of 102 patients (mean age 43 years; 65% women) were included. Thirty-four patients (33.3%) had VCIND. VCIND was mild in 20/34 (59%), moderate in 8/34 (23%), and severe in 6/34 (18%) patients. Executive function was the most widely affected (25.5%), followed by attention and processing speed (24.8%). In univariable analyses, VCIND was associated with ischemic stroke at diagnosis and the presence of ischemic lesions on MRI. CONCLUSIONS: VCIND is highly prevalent in adults with MMA. Executive functions and processing speed are predominantly affected. These findings may guide clinicians in their evaluation of patients with MMA. Further research should assess the effect of revascularization therapies on cognitive functions.

ITPR1: The missing gene in miosis-ataxia syndrome?

The association of early-onset non-progressive ataxia and miosis is an extremely rare phenotypic entity occasionally reported in the literature. To date, only one family (two siblings and their mother) has benefited from a genetic diagnosis by the identification of a missense heterozygous variant (p.Arg36Cys) in the ITPR1 gene. This gene encodes the inositol 1,4,5-trisphosphate receptor type 1, an intracellular channel that mediates calcium release from the endoplasmic reticulum. Deleterious variants in this gene are known to be associated with two types of spinocerebellar ataxia, SCA15 and SCA29, and with Gillespie syndrome that is associated with ataxia, partial iris hypoplasia, and intellectual disability. In this work, we describe a novel individual carrying a heterozygous missense variant (p.Arg36Pro) at the same position in the N-terminal suppressor domain of ITPR1 as the family previously reported, with the same phenotype associating early-onset non-progressive ataxia and miosis. This second report confirms the implication of ITPR1 in the miosis-ataxia syndrome and therefore broadens the clinical spectrum of the gene. Moreover, the high specificity of the phenotype makes it a recognizable syndrome of genetic origin.

MRI hypoperfusion as a determinant of cognitive impairment in adults with Moyamoya angiopathy.

INTRODUCTION: In Moyamoya angiopathy (MMA), mechanisms underlying cognitive impairment remain debated. We aimed to assess the association of cognitive impairment with the degree and the topography of cerebral hypoperfusion in MMA. METHODS: A retrospective analysis of neuropsychological and perfusion MRI data from adults with MMA was performed. Ischemic and haemorrhagic lesion masks were created to account for cerebral lesions in the analysis of cerebral perfusion. Whole brain volume of hypoperfused parenchyma was outlined on perfusion maps using different Tmax thresholds from 4 to 12 s. Regional analysis produced mean Tmax values at different regions of interest. Analyses compared perfusion ratios in patients with and without cognitive impairment, with multivariable logistic regression analysis to identify predictive factors. RESULTS: Cognitive impairment was found in 20/48 (41.7%) patients. Attention/processing speed and memory were equally impaired (24%) followed by executive domain (23%). After adjustment, especially for lesion volume, hypoperfused parenchyma volume outlined by Tmax > 4 s or Tmax > 5 s thresholds was an independent factor of cognitive impairment (OR for Tmax > 4 s = 1.06 [CI 95% 1.008-1.123]) as well as attention/processing speed (OR for Tmax > 4 s = 1.07 [CI 95% 1.003-1.133]) and executive domains (OR for Tmax > 5 s = 1.08 [CI 95% 1.004-1.158]). Regarding cognitive functions, patients with processing speed and flexibility impairment had higher frontal Tmax compared to other ROIs and to patients with normal test scores. DISCUSSION: Cerebral hypoperfusion emerged as an independent factor of cognitive impairment in MMA particularly in attention/processing speed and executive domains, with a strong contribution of frontal areas. CONCLUSION: Considering this association, revascularization surgery could improve cognitive impairment.

Cerebrovascular and cardiovascular autonomic regulation in sickle cell patients with white matter lesions.

BACKGROUND AND PURPOSE: White matter lesions (WMLs) are frequent in sickle cell disease (SCD), with a prevalence described to be as high as 53% by age 30. Cerebrovascular regulation and cardiovascular autonomic regulation, more specifically the sympatho-vagal balance, can be altered in SCD. In this study the association between WMLs, cerebrovascular regulation and sympatho-vagal balance was assessed in SCD patients. METHODS AND RESULTS: Sickle cell disease patients with no history of stroke were prospectively evaluated for cerebrovascular reactivity using the breath-holding test (BHT), the sympatho-vagal balance (ratio low frequency/high frequency [HF]) using heart rate variability parameters and cerebral autoregulation in the time domain using correlation index Mx, and arterial cerebral compliance based on continuous assessment of cerebral blood flow velocities using transcranial Doppler ultrasound and arterial blood pressure with photo-plethysmography. WMLs were assessed with magnetic resonance imaging using Fazekas score grading and the presence of lacunes. Forty-one patients (F/M 25/16) were included. Median age was 37.5 years (19-65). Twenty-nine (70.7%) patients had SS genotype. Eleven patients had WMLs (26.8%). Patients with WMLs were significantly older (p < 0.001), had a lower HF (p < 0.005) and an impaired cerebral arterial compliance (p < 0.014). The receiver operating curve for the regression model including age and HF showed a higher area under the curve compared to age alone (0.946 vs. 0.876). BHT and Mx did not significantly differ between the two groups. CONCLUSIONS: Lower parasympathetic activity and impaired cerebral arterial compliance were associated with WMLs in adults with SCD. This could potentially yield to a better understanding of pathophysiological parameters leading to premature cerebrovascular ageing in SCD.

Immunohistologic Features of Cerebral Venous Thrombosis Due to Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia (VITT), a recently described entity characterized by thrombosis at unusual locations such as cerebral venous sinus and splanchnic vein, has been rarely described after adenoviral-encoded COVID-19 vaccines. In this study, we report the immunohistological correlates in 3 fatal cases of cerebral venous thrombosis related to VITT analyzed at an academic medical center. METHODS: Detailed neuropathologic studies were performed in 3 cases of cerebral venous thrombosis related to VITT after adenoviral COVID-19 vaccination. RESULTS: Autopsy revealed extensive cerebral vein thrombosis in all 3 cases. Polarized thrombi were observed with a high density of neutrophils in the core and a low density in the tail. Endothelial cells adjacent to the thrombus were largely destroyed. Markers of neutrophil extracellular trap and complement activation were present at the border and within the cerebral vein thrombi. SARS-CoV-2 spike protein was detected within the thrombus and in the adjacent vessel wall. DISCUSSION: Data indicate that neutrophils and complement activation associated with antispike immunity triggered by the vaccine is probably involved in the disease process.

Specific profiles of new-onset vs. non-inaugural status epilepticus: From diagnosis to 1-year outcome.

While new-onset status epilepticus (NOSE) is a harbinger of chronic epilepsy, prospective medical data are sparse in terms of specifying whether the evolution of status epilepticus (SE) and seizure expression in NOSE resembles what occurs in patients who have already been diagnosed with epilepsy [non-inaugural SE (NISE)] in all aspects apart from its inaugural nature. The aim of this study was to compare the clinical, MRI, and EEG features that could distinguish NOSE from NISE. We conducted a prospective monocentric study in which all patients ≥18 years admitted for SE over a 6-month period were included. A total of 109 patients (63 NISE and 46 NOSE cases) were included. Despite similar modified Rankin scores before SE, several aspects of the clinical history distinguished NOSE from NISE patients. NOSE patients were older and frequently had neurological comorbidity and preexisting cognitive decline, but they had a similar prevalence of alcohol consumption to NISE patients. NOSE and NISE evolve in the same proportions as refractory SE (62.5% NOSE, 61% NISE) and share common features such as the same incidence (33% NOSE, 42% NISE, and p = 0.53) and volumes of peri-ictal abnormalities on MRI. However, in NOSE patients, we observed greater non-convulsive semiology (21.7% NOSE, 6% NISE, and p = 0.02), more periodic lateral discharges on EEG (p = 0.004), later diagnosis, and higher severity according to the STESS and EMSE scales (p < 0.0001). Mortality occurred in 32.6% of NOSE patients and 21% of NISE patients at 1 year (p = 0.19), but with different causes of death occurring at different time points: more early deaths directly linked to SE at 1 month occurred in the NOSE group, while there were more remote deaths linked to causal brain lesions in the NISE group at final follow-up. In survivors, 43.6% of the NOSE cases developed into epilepsy. Despite acute causal brain lesions, the novelty related to its inaugural nature is still too often associated with a delay in diagnosing SE and a poorer outcome, which justifies the need to more clearly specify the various types of SE to constantly raise awareness among clinicians. These results highlight the relevance of including novelty-related criteria, clinical history, and temporality of occurrence in the nosology of SE.

The Use of Intracranial Vessel Wall Imaging in Clinical Practice.

Three-dimensional vessel wall MR imaging has gained popularity in the diagnosis and management of patients with cerebrovascular disease in clinical practice. Vessel wall MR imaging is an imaging technique that delivers a fundamentally different viewpoint by emphasizing on the pathology of the vessel wall as opposed to traditional descriptions that focus on the vessel lumen. It shows a crucial power in detecting vessel wall changes in patients with diseases including, but not limited to, central nervous system vasculitis, moyamoya disease, aneurysms, dissections, and intracranial atherosclerotic disease.

CNS tumor with EP300::BCOR fusion: discussing its prevalence in adult population.

The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification.

Diagnostic imaging strategies of acute intracerebral hemorrhage in European academic hospitals-a decision-making analysis.

PURPOSE: To evaluate and compare which factors are relevant to the diagnostic decision-making and imaging workup of intracerebral hemorrhages in large, specialized European centers. METHODS: Expert neuroradiologists from ten large, specialized centers (where endovascular stroke treatment is routinely performed) in nine European countries were selected in cooperation with the European Society of Neuroradiology (ESNR). The experts were asked to describe how and when they would investigate specific causes in a patient who presented with an acute, atraumatic, intracerebral hemorrhage for two given locations: (1) basal ganglia, thalamus, pons or cerebellum; (2) lobar hemorrhage. Answers were collected, and decision trees were compared. RESULTS: Criteria that were considered relevant for decision-making reflect recommendations from current guidelines and were similar in all participating centers. CT Angiography or MR angiography was considered essential by the majority of centers regardless of other factors. Imaging in clinical practice tended to surpass guideline recommendations and was heterogeneous among different centers, e.g., in a scenario suggestive of typical hypertensive hemorrhage, recommendations ranged from no further follow-up imaging to CT angiography and MR angiography. In no case was a consensus above 60% achieved. CONCLUSION: In European clinical practices, existing guidelines for diagnostic imaging strategies in ICH evaluation are followed as a basis but in most cases, additional imaging investigation is undertaken. Significant differences in imaging workup were observed among the centers. Results suggest a high level of awareness and caution regarding potentially underlying pathology other than hypertensive disease.

Prevalence and characterization of cerebral small vessel disease in young adults with intracerebral hemorrhage.

BACKGROUND AND AIMS: Cerebral small vessel disease (CSVD) is the main cause of intracerebral hemorrhage (ICH) in older individuals but has not been systematically studied in younger people. We aimed to evaluate the prevalence and characteristics of CSVD in young adults with symptomatic ICH. METHODS: We conducted a cohort study of consecutive adults aged 18-50 years with non-traumatic ICH. All patients were evaluated with brain and vascular imaging. Using validated imaging markers (cerebral microbleeds (CMBs), white matter hyperintensities and/or lacunes), patients were categorized as having CSVD-related ICH or non-CSVD-related ICH. Factors associated with CSVD were evaluated using multivariable analyses. CSVD subtypes were characterized using pre-specified criteria. RESULTS: Of 146 young adults with ICH (mean age = 37.7), CSVD was present in 41 patients (28.1%; 95% confidence interval (CI) = 21.0-36.1). In multivariable analysis, older age, male sex, and hypertension were independently associated with the presence of CSVD. Deep perforator arteriopathy (48.8%) and mixed CSVD (31.7%) were the most common CSVD subtypes. CONCLUSION: Our results suggest that CSVD is a frequent cause of ICH in young adults and provide new insights into the characterization of the disease. These findings may have important implications since the treatment and management differ from other causes of ICH.

Fatal mucormycosis and aspergillosis coinfection associated with haemophagocytic lymphohistiocytosis: A case report and literature review.

Invasive mould infections are life-threatening and mainly occur in immunocompromised patients. Whereas aspergillosis is described during haemophagocytic lymphohistiocytosis (HLH), only a few cases of concomitant mucormycosis with HLH have been reported. Here, we present an uncommon coinfection of mucormycosis and aspergillosis associated with HLH probably due to a varicella zoster virus (VZV) viraemia which was unresponsive to triple antifungal therapy (liposomal amphotericin B combined with isavuconazole and caspofungin). A review of the cases of mucormycosis with HLH showed that this uncommon association was always lethal and underscored the relevance of screening for mould infections in patients with HLH.

Is systematic Gadolinium injection relevant during MRI follow-up for non-functioning pituitary macroadenomas?

OBJECTIVE: To compare the performance of coronal contrast-enhanced T1-weighted (ceT1-w) and T2-weighted (T2-w) sequences for diagnosing progression during the MRI follow-up of Non-Functioning Pituitary MacroAdenomas (NFPMAs). PATIENTS AND METHODS: 106 patients, who had at least two MRIs for the follow-up of NFPMA, were enrolled retrospectively. The largest adenoma diameter was measured on coronal ceT1-w sequences and separately on T2-w sequences for all follow-up MRIs. Interobserver variability was also assessed by 2 independent neuroradiologists in a sample series of 100 examinations. Progression was defined by an increase ≥ 2 mm in diameter between 2 MRIs. Progression thresholds of 3 and 4 mm were also tested. The results of ceT1-w and T2-w sequences were analysed for concordance. RESULTS: 93.1% concordance was achieved between ceT1-w and T2-w coronal sequences in 580 follow-up MRIs. In the case of progression detected on at least one sequence, 64.4% concordance was documented for a 2-mm threshold, 87.7% for 3-mm and 97.1% for 4-mm. Discordance was mainly observed on the first postoperative MRI and in case of NFPMAs with multiple recurrences. Kappa was better for diagnosing progression on T2-w than on ceT1-w sequences (0.67 vs. 0.54). It should be noted that 100% agreement was observed between the 2 sequences in the 82 follow-up MRIs of patients with complete surgical resection. CONCLUSION: 93.1% concordance was achieved for coronal ceT1-w and T2-w sequences during the MRI follow-up of NFPMAs, thus challenging systematic injection of gadolinium. If MRI without gadolinium injection is a first-line option, our results suggest that ceT1-w sequences should be reserved for the first postoperative MRI and for the follow-up of aggressive and recurrent NFPMAs.

Location-weighted versus Volume-weighted Mismatch at MRI for Response to Mechanical Thrombectomy in Acute Stroke.

Background A target mismatch profile can identify good clinical response to recanalization after acute ischemic stroke, but does not consider region specificities. Purpose To test whether location-weighted infarction core and mismatch, determined from diffusion and perfusion MRI performed in patients with acute stroke, could improve prediction of good clinical response to mechanical thrombectomy compared with a target mismatch profile. Materials and Methods In this secondary analysis, two prospectively collected independent stroke data sets (2012-2015 and 2017-2019) were analyzed. From the brain before stroke (BBS) study data (data set 1), an eloquent map was computed through voxel-wise associations between the infarction core (based on diffusion MRI on days 1-3 following stroke) and National Institutes of Health Stroke Scale (NIHSS) score. The French acute multimodal imaging to select patients for mechanical thrombectomy (FRAME) data (data set 2) consisted of large vessel occlusion-related acute ischemic stroke successfully recanalized. From acute MRI studies (performed on arrival, prior to thrombectomy) in data set 2, target mismatch and eloquent (vs noneloquent) infarction core and mismatch were computed from the intersection of diffusion- and perfusion-detected lesions with the coregistered eloquent map. Associations of these imaging metrics with early neurologic improvement were tested in multivariable regression models, and areas under the receiver operating characteristic curve (AUCs) were compared. Results Data sets 1 and 2 included 321 (median age, 69 years [IQR, 58-80 years]; 207 men) and 173 (median age, 74 years [IQR, 65-82 years]; 90 women) patients, respectively. Eloquent mismatch was positively and independently associated with good clinical response (odds ratio [OR], 1.14; 95% CI: 1.02, 1.27; P = .02) and eloquent infarction core was negatively associated with good response (OR, 0.85; 95% CI: 0.77, 0.95; P = .004), while noneloquent mismatch was not associated with good response (OR, 1.03; 95% CI: 0.98, 1.07; P = .20). Moreover, adding eloquent metrics improved the prediction accuracy (AUC, 0.73; 95% CI: 0.65, 0.81) compared with clinical variables alone (AUC, 0.65; 95% CI: 0.56, 0.73; P = .01) or a target mismatch profile (AUC, 0.67; 95% CI: 0.59, 0.76; P = .03). Conclusion Location-weighted infarction core and mismatch on diffusion and perfusion MRI scans improved the identification of patients with acute stroke who would benefit from mechanical thrombectomy compared with the volume-based target mismatch profile. Clinical trial registration no. NCT03045146 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Nael in this issue.

Assessment of the hypervascularized fraction of glioblastomas using a volume analysis of dynamic susceptibility contrast-enhanced MRI may help to identify pseudoprogression.

PURPOSE: Although perfusion magnetic resonance imaging (MRI) is widely used to identify pseudoprogression, this advanced technique lacks clinical reliability. Our aim was to develop a parameter assessing the hypervascularized fraction of glioblastomas based on volume analysis of dynamic susceptibility contrast-enhanced MRI and evaluate its performance in the diagnosis of pseudoprogression. METHODS: Patients with primary glioblastoma showing lesion progression on the first follow-up MRI after chemoradiotherapy were enrolled retrospectively. On both initial and first follow-up MRIs, the leakage-corrected cerebral blood volume (CBV) maps were post-processed using the conventional hot-spot method and a volume method, after manual segmentation of the contrast-enhanced delineated lesion. The maximum CBV (rCBVmax) was calculated with both methods. Secondly, the threshold of 2 was applied to the CBV values contained in the entire segmented volume, defining our new parameter: %rCBV>2. The probability of pseudoprogression based on rCBVmax and %rCBV>2 was calculated in logistic regression models and diagnostic performance assessed by receiving operator characteristic curves. RESULTS: Out of 25 patients, 11 (44%) were classified with pseudoprogression and 14 (56%) with true progression based on the Response Assessement in Neuro-Oncology criteria. rCBVmax was lower for pseudoprogression (3.4 vs. 7.6; p = 0.033) on early follow-up MRI. %rCBV>2, was lower for pseudoprogression on both initial (57.5% vs. 71.3%; p = 0.033) and early follow-up MRIs (22.1% vs. 51.8%; p = 0.0006). On early follow-up MRI, %rCBV>2 had the largest area under the curve for the diagnosis of pseudoprogression: 0.909 [0.725-0.986]. CONCLUSION: The fraction of hypervascularization of glioblastomas as assessed by %rCBV>2 was lower in tumours that subsequently developed pseudoprogression both on the initial and early follow-up MRIs. This fractional parameter may help identify pseudoprogression with greater accuracy than rCBVmax.

Insular functional connectivity in migraine with aura.

INTRODUCTION: Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA. METHODS: Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis. RESULTS: Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO. DISCUSSION: The anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA. CONCLUSION: The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA. TRIAL REGISTRATION: NCT02708797.

Perfusion Imaging and Clinical Outcome in Acute Minor Stroke With Large Vessel Occlusion.

BACKGROUND: Whether bridging therapy (intravenous thrombolysis [IVT] followed by mechanical thrombectomy) is superior to IVT alone in minor stroke with large vessel occlusion is unknown. Perfusion imaging may identify subsets of large vessel occlusion-related minor stroke patients with distinct response to bridging therapy. METHODS: We conducted a multicenter international observational study of consecutive IVT-treated patients with minor stroke (National Institutes of Health Stroke Scale score ≤5) who had an anterior circulation large vessel occlusion and perfusion imaging performed before IVT, with a subset undergoing immediate thrombectomy. Propensity score with inverse probability of treatment weighting was used to account for baseline between-groups differences. The primary outcome was 3-month modified Rankin Scale score 0 to 1. We searched for an interaction between treatment group and mismatch volume (critical hypoperfusion-core volume). RESULTS: Overall, 569 patients were included (172 and 397 in the bridging therapy and IVT groups, respectively). After propensity-score weighting, the distribution of baseline variables was similar across the 2 groups. In the entire population, bridging was associated with lower odds of achieving modified Rankin Scale score 0 to 1: odds ratio, 0.73 [95% CI, 0.55-0.96]; P=0.03. However, mismatch volume modified the effect of bridging on clinical outcome (Pinteraction=0.04 for continuous mismatch volume); bridging was associated with worse outcome in patients with, but not in those without, mismatch volume <40 mL (odds ratio, [95% CI] for modified Rankin Scale score 0-1: 0.48 [0.33-0.71] versus 1.14 [0.76-1.71], respectively). Bridging was associated with higher incidence of symptomatic intracranial hemorrhage in the entire population, but this effect was present in the small mismatch subset only (Pinteraction=0.002). CONCLUSIONS: In our population of large vessel occlusion-related minor stroke patients, bridging therapy was associated with lower rates of good outcome as compared with IVT alone. However, mismatch volume was a strong modifier of the effect of bridging therapy over IVT alone, notably with worse outcome with bridging therapy in patients with mismatch volume ≤40 mL. Randomized trials should consider adding perfusion imaging for patient selection.