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BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220.FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]).INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow.FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

The definitive diagnosis of Cushing’s disease (CD) in the presence of pituitary microadenoma remains a continuous challenge. Novel available pituitary imaging techniques are emerging. This study aimed to provide a structured analysis of the diagnostic accuracy as well as the clinical use of molecular imaging in patients with ACTH-dependent Cushing’s syndrome (CS). We also discuss the role of multidisciplinary counseling in decision making. Additionally, we propose a complementary diagnostic algorithm for both de novo and recurrent or persistent CD. A structured literature search was conducted and two illustrative CD cases discussed at our Pituitary Center are presented. A total of 14 CD (n = 201) and 30 ectopic CS (n = 301) articles were included. MRI was negative or inconclusive in a quarter of CD patients. 11C-Met showed higher pituitary adenoma detection than 18F-FDG PET–CT (87% versus 49%). Up to 100% detection rates were found for 18F-FET, 68Ga-DOTA-TATE, and 68Ga-DOTA-CRH, but were based on single studies. The use of molecular imaging modalities in the detection of pituitary microadenoma in ACTH-dependent CS is of added and complementary value, serving as one of the available tools in the diagnostic work-up. In selected CD cases, it seems justified to even refrain from IPSS.

Background and Purpose: The benefit of endovascular treatment (EVT) for posterior circulation stroke (PCS) remains uncertain, and little is known on treatment outcomes in clinical practice. This study evaluates outcomes of a large PCS cohort treated with EVT in clinical practice. Simultaneous to this observational study, several intervention centers participated in the BASICS trial (Basilar Artery International Cooperation Study), which tested the efficacy of EVT for basilar artery occlusion in a randomized setting. We additionally compared characteristics and outcomes of patients treated outside BASICS in trial centers to those from nontrial centers. Methods: We included patients with PCS from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry: a prospective, multicenter, observational study of patients who underwent EVT in the Netherlands between 2014 and 2018. Primary outcome was a score of 0 to 3 on the modified Rankin Scale at 90 days. Secondary outcomes included reperfusion status and symptomatic intracranial hemorrhage. For outcome comparison between patients treated in trial versus nontrial centers, we used ordinal logistic regression analysis. Results: We included 264 patients of whom 135 (51%) had received intravenous thrombolysis. The basilar artery was most often involved (77%). Favorable outcome (modified Rankin Scale score 0–3) was observed in 115/252 (46%) patients, and 109/252 (43%) patients died. Successful reperfusion was achieved in 178/238 (75%), and symptomatic intracranial hemorrhage occurred in 9/264 (3%). The 154 nontrial patients receiving EVT in BASICS trial centers had similar characteristics and outcomes as the 110 patients treated in nontrial centers (modified Rankin Scale adjusted cOR: 0.77 [95% CI, 0.5–1.2]). Conclusions: Our study shows that high rates of favorable clinical outcome and successful reperfusion can be achieved with EVT for PCS, despite high mortality. Characteristics and outcomes of patients treated in trial versus nontrial centers were similar indicating that our cohort is representative of clinical practice in the Netherlands. Randomized studies using modern treatment approaches are needed for further insight in the benefit of EVT for PCS.

Supplemental Digital Content is available in the text., Background and Purpose: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice. Methods: We used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0–2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic. Results: We included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72–0.77) in HERMES and, after model updating, 0.80 (0.78–0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%–14.4%). Patients with low (

BackgroundIntracranial hemorrhage (ICH) is a frequent complication after endovascular stroke treatment.ObjectiveTo assess the association of the occurrence and type of ICH after endovascular treatment (EVT) with functional outcome.MethodsWe analyzed data from the MR CLEAN-NO IV and MR CLEAN-MED trials. Both trials included adult patients with ischemic stroke with a large vessel occlusion in the anterior circulation, who were eligible for EVT. ICH was classified (1) as asymptomatic or symptomatic (concomitant neurological deterioration of ≥4 points on the NIHSS, or ≥2 points on 1 NIHSS item), and (2) according to the Heidelberg Bleeding Classification. We used multivariable ordinal logistic regression analyses to assess the association of the occurrence and type of ICH with the modified Rankin Scale score at 90 days.ResultsOf 1017 included patients, 331 (33%) had an asymptomatic ICH, and 90 (9%) had a symptomatic ICH. Compared with no ICH, both asymptomatic (adjusted common OR (acOR)=0.76; 95% CI 0.58 to 0.98) and symptomatic (acOR=0.07; 95% CI 0.04 to 0.14) ICH were associated with worse functional outcome. In particular, isolated parenchymal hematoma type 2 (acOR=0.37; 95% CI 0.14 to 0.95), combined parenchymal hematoma with hemorrhage outside infarcted brain tissue (acOR=0.17; 95% CI 0.10 to 0.30), and combined hemorrhages outside infarcted brain tissue (acOR=0.14; 95% CI 0.03 to 0.74) were associated with worse functional outcome than no ICH.Strength of the association of ICH with functional outcome depends on the type of ICH. Although the association is stronger for symptomatic ICH, asymptomatic ICH after EVT is also associated with worse functional outcome.

Background: Symptomatic intracranial hemorrhage (sICH) is a serious complication after endovascular treatment for ischemic stroke. We aimed to identify determinants of its occurrence and location. Methods: We retrospectively analyzed data from the Dutch MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) and MR CLEAN registry. We included adult patients with a large vessel occlusion in the anterior circulation who underwent endovascular treatment within 6.5 hours of stroke onset. We used univariable and multivariable logistic regression analyses to identify determinants of overall sICH occurrence, sICH within infarcted brain tissue, and sICH outside infarcted brain tissue. Results: SICH occurred in 203 (6%) of 3313 included patients and was located within infarcted brain tissue in 50 (25%), outside infarcted brain tissue in 23 (11%), and both within and outside infarcted brain tissue in 116 (57%) patients. In 14 patients (7%), data on location were missing. Prior antiplatelet use, baseline systolic blood pressure, baseline plasma glucose levels, post-endovascular treatment modified treatment in cerebral ischemia score, and duration of procedure were associated with all outcome parameters. In addition, determinants of sICH within infarcted brain tissue included history of myocardial infarction (adjusted odds ratio, 1.65 [95% CI, 1.06–2.56]) and poor collateral score (adjusted odds ratio, 1.42 [95% CI, 1.02–1.95]), whereas determinants of sICH outside infarcted brain tissue included level of occlusion on computed tomography angiography (internal carotid artery or internal carotid artery terminus compared with M1: adjusted odds ratio, 1.79 [95% CI, 1.16–2.78]). Conclusions: Several factors, some potentially modifiable, are associated with sICH occurrence. Further studies should investigate whether modification of baseline systolic blood pressure or plasma glucose level could reduce the risk of sICH. In addition, determinants differ per location of sICH, supporting the hypothesis of varying underlying mechanisms. Registration: URL: https://www.isrctn.com/ ; Unique identifier: ISRCTN10888758.

Background: In patients with large vessel occlusion stroke of the anterior circulation, underlying cause is a determinant of outcome. Whether this is the case for posterior circulation large vessel occlusion stroke has yet to be determined. We aimed to report on cause in patients with posterior circulation stroke treated with endovascular thrombectomy and to analyze the association with functional outcome. Methods: We used data of patients with posterior circulation stroke included in the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) registry, a prospective multicenter observational study, between 2014 and 2018. Stroke cause was categorized into large artery atherosclerosis (LAA), cardioembolism, arterial dissection, embolic stroke of undetermined source (ESUS), other determined cause, or undetermined cause. For primary analysis on the association between cause and outcome, we used multivariable ordinal logistic regression analysis to estimate the adjusted common odds ratio for a shift towards a better functional outcome on the modified Rankin Scale at 90 days with LAA as a reference group. Secondary outcomes included favorable functional outcome (modified Rankin Scale score 0–3), National Institutes of Health Stroke Scale score at 24 to 48 hours, reperfusion on digital subtraction angiography, and stroke progression. Results: Of 264 patients with posterior circulation stroke, 84 (32%) had LAA, 48 (18%) cardioembolism, 31 (12%) dissection, and 14 (5%) ESUS. Patients with a dissection were younger (48 [interquartile range, 43–60] years) and had a lower National Institutes of Health Stroke Scale at baseline (12 [interquartile range, 6–31]) than patients with other cause. Functional outcome was better for patients with cardioembolism and ESUS compared to LAA (modified Rankin Scale adjusted common odds ratio, 2.4 [95% CI, 1.1–5.2], respectively adjusted common odds ratio, 3.1 [95% CI, 1.0–9.3]). Patients with a dissection had a lower chance of successful reperfusion compared with LAA (adjusted odds ratio, 0.20 [95% CI, 0.06–0.70]). Conclusions: Unlike the anterior circulation, most frequent cause in our posterior large vessel occlusion stroke cohort is LAA followed by cardioembolism, dissection, and ESUS. Patients with cardioembolism and ESUS have a better prognosis for functional outcome after endovascular thrombectomy than patients with LAA.

Background: We evaluated data from all patients in the Netherlands who underwent endovascular treatment for acute ischemic stroke in the past 3.5 years, to identify nationwide trends in time to treatment and procedural success, and assess their effect on clinical outcomes. Methods: We included patients with proximal occlusions of the anterior circulation from the second and first cohorts of the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry (March 2014 to June 2016; June 2016 to November 2017, respectively). We compared workflow times and rates of successful reperfusion (defined as an extended Thrombolysis in Cerebral Infarction score of 2B-3) between cohorts and chronological quartiles (all included patients stratified in chronological quartiles of intervention dates to create equally sized groups over the study period). Multivariable ordinal logistic regression was used to assess differences in the primary outcome (ordinal modified Rankin Scale at 90 days). Results: Baseline characteristics were similar between cohorts (second cohort n=1692, first cohort n=1488) except for higher age, poorer collaterals, and less signs of early ischemia on computed tomography in the second cohort. Time from stroke onset to groin puncture and reperfusion were shorter in the second cohort (median 185 versus 210 minutes; P P P Conclusions: Clinical outcomes after endovascular treatment for acute ischemic stroke in routine clinical practice have improved over the past years, likely resulting from improved workflow times and higher successful reperfusion rates.

Background Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this “off-hours effect” also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. Methods Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009–2015, EVT: 2014–2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. Results In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7–4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI − 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. Conclusion Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

The carotid web is a proposed stroke mechanism that may underlie cryptogenic stroke, particularly in younger patients without vascular risk factors. The web appears as a shelf-like projection into the lumen of the proximal cervical internal carotid artery without evidence of calcification. It is pathologically defined as intimal fibromuscular dysplasia. Altered haemodynamics distal to the web cause flow stagnation and remote embolisation of fibrin-based clots. It is best demonstrated and diagnosed on CT angiography (CTA) of the neck because of its ability to resolve calcium and create multiplanar reconstructions. Although they can be readily visualised on CTA, carotid webs may be missed or misinterpreted because they do not typically cause haemodynamically significant stenosis and can mimic arterial dissection, non-calcified atherosclerotic plaque and intraluminal thrombus. Options for management include antiplatelet therapy, carotid endarterectomy and carotid artery stenting. Modern management strategies for cryptogenic stroke include long-term cardiac monitoring, further investigation for structural cardiac disease and a diagnostic workup for arterial hypercoagulability, however, these strategies are not likely to capture the possibility of a carotid web. Carotid webs should be suspected in a young patient presenting with recurrent unihemispheric strokes particularly when conventional vascular risk factors are not present.

Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9 to 14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds, and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32, and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

ObjectiveTo assess and compare the diagnostic performance of qualitative and (semi-)quantitative MRI and ultrasound for distinguishing chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) from segmental spinal muscular atrophy (sSMA).MethodsPatients with CIDP (n = 13), MMN (n = 10), or sSMA (n = 12) and healthy volunteers (n = 30) were included. MRI of the brachial plexus, using short tau inversion recovery (STIR), nerve-specific T2-weighted (magnetic resonance neurography [MRN]), and diffusion tensor imaging (DTI) sequences, was evaluated. Furthermore, with ultrasound, cross-sectional areas of the nerves were evaluated. Three radiologists blinded for diagnosis qualitatively scored hypertrophy and increased signal intensity (STIR and MRN), and intraobserver and interobserver agreement was assessed. For the (semi-)quantitative modalities, group differences and receiver operator characteristics were calculated.ResultsHypertrophy and increased signal intensity were found in all groups including healthy controls. Intraobserver and interobserver agreements varied considerably (intraclass correlation coefficients 0.00–0.811 and 0.101–0.491, respectively). DTI showed significant differences (p < 0.05) among CIDP, MMN, sSMA, and controls for fractional anisotropy, axial diffusivity, and radial diffusivity in the brachial plexus. Ultrasound showed significant differences in cross-sectional area (p < 0.05) among CIDP, MMN, and sSMA in upper arm and brachial plexus. For distinguishing immune-mediated neuropathies (CIDP and MMN) from sSMA, ultrasound yielded the highest area under the curve (0.870).ConclusionQualitative assessment of hypertrophy and signal hyperintensity on STIR or MRN is of limited value. DTI measures may discriminate among CIDP, MMN, and sSMA. Currently, ultrasound may be the most appropriate diagnostic imaging aid in the clinical setting.

Introduction: The brain magnetic resonance imaging (MRI) result is a major predictor for the outcome of term infants with perinatal asphyxia who underwent therapeutic hypothermia. In daily practice, no uniform method is used to assess these images. Purpose: The aim of this study was to determine which MRI-score best predicts adverse outcome at 24 months of age and has the highest inter-rater reliability. Methods: Four MRI scoring systems for term infants with perinatal asphyxia were selected: Rutherford score, Trivedi score, Weeke score, and NICHD NRN score. Experienced blinded raters retrospectively evaluated the brain MR Images of 161 infants using all four scoring systems. Long-term outcome (the composite outcome death or adverse outcome, and its separate components) were routinely assessed by standardized testing at the age of 24 months. The predictive accuracy was assessed by logistic regression analyses and expressed as area under the ROC curve (AUC). The inter-rater reliability of the scores was calculated by the weighted Kappa or intraclass correlation. A sensitivity analysis using only high-quality MRI scans was performed. Results: All four MRI scoring systems demonstrated an AUC of >0.66 for the prediction of adverse outcome and ≥0.80 for the prediction of death. The inter-rater reliability analyses demonstrated the highest reliability for the Weeke and Trivedi scores. When only assessing the high-quality scans, the AUC increased further. Conclusion: All four MRI brain scores proved reliable predictors for an adverse outcome at 24 months of age. The Weeke and Trivedi score demonstrated the highest inter-rater reliability. The use of high-quality MRI further improved prediction.

Background Time to reperfusion in patients with ischemic stroke is strongly associated with functional outcome and may differ between hospitals and between patients within hospitals. Improvement in time to reperfusion can be guided by between‐hospital and within‐hospital comparisons and requires insight in specific targets for improvement. We aimed to quantify the variation in door‐to‐reperfusion time between and within Dutch intervention hospitals and to assess the contribution of different time intervals to this variation. Methods and Results We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. The door‐to‐reperfusion time was subdivided into time intervals, separately for direct patients (door‐to‐computed tomography, computed tomography‐to‐computed tomography angiography [CTA], CTA‐to‐groin, and groin‐to‐reperfusion times) and for transferred patients (door‐to‐groin and groin‐to‐reperfusion times). We used linear mixed models to distinguish the variation in door‐to‐reperfusion time between hospitals and between patients. The proportional change in variance was used to estimate the amount of variance explained by each time interval. We included 2855 patients of 17 hospitals providing endovascular treatment. Of these patients, 44% arrived directly at an endovascular treatment hospital. The between‐hospital variation in door‐to‐reperfusion time was 9%, and the within‐hospital variation was 91%. The contribution of case‐mix variables on the variation in door‐to‐reperfusion time was marginal (2%–7%). Of the between‐hospital variation, CTA‐to‐groin time explained 83%, whereas groin‐to‐reperfusion time explained 15%. Within‐hospital variation was mostly explained by CTA‐to‐groin time (33%) and groin‐to‐reperfusion time (42%). Similar results were found for transferred patients. Conclusions Door‐to‐reperfusion time varies between, but even more within, hospitals providing endovascular treatment for ischemic stroke. Quality of stroke care improvements should not only be guided by between‐hospital comparisons, but also aim to reduce variation between patients within a hospital, and should specifically focus on CTA‐to‐groin time and groin‐to‐reperfusion time.

Supplemental Digital Content is available in the text., Background: Cerebral white matter lesions (WMLs) have been associated with a greater risk of poor functional outcome after ischemic stroke. We assessed the relations between WML burden and radiological and clinical outcomes in patients treated with endovascular treatment in routine practice. Methods: We analyzed data from the MR CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands)—a prospective, multicenter, observational cohort study of patients treated with endovascular treatment in the Netherlands. WMLs were graded on baseline noncontrast computed tomography using a visual grading scale. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included early neurological recovery, successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b), futile recanalization (modified Rankin Scale score ≥3 despite successful reperfusion), and occurrence of symptomatic intracranial hemorrhage. We used multivariable logistic regression models to assess associations between WML severity and outcomes, taking the absence of WML on noncontrast computed tomography as the reference category. Results: Of 3180 patients included in the MR CLEAN Registry between March 2014 and November 2017, WMLs were graded for 3046 patients and categorized as none (n=1855; 61%), mild (n=608; 20%), or moderate to severe (n=588; 19%). Favorable outcome (modified Rankin Scale score, 0–2) was achieved in 838 patients (49%) without WML, 192 patients (34%) with mild WML, and 130 patients (24%) with moderate-to-severe WML. Increasing WML grades were associated with a shift toward poorer functional outcome in a dose-dependent manner (adjusted common odds ratio, 1.34 [95% CI, 1.13–1.60] for mild WML and 1.67 [95% CI, 1.39–2.01] for moderate-to-severe WML; Ptrend

BackgroundRandomised controlled trials with perfusion selection have shown benefit of endovascular treatment (EVT) for ischaemic stroke between 6 and 24 hours after symptom onset or time last seen well. However, outcomes after EVT in these late window patients without perfusion imaging are largely unknown. We assessed their characteristics and outcomes in routine clinical practice.MethodsThe Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry, a prospective, multicentre study in the Netherlands, included patients with an anterior circulation occlusion who underwent EVT between 2014 and 2017. CT perfusion was no standard imaging modality. We used adjusted ordinal logistic regression analysis to compare patients treated within versus beyond 6.5 hours after propensity score matching on age, prestroke modified Rankin Scale (mRS), National Institutes of Health Stroke Scale, Alberta Stroke Programme Early CT Score (ASPECTS), collateral status, location of occlusion and treatment with intravenous thrombolysis. Outcomes included 3-month mRS score, functional independence (defined as mRS 0–2), and death.ResultsOf 3264 patients who underwent EVT, 106 (3.2%) were treated beyond 6.5 hours (median 8.5, IQR 6.9–10.6), of whom 93 (87.7%) had unknown time of stroke onset. CT perfusion was not performed in 87/106 (80.2%) late window patients. Late window patients were younger (mean 67 vs 70 years, pConclusionsWithout the use of CT perfusion selection criteria, EVT in the 6.5–24-hour time window was not associated with poorer outcome in selected patients with favourable clinical and CT/CT angiography characteristics. randomised controlled trials with lenient inclusion criteria are needed to identify more patients who can benefit from EVT in the late window.

Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.

Background and Purpose: Thrombectomy with stent retriever and direct aspiration are equally effective in the endovascular treatment of anterior circulation acute ischemic stroke. We report efficacy and safety of initial treatment technique per occlusion segment. Methods: For this study, we analyzed data from the MR CLEAN Registry, a prospective, observational study in all centers that perform endovascular therapy in the Netherlands. We used ordinal logistic regression analysis to compare clinical and technical results of first line direct aspiration treatment with that of stent retriever thrombectomy stratified for occlusion segment. Primary outcome measure was functional outcome at 3 months. Secondary outcome measures included reperfusion grade expressed as the extended Thrombolysis in Cerebral Infarction score, periprocedural complication risk, time to reperfusion, and mortality. Results: Of the 2282 included patients, 1658 (73%) were initially treated with stent retriever and 624 (27%) with aspiration. Four hundred sixty-two patients had an occlusion of the intracranial part of the carotid artery, 1349 of the proximal middle cerebral artery, and 471 of the distal parts of the middle cerebral artery. There was no difference in functional outcome between aspiration and stent retriever thrombectomy (odds ratio, 1.0 [95% CI, 0.9–1.2]) in any of the occlusion segments ( P value for interaction=0.2). Reperfusion rate was higher in the aspiration group (odds ratio, 1.4 [95% CI, 1.1–1.6]) and did not differ between occlusion segments ( P value for interaction=0.6). Procedure times were shorter in the aspiration group (minutes 50 versus 65 minutes; P Conclusions: In unselected patients with anterior circulation infarcts, we observed equal functional outcome of aspiration and stent retriever thrombectomy in all occlusion segments. When aspiration was the first line treatment modality, reperfusion rates were higher and procedure times shorter in all occlusion segments.

Contains fulltext : 220823.pdf (Publisher’s version ) (Closed access) Before 2015, endovascular treatment (EVT) for acute ischemic stroke was considered a promising treatment option. Based on limited evidence, it was performed in several dedicated stroke centers worldwide on selected patients. Since 2015, EVT for patients with intracranial large vessel occlusion has quickly been implemented as standard treatment in many countries worldwide, supported by the revised international guidelines based on solid evidence from multiple clinical trials. We describe the development in use of EVT in the Netherlands before, during, and after the pivotal EVT trials. We used data from all patients who were treated with EVT in the Netherlands from January 2002 until December 2018. We undertook a time-series analysis to examine trends in the use of EVT using Poisson regression analysis. Incidence rate ratios per year with 95% CIs were obtained to demonstrate the impact and implementation after the publication of the EVT trial results. We made regional observation plots, adjusted for stroke incidence, to assess the availability and use of the treatment in the country. In the buildup to the MR CLEAN (Multicenter Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands), a slow increase of EVT patients was observed, with 0.2% of all ischemic stroke patients receiving EVT. Before the trial results were formally announced, a statistically significant increase in EVT-treated patients per year was observed (incidence rate ratio, 1.72 [95% CI, 1.46-2.04]), and after the trial publication, an immediate steep increase was seen, followed by a more gradual increase (incidence rate ratio, 2.14 [95% CI, 1.77-2.59]). In 2018, the percentage of ischemic stroke patients receiving EVT increased to 5.8%. A well-developed infrastructure, a pragmatic approach toward the use of EVT in clinical practice, in combination with a strict adherence by the regulatory authorities to national evidence-based guidelines has led to successful implementation of EVT in the Netherlands. Ongoing efforts are directed at further increasing the proportion of stroke patients with EVT in all regions of the country.

Importance: To date, only uncontrolled studies have evaluated the efficacy and safety of endovascular treatment (EVT) in patients with cerebral venous thrombosis (CVT), leading to the lack of recommendations on EVT for CVT.Objective: To evaluate the efficacy and safety of EVT in patients with a severe form of CVT.Design, Setting, and Participants: TO-ACT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis) was a multicenter, open-label, blinded end point, randomized clinical trial conducted in 8 hospitals in 3 countries (the Netherlands, China, and Portugal). Patients were recruited from September 2011 to October 2016, and follow-up began in March 2012 and was completed in December 2017. Adult patients with radiologically confirmed CVT who had at least 1 risk factor for a poor outcome (mental status disorder, coma state, intracerebral hemorrhage, or thrombosis of the deep venous system) were included. Data were analyzed according to the intention-to-treat principle from March 2018 to February 2019. The trial was halted after the first interim analysis for reasons of futility.Interventions: Patients were randomized to receive either EVT with standard medical care (intervention group) or guideline-based standard medical care only (control group). The EVT consisted of mechanical thrombectomy, local intrasinus application of alteplase or urokinase, or a combination of both strategies. Patients in the intervention group underwent EVT as soon as possible but no later than 24 hours after randomization.Main Outcomes and Measures: Primary end point was the proportion of patients with a good outcome at 12 months (recovered without a disability; modified Rankin Scale [mRS] score of 0-1). Secondary end points were the proportion of patients with an mRS score of 0 to 1 at 6 months and an mRS score of 0 to 2 at 6 and 12 months, outcome on the mRS across the ordinal continuum at 12 months, recanalization rate, and surgical interventions in relation to CVT. Safety end points included symptomatic intracranial hemorrhage.Results: Of the 67 patients enrolled and randomized, 33 (49%) were randomized to the intervention group and 34 (51%) were randomized to the control group. Patients in the intervention group vs those in the control group were slightly older (median [interquartile range (IQR)] age, 43 [33-50] years vs 38 [23-48] years) and comprised fewer women (23 women [70%] vs 27 women [79%]). The median (IQR) baseline National Institutes of Health Stroke Scale score was 12 (7-20) in the EVT group and 12 (5-20) in the standard care group. At the 12-month follow-up, 22 intervention patients (67%) had an mRS score of 0 to 1 compared with 23 control patients (68%) (relative risk ratio, 0.99; 95% CI, 0.71-1.38). Mortality was not statistically significantly higher in the EVT group (12% [n = 4] vs 3% [n = 1]; P = .20). The frequency of symptomatic intracerebral hemorrhage was not statistically significantly lower in the intervention group (3% [n = 1] vs 9% [n = 3]; P = .61).Conclusions and Relevance: The TO-ACT trial showed that EVT with standard medical care did not appear to improve functional outcome of patients with CVT. Given the small sample size, the possibility exists that future studies will demonstrate better recovery rates after EVT for this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204333.

Contains fulltext : 229605.pdf (Publisher’s version ) (Open Access) BACKGROUND: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome. METHODS: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated. RESULTS: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was, Patients with classical galactosemia frequently suffer from complications affecting the brain for which prognostic factors are lacking. In our cohort of classical galactosemia patients, we demonstrated a highly variable outcome, distinguished a subgroup of milder ‘variant patients’ and found an association between MRI abnormalities and lower intellectual outcomes and movement disorders., Graphical Abstract Graphical Abstract

Introduction: For the detection of local recurrences of head and neck squamous cell carcinomas (HNSCC) after (chemo)radiation, diagnostic imaging is generally performed. Diffusion weighted magnetic resonance imaging (DW-MRI) has been proven to be able to adequately diagnose the presence of cancer. However evaluation of DW-MR images for recurrences is difficult and could be subject to individual interpretation.Aim: To determine the interobserver agreement, intraobserver agreement and influence of experience of radiologists in the assessment of DW-MRI in patients clinically suspected of local recurrent HNSCC after (chemo) radiation.Methods: Ten experienced head and neck radiologists assessed follow-up MRI including DW-MRI series of 10 patients for the existence of local recurrence on a two point decision scale (local recurrence or local control). Patients were clinically suspected for a recurrence of laryngeal (n = 3), hypopharyngeal (n = 3) or oropharyngeal (n = 4) cancer after (chemo)radiation with curative intent. Fleiss' and Cohen's Kappa were used to determine interobserver agreement and intraobserver agreement, respectively.Results: Interobserver agreement was kappa = 0.55. Intraobserver agreement was kappa = 0.80. Prior experience within the field of radiology and with DW-MRI had no significant influence on the scoring.Conclusion: For the assessment of HNSCC recurrence after (chemo)radiation by DW-MRI, moderate interobserver agreement and substantial intraobserver agreement was found.

Background. It is unclear how often lumbar puncture (LP) is complicated by cerebral herniation in patients with bacterial meningitis and whether cranial computed tomography (CT) can be used to identify patients at risk for herniation. Methods. We performed a nationwide prospective cohort study of patients with community-acquired bacterial meningitis from 2006 to 2014 and identified patients with clinical deterioration possibly caused by LP. For systematic evaluation of contraindications for LP on cranial CT, these patients were matched to patients in the cohort without deterioration. Four experts, blinded for outcome, scored cranial CT results for contraindications for LP. A Fleiss' generalized ? for this assessment was determined. Results. Of 1533 episodes, 47 (3.1%) had deterioration possibly caused by LP. Two patients deteriorated within 1 hour after LP (0.1%). In 43 of 47 patients with deterioration, cranial CT was performed prior to LP, so CT results were matched with 43 patients without deterioration. The interrater reliability of assessment of contraindications for LP on cranial CT was moderate (Fleiss' generalized ? = 0.47). A contraindication for LP was reported by all 4 raters in 6 patients ith deterioration (14%) and in 5 without deterioration (11%). Conclusions. LP can be performed safely in the large majority of patients with bacterial meningitis, as it is only very rarely complicated by cerebral herniation. Cranial CT can be considered a screening method for contraindications for LP, but the interrater reliability of this assessment is moderate.

Investigate how often cerebral herniation occurs following lumbar puncture (LP) in patients with bacterial meningitis, and whether cranial computed tomography (CT) can be used to identify patients at a higher risk of cerebral herniation.Prospective, nationwide cohort study covering the period March 2006 - November 2014.We identified patients with community-acquired bacterial meningitis who showed signs of clinical deterioration, possibly caused by LP. For systematic evaluation of contraindications for LP on cranial CT, the included patients were matched to bacterial meningitis patients without deterioration. Four experts, blinded for patient outcome, scored cranial CT scan imaging for the cases as well as control patients in relation to contraindications for LP. Inter-assessor reliability was determined with Fleiss' generalized κ.Of the 1533 bacterial meningitis patients included, 47 (3.1%) exhibited clinical deterioration possibly caused by LP. Two patients deteriorated within 1 hour after LP (0.1%). In 43 of 47 patients that showed signs of clinical deterioration, cranial CT was performed prior to LP. The inter-rater reliability of assessment of contraindications for LP on cranial CT was moderate (Fleiss' generalized κ = 0.47). A contraindication for LP was reported by all four raters in 6 patients with clinical deterioration (14%) and in 5 patients without clinical deterioration (11%).LP can be performed safely in the large majority of patients with bacterial meningitis, as it only very rarely results in cerebral herniation. Cranial CT can be considered a screening method to identify patients who are at a higher risk of cerebral herniation, but the inter-rater reliability of the CT scan assessment for contraindications of LP is moderate.

Introduction: We aimed to investigate the outcome of endovascular treatment (EVT) for acute ischemic stroke in patients with low Alberta Stroke Program Early CT Score (ASPECTS). Methods: This study reports on MR CLEAN Registry patients with available baseline ASPECTS (N=1423). ASPECTS was trichotomized in 0-4, 5, and 6-10 in order to create low ASPECTS groups of similar size. Primary outcome was modified Rankin Scale score (mRS) at 90 days. Secondary outcomes were symptomatic intracranial hemorrhage (sICH) and mortality. Benefit of reperfusion (defined as extended thrombolysis in cerebral infarction [eTICI] score 2B-3) was assessed by multivariable ordinal logistic regression analysis, including an interaction term of reperfusion and ASPECTS, and it was expressed as an adjusted common odds ratio (acOR). A comparison with the MR CLEAN trial control arm was made to assess benefit of EVT. Results: Higher trichotomized ASPECTS was associated with improved mRS (acOR 1.4, 95%CI 1.2-1.7). For ASPECTS 0-4 (n=93) successful reperfusion was not associated with improved mRS (acOR 1.4, 95%CI 0.6-2.9). ASPECTS 5 (n=63) and ASPECTS 6-10 subgroups (n=1267) however, did show significant benefit of reperfusion (acOR 3.9, 95%CI 1.3-11.8; acOR 2.7, 95%CI 2.2-3.3, respectively)(Fig1). Interaction between trichotomized ASPECTS and reperfusion was not significant ( p =0.13). Comparison with the MR CLEAN trial control group showed that trichotomized ASPECTS did not modify the effect of EVT ( p =0.14). Patients with lower trichotomized ASPECTS had a higher risk of mortality (aOR 0.9, 95%CI 0.9-1.0), but not of sICH (aOR 1.0, 95%CI 0.9-1.1). Conclusion: ASPECTS does not modify effect of reperfusion or EVT on functional outcome after acute ischemic stroke. Patients with ASPECTS 5 or higher seem to benefit from successful reperfusion.

Supplemental Digital Content is available in the text., Background and Purpose— It is unclear whether endovascular treatment (EVT) is beneficial for patients with acute ischemic stroke with occlusion of the M2 segment of the middle cerebral artery. We aimed to compare functional outcomes, technical aspects, and complications of EVT between patients with acute ischemic stroke because of M2 and M1 occlusions in clinical practice. Furthermore, outcome and complications after EVT in dominant and nondominant caliber M2 division occlusions were studied. Methods— Data were obtained from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) which is an ongoing observational study in 16 Dutch centers performing EVT in the Netherlands. Functional outcome was measured with the modified Rankin Scale score at 90 days. Neurological recovery (delta National Institutes of Health Stroke Scale), successful reperfusion rates (extended Thrombolysis in Cerebral Infarction ≥2B), and safety outcomes were also investigated. Associations between occlusion location and outcome were analyzed with ordinal logistic regression models, with adjustment for other prognostic factors. Results— In total, 244 (24%) patients with an M2 and 759 (76%) patients with an M1 occlusion who underwent EVT were analyzed. Functional outcomes were not significantly different between patients with M2 versus M1 occlusions (adjusted common odds ratio, 1.24; 95% CI, 0.87–1.73). Occurrence of symptomatic intracerebral hemorrhage was also similar for M2 and M1 occlusions (6.6% versus 5.9%; P=0.84). Further analysis about dominance of an M2 branch was performed in 175 (72%) patients. Neurological recovery was comparable (mean delta National Institutes of Health Stroke Scale, −2±10 for dominant M2, −5±5 for nondominant M2, and −4±9 [P=0.24] for M1 occlusions). Furthermore, the effect of reperfusion status on functional outcome was comparable between occlusion divisions (common odds ratio, 1.27; 95% CI, 1.06–1.53 for dominant M2; common odds ratio, 1.32; 95% CI, 0.93–1.87 for nondominant M2; and common odds ratio, 1.35; 95% CI, 1.24–1.46 for M1 occlusions). Conclusions— Outcomes and complication rates after EVT were similar in patients with M2 and M1 occlusions. Although based on observational data and a limited sample size, a similar association of reperfusion status with functional outcome for all subgroups provides no evidence that patients with either a dominant or a nondominant M2 occlusion should be routinely excluded from EVT.

Background: In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML). Objective: To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability. Methods: In this retrospective diagnostic study, four blinded neuroradiologists assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with new asymptomatic PML lesions ( n = 21) or new MS lesions ( n = 20) or no new lesions ( n = 7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation, and PML detection were determined. Interrater agreement was calculated. Results: Overall sensitivity and specificity for the detection of new lesions, regardless of the nature of the lesions, were 77.4% and 89.3%, respectively; for PML-MS lesion differentiation, 74.2% and 84.7%, respectively; and for asymptomatic PML lesion detection, 59.5% and 91.7%, respectively. Interrater agreement for the tested categories was fair to moderate. Conclusion: The diagnostic performance of trained neuroradiologists using brain MRI in pharmacovigilance of natalizumab-treated MS patients is moderately good. Interrater agreement among trained readers is fair to moderate.

A 65-year-old man presented with a 2-year history of progressive eye movement abnormalities, bilateral limb weakness, and gait instability. MRI (figure 1) showed T2 hyperintensities in brainstem and cerebellum with enhancement, which were initially diagnosed as tumor. Closer inspection revealed prominent vascular structures at the tentorium. Digital subtraction angiography (DSA) showed an infratentorial dural arteriovenous fistula (DAVF) (figure 2). Following embolization with glue, the bilateral limb weakness improved and the other symptoms had resolved at discharge the next day.

Background: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear. Objectives: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment. Methods: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing–remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression. Results: Grey matter volume was lower in relapsing–remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing–remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume. Conclusions: Our findings show that grey matter volume is lower in secondary-progressive than in relapsing–remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume.

To investigate changes in hippocampal functional connectivity and structural measures of hippocampal damage in multiple sclerosis (MS) patients with intact spatial memory, a cognitive domain frequently affected in progressive MS.The study protocol was approved by the institutional ethics review board; all subjects gave written informed consent prior to participation. Twenty-five MS patients with intact spatial memory function were compared with 30 age- and sex-matched controls. Hippocampal volume differences, based on manually drawn masks, were evaluated by using the Student t test. Additionally, focal hippocampal lesions and mean diffusivity were obtained as descriptive measures of structural hippocampal damage. Multiple regression analyses of the resting-state functional magnetic resonance (MR) imaging data were performed for each subject by using hippocampal time series. Between-group analyses were conducted with a mixed-effects model, corrected for multiple comparisons by a cluster defining threshold level of z = 2 and a corrected cluster size significance level of P.05.Right hippocampal volume was significantly lower in MS patients as compared with controls (P.01). Left hippocampal volume was also lower in MS patients compared with controls, but not significantly so (P = .09). Resting-state functional connectivity between the hippocampus and its anatomic input or target areas, including the anterior cingulate gyrus, thalamus, and prefrontal cortex, were significantly decreased in MS patients. Decreased hippocampal functional connectivity was more pronounced in a subgroup of MS patients with hippocampal atrophy, although subtle decreases of functional connectivity were also found in patients with normal hippocampal volume.In MS patients, substantial abnormalities of hippocampal functional connectivity are already present before spatial memory function is impaired, especially in those patients with more pronounced hippocampal atrophy. Longitudinal studies should now assess whether these functional connectivity and structural changes may precede memory impairment in MS.

Purpose: To assess the effect on diffusion tensor (DT) magnetic resonance imaging (MRI) of acquiring data with different scanners. Materials and Methods: Forty-four healthy controls and 36 multiple sclerosis patients with low disability were studied using eight MR scanners with acquisition protocols that were as close to a standard protocol as possible. Between 7 and 13 subjects were studied in each center. Region-of-interest (ROI) and histogram-based analyses of fractional anisotropy (FA), axial (Dax), radial (Drad), and mean diffusivity (MD) were performed. The influence of variables such as the acquisition center and the control/patient group was determined with an analysis of variance (ANOVA) test. Results: The patient/control group explained ≈25% of data variability of FA and Drad from midsagittal corpus callosum (CC) ROIs. Global FA, MD, and Drad in the white matter differentiated patients from controls, but with lower discriminatory power than for the CC. In the gray matter, MD discriminated patients from controls (30% of variability explained by group vs. 17% by center). Conclusion: Significant variability of DT-MRI data can be attributed to the acquisition center, even when a standardized protocol is used. The use of appropriate segmentation methods and statistical models allows DT-derived metrics to differentiate patients from healthy controls. J. Magn. Reson. Imaging 2010;31:1458–1468. © 2010 Wiley-Liss, Inc.

Diffusion tensor imaging (DTI) measures have shown to be sensitive to white matter (WM) damage in multiple sclerosis (MS), not only inside focal lesions but also in user-defined regions in the so-called normal-appearing white matter (NAWM). New analysis techniques for DTI measures are now available that allow for hypothesis-free localization of damage. We performed DTI measurements of 30 MS patients selected for low focal lesion loads, and of 31 age-matched healthy controls and analyzed these using tract-based spatial statistics (TBSS). Patients were found to have a lower fractional anisotropy (FA) compared to controls in a number of brain regions, including the fornices, the left corona radiata, the inferior longitudinal fasciculus in both hemispheres, both optic radiations, and parts of the corpus callosum. In the regions of reduced FA, an increase in radial diffusivity and a less pronounced increase of axial diffusivity were found. Neurocognitive assessment showed that patients had normal visuospatial memory performance, just-normal attention, and impaired processing speed; the latter was associated with abnormal FA in the corpus callosum, an area which was relatively devoid of lesions visible on proton density-weighted images in our patients. TBSS can be useful in future studies with other MS patient samples to provide an unbiased localization of damage and generate location-specific hypotheses.

Background Gray matter (GM) lesions are frequently found in multiple sclerosis (MS) and their in-vivo detection has been improved using new magnetic resonance imaging sequences, such as double inversion recovery (DIR). However, little is known about progression of GM lesions over time. Objective To study the longitudinal behavior of GM lesions and to explore their relation to cognitive impairment in MS. Methods DIR images were acquired from 13 MS patients and seven healthy controls at two time points with a median interval of 3 years. At follow-up, all subjects underwent cognitive testing. Lesions were classified as white matter, cortical or hippocampal lesions. Results In patients, median cortical lesion number had increased from 18 to 26 at follow-up ( P = 0.01), median white matter (WM) lesion number had increased from 56 to 65 ( P = 0.02), and no significant increase over time was found for hippocampal lesions. Cortical lesion number at follow-up was significantly higher in secondary progressive (SP) than in relapsing-remitting patients. Significant relations were found between cortical and WM lesion number at follow-up on the one hand and visuospatial memory and processing speed on the other hand. Hippocampal lesion number was related to visuospatial memory. Conclusion Cortical lesions increase significantly over a 3-year time period, are most frequent in SP patients, and are associated with cognitive impairment.

To describe signal and contrast properties of an isotropic, single-slab 3D dataset [double inversion-recovery (DIR), fluid-attenuated inversion recovery (FLAIR), T2, and T1-weighted magnetization prepared rapid acquisition gradient-echo (MPRAGE)] and to evaluate its performance in detecting multiple sclerosis (MS) brain lesions compared to 2D T2-weighted spin-echo (T2SE). All single-slab 3D sequences and 2D-T2SE were acquired in 16 MS patients and 9 age-matched healthy controls. Lesions were scored independently by two raters and characterized anatomically. Two-tailed Bonferroni-corrected Student's t-tests were used to detect differences in lesion detection between the various sequences per anatomical area after log-transformation. In general, signal and contrast properties of the 3D sequences enabled improved detection of MS brain lesions compared to 2D-T2SE. Specifically, 3D-DIR showed the highest detection of intracortical and mixed WM-GM lesions, whereas 3D-FLAIR showed the highest total number of WM lesions. Both 3D-DIR and 3D-FLAIR showed the highest number of infratentorial lesions. 3D-T2 and 3D-MPRAGE did not improve lesion detection compared to 2D-T2SE. Multi-contrast, isotropic, single-slab 3D MRI allowed an improved detection of both GM and WM lesions compared to 2D-T2SE. A selection of single-slab 3D contrasts, for example, 3D-FLAIR and 3D-DIR, could replace 2D sequences in the radiological practice.

Memory impairment is especially prominent within the spectrum of cognitive deficits in multiple sclerosis (MS), and a crucial role for hippocampal pathology may therefore be expected in this disease. This study is the first to systematically assess hippocampal demyelination in MS. Hippocampal tissue samples of 19 chronic MS cases and 7 controls with non-neurologic disease were stained immunohistochemically for myelin proteolipid protein. Subsequently, number, location, and size of demyelinated lesions were assessed. Furthermore, the specimens were stained for HLA-DR to investigate microglia/macrophage activity. An unexpectedly high number of lesions (n = 37) was found in 15 of the 19 MS cases. Mixed intrahippocampal-perihippocampal lesions, which were more often found in cases with cognitive decline, were large and did not respect anatomical borders. Moderate microglial activation was frequently observed at the edges of these mixed lesions. Isolated intrahippocampal lesions were also frequently found. These were smaller than the mixed lesions and had a specific anatomical predilection: the cornu ammonis 2 subregion and the hilus of the dentate gyrus were consistently spared. Microglial activation was rare in isolated intrahippocampal lesions. Our results indicate that hippocampal demyelination is frequent and extensive in MS and that anatomical localization, size, and inflammatory activity vary for different lesion types. © 2007 American Association of Neuropathologists, Inc.

Multiple sclerosis (MS) is a common disease of the central nervous system, with various clinical symptoms and a heterogeneous disease course. MRI can depict focal and diffuse manifestations of the disease, and accurately measure progression over time. The precise pathogenesis of MS is unknown. Nevertheless, genetic influences have been found for susceptibility to MS in linkage and association studies. More recent genome-wide association studies have revealed other genes to be related to disease susceptibility and severity, explaining part of the variability in symptoms, radiological manifestations and disease course. Studies relating genetics and imaging in MS are discussed in this paper.

In addition to MRI for use in diagnostic imaging we now also have functional MRI (fMRI) at our disposal. This can be used to map activity in different areas of the brain. Since its introduction, this technique has been used extensively in preoperative analysis of brain tumours. Emotional centres can also be mapped. Various applications and limitations of fMRI for studying emotions are discussed in this article.

During the first 6-7 years of life children undergo a period of major neurocognitive develop- ment. Higher-order cognitive functions such as executive control of attention, encoding and retrieving of stored information and goal-directed behavior are present but less developed compared to older individ- uals. There is only very limited information from functional magnetic resonance imaging (fMRI) studies about the level of organization of functional networks in children in the early school period. In this study we perform continuous resting-state functional connectivity MRI in 5- to 8-year-old children in an awake state to identify and characterize resting-state networks (RSNs). Temporal concatenation independent component analysis (ICA) approach was applied to analyze the data. We identified 14 components con- sisting of regions known to be involved in visual and auditory processing, motor function, attention con- trol, memory, and the default mode network (DMN). Most networks, in particular those supporting basic motor function and sensory related processing, had a robust functional organization similar to mature adult patterns. In contrast, the DMN and other RSNs involved in higher-order cognitive func- tions had immature characteristics, revealing incomplete and fragmented patterns indicating less devel- oped functional connectivity. We therefore conclude that the DMN and other RSNs involved in higher order cognitive functioning are detectable, yet in an immature state, at an age when these cognitive abil- ities are mastered. Hum Brain Mapp 33:1189-1201, 2012. V C 2011 Wiley Periodicals, Inc.

Background: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications. Objectives: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function. Methods: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined. Results: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory ( r = −0.6 and r = −0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women. Conclusions: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.

Voxel‐based morphometry (VBM) has been used repeatedly in single‐center studies to investigate regional gray matter (GM) atrophy in multiple sclerosis (MS). In multi‐center trials, across‐scanner variations might interfere with the detection of disease‐specific structural abnormalities, thereby potentially limiting the use of VBM. Here we evaluated longitudinally inter‐site differences and inter‐site comparability of regional GM in MS using VBM. Baseline and follow up 3D T1‐weighted magnetic resonance imaging (MRI) data of 248 relapsing‐remitting (RR) MS patients, recruited in two clinical centers, (center1/2: n = 129/119; mean age 42.6 ± 10.7/43.3 ± 9.3; male:female 33:96/44:75; median disease duration 150 [72–222]/116 [60–156]) were acquired on two different 1.5T MR scanners. GM volume changes between baseline and year 2 while controlling for age, gender, disease duration, and global GM volume were analyzed. The main effect of time on regional GM volume was larger in data of center two as compared to center one in most of the brain regions. Differential effects of GM volume reductions occured in a number of GM regions of both hemispheres, in particular in the fronto‐temporal and limbic cortex (cluster P corrected

Memory deficits are highly prevalent in multiple sclerosis (MS). As the hippocampus is crucial to memory processing, a functional magnetic resonance imaging (fMRI) task was used to investigate changes in hippocampal function in MS patients with and without cognitive decline. Fifty patients with MS, (34 cognitively preserved (CP) and 16 cognitively impaired (CI)) and 30 healthy controls completed an episodic memory fMRI task (encoding and retrieval) that was used to specifically activate the hippocampus. During encoding of correctly remembered items, increased brain activation was seen in the parahippocampal areas bilaterally and in the left anterior cingulate gyrus in the CP patients compared to the controls (unclustered, Z ≥ 3.1, P ≤ 0.001). No brain areas showed less activation. In CI patients the right (para)hippocampal areas and the prefrontal cortex showed less brain activation compared to controls (cluster-corrected, P < 0.05). The posterior cingulate gyrus and the left precuneus showed increased activation in CI patients when compared to controls (unclustered Z ≥ 3.1, P ≤ 0.001). No significant differences were found on structural MRI measures between the CP and CI patients. These results suggest the presence of functional adaptation in the memory network before cognitive decline becomes evident in MS, as displayed by the increased brain activation in the hippocampal-cingulate memory system in CP patients. Interestingly, CI patients showed less activation in the hippocampal network during correct encoding. These findings are important for future cognitive therapeutic studies, since cognitive intervention might be most effective before cognitive impairment is present and when adaptive changes of the brain are most prominent. Hum Brain Mapp 33:2268–2280, 2012. © 2011 Wiley Periodicals, Inc.

We present the case of a 21-year-old woman with acute memory impairment. It was initially not recognized as organic in nature. Repeated neuropsychological testing confirmed severely disturbed encoding and recall. Three-dimensional double inversion recovery (3D-DIR) MRI confirmed hippocampal and cortical lesions. Further clinical symptoms, visual evoked potential and MRI suggested a diagnosis of multiple sclerosis (MS). The amnestic syndrome has remained for 5 years. This case illustrates that MS can present with acute cortical symptoms which can be difficult to recognize. The hippocampus can be acutely affected and DIR MRI imaging can help to demonstrate cortical lesions that explain the clinical picture.

Task-functional magnetic resonance imaging studies have shown that early cortical recruitment exists in multiple sclerosis, which can partly explain the discrepancy between conventional magnetic resonance imaging and clinical disability. The study of the brain 'at rest' may provide additional information, because task-induced metabolic changes are relatively small compared to the energy use of the resting brain. We therefore questioned whether functional changes exist at rest in the early phase of multiple sclerosis, and addressed this question by a network analysis of no-task functional magnetic resonance imaging data. Fourteen patients with symptoms suggestive of multiple sclerosis (clinically isolated syndrome), 31 patients with relapsing remitting multiple sclerosis and 41 healthy controls were included. Resting state functional magnetic resonance imaging data were brought to standard space using non-linear registration, and further analysed using multi-subject independent component analysis and individual time-course regression. Eight meaningful resting state networks were identified in our subjects and compared between the three groups with non-parametric permutation testing, using threshold-free cluster enhancement to correct for multiple comparisons. Additionally, quantitative measures of structural damage were obtained. Grey and white matter volumes, normalized for head size, were measured for each subject. White matter integrity was investigated with diffusion tensor measures that were compared between groups voxel-wise using tract-based spatial statistics. Patients with clinically isolated syndrome showed increased synchronization in six of the eight resting state networks, including the default mode network and sensorimotor network, compared to controls or relapsing remitting patients. No significant decreases were found in patients with clinically isolated syndrome. No significant resting state synchronization differences were found between relapsing remitting patients and controls. Normalized grey matter volume was decreased and white matter diffusivity measures were abnormal in relapsing remitting patients compared to controls, whereas no atrophy or diffusivity changes were found for the clinically isolated syndrome group. Thus, early synchronization changes are found in patients with clinically isolated syndrome that are suggestive of cortical reorganization of resting state networks. These changes are lost in patients with relapsing remitting multiple sclerosis with increasing brain damage, indicating that cortical reorganization of resting state networks is an early and finite phenomenon in multiple sclerosis.