Widespread inflammation in CLIPPERS syndrome indicated by autopsy and ultra-high-field 7T MRI

OBJECTIVE: To examine if there is widespread inflammation in the brain of patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome by using histology and ultra-high-field MRI at 7.0T. METHODS: We performed a detailed neuropathologic examination in 4 cases, including 1 autopsy case, and studied 2 additional patients by MRI at 7.0T to examine (1) extension of inflammation to areas appearing normal on 3.0T MRI, (2) potential advantages of 7.0T MRI compared to 3.0T MRI in reflecting widespread inflammation, perivascular pathology, and axonal damage, and (3) the possibility of lymphoma. RESULTS: In the autopsy case, perivascular inflammation dominated by CD4+ T cells was not only detected in the brainstem and cerebellum but also in brain areas with normal appearance on 3.0T MRI, including supratentorial regions and cranial nerve roots. There was no evidence of lymphoma in any of the 4 patients. The 7.0T MRI in clinical remission also revealed supratentorial lesions and perivascular pathology in vivo with contrast-enhancing lesions centered around a small venous vessel. Ultra-high-field MRI at 7.0T disclosed prominent T1 hypointensities in the brainstem, which were not seen on 3.0T MRI. This corresponded to neuropathologic detection of axonal injury in the autopsy case. CONCLUSION: Our findings suggest more widespread perivascular inflammation and postinflammatory axonal injury in patients with CLIPPERS

7 Tesla MRI of Balo's concentric sclerosis versus multiple sclerosis lesions

Background: Baló’s concentric sclerosis (BCS) is a rare condition characterized by concentrically layered white matter lesions. While its pathogenesis is unknown, hypoxia-induced tissue injury and chemotactic stimuli have been proposed as potential causes of BCS lesion formation. BCS has been suggested to be a variant of multiple sclerosis (MS). Here, we aimed to elucidate similarities and differences between BCS and MS by describing lesion morphology and localization in high-resolution 7 Tesla (7 T) magnetic resonance imaging (MRI) scans. Methods: Ten patients with Baló-type lesions underwent 7 T MRI, and 10 relapsing remitting MS patients served as controls. The 7 T MR imaging protocol included 3D T1-weighted (T1w) magnetization-prepared rapid gradient echo, 2D high spatial resolution T2*-weighted (T2*w) fast low-angle shot and susceptibility-weighted imaging. Results: Intralesional veins were visible in the center of all but one Baló-type lesion. Four Baló-type lesions displayed inhomogeneous intralesional T2*w signal intensities, which are suggestive of microhemorrhages or small ectatic venules. Eight of 10 BCS patients presented with 97 additional lesions, 36 of which (37%) had a central vein. Lesions involving the cortical gray matter and the U-fibers were not detected in BCS patients. Conclusion: Our findings support the hypothesis that BCS and MS share common pathogenetic mechanisms but patients present with different lesion phenotypes

Paramagnetic rims are a promising diagnostic imaging biomarker in multiple sclerosis

MRI; Multiple sclerosis; BiomarkersRessonància magnètica; Esclerosi múltiple; BiomarcadorsResonancia magnética; Esclerosis múltiple; BiomarcadoresBackground: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). Objective: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. Method: This retrospective international study reviewed MRI scans of patients with MS (n = 254), MS mimics (n = 91) and older healthy controls (n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. Results: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%–99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%–36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion (n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%–100.0%) but equally low sensitivity (21.3%, CI = 16.4%–26.81%) Conclusion: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS

Evaluation of the ‘ring sign’ and the ‘core sign’ as a magnetic resonance imaging marker of disease activity and progression in clinically isolated syndrome and early multiple sclerosis

Background: Brain lesions with a hypointense ring or core were described in multiple sclerosis on susceptibility weighted imaging. Objective: The purpose of this study was to study the evolution and prognostic relevance of susceptibility weighted imaging hypointense lesions in clinically isolated syndrome and early multiple sclerosis. Methods: Sixty-six early multiple sclerosis and clinically isolated syndrome patients were followed over a median period of 2.9 years (range 1.6-4.6 years) and underwent 3T magnetic resonance imaging including 3D susceptibility weighted imaging and T2-weighted fluid-attenuated inversion recovery. We assessed the presence of susceptibility weighted imaging hypointense core or ring lesions, and Expanded Disability Status Scale at baseline and follow-up. Results: Of 611 lesions at baseline, 64 (10.5%) had a susceptibility weighted imaging hypointense core, and 28 (4.6%) had a susceptibility weighted imaging hypointense ring. Hypointense ring lesions were larger (p < 0.001) and more T1w hypointense (p = 0.002) than others. During follow-up, hypointense core lesions became susceptibility weighted imaging isointense (52 lesions, 81%); few developed into hypointense ring lesions (two lesions, 3%). Hypointense ring lesions did not shrink on T2-weighted fluid-attenuated inversion recovery images (p = 0.077, trend towards more enlargement compared to others), while hypointense core lesions more often shrunk in comparison to lesions without a hypointense core (p = 0.002). The number of susceptibility weighted imaging hypointense ring lesions at baseline correlated with Expanded Disability Status Scale progression at follow-up (p = 0.021, R = 0.289). Conclusion: In our cohort of patients with clinically isolated syndrome or early multiple sclerosis, susceptibility weighted imaging hypointense ring lesions were only rarely detectable, but did not shrink and were associated with future disability progression

Progressive Multifocal Leukoencephalopathy in a Multiple Sclerosis Patient Diagnosed after Switching from Natalizumab to Fingolimod

Background. Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion. We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed

Sex differences of vascular brain lesions in patients with atrial fibrillation.

OBJECTIVE To examine sex differences in prevalence, volume and distribution of vascular brain lesions on MRI among patients with atrial fibrillation (AF). METHODS In this cross-sectional analysis, we included 1743 patients with AF (27% women) from the multicentre Swiss Atrial Fibrillation study (SWISS-AF) with available baseline brain MRI. We compared presence and total volume of large non-cortical or cortical infarcts (LNCCIs), small non-cortical infarcts, microbleeds (MB) and white matter hyperintensities (WMH, Fazekas score ≥2 for moderate or severe degree) between men and women with multivariable logistic regression. We generated voxel-based probability maps to assess the anatomical distribution of lesions. RESULTS We found no strong evidence for an association of female sex with the prevalence of all ischaemic infarcts (LNCCI and SNCI combined; adjusted OR 0.86, 95% CI 0.67 to 1.09, p=0.22), MB (adjusted OR 0.91, 95% CI 0.68 to 1.21, p=0.52) and moderate or severe WMH (adjusted OR 1.15, 95% CI 0.90 to 1.48, p=0.27). However, total WMH volume was 17% larger among women than men (multivariable adjusted multiplicative effect 1.17, 95% CI 1.01 to 1.35; p=0.04). Lesion probability maps showed a right hemispheric preponderance of ischaemic infarcts in both men and women, while WMH were distributed symmetrically. CONCLUSION Women had higher white matter disease burden than men, while volume and prevalence of other lesions did not differ. Our findings highlight the importance of controlling risk factors for cerebral small vessel disease in patients with AF, especially among women

Extended Technical and Clinical Validation of Deep Learning-Based Brainstem Segmentation for Application in Neurodegenerative Diseases.

Disorders of the central nervous system, including neurodegenerative diseases, frequently affect the brainstem and can present with focal atrophy. This study aimed to (1) optimize deep learning-based brainstem segmentation for a wide range of pathologies and T1-weighted image acquisition parameters, (2) conduct a systematic technical and clinical validation, (3) improve segmentation quality in the presence of brainstem lesions, and (4) make an optimized brainstem segmentation tool available for public use. An intentionally heterogeneous ground truth dataset (n = 257) was employed in the training of deep learning models based on multi-dimensional gated recurrent units (MD-GRU) or the nnU-Net method. Segmentation performance was evaluated against ground truth labels. FreeSurfer was used for benchmarking in subsequent validation. Technical validation, including scan-rescan repeatability (n = 46) and inter-scanner reproducibility (n = 20, 3 different scanners) in unseen data, was conducted in patients with cerebral small vessel disease. Clinical validation in unseen data was performed in 1-year follow-up data of 16 patients with multiple system atrophy, evaluating the annual percentage volume change. Two lesion filling algorithms were investigated to improve segmentation performance in 23 patients with multiple sclerosis. The MD-GRU and nnU-Net models demonstrated very good segmentation performance (median Dice coefficients ≥ 0.95 each) and outperformed a previously published model trained on a narrower dataset. Scan-rescan repeatability and inter-scanner reproducibility yielded similar Bland-Altman derived limits of agreement for longitudinal FreeSurfer (total brainstem volume repeatability/reproducibility 0.68/1.85), MD-GRU (0.72/1.46), and nnU-Net (0.48/1.52). All methods showed comparable performance in the detection of atrophy in the total brainstem (atrophy detected in 100% of patients) and its substructures. In patients with multiple sclerosis, lesion filling further improved the accuracy of brainstem segmentation. We enhanced and systematically validated two fully automated deep learning brainstem segmentation methods and released them publicly. This enables a broader evaluation of brainstem volume as a candidate biomarker for neurodegeneration

Physical activity and brain health in patients with atrial fibrillation

Background and purpose: Vascular brain lesions, such as ischemic infarcts, are common among patients with atrial fibrillation (AF) and are associated with impaired cognitive function. The role of physical activity (PA) in the prevalence of brain lesions and cognition in AF has not been investigated. Methods: Patients from the multicenter Swiss‐AF cohort study were included in this cross‐sectional analysis. We assessed regular exercise (RE; at least once weekly) and minutes of weekly PA using a validated questionnaire. We studied associations with ischemic infarcts, white matter hyperintensities, cerebral microbleeds, and brain volume on brain magnetic resonance imaging and with global cognition measured with a cognitive construct (CoCo) score.ResultsAmong 1490 participants (mean age = 72 ± 9 years), 730 (49%) engaged in RE. In adjusted regression analyses, RE was associated with a lower prevalence of ischemic infarcts (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.63–0.98, p = 0.03) and of moderate to severe white matter hyperintensities (OR = 0.78, 95% CI = 0.62–0.99, p = 0.04), higher brain volume (β‐coefficient = 10.73, 95% CI = 2.37–19.09, p = 0.01), and higher CoCo score (β‐coefficient = 0.08, 95% CI = 0.03–0.12, p < 0.001). Increasing weekly PA was associated with higher brain volume (β‐coefficient = 1.40, 95% CI = 0.65–2.15, p < 0.001). Conclusions: In AF patients, RE was associated with a lower prevalence of ischemic infarcts and of moderate to severe white matter disease, with larger brain volume, and with better cognitive performance. Prospective studies are needed to investigate whether these associations are causal. Until then, our findings suggest that patients with AF should be encouraged to remain physically active

Biomarker, Imaging, and Clinical Factors Associated With Overt and Covert Stroke in Patients With Atrial Fibrillation.

BACKGROUND Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA2DS2-VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up. METHODS Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA2DS2-VASc score. RESULTS We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA2DS2-VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70]). CONCLUSIONS In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures

Association of Heart Rate Variability With Silent Brain Infarcts in Patients With Atrial Fibrillation

Purpose: Silent brain infarcts (SBI) are frequently detected in patients with atrial fibrillation (AF), but it is unknown whether SBI are linked to autonomic dysfunction. We aimed to explore the association of autonomic dysfunction with SBI in AF patients. Methods: 1,358 AF patients without prior stroke or TIA underwent brain MRI and 5-min resting ECG. We divided our cohort into AF patients who presented in sinus rhythm (SR-group, n = 816) or AF (AF-group, n = 542). HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, mean heart rate, root mean square root of successive differences of normal-to-normal intervals, 5-min total power and power in the low frequency, high frequency and very low frequency range were calculated. Primary outcome was presence of SBI in the SR group, defined as large non-cortical or cortical infarcts. Secondary outcomes were SBI volumes and topography. Results: Mean age was 72 ± 9 years, 27% were female. SBI were detected in 10.5% of the SR group and in 19.9% of the AF group (p < 0.001). HRVI <15 was the only HRV parameter associated with the presence of SBI after adjustment for clinical covariates in the SR group [odds ratio (OR) 1.67; 95% confidence interval (CI): 1.03–2.70; p = 0.037]. HRVI <15 was associated with larger brain infarct volumes [β (95% CI) −0.47 (−0.84; −0.09), p = 0.016] in the SR group and was more frequently observed in patients with right- than left-hemispheric SBI (p = 0.017). Conclusion: Impaired HRVI is associated with SBI in AF patients. AF patients with autonomic dysfunction might undergo systematic brain MRI screening to initiate intensified medical treatment