Cerebral Microbleeds and Leukoencephalopathy in Critically Ill Patients With COVID-19.
ABSTRACT: BACKGROUND AND PURPOSE:We conducted this study to investigate the prevalence and distribution of cerebral microbleeds and leukoencephalopathy in hospitalized patients with coronavirus disease 2019 (COVID-19) and correlate with clinical, laboratory, and functional outcomes. METHODS:We performed a retrospective chart review of 4131 COVID-19 positive adult patients who were admitted to 3 tertiary care hospitals of an academic medical center at the epicenter of the COVID-19 pandemic in New York City from March 1, 2020, to May 10, 2020, to identify patients who had magnetic resonance imaging (MRI) of the brain. We evaluated the MRIs in detail, and identified a subset of patients with leukoencephalopathy and/or cerebral microbleeds. We compared clinical, laboratory, and functional outcomes for these patients to patients who had a brain MRI that did not show these findings. RESULTS:Of 115 patients who had an MRI of the brain performed, 35 (30.4%) patients had leukoencephalopathy and/or cerebral microbleeds. Patients with leukoencephalopathy and/or cerebral microbleeds had neuroimaging performed later during the hospitalization course (27 versus 10.6 days; P<0.001), were clinically sicker at the time of brain MRI (median GCS 6 versus 14; P<0.001), and had higher peak D-dimer levels (8018±6677 versus 3183±3482; P<0.001), lower nadir platelet count (116.9±62.2 versus 158.3±76.2; P=0.03), higher peak international normalized ratio (2.2 versus 1.57; P<0.001) values when compared with patients who had a brain MRI that did not show these findings. They required longer ventilator support (34.6 versus 9.1 days; P<0.001) and were more likely to have moderate and severe acute respiratory distress syndrome score (88.6% versus 23.8%, P<0.001). These patients had longer hospitalizations (42.1 versus 20.9 days; P<0.001), overall worse functional status on discharge (mRS 5 versus 4; P=0.001), and higher mortality (20% versus 9%; P=0.144). CONCLUSIONS:The presence of leukoencephalopathy and/or cerebral microbleeds is associated with a critical illness, increased mortality, and worse functional outcome in patients with COVID-19.
Project description:BACKGROUND:Anterior temporal lobe hyperintensities detected by brain MRI are a recognized imaging hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Because similar findings may be present in patients with myotonic dystrophy type 1 (DM1), the brain MRI in these two diseases is often misinterpreted. We compared the MRI findings between the two entities to examine whether they display distinctive characteristics. METHODS:This retrospective, cross-sectional study reviewed medical records of patients with DM1 or CADASIL admitted to Asan Medical Center between September 1999 and September 2017. We compared the frequency and grades of white matter changes in specific spatial regions between the groups according to age-related white matter change scores. We also evaluated the presence of cerebral microbleeds. RESULTS:A total of 29 patients with DM1 and 68 with CADASIL who had undergone MRI were included in the analysis. The overall prevalence of white matter hyperintensities was 20 (69%) and 66 (97%) in DM1 and CADASIL, respectively (p < 0.001), whereas the frequency of anterior temporal lobe hyperintensities was comparable between the groups (10 [34.5%] in DM1 vs. 35 [51.5%] in CADASIL, p = 0.125). The brain MRI of patients with DM1 revealed more limited involvement of the frontal, parieto-occipital, external capsule and basal ganglia regions compared with imaging in patients with CADASIL. Cerebral microbleeds were not observed in any case of DM1 but were present in 31 of 45 (68.9%) cases of CADASIL. CONCLUSIONS:Anterior temporal lobe involvement in DM1 is not infrequent compared with CADASIL. However, because brain MRI in patients with DM1 lacks other distinctive features seen in CADASIL, imaging might assist in differentiating these two conditions.
Project description:OBJECTIVE:This systematic review aimed to synthesize early data on typology and topography of brain abnormalities in adults with COVID-19 in acute/subacute phase. METHODS:We performed systematic literature search via PubMed, Google Scholar and ScienceDirect on articles published between January 1 and July 05, 2020, using the following strategy and key words: ((covid[Title/Abstract]) OR (sars-cov-2[Title/Abstract]) OR (coronavirus[Title/Abstract])) AND (brain[Title/Abstract]). A total of 286 non-duplicate matches were screened for original contributions reporting brain imaging data related to SARS-Cov-2 presentation in adults. RESULTS:The selection criteria were met by 26 articles (including 21 case reports, and 5 cohort studies). The data analysis in a total of 361 patients revealed that brain abnormalities were noted in 124/361 (34%) reviewed cases. Neurologic symptoms were the primary reason for referral for neuroimaging across the studies. Modalities included CT (-angiogram, -perfusion, -venogram), EEG, MRI (-angiogram, functional), and PET. The most frequently reported brain abnormalities were brain white matter (WM) hyperintensities on MRI 66/124 (53% affected cases) and hypodensities on CT (additional 23% affected cases), followed by microhemorrhages, hemorrhages and infarcts, while other types were found in <5% affected cases. WM abnormalities were most frequently noted in bilateral anterior and posterior cerebral WM (50% affected cases). CONCLUSION:About a third of acute/subacute COVID-19 patients referred for neuroimaging show brain abnormalities suggestive of COVID-19-related etiology. The predominant neuroimaging features were diffuse cerebral WM hypodensities / hyperintensities attributable to leukoencephalopathy, leukoaraiosis or rarefield WM.
Project description:BACKGROUND:Characteristics of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cysteine-sparing NOTCH3 mutations are relatively unknown. This study compared clinical and imaging characteristics between patients with CADASIL and cysteine-sparing NOTCH3 mutations and those with CADASIL and cysteine-involving NOTCH3 mutations. METHODS:We retrospectively reviewed medical records of patients with CADASIL admitted to the Asan Medical Center between September 1999 and September 2017. We compared clinical and brain magnetic resonance imaging (MRI) characteristics based on the presence or absence of cysteine-involving NOTCH3 gene mutations. We compared white matter change frequencies and grades in specific spatial regions between the groups according to age-related white matter change (ARWMC) scores. We evaluated the presence, number, and anatomical distributions of cerebral microbleeds according to the microbleed anatomical rating scale. RESULTS:We reviewed data from 79 patients (55 cysteine-involving, 24 cysteine-sparing NOTCH3 mutations). Clinical symptoms and signs did not differ significantly between the groups. The white matter change frequency and ARWMC scores (adjusted for age and stroke risk factors) in the anterior temporal lobes were lower in cysteine-sparing patients than in cysteine-involving patients. Frequencies and grades of the other brain region's white matter changes and cerebral microbleeds were similar between the groups. CONCLUSIONS:Patients with CADASIL and cysteine-sparing NOTCH3 mutations showed less involvement of the anterior temporal lobes in brain MRI than those with CADASIL and cysteine-involving NOTCH3 mutations, although both groups showed similar clinical characteristics.
Project description:Cerebral microbleeds, a marker of small vessel disease, are thought to be of importance in cognitive impairment. We aimed to study topographical distribution of cerebral microbleeds, and their involvement in disease pathophysiology, reflected by cerebrospinal fluid biomarkers; 1039 patients undergoing memory investigation underwent lumbar puncture and a brain magnetic resonance imaging scan. Cerebrospinal fluid samples were analyzed for amyloid ?(A?)42, total tau(T-tau), tau phosphorylated at threonine 18(P-tau) and cerebrospinal fluid/serum albumin ratios. Magnetic resonance imaging sequences were evaluated for small vessel disease markers, including cerebral microbleeds, white matter hyperintensities and lacunes. Low A?42 levels were associated with lobar cerebral microbleeds in the whole cohort and Alzheimer's disease ( P?<?0.001). High cerebrospinal fluid/serum albumin ratios were seen with increased number of cerebral microbleeds in the brainstem ( P?<?0.001). There were tendencies for increased A?42 levels and decreased Tau levels with deep and infratentorial cerebral microbleeds ( P?<?0.05). Lobar cerebral microbleeds were associated with white matter hyperintensities and lacunes ( P?<?0.001). Probable cerebral amyloid angiopathy-related cerebral microbleeds were associated with low A?42 levels and lacunes, whereas probable cerebral amyloid angiopathy-unrelated cerebral microbleeds were associated with white matter hyperintensities ( P?<?0.001). Our findings show that cerebral microbleed distribution is associated with different patterns of cerebrospinal fluid biomarkers, supporting different pathogenesis of deep/infratentorial and lobar cerebral microbleeds.
Project description:Diffuse leukoencephalopathy and juxtacortical and/or callosal microhemorrhages were brain imaging features in critically ill patients with coronavirus disease 2019. Coronavirus disease 2019 (COVID-19) has been reported in association with a variety of brain imaging findings such as ischemic infarct, hemorrhage, and acute hemorrhagic necrotizing encephalopathy. Herein, the authors report brain imaging features in 11 critically ill patients with COVID-19 with persistently diminished mental status who underwent MRI between April 5 and April 25, 2020. These imaging features include (a) confluent T2 hyperintensity and mild restricted diffusion in bilateral supratentorial deep and subcortical white matter (in 10 of 11 patients) and (b) multiple punctate microhemorrhages in juxtacortical and callosal white matter (in seven of 11 patients). The authors also discuss potential pathogeneses.
Project description:Objectives: Hypertension is a major risk factor for white matter hyperintensities (WMH), lacunes, cerebral microbleeds, and perivascular spaces, which are MRI markers of cerebral small vessel disease (SVD). Studies have shown associations between these individual MRI markers and cognitive functioning and decline. Recently, a "total SVD score" was proposed in which the different MRI markers were combined into one measure of SVD, to capture total SVD-related brain damage. We investigated if this SVD score was associated with cognitive decline over 4 years in patients with hypertension. Methods: In this longitudinal cohort study, 130 hypertensive patients (91 patients with uncomplicated hypertension and 39 hypertensive patients with a lacunar stroke) were included. They underwent a neuropsychological assessment at baseline and after 4 years. The presence of WMH, lacunes, cerebral microbleeds, and perivascular spaces were rated on baseline MRI. Presence of each individual marker was added to calculate the total SVD score (range 0-4) in each patient. Results: Uncorrected linear regression analyses showed associations between SVD score and decline in overall cognition (p = 0.017), executive functioning (p < 0.001) and information processing speed (p = 0.037), but not with memory (p = 0.911). The association between SVD score and decline in overall cognition and executive function remained significant after adjustment for age, sex, education, anxiety and depression score, potential vascular risk factors, patient group, and baseline cognitive performance. Conclusion: Our study shows that a total SVD score can predict cognitive decline, specifically in executive function, over 4 years in hypertensive patients. This emphasizes the importance of considering total brain damage due to SVD.
Project description:<h4>Background</h4>Magnetic resonance imaging-visible perivascular spaces (PVS) are related to interstitial fluid clearance pathways (including amyloid-?) in the brain and are suggested to be a marker of cerebral small vessel disease. We investigated the role, topography, and possible implications of PVS in cognitive impairment.<h4>Methods and results</h4>A total of 1504 patients undergoing memory clinic investigation and an associated brain magnetic resonance imaging scan were included in this cross-sectional study. Magnetic resonance images were assessed for markers of small vessel disease. Additionally, 1039 patients had cerebrospinal fluid analysis of amyloid-? 42, total tau (T-tau), and phosphorylated tau (<i>P</i>-tau); 520 patients had apoE genotyping done. Results were analyzed with generalized linear models. A total of 289 (19%; 95% confidence interval, 17-21) had a high-grade PVS in the centrum semiovale (CSO) and 65 (4%; 95% confidence interval: 3%-5%) in the basal ganglia (BG). Centrum semiovale- and BG-PVS were both associated with high age (<i>P</i><0.001), hypertension (<i>P</i><0.001), probable cerebral amyloid angiopathy (<i>P</i><0.05), moderate-to-severe white matter hyperintensities (<i>P</i><0.001), cortical superficial siderosis (<i>P</i><0.001), cerebral microbleeds (<i>P</i><0.001), and PVS. centrum semiovale-PVS was separately associated with strictly lobar cerebral microbleeds (<i>P</i>=0.057). BG-PVS was associated with strictly deep cerebral microbleeds (<i>P</i><0.001), lacunes (<i>P</i><0.001), and vascular dementia (<i>P</i>=0.04). BG-PVS showed a tendency to be associated with high cerebrospinal fluid tau (B=0.002, <i>P</i>=0.04) in the whole cohort and in Alzheimer's disease (B=0.005; <i>P</i>=0.02). No other associations with cerebrospinal fluid or the apoE e4 allele was observed.<h4>Conclusions</h4>Centrum semiovale-PVS and BG-PVS have different underlying etiology, being associated with cerebral amyloid angiopathy and hypertensive vasculopathy, respectively, although a significant overlap between these pathologies is likely to exist.
Project description:AIMS:Cerebral small vessel disease (SVD) is the leading cause of vascular dementia. Although the most of cases are sporadic, familial monogenic causes have been identified in a growing minority of patients. CADASIL, due to mutations of NOTCH3 gene, is the most common genetic SVD, and CARASIL, linked to HTRA1 gene mutations, is a rare but well known autosomal recessive SVD. Recently, also heterozygous HTRA1 mutations have been described in patients with familial SVD. To detect a genetic cause of familial SVD, we performed mutational analysis of HTRA1 gene in a large cohort of Italian NOTCH3-negative patients. METHODS:We recruited 142 NOTCH3-negative patients and 160 healthy age-matched controls. Additional control data were obtained from five pathogenicity prediction software. RESULTS:Five different HTRA1 heterozygous mutations were detected in nine patients from five unrelated families. Clinical phenotype was typical of SVD, and the onset was presenile. Brain magnetic resonance imaging (MRI) showed a subcortical leukoencephalopathy, with involvement of the external and internal capsule, corpus callosum, and multiple lacunar infarcts. Cerebral microbleeds were also seen, while anterior temporal lobes involvement was not present. CONCLUSION:Our observation further supports the pathogenic role of the heterozygous HTRA1 mutations in familial SVD.
Project description:Small, asymptomatic microbleeds commonly accompany larger symptomatic macrobleeds. It is unclear whether microbleeds and macrobleeds represent arbitrary categories within a single continuum versus truly distinct events with separate pathophysiologies.We performed 2 complementary retrospective analyses. In a radiographic analysis, we measured and plotted the volumes of all hemorrhagic lesions detected by gradient-echo MRI among 46 consecutive patients with symptomatic primary lobar intracerebral hemorrhage diagnosed as probable or possible cerebral amyloid angiopathy. In a second neuropathologic analysis, we performed blinded qualitative and quantitative examinations of amyloid-positive vessel segments in 6 autopsied subjects whose MRI scans demonstrated particularly high microbleed counts (>50 microbleeds on MRI, n=3) or low microbleed counts (<3 microbleeds, n=3).Plotted on a logarithmic scale, the volumes of 163 hemorrhagic lesions identified on scans from the 46 subjects fell in a distinctly bimodal distribution with mean volumes for the 2 modes of 0.009 cm(3) and 27.5 cm(3). The optimal cut point for separating the 2 peaks (determined by receiver operating characteristics) corresponded to a lesion diameter of 0.57 cm. On neuropathologic analysis, the high microbleed-count autopsied subjects showed significantly thicker amyloid-positive vessel walls than the low microbleed-count subjects (proportional wall thickness 0.53+/-0.01 versus 0.37+/-0.01; P<0.0001; n=333 vessel segments analyzed).These findings suggest that cerebral amyloid angiopathy-associated microbleeds and macrobleeds comprise distinct entities. Increased vessel wall thickness may predispose to formation of microbleeds relative to macrobleeds.
Project description:Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.