Identification of the Somatomotor Network from Language Task-based fMRI Compared with Resting-State fMRI in Patients with Brain Lesions.

Background Resting-state functional MRI (rs-fMRI) is a potential alternative to task-based functional MRI (tb-fMRI) for somatomotor network (SMN) identification. Brain networks can also be generated from tb-fMRI by using independent component analysis (ICA). Purpose To investigate whether the SMN can be identified by using ICA from a language task without a motor component, the sentence completion functional MRI (sc-fMRI) task, compared with rs-fMRI. Materials and Methods The sc-fMRI and rs-fMRI scans in patients who underwent presurgical brain mapping between 2012 and 2016 were analyzed, using the same imaging parameters (other than scanning time) on a 3.0-T MRI scanner. ICA was performed on rs-fMRI and sc-fMRI scans with use of a tool to separate data sets into their spatial and temporal components. Two neuroradiologists independently determined the presence of the dorsal SMN (dSMN) and ventral SMN (vSMN) on each study. Groups were compared by using t tests, and logistic regression was performed to identify predictors of the presence of SMNs. Results One hundred patients (mean age, 40.9 years ± 14.8 [standard deviation]; 61 men) were evaluated. The dSMN and vSMN were identified in 86% (86 of 100) and 76% (76 of 100) of rs-fMRI scans and 85% (85 of 100) and 69% (69 of 100) of sc-fMRI scans, respectively. The concordance between rs-fMRI and sc-fMRI for presence of dSMN and vSMN was 75% (75 of 100 patients) and 53% (53 of 100 patients), respectively. In 10 of 14 patients (71%) where rs-fMRI did not show the dSMN, sc-fMRI demonstrated it. This rate was 67% for the vSMN (16 of 24 patients). Conclusion In the majority of patients, independent component analysis of sentence completion task functional MRI scans reliably demonstrated the somatomotor network compared with resting-state functional MRI scans. Identifying target networks with a single sentence completion scan could reduce overall functional MRI scanning times by eliminating the need for separate motor tasks. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Field and Birn in this issue.

Using transcranial magnetic stimulation of the undamaged brain to identify lesion sites that predict language outcome after stroke.

Transcranial magnetic stimulation focused on either the left anterior supramarginal gyrus or opercular part of the left inferior frontal gyrus has been reported to transiently impair the ability to perform phonological more than semantic tasks. Here we tested whether phonological processing abilities were also impaired following lesions to these regions in right-handed, English speaking adults, who were investigated at least 1 year after a left-hemisphere stroke. When our regions of interest were limited to 0.5 cm3 of grey matter centred around sites that had been identified with transcranial magnetic stimulation-based functional localization, phonological impairments were observed in 74% (40/54) of patients with damage to the regions and 21% (21/100) of patients sparing these regions. This classification accuracy was better than that observed when using regions of interest centred on activation sites in previous functional magnetic resonance imaging studies of phonological processing, or transcranial magnetic stimulation sites that did not use functional localization. New regions of interest were generated by redefining the borders of each of the transcranial magnetic stimulation sites to include areas that were consistently damaged in the patients with phonological impairments. This increased the incidence of phonological impairments in the presence of damage to 85% (46/54) and also reduced the incidence of phonological impairments in the absence of damage to 15% (15/100). The difference in phonological processing abilities between those with and without damage to these 'transcranial magnetic stimulation-guided' regions remained highly significant even after controlling for the effect of lesion size. The classification accuracy of the transcranial magnetic stimulation-guided regions was validated in a second sample of 108 patients and found to be better than that for (i) functional magnetic resonance imaging-guided regions; (ii) a region identified from an unguided lesion overlap map; and (iii) a region identified from voxel-based lesion-symptom mapping. Finally, consistent with prior findings from functional imaging and transcranial magnetic stimulation in healthy participants, we show how damage to our transcranial magnetic stimulation-guided regions affected performance on phonologically more than semantically demanding tasks. The observation that phonological processing abilities were impaired years after the stroke, suggests that other brain regions were not able to fully compensate for the contribution that the transcranial magnetic stimulation-guided regions make to language tasks. More generally, our novel transcranial magnetic stimulation-guided lesion-deficit mapping approach shows how non-invasive stimulation of the healthy brain can be used to guide the identification of regions where brain damage is likely to cause persistent behavioural effects.

Slowly eroding lesions in multiple sclerosis.

BACKGROUND: At autopsy, 20%-40% of chronic multiple sclerosis (MS) lesions are labeled "slowly expanding" and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured. OBJECTIVE: To study long-term volume changes in individual MS lesions. METHODS: Volumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes. RESULTS: The mean (standard deviation) lesion volume at baseline was 142 (82) mL, falling to 74 (51) mL after 16 (3) years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume ( p = 0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue. CONCLUSION: We noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as "slowly expanding," is likely to be tissue loss.

A longitudinal study of cortical grey matter lesion subtypes in relapse-onset multiple sclerosis.

BACKGROUND: Cortical grey matter (GM) lesions are common in multiple sclerosis (MS), but little is known about their temporal evolution. We investigated this in people with relapsing-remitting (RR) and secondary progressive (SP) MS. METHODS: 27 people with RRMS, and 22 with SPMS were included in this study. Phase-sensitive inversion recovery scans were acquired on 2 occasions. Cortical GM lesions were classified as intracortical (IC, only involving GM) and leucocortical (LC, mixed GM-white matter (WM)); WM lesions touching the cortex as juxtacortical (JC). On follow-up scans, new IC, LC and JC lesions were identified, and any change in classification of lesions previously observed was noted. WM lesion counts in the whole brain were assessed on PD/T2-weighted scans. RESULTS: Over a mean (SD) of 21.0 (5.8) months, the number of new IC lesions per person per year was greater in SPMS (1.6 (1.9)) than RRMS (0.8 (1.9)) (Mann-Whitney p=0.039). All new LC lesions arose from previously seen IC lesions (SPMS 1.4 (1.8) per person per year, and RRMS 1.1 (1.0)), and none arose de novo, or from previously seen JC lesions. Changes in cortical GM (either new IC or IC converting to LC) lesion counts did not correlate with the changes in WM lesion counts. CONCLUSIONS: New cortical GM lesions rarely arise from the WM and the rate of new IC lesion formation is not closely linked with WM lesion accrual. IC lesion formation appears to be more common in SPMS than RRMS.

DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime?

BACKGROUND: The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) are increasingly recognised. GM pathology may present as focal lesions, which can be visualised using double inversion recovery (DIR) MRI, or as diffuse pathology, which can manifest as atrophy. It is, however, unclear whether the diffuse atrophy centres on focal lesions. This study aimed to determine if GM lesions and GM atrophy colocalise, and to assess their independent relationship with motor and cognitive deficits in MS. METHODS: Eighty people with MS and 30 healthy controls underwent brain volumetric T1-weighted and DIR MRI at 3 T, and had a comprehensive neurological and cognitive assessment. Probability mapping of GM lesions marked on the DIR scans and voxel- based morphometry (assessing GM atrophy) were carried out. The associations of GM lesion load and GM volume with clinical scores were tested. RESULTS: DIR-visible GM lesions were most commonly found in the right cerebellum and most apparent in patients with primary progressive MS. Deep GM structures appeared largely free from lesions, but showed considerable atrophy, particularly in the thalamus, caudate, pallidum and putamen, and this was most apparent in secondary progressive patients with MS. Very little co-localisation of GM atrophy and lesions was seen, and this was generally confined to the cerebellum and postcentral gyrus. In both regions, GM lesions and volume independently correlated with physical disability and cognitive performance. CONCLUSIONS: DIR-detectable GM lesions and GM atrophy do not significantly overlap in the brain but, when they do, they independently contribute to clinical disability.

Relationship of grey and white matter abnormalities with distance from the surface of the brain in multiple sclerosis.

OBJECTIVE: To assess the association between proximity to the inner (ventricular and aqueductal) and outer (pial) surfaces of the brain and the distribution of normal appearing white matter (NAWM) and grey matter (GM) abnormalities, and white matter (WM) lesions, in multiple sclerosis (MS). METHODS: 67 people with relapse-onset MS and 30 healthy controls were included in the study. Volumetric T1 images and high-resolution (1 mm3) magnetisation transfer ratio (MTR) images were acquired and segmented into 12 bands between the inner and outer surfaces of the brain. The first and last bands were discarded to limit partial volume effects with cerebrospinal fluid. MTR values were computed for all bands in supratentorial NAWM, cerebellar NAWM and brainstem NA tissue, and deep and cortical GM. Band WM lesion volumes were also measured. RESULTS: Proximity to the ventricular surfaces was associated with progressively lower MTR values in the MS group but not in controls in supratentorial and cerebellar NAWM, brainstem NA and in deep and cortical GM. The density of WM lesions was associated with proximity to the ventricles only in the supratentorial compartment, and no link was found with distance from the pial surfaces. CONCLUSIONS: In MS, MTR abnormalities in NAWM and GM are related to distance from the inner and outer surfaces of the brain, and this suggests that there is a common factor underlying their spatial distribution. A similar pattern was not found for WM lesions, raising the possibility that different factors promote their formation.

White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis.

BACKGROUND: While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. OBJECTIVE: The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. METHODS: Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). RESULTS: A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance (R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. CONCLUSION: Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients.

Characteristics of lesional and extra-lesional cortical grey matter in relapsing-remitting and secondary progressive multiple sclerosis: A magnetisation transfer and diffusion tensor imaging study.

BACKGROUND: In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed. OBJECTIVE: To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS. METHODS: Seventy-two people with MS (46 relapsing-remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter. RESULTS: Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability. CONCLUSION: Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability.

Magnetization transfer ratio measures in normal-appearing white matter show periventricular gradient abnormalities in multiple sclerosis.

In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken. The present study investigates this relationship in vivo using quantitative magnetic resonance imaging and compares the abnormalities between secondary progressive and relapsing remitting multiple sclerosis. Forty-three patients with relapsing remitting and 28 with secondary progressive multiple sclerosis, and 38 healthy control subjects were included in this study. T1-weighted volumetric, magnetization transfer and proton density/T2-weighted scans were acquired for all subjects. From the magnetization transfer data, magnetization transfer ratio maps were prepared. White matter tissue masks were derived from SPM8 segmentations of the T1-weighted images. Normal-appearing white matter masks were generated by subtracting white matter lesions identified on the proton density/T2 scan, and a two-voxel perilesional ring, from the SPM8 derived white matter masks. White matter was divided in concentric bands, each ∼1-mm thick, radiating from the ventricles toward the cortex. The first periventricular band was excluded from analysis to mitigate partial volume effects, and normal-appearing white matter and lesion magnetization transfer ratio values were then computed for the 10 bands nearest to the ventricles. Compared with controls, magnetization transfer ratio in the normal-appearing white matter bands was significantly lower in patients with multiple sclerosis. In controls, magnetization transfer ratio was highest in the band adjacent to the ventricles and declined with increasing distance from the ventricles. In the multiple sclerosis groups, relative to controls, reductions in magnetization transfer ratio were greater in the secondary progressive multiple sclerosis compared with relapsing remitting multiple sclerosis group, and these reductions were greatest next to the ventricles and became smaller with distance from them. White matter lesion magnetization transfer ratio reductions were also more apparent adjacent to the ventricle and decreased with distance from the ventricles in both the relapsing remitting and secondary progressive multiple sclerosis groups. These findings suggest that in people with multiple sclerosis, and more so in secondary progressive than relapsing remitting multiple sclerosis, tissue structural abnormalities in normal-appearing white matter and white matter lesions are greatest near the ventricles. This would be consistent with a cerebrospinal fluid or ependymal mediated pathogenesis.

The grey matter correlates of impaired decision-making in multiple sclerosis.

OBJECTIVE: People with multiple sclerosis (MS) have difficulties with decision-making but it is unclear if this is due to changes in impulsivity, risk taking, deliberation or risk adjustment, and how this relates to brain pathology. METHODS: We assessed these aspects of decision-making in 105 people with MS and 43 healthy controls. We used a novel diffusion MRI method, diffusion orientational complexity (DOC), as an index of grey matter pathology in regions associated with decision-making and also measured grey matter tissue volumes and white matter lesion volumes. RESULTS: People with MS showed less adjustment to risk and slower decision-making than controls. Moreover, impaired decision-making correlated with reduced executive function, memory and processing speed. Decision-making impairments were most prevalent in people with secondary progressive MS. They were seen in patients with cognitive impairment and those without cognitive impairment. On diffusion MRI, people with MS showed DOC changes in all regions except the occipital cortex, relative to controls. Risk adjustment correlated with DOC in the hippocampi and deliberation time with DOC in the medial prefrontal, middle frontal gyrus, anterior cingulate and caudate parcellations and with white matter lesion volumes. CONCLUSIONS: These data clarify the features of decision-making deficits in MS, and provide the first evidence that they relate to grey and white matter abnormalities seen using MRI.

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: a voxel-based analysis study.

BACKGROUND: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). METHODS: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. RESULTS: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. CONCLUSIONS: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently.

Investigation of outer cortical magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups.

BACKGROUND: Pathological abnormalities including demyelination and neuronal loss are reported in the outer cortex in multiple sclerosis (MS). OBJECTIVE: We investigated for in vivo evidence of outer cortical abnormalities by measuring the magnetisation transfer ratio (MTR) in MS patients of different subgroups. METHODS: Forty-four relapsing-remitting (RR) (mean age 41.9 years, median Expanded Disability Status Scale (EDSS) 2.0), 25 secondary progressive (SP) (54.1 years, EDSS 6.5) and 19 primary progressive (PP) (53.1 years, EDSS 6.0) MS patients and 35 healthy control subjects (mean age 39.2 years) were studied. Three-dimensional (3D) 1×1×1mm(3) T1-weighted images and MTR data were acquired. The cortex was segmented, then subdivided into outer and inner bands, and MTR values were calculated for each band. RESULTS: In a pairwise analysis, mean outer cortical MTR was lower than mean inner cortical MTR in all MS groups and controls (p<0.001). Compared with controls, outer cortical MTR was decreased in SPMS (p<0.001) and RRMS (p<0.01), but not PPMS. Outer cortical MTR was lower in SPMS than PPMS (p<0.01) and RRMS (p<0.01). CONCLUSIONS: Lower outer than inner cortical MTR in healthy controls may reflect differences in myelin content. The lowest outer cortical MTR was seen in SPMS and is consistent with more extensive outer cortical (including subpial) pathology, such as demyelination and neuronal loss, as observed in post-mortem studies of SPMS patients.

Diffusion MRI-based cortical complexity alterations associated with executive function in multiple sclerosis.

PURPOSE: To report a novel magnetic resonance imaging measure (diffusion orientational complexity [DOC]) in a study of people with multiple sclerosis (MS) and healthy controls and to determine patterns of abnormality, correlations with conventional diffusion measures, and associations with cognitive function. MATERIALS AND METHODS: We performed high angular resolution diffusion imaging (HARDI) and measured DOC, mean diffusivity (MD), and fractional anisotropy (FA) in 51 MS patients and 28 healthy controls. All subjects had a 2-mm isotropic HARDI scan on a 3 T scanner using a 32-channel head receiver coil. DOC, MD, and FA were measured in three regions of interest (ROIs) in frontal cortex linked to executive function, two ROIs in occipital cortex thought unlikely to affect cognition, and in the whole cortex. RESULTS: Frontal cortex DOC was significantly decreased in MS patients. DOC correlated mostly with FA but not MD in controls and with MD but not FA in people with MS. In regression models that included all three diffusion-based measures, frontal cortex DOC and frontal cortex FA independently predicted executive function scores. CONCLUSION: DOC is a new useful measure of functionally relevant cortical pathology in MS, providing information that complements conventional diffusion measures.

Novel, biocompatible, and disease modifying VIP nanomedicine for rheumatoid arthritis.

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.

Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI.

OBJECTIVE: Cortical grey matter lesions are common in multiple sclerosis (MS), but usually not seen on MRI. The authors compared the performance of double inversion recovery (DIR, currently considered the best available imaging sequence for detecting cortical lesions) with phase-sensitive inversion recovery (PSIR, a sequence allowing much higher resolution scans to be obtained in a clinically feasible time). METHODS: Sixty MS patients and 30 healthy controls underwent MRI scanning on a 3 Tesla scanner. The authors compared intracortical (IC) and leucocortical (LC) lesion counts obtained with a standard DIR sequence (1×1×3 mm resolution, obtained in 4 min) and a PSIR sequence (0.5×0.5×2 mm, 11 min). Lesions were marked separately on DIR and PSIR scans. RESULTS: In the whole MS cohort, more cortical lesions were seen on the higher-resolution PSIR than the DIR scans (IC mean±SD: 18.1±9.8 vs 5.9±4.5, p<0.001; LC mean±SD: 13.4±12.9 vs 7.3±8.0, p<0.001). On PSIR, ≥1 IC lesion was seen in 60/60 MS patients and 1/30 controls, and ≥1 LC lesion in 60/60 patients and 6/30 controls. On DIR, ≥1 IC lesion was seen in 50/60 patients and 0/30 controls, and ≥1 LC lesion(s) in 60/60 patients and 5/30 controls. CONCLUSIONS: Compared with DIR, using PSIR the authors are able to detect a significantly greater number of cortical grey matter lesions. The presence of at least one IC lesion in every MS patient, but very few healthy controls, suggests that it may be a useful adjunct to conventional MRI when a diagnosis of MS is suspected but not confirmed.

Longer than 2 hours to antibiotics is associated with doubling of mortality in a multinational community-acquired bacterial meningitis cohort.

To optimally define the association between time to effective antibiotic therapy and clinical outcomes in adult community-acquired bacterial meningitis. A systematic review of the literature describing the association between time to antibiotics and death or neurological impairment due to adult community-acquired bacterial meningitis was performed. A retrospective cohort, multivariable and propensity-score based analyses were performed using individual patient clinical data from Australian, Danish and United Kingdom studies. Heterogeneity of published observational study designs precluded meta-analysis of aggregate data (I2 = 90.1%, 95% CI 71.9-98.3%). Individual patient data on 659 subjects were made available for analysis. Multivariable analysis was performed on 180-362 propensity-score matched data. The risk of death (adjusted odds ratio, aOR) associated with treatment after two hours was 2.29 (95% CI 1.28-4.09) and increased substantially thereafter. Similarly, time to antibiotics of greater than three hours was associated with an increase in the occurrence of neurological impairment (aOR 1.79, 95% CI 1.03-3.14). Among patients with community-acquired bacterial meningitis, odds of mortality increase markedly when antibiotics are given later than two hours after presentation to the hospital.

Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo.

Importance: In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target. Objective: To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. Design, Setting, Participants: We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). Main Outcomes and Measures: (1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. Results: Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation. Conclusions and Relevance: Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.

Bupivacaine, but not lidocaine, disrupts cardiolipin-containing small biomimetic unilamellar liposomes.

Inadvertent intravenous administration of bupivacaine, unlike that of lidocaine, is associated with significant cardiotoxicity. However, the mechanism(s) underlying this phenomenon is uncertain. High concentrations of cardiolipin, an anionic phospholipid, are found in the mitochondria membrane of cardiomyocytes. We hypothesized that bupivacaine, but not lidocaine, interacts avidly with cardiolipin in the mitochondria membrane of cardiomyocytes and alters its integrity thereby accounting, in part, for cardiotoxicity. Accordingly, the purpose of this study was to begin to address this issue by determining the effects of bupivacaine and lidocaine on permeability of cardiolipin-containing biomimetic small unilamellar liposomes. We found that bupivacaine, but not lidocaine, elicited a significant, concentration-dependent increase in carboxyfluorescein release from cardiolipin-containing small unilamellar liposomes (size, 165nm) composed of egg yolk phosphatidylcholine and cholesterol (p<0.05). Both drugs had no significant effects on carboxyfluorescein release from liposomes devoid of cardiolipin (p>0.5). Collectively, these data indicate that bupivacaine, but not lidocaine, interacts avidly and selectively with biomimetic small unilamellar liposomes containing cardiolipin and disrupts their integrity. We suggest that these interactions underlie, in part, bupivacaine-induced cardiotoxicity.

7T MRI Visualization of Cortical Lesions in Adolescents and Young Adults with Pediatric-Onset Multiple Sclerosis.

BACKGROUND: Cortical pathology in multiple sclerosis (MS) has been associated with prolonged and progressive disease. 7T magnetic resonance imaging (MRI) provides enhanced visualization of cortical lesions (CLs). Hence, we conducted a pilot study to explore whether CLs occur early in MS, as evidenced by pediatric-onset patients. METHODS: A total of 8 pediatric-onset MS patients were imaged using 7T MRI. CLs were annotated on T1-weighted magnetization-prepared rapid acquisition of gradient echoes images as leukocortical (LC), intracortical, or subpial. Total CLs, age at onset, age at scan, disease duration, total relapses, and Expanded Disability Status Scale (EDSS) score were recorded. RESULTS: A median of 120 (range: 48-144) CLs was identified in 8 MS patients (3 female, all with relapsing remitting MS, mean age at scan 21 years ± 3.5 SD, mean age of disease onset 15 years ± 2.3 SD, mean disease duration 5.3 years ± 3.4 SD, median EDSS 2.0). Nearly all the lesions identified were LC. CONCLUSIONS: Many CLs are detectable using 7T MRI in patients with pediatric-onset MS despite relatively brief disease duration, absence of progressive disease, and very limited physical disability-supporting early cortical involvement in MS.

Hydrocele in the Canal of Nuck - CT appearance of a developmental groin anomaly.

Hydrocele in the Canal of Nuck is a condition of female fetal development. The Canal of Nuck is a patent tubular peritoneal fold that travels with the round ligament to its attachment on the labia major. Failure of complete obliteration of the Canal of Nuck during fetal development predisposes females to development of a hydrocele or an inguinal hernia during post-pubertal or adult stages. We present a case of a 21 year old female with a tender reducible labial mass diagnosed as a Hydrocele in the Canal of Nuck.