Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

OBJECTIVE: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. METHODS: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. RESULTS: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data). INTERPRETATION: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

A Noonan-like pediatric patient with a de novo CBL pathogenic variant and an RNF213 polymorphism p.R4810K presenting with cardiopulmonary arrest due to left main coronary artery ostial atresia.

Left main coronary artery ostial atresia (LMCAOA) is an extremely rare condition. Here, we report the case of a 14-year-old boy with Noonan syndrome-like disorder in whom LMCAOA was detected following cardiopulmonary arrest. The patient had been diagnosed with Noonan syndrome-like disorder with a pathogenic splice site variant of CBL c.1228-2 A > G. He suddenly collapsed when he was running. After administering two electric shocks using an automated external defibrillator, the patient's heartbeat resumed. Cardiac catheterization confirmed the diagnosis of LMCAOA. Left main coronary artery angioplasty was performed. The patient was discharged without neurological sequelae. Brain magnetic resonance imaging revealed asymptomatic Moyamoya disease. In addition, RNF213 c.14429 G > A p.R4810K was identified. There are no reports on congenital coronary malformations of compound variations of RNF213 and CBL. In contrast, the RNF213 p.R4810K polymorphism has been established as a risk factor for angina pectoris and myocardial infarction in adults, and several congenital coronary malformations due to genetic abnormalities within the RAS/MAPK signaling pathway have been reported. This report aims to highlight the risk of sudden death in patients with RASopathy and RNF213 p.R4810K polymorphism and emphasize the significance of actively searching for coronary artery morphological abnormalities in these patients.

Periodic discharges plus fast activity on electroencephalogram predict worse outcomes in poststroke epilepsy.

OBJECTIVE: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. METHODS: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. RESULTS: In this study, 307 patients with PSE (median age = 75 years, range = 35-97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 [20%] vs. 8 [3.2%], p < .001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44-12.6, p = .009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = .003), prolonged hyperperfusion (100% vs. 62%, p = .023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87-259.4, p = .014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR = 4.21, 95% CI = 1.27-13.88, p = .018). SIGNIFICANCE: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short- and long-term functional decline.

Harboring Cnm-expressing Streptococcus mutans in the oral cavity relates to both deep and lobar cerebral microbleeds.

BACKGROUND: Cerebral microbleeds (CMBs) influence long-term prognoses of stroke patients. Streptococcus mutans expressing the collagen-binding protein Cnm induces cerebrovascular inflammation, impairing blood brain barrier integrity and causing cerebral bleeding. Here, we examine the association of Cnm-positive S. mutans with CMBs. METHODS: Acute stroke patients were selected from a single-center registry database. Oral carriage of Cnm-positive or Cnm-negative S. mutans was determined using polymerase chain reaction assays. The associations of Cnm-positive S. mutans with CMB number and specifically the presence of >10 CMBs were examined using quasi-Poisson and logistic regression models, respectively. RESULTS: This study included 3154 stroke patients, of which 428 patients (median [interquartile range] age, 73.0 [63.0-81.0] years; 269 men [62.9%]) underwent oral bacterial examinations. In total, 326 patients harbored S. mutans. After excluding four patients without imaging data, we compared patients with Cnm-positive (n = 72) and Cnm-negative (n = 250) S. mutans. Harboring Cnm-positive S. mutans was independently associated with the presence of >10 CMBs (adjusted odds ratio 2.20 [1.18-4.10]) and higher numbers of deep and lobar CMBs (adjusted risk ratio 1.61 [1.14-2.27] for deep; 5.14 [2.78-9.51] for lobar), but not infratentorial CMBs, after adjusting for age, sex, hypertension, stroke type, National Institutes of Health Stroke Scale score, and cerebral amyloid angiopathy. CONCLUSIONS: Harboring Cnm-positive S. mutans was independently associated with a higher number of CMBs in deep and lobar locations. Reducing Cnm-positive S. mutans in the oral cavity may serve as a novel therapeutic approach for stroke.

Clinical and imaging features of nonmotor onset seizure in poststroke epilepsy.

OBJECTIVE: Motivated by the challenges raised by diagnosing poststroke epilepsy (PSE), especially in nonmotor onset seizure (non-MOS), we aimed to investigate the features of non-MOS, including seizure sequences, patient characteristics, and electrophysiological and imaging findings in PSE. METHODS: This observational cohort study enrolled patients with PSE whose seizure onset was witnessed. According to the International League Against Epilepsy (ILAE) 2017 seizure classification, we classified seizure-onset symptoms into the non-MOS and MOS groups. We compared the different clinical characteristics between the two groups. RESULTS: Between 2011 and 2018, we enrolled 225 patients with PSE (median age, 75 years), consisting of 97 (43%) with non-MOS and 128 (57%) with MOS. Overall, 65 (67%) of the patients without MOS had no subsequent convulsions. Multivariable logistic regression analysis showed significant associations of non-MOS with absence of poststroke hemiparesis (adjusted odds ratio [OR], 1.88; 95% confidence interval [CI], 1.03-3.42), frontal stroke lobe lesions (OR, 2.11; 95% CI, 1.14-3.91), and putaminal stroke lesions (OR, 2.51; 95% CI, 1.22-5.18) as negative indicators. Postictal single-photon emission computed tomography (SPECT) detected prolonged hyperperfusion in the temporal lobe more frequently in the non-MOS than in the MOS group (48% vs 31%; p = .02). The detection rate was higher than spikes/sharp waves in scalp electroencephalography, both in the non-MOS group (72% vs 33%; p < .001) and the MOS group (68% vs 29%; p < .001). SIGNIFICANCE: This study provides the clinical features of non-MOS in patients with PSE. Compared with the patients with MOS, patients with non-MOS showed less likely subsequent convulsive seizures, highlighting the clinical challenges. Postictal perfusion imaging and negative indicators of the non-MOS type may help diagnose and stratify PSE.

Oral Carriage of Streptococcus mutans Harboring the cnm Gene Relates to an Increased Incidence of Cerebral Microbleeds.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) are associated with stroke and cognitive impairment. We previously reported a high prevalence of CMB in people with Streptococcus mutans expressing Cnm, a collagen-binding protein in the oral cavity. S.mutans is a major pathogen responsible for dental caries. Repeated challenge with S.mutans harboring the cnm gene encoding Cnm induced cerebral bleeding in stroke-prone spontaneously hypertensive rats. The purpose of this longitudinal study is to examine the relationship of cnm-positive S.mutans to the development of CMB. METHODS: We retrospectively investigated patients with stroke receiving oral microbiological examination and head 3T magnetic resonance imaging evaluations twice in the period 2014 to 2019, allowing >180-day interval. Patients with cnm-positive S.mutans were compared with those without. Quasi-Poisson regression models were used to explore associations between cnm-positive S.mutans and the increase in number of CMB between the 2 magnetic resonance imaging scans. RESULTS: A total of 111 patients were identified; 21 (19%) with cnm-positive S.mutans and 90 (81%) without. Clinical history, including blood pressure and the use of antithrombotic agents, were comparable between the 2 groups. New CMB were more commonly observed in patients with cnm-positive S.mutans (52% versus 23%; P=0.008). The incidence of CMB was significantly higher in the group with cnm-positive S.mutans, especially in deep areas, (incidence rate ratios [95% CI], 5.1 [1.9-13.6] for CMB in any brain region; 15.0 [5.4-42.0] for deep CMB), which persisted after adjusting for age, sex, hypertension, and renal impairment (4.7 [1.8-11.9] for CMB in any brain region; 13.9 [4.3-44.5] for deep CMB). CONCLUSIONS: This study demonstrates that cnm-positive S.mutans is associated with an increased incidence of CMB. Treatment for cnm-positive S.mutans infection may be a novel microbiota-based therapeutic approach for stroke and cognitive impairment.

Detrimental Effect of Chronic Hypertension on Leptomeningeal Collateral Flow in Acute Ischemic Stroke.

Background and Purpose- We aimed to evaluate the effect of chronic hypertension on acute leptomeningeal collateral flow in patients with large-vessel ischemic stroke using digital subtraction angiography, which is the gold standard for the assessment of collateral circulation. Methods- Of the consecutive ischemic stroke patients from October 2011 to December 2017 seen in our institution, patients with acute occlusion of the M1 segment of the middle cerebral artery confirmed on initial digital subtraction angiography were enrolled. Chronic hypertension was defined as its documentation before the index stroke or as the administration of antihypertensive medications before onset. Angiographic leptomeningeal collateral flow was evaluated according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology Collateral Flow Grading System and dichotomized the findings into excellent (grade 3-4) or poor (grade 0-2) collateral status for analysis. Results- Of the 3759 consecutive ischemic stroke patients, 100 patients were analyzed. Thirty-nine patients (39%) had poor collateral status. Patients with poor collateral status were older, more frequently male, and had chronic hypertension more frequently, shorter time from onset to angiography, and higher admission systolic blood pressure than those with excellent collateral status. Multivariable logistic analysis with prespecified covariates showed a significantly positive association between chronic hypertension and poor collateral status (odds ratio, 2.80; 95% CI, 1.08-7.70; P=0.034). This association was independent of admission systolic blood pressure. The proportion of patients with poor collateral status increased in a stepwise manner in patients without chronic hypertension, hypertensive patients with premorbid antihypertensive medications, and hypertensive patients without antihypertensive medications ( P for trend <0.001). Conclusions- Our data suggest that chronic hypertension has a detrimental effect on acute leptomeningeal collateral flow in patients with cerebral large-vessel occlusion. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02251665.

Morning headache caused by obstructive sleep apnea misdiagnosed as temporomandibular disorders-related headache: A case report.

PATIENT: A 67-year-old woman presented to our clinic with chief complaints of headache and mandibular heaviness. Physical examination revealed bilateral tenderness in the temporalis and masseter muscles, corresponding to the patient's chief complaint. Thus, a diagnosis of temporomandibular disorders (TMDs)-related headache was made. However, sleep disorders were identified after further consultation. Hence, sleep apnea-related headache was suspected due to a snoring habit with a Mallampati classification of Class IV. Out-of-center sleep testing (OCST) revealed a respiratory event index (REI) of 10.1/h and a low peripheral oxygen saturation (SpO2) of 76%. Consequently, a diagnosis of obstructive sleep apnea (OSA) was made, and treatment using the mandibular advancement device (MAD) was recommended. Following MAD treatment, the patient's sleep quality improved, and morning headaches ceased. Subsequent OCST performed while wearing the MAD showed a significant reduction in the REI to 1.6/h and an increase in the SpO2 to 86%, indicating the therapeutic efficacy of the MAD in treating OSA. DISCUSSION: MAD treatment effectively alleviated the patient's morning headaches, suggesting that sleep bruxism should not be considered the only cause of headaches. OSA should also be considered and addressed when investigating the potential causes of morning headaches in patients. CONCLUSIONS: In patients experiencing TMDs symptoms and morning headaches, TMDs should not be presumed as the sole cause. Dentists should discuss the likelihood of sleep disorders during consultations. If sleep disorders are suspected, the possibility of OSA should be considered, and sleep tests should be conducted when necessary.

Cardioembolism after thoracoscopic left atrial appendage clipping in a patient on oral anticoagulation therapy.

Cardioembolism associated with atrial fibrillation is a major cause of ischemic stroke. Left atrial appendage occlusion in atrial fibrillation patients undergoing cardiac surgery reduces the risk of postoperative stroke. A 78-year-old man with a history of atrial fibrillation and severe mitral regurgitation underwent thoracoscopic mitral valve repair with left atrial appendage clipping and the cryo-maze procedure 4 years previously. He was taking a direct oral anticoagulant for stroke prevention because his atrial fibrillation had recurred. He presented with acute onset disturbed consciousness, omnidirectional gaze palsy, left facial palsy, severe dysarthria, bilateral limb ataxia, and sensory disturbance. National Institutes of Health Stroke Scale score was 16. Although non-contrast computed tomography showed no early ischemic changes, computed tomography angiography revealed occlusion of the basilar artery. Intravenous thrombolysis was performed, which resulted in recanalization. Transesophageal echocardiography showed left atrial spontaneous echo contrast and thrombus in the left atrial appendage. Contrast-enhanced chest computed tomography confirmed incomplete left atrial appendage occlusion. Cardioembolic stroke was diagnosed, and warfarin was initiated. Cardioembolism may occur after thoracoscopic left atrial appendage clipping despite direct oral anticoagulant therapy, particularly if appendage occlusion is incomplete. Occlusion status should be evaluated after thoracoscopic clipping. Learning objective: To illustrate, incomplete left atrial appendage closure may increase the risk of ischemic stroke even after thoracoscopic left atrial appendage clipping is performed to prevent embolism.

Stent Retriever Angioplasty for Intracranial Atherosclerotic Disease-Related Medium Vessel Occlusion: A Case Report and Literature Review.

Objective: Stent retriever (SR) angioplasty is an adjunctive technique for acute large vessel occlusion stroke due to underlying intracranial atherosclerotic disease (ICAD-LVO). Prolonged SR deployment maintains blood flow distal to the atherosclerotic lesion until the antiplatelet agent has exerted its effect. Although SR angioplasty for ICAD-LVO has been reported, few reports are available on SR angioplasty for medium vessel occlusion stroke due to underlying ICAD (ICAD-MeVO). Here, we describe a case of SR angioplasty for acute occlusion of the left M2 segment of the middle cerebral artery (MCA) due to underlying ICAD. Case Presentation: A 79-year-old man with a history of left MCA M2 segment stenosis presented with motor aphasia and dysarthria. Diffusion-weighted MRI showed no high-signal intensity areas, and MRA showed occlusion of the left MCA M2 segment. The patient was diagnosed with ICAD-MeVO. After performing an MRI, the patient's symptoms progressed to total aphasia. SR angioplasty was performed for the occlusion of the left M2 segment of the MCA. Diffusion-weighted MRI the day after the procedure showed a small area of high-signal intensity exclusively in the left putamen, while MRA confirmed recanalization of the left MCA M2 segment. Aphasia improved after the procedure. No re-occlusion was observed for 90 days, and the modified Rankin Scale score at 90 days was 2. Conclusion: SR angioplasty appears to be a safe option for managing MCA M2 segment occlusion.

Blended Phenotype of NOTCH3 and RNF213 Variants With Accelerated Large and Small Artery Crosstalk: A Case Report and Literature Review.

Objectives: Recent advancements in genome research have revealed not only the importance of variants associated with cerebrovascular diseases but also a notably high frequency of carriers harboring multiple variants, presenting with an elusive blended phenotype. In this study, we report the case of a 66-year-old man who experienced 3 stroke episodes over a 4-year period, starting at the age of 62 years. The patient presented with isolated infarcts in the left temporal pole with progressive stenosis in the ipsilateral middle cerebral artery based on large and small artery crosstalk. Methods: Exons 2-24 of the NOTCH3 gene were analyzed by direct genomic DNA sequencing. The presence of the p.Arg4810Lys variant of the ring finger protein 213 (RNF213) gene was evaluated using real-time PCR. Results: Diagnoses of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and RNF213-related vasculopathy were made based on the early-onset recurrent stroke episode, progressive intracranial artery stenosis, and presence of the heterozygous NOTCH3 p.Cys1250Arg and RNF213 p.Arg4810Lys variants. Discussion: Temporal pole infarcts could represent a blended phenotype of both variants. This case highlights the importance of large and small artery crosstalk and the pivotal role of genetic analysis in determining the pathogenesis of stroke and dementia.

Efficacy of initial conservative treatment options for temporomandibular disorders: A network meta-analysis of randomized clinical trials.

PURPOSE: This network meta-analysis (NMA) of randomized controlled trials (RCTs) aimed to identify effective initial conservative treatment strategies for patients with temporomandibular joint disorders (TMD). STUDY SELECTION: RCTs comparing treatment options for TMD published between January 2000 and July 2021 were retrieved from the databases of PubMed and Embase via a comprehensive electronic search. Patients diagnosed with myalgia (muscle pain) or arthralgia (joint pain) according to pain-related Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were eligible for inclusion. Twelve treatment options and a placebo were included in the mutual comparisons. The risk of bias was assessed using Risk of Bias 2.0. Forest plots of direct comparisons between individual studies were created using MetaInsight. NMA was performed using R statistical software (netmeta). RESULTS: Twenty-four RCTs involving 1336 patients assessing pain and 12 RCTs involving 614 patients assessing maximal mouth opening were identified. Low-level laser therapy (standard mean difference [SMD]: -2.12, 95% confidence interval [CI]: -3.18, -1.06), self-exercise (SMD: -1.51, 95% CI: -2.82, -0.2), and stabilization splints (SMD: -1.16, 95% CI: -2.02, -0.29) were effective in improving pain; however, the certainty of evidence was very low. Self-exercise (SMD: 0.71, 95% CI: -0.58, 2.01), stabilization splints (SMD: 0.65, 95% CI: -0.09, 1.39), and low-level laser therapy (SMD: 0.63, 95% CI: -0.34, 1.6) were effective in improving maximal mouth opening; however, the certainty of evidence was very low. CONCLUSIONS: Stabilization splints, self-exercise, and low-level laser therapy may be effective in the initial treatment of TMD.

High pillow and spontaneous vertebral artery dissection: A case-control study implicating "Shogun pillow syndrome".

INTRODUCTION: The underlying causes of spontaneous vertebral artery dissection (sVAD) remain insufficiently understood. This study aimed to determine whether high-pillow usage is associated with an increased risk of sVAD and evaluate the frequency of sVAD attributable to high-pillow usage. PATIENTS AND METHODS: This case-control study identified patients with sVAD and age- and sex-matched non-sVAD controls (case-to-control ratio: 1:1) treated at a certified comprehensive stroke center in Japan between 2018 and 2023. The pillow height used at the onset of the index disease was measured and classified into three categories between 12 and 15 cm boundaries. Univariable logistic regression was performed to assess the odds ratio (OR) with a 95% confidence interval (CI) of high-pillow usage for sVAD development. A subgroup of sVAD attributable to high-pillow usage was defined with the following three conditions: high-pillow usage (⩾12 or ⩾15 cm); no minor preceding trauma; and wake-up onset. RESULTS: Fifty-three patients with sVAD and 53 non-sVAD controls (42% women, median age: 49 years) were identified. High-pillow usage (⩾12 and ⩾15 cm) was more common in the sVAD group than in the non-sVAD group (34 vs 15%; OR = 2.89; 95%CI = 1.13-7.43 and 17 vs 1.9%; OR = 10.6; 95%CI = 1.30-87.3, respectively). The subgroup of sVAD attributed to high-pillow usage (⩾12 and ⩾15 cm) was found in 11.3% (95%CI = 2.7%-19.8%) and 9.4% (95%CI = 1.5%-17.3%), respectively. CONCLUSION: High-pillow usage was associated with an increased risk of sVAD and accounted for approximately 10% of all sVAD cases. This tentative subgroup of sVAD may represent a distinct spectrum of disease-Shogun pillow syndrome.

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Tmax Mismatch Ratio to Identify Intracranial Atherosclerotic Stenosis-Related Large-Vessel Occlusion Before Endovascular Therapy.

Background We aimed to clarify which time-to-maximum of the tissue residue function (Tmax) mismatch ratio is useful in predicting anterior intracranial atherosclerotic stenosis (ICAS)-related large-vessel occlusion (LVO) before endovascular therapy. Methods and Results Patients with ischemic stroke who underwent perfusion-weighted imaging before endovascular therapy for anterior intracranial LVO were divided into those with ICAS-related LVO and those with embolic LVO. Tmax ratios of >10 s/>8 s, >10 s/>6 s, >10 s/>4 s, >8 s/>6 s, >8 s/>4 s, and >6 s/>4 s were considered Tmax mismatch ratios. Binominal logistic regression was used to identify ICAS-related LVO, and the adjusted odds ratio (aOR) and 95% CI for each Tmax mismatch ratio increase of 0.1 were calculated. A similar analysis was performed for ICAS-related LVO with and without embolic sources, using embolic LVO as the reference. Of 213 patients (90 women [42.0%]; median age, 79 years), 39 (18.3%) had ICAS-related LVO. The aOR (95% CI) per 0.1 increase in Tmax mismatch ratio in ICAS-related LVO with embolic LVO as reference was lowest with Tmax mismatch ratio >10 s/>6 s (0.56 [0.43-0.73]). Multinomial logistic regression analysis also showed the lowest aOR (95% CI) per 0.1 increase in Tmax mismatch ratio with Tmax >10 s/>6 s (ICAS-related LVO without embolic source: 0.60 [0.42-0.85]; ICAS-related LVO with embolic source: 0.55 [0.38-0.79]). Conclusions A Tmax mismatch ratio of >10 s/>6 s was the optimal predictor of ICAS-related LVO compared with other Tmax profiles, with or without an embolic source before endovascular therapy. Registration clinicaltrials.gov. Identifier NCT02251665.

Plasma mid-regional pro-adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke.

Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (rs  = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.

Detrimental effect of anemia after mechanical thrombectomy on functional outcome in patients with ischemic stroke.

Background: Anemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown. Methods: In a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11-13 g/dL and 10-12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations <11 g/dL and < 10 g/dL, respectively). A 3-month modified Rankin Scale score of 0-2 indicated a favorable outcome. Results: Of 470 patients, 166 were classified into the no anemia group, 168 into the mild anemia group, and 136 into the moderate-to-severe anemia group. Patients in the moderate-to-severe anemia group were older and more commonly had congestive heart failure than those in the other groups. Patients in the moderate-to-severe anemia group also had more device passes than those in the other groups (p < 0.001). However, no difference was observed in the rate of final extended thrombolysis in cerebral infarction ≥2b reperfusion or intracranial hemorrhage among the groups. A favorable outcome was less frequently achieved in the moderate-to-severe anemia group than in the no anemia group (adjusted odds ratio, 0.46; 95% confidence interval, 0.26-0.81) independent of the baseline Hb concentration. A restricted cubic spline model with three knots showed that the adjusted odds ratio for a favorable outcome was lower in patients with lower Hb concentrations within 24 h after MT. Conclusion: Moderate-to-severe anemia within 24 h after MT is independently associated with a reduced likelihood of a favorable outcome. Clinical trial registration: https://www.clinicaltrials.gov, NCT02251665.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Effects of Jaw-Opening Exercises with/without Pain for Temporomandibular Disorders: A Pilot Randomized Controlled Trial.

This study aimed to evaluate the effects of jaw-opening exercises with and without pain on temporomandibular disorders (TMDs), specifically in relation to pain intensity and range-of-mouth opening in patients with TMDs. Participants were randomly assigned to either the jaw-opening exercise with pain (JE w/pain) or the jaw-opening exercise without pain (JE w/o pain) groups, and each exercise was performed for eight weeks. TMDs pain intensity was assessed using a 100-mm visual analog scale (VAS), and the range-of-mouth opening was evaluated at the baseline (T0), 2 weeks (T1), 4 weeks (T2), and 8 weeks (T3). Of the 61 participants, 57 (JE w/pain group, n = 30; JE w/o pain group, n = 27) were included in the analysis. The range-of-mouth opening and TMDs pain intensity improved from T1 to T3 in both groups. The JE w/pain group showed significant differences at T3 compared to T1 (pain-free unassisted mouth opening, p = 0.006; jaw-opening pain, p = 0.014; chewing pain, p = 0.018). In addition, the JE w/pain group showed significantly greater changes in the maximum unassisted mouth opening at T2 and T3 than the JE w/o pain group (T2, p < 0.001; T3, p = 0.003). Thus, jaw-opening exercises, until the occurrence of pain, may be effective in patients with TMDs.