IMPORTANCE: Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they ...create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow. OBSERVATIONS: When the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis. Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD). During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS. CONCLUSIONS AND RELEVANCE: Questions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process. The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use. Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored. Recent advances in mapping the brain vasculome may generate new hypotheses. The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms.
Prions: Beyond a Single Protein Das, Alvin S; Zou, Wen-Quan
Clinical microbiology reviews,
07/2016, Letnik:
29, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Since the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants ...and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a "prion." Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins-not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease.
Cerebral small vessel disease (CSVD) is a common group of neurological conditions that confer a significant burden of morbidity and mortality worldwide. In most cases, CSVD is only recognized in its ...advanced stages once its symptomatic sequelae develop. However, its significance in asymptomatic healthy populations remains poorly defined. In population-based studies of presumed healthy elderly individuals, CSVD neuroimaging markers including white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, cortical superficial siderosis, and cerebral microinfarcts are frequently detected. While the presence of these imaging markers may reflect unique mechanisms at play, there are likely shared pathways underlying CSVD. Herein, we aim to assess the etiology and significance of these individual biomarkers by focusing in asymptomatic populations at an epidemiological level. By primarily examining population-based studies, we explore the risk factors that are involved in the formation and progression of these biomarkers. Through a critical semi-systematic review, we aim to characterize "asymptomatic" CSVD, review screening modalities, and draw associations from observational studies in clinical populations. Lastly, we highlight areas of research (including therapeutic approaches) in which further investigation is needed to better understand asymptomatic CSVD.
IMPORTANCE: Cerebral amyloid angiopathy–related inflammation (CAA-ri), a distinct subtype of cerebral amyloid angiopathy, is characterized by an autoimmune reaction to cerebrovascular β-amyloid ...deposits. Outcomes and response to immunosuppressive therapy for CAA-ri are poorly understood. OBJECTIVE: To identify clinical, neuroimaging, laboratory, pathologic, or treatment-related associations with outcomes after an episode of CAA-ri. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of prospectively identified individuals who presented from July 3, 1998, to November 27, 2017, with a median follow-up of 2.7 years (interquartile range, 1.0-5.5 years). The study included 48 consecutive patients with CAA-ri meeting diagnostic criteria who had at least 1 disease episode and subsequent outcome data. No patients refused or were excluded. EXPOSURES: Prespecified candidate variables were immunosuppressive therapies, cerebrospinal fluid pleocytosis, magnetic resonance imaging findings of recent infarcts or contrast enhancement, and histopathologic evidence of vessel wall inflammation. MAIN OUTCOMES AND MEASURES: Clinical improvement and worsening were defined by persistent changes in signs or symptoms, radiographic improvement by decreased subcortical foci of T2 hyperintensity or T1 enhancement, and radiographic worsening by increased subcortical T2 hyperintensity, T1 enhancement, or infarcts. Disease recurrence was defined as new-onset clinical symptoms associated with new imaging findings. RESULTS: The 48 individuals in the study included 29 women and had a mean (SD) age of 68.9 (9.9) years. Results of presenting magnetic resonance imaging revealed that 10 of 29 patients with CAA-ri (34%) had T1 contrast enhancement, 30 of 32 (94%) had subcortical T2 hyperintensity (22 of 30 73% asymmetric), 7 of 32 (22%) had acute or subacute punctate infarcts, and 27 of 31 (87%) had microbleeds. Immunosuppressive treatments after first episodes included corticosteroids (33 69%), cyclophosphamide (6 13%), and mycophenolate (2 4%); 14 patients (29%) received no treatment. Clinical improvement and radiographic improvement were each more likely in individuals treated with an immunosuppressive agent than with no treatment (clinical improvement: 32 of 34 94% vs 7 of 14 50%; odds ratio, 16.0; 95% CI, 2.72-94.1; radiographic improvement: 24 of 28 86% vs 4 of 14 29%; odds ratio, 15.0; 95% CI, 3.12-72.1). Recurrence was less likely if CAA-ri was treated with any immunosuppressant agent than not (9 of 34 26% vs 10 of 14 71%; hazard ratio, 0.19; 95% CI, 0.07-0.48). When controlling for treatment, no variables were associated with outcomes aside from an association between APOE ɛ4 and radiographic improvement (odds ratio, 4.49; 95% CI, 1.11-18.2). CONCLUSIONS AND RELEVANCE: These results from a relatively large series of patients with CAA-ri support the effectiveness of immunosuppressive treatment and suggest that early treatment may both improve the initial disease course and reduce the likelihood of recurrence. These results raise the possibility that early blunting of CAA-ri and the autoimmune response may have long-term benefits for the subsequent disease course.
Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage ...(mixed ICH). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in patients with mixed ICH with cortical superficial siderosis (cSS), a marker strongly associated with CAA.
Brain MRIs from a prospective database of consecutive patients with nontraumatic ICH admitted to a referral center were reviewed for the presence of CMBs, cSS, and nonhemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces CSO-EPVS, and multispot white matter hyperintensity WMH pattern). The frequencies of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between patients with mixed ICH with cSS (mixed ICH/cSS+) and without cSS (mixed ICH/cSS-) in univariate and multivariable models.
Of 1,791 patients with ICH, 40 had mixed ICH/cSS(+) and 256 had mixed ICH/cSS(-). LVH was less common in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-) (34% vs 59%,
= 0.01). The frequencies of CAA imaging markers, namely multispot pattern (18% vs 4%,
< 0.01) and severe CSO-EPVS (33% vs 11%,
< 0.01), were higher in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-). In a logistic regression model, older age (adjusted odds ratio aOR 1.04 per year, 95% CI 1.00-1.07,
= 0.04), lack of LVH (aOR 0.41, 95% CI 0.19-0.89,
= 0.02), multispot WMH pattern (aOR 5.25, 95% CI 1.63-16.94,
= 0.01), and severe CSO-EPVS (aOR 4.24, 95% CI 1.78-10.13,
< 0.01) were independently associated with mixed ICH/cSS(+) after further adjustment for hypertension and coronary artery disease. Among ICH survivors, the adjusted hazard ratio of ICH recurrence in patients with mixed ICH/cSS(+) was 4.65 (95% CI 1.38-11.38,
< 0.01) compared with that in patients with mixed ICH/cSS(-).
The underlying microangiopathy of mixed ICH/cSS(+) likely includes both HTN-cSVD and CAA, whereas mixed ICH/cSS(-) is likely driven by HTN-cSVD. These imaging-based classifications can be important to stratify ICH risk but warrant confirmation in studies incorporating advanced imaging/pathology.
Background/Objective
Before approval of andexanet alfa, off‐label treatment with 4‐factor prothrombin complex concentrate (4F‐PCC) was often utilized for the management of life‐threatening ...hemorrhages associated with oral factor Xa inhibitors. We evaluated the operational processes and outcomes of patients with oral factor Xa inhibitor‐associated intracranial hemorrhages (ICH) treated with andexanet alfa or 4F‐PCC.
Methods
We performed a retrospective, single‐center case series of rivaroxaban or apixaban‐associated ICH between 2016‐2019 treated with andexanet alfa or 4F‐PCC. Good or excellent hemostatic effectiveness, good functional outcome (Glasgow Outcome Score GOS> 3) at hospital discharge, and incidence of thrombosis within 30 days were reported.
Results
Eighteen patients were included in the andexanet alfa cohort and 11 in the 4F‐PCC cohort. Excellent or good hemostasis occurred in 88.9% of andexanet alfa‐treated patients and 60% of 4F‐PCC‐treated patients. Good functional outcome on discharge occurred in 55.6% of andexanet alfa‐treated patients and 9.1% of 4F‐PCC‐treated patients. Thrombotic complications occurred in 16.7% of andexanet alfa‐treated patients and 9.1% of 4F‐PCC‐treated patients. Median order‐to‐administration time was 1.1 hours 0.8‐1.4 versus 0.5 hours 0.1‐0.8 in the andexanet alfa and 4F‐PCC group, respectively. The median cost of therapy was $29970/patient versus $6925/patient in the andexanet alfa and 4F‐PCC group, respectively.
Conclusions
We observed higher rates of occurrence of good or excellent hemostasis and GOS > 3 on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F‐PCC for oral factor Xa inhibitor reversal. However, patients receiving 4F‐PCC had lower pre‐reversal Glasgow Coma Scale (GCS)score and larger pre‐reversal ICH volume.
Background
Ischemic strokes (IS) occurring in patients taking non-vitamin K antagonist oral anticoagulants (NOACs) are becoming increasingly more frequent. We aimed to determine the clinical, ...echocardiographic, and neuroimaging markers associated with developing IS in patients taking NOACs for atrial fibrillation.
Methods
From a quaternary care center, clinical/radiologic data were collected from consecutive NOAC users with IS and age-matched controls without IS. Brain MRIs were reviewed for markers of cerebral small vessel disease. Variables with significant differences between groups were entered into a multivariable regression model to determine predictors of IS. Among IS patients, a Cox regression analysis was constructed to determine predictors of IS recurrence during follow-up.
Results
112 patients with IS and 94 controls were included in the study. Variables significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI 6.02–94.48), HbA1c levels (aOR 2.36, 95% CI 1.39–3.99), left ventricular hypertrophy (aOR 2.73, 95% CI 1.11–6.71) and left atrial volume index (aOR 1.05, 95% CI 1.01–1.08) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI 0.16–0.92). Malignancy was associated with IS recurrence (aHR 4.90, 95% CI 1.35–18.42) after adjustment for age and chronic renal failure.
Conclusions
Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and increased left atrial size are risk factors for developing an IS among NOAC users.
Neurological complications following infective endocarditis (IE) directly contribute to long-term morbidity. We examined the risk factors for different neurological complications of left-sided IE.
...Using a database of consecutive adults admitted to a health system with left-sided IE from 2015 to 2019, the frequency of cerebral infarcts, intraparenchymal hemorrhage, cerebral microbleeds (CMB), mycotic aneurysm, and encephalopathy was determined. Variables with significant differences comparing each neurological complication (p < 0.1) were entered into regression models along with age to determine predictors.
211 patients with mean age 54 (±18) years, and 69 (33%) females were included. Infarcts were found in 118 (56%) patients, intraparenchymal hemorrhage was found in 17 (8%) patients, CMB were found in 58 (27%) patients, mycotic aneurysms were found in 22 (10%) patients, and encephalopathy occurred in 16 (8%) patients. In multivariable models, vegetation size ≥15 mm was associated with a higher risk of infarcts (aOR 2.26, 95% CI (1.12–4.57)), and the presence of a mycotic aneurysm was a risk factor for intraparenchymal hemorrhage (aOR 18.79, 95% CI (3.97–88.97)). Prosthetic valves (aOR 2.89, 95% CI (1.11–7.54)) and Staphylococcus aureus infection (aOR 3.50, 95% CI (1.08–11.36)) were associated with CMB. No risk factors emerged as predictors of encephalopathy.
Large vegetation size is associated with stroke in patients with IE. Mycotic aneurysms are found at a higher frequency in young patients and are the primary cause of intraparenchymal hemorrhage. CMB may be related to prosthetic valves and Staphylococcus aureus infection.
•Large vegetations are a risk factor for stroke in infective endocarditis (IE)•Staphylococcus aureus infection is a risk factor for cerebral microbleeds in IE•Younger individuals are at a higher risk of developing mycotic aneurysms in IE
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