Changes in plasma concentrations of novel vascular and inflammatory biomarkers in obstructive sleep apnea patients pre- and post-stroke.

BACKGROUND: Obstructive sleep apnea (OSA) is increasingly recognized as a common condition in the general population and causes significant OSA-associated morbidities including cardiovascular and cerebrovascular events such as cerebral small vessel disease (CSVD) and stroke. METHODS: In this study, using sensitive ELISA immunoassays, we measured subset of endothelial/vascular and inflammatory biomarkers as well as neurofilament light chain (NfL), a sensitive marker for neuroaxonal injury, using plasma from OSA patients post-stroke (Acute Cerebral Infarction (ACI), N = 26) to determine their usefulness as potential prognostic markers in disease progression. RESULTS: Our results showed significantly increased plasma TNFα and NfL concentrations and decreased concentrations of platelet derived growth factor (PDGF-AA) in post-stroke OSA patients with more severe white matter hyperintensities (WMHs). And after separating the patients based on sex, compared to females, male post-stroke OSA patients with severe WMHs have increased circulating levels of inflammatory chemokine CXCL10 and cytokine Interleukin-10 (IL-10) and significantly decreased levels of Angiopoietin-1 (Ang-1) an important protein responsible for endothelial/vascular integrity functions. Importantly, in a subset of newly diagnosed OSA patients (without prior history of stroke), significantly increased plasma CXCL10 levels and decreased plasma Ang-1 levels were also readily observed when compared to healthy controls, indicating possible altered endothelial integrity and ongoing vascular inflammation in these newly diagnosed OSA patients. CONCLUSIONS: In summary, our study has identified a novel set of plasma biomarkers including PDGF-AA, CXCL10 and Ang-1 for their potential prognostic value for disease outcomes pre- and post-stroke in OSA patients and use as surrogate markers to measure efficacy of treatment modalities.

Novel grading system for CADASIL severity: A multicenter cross-sectional study.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited progressive cerebral microangiopathy with considerable phenotypic variability. The purpose of this study was to describe the generalizability of a recently proposed grading system of CADASIL across multiple centers in the United States. Methods: Electronic medical records (EMR) of an initial neurological assessment of adult patients with confirmed CADASIL were reviewed across 5 tertiary referral medical centers with expertise in CADASIL. Demographic, vascular risk factors, and neuroimaging data were abstracted from EMR. Patients were categorized into groups according to the proposed CADASIL grading system: Grade 0 (asymptomatic), Grade 1 (migraine only), Grade 2 (stroke, TIA, or MCI), Grade 3 (gait assistance or dementia), and Grade 4 (bedbound or end-stage). Inter-rater reliability (IRR) of grading was tested in a subset of cases. Results: We identified 138 patients with a mean age of 50.9 ± 13.1 years, and 57.2% were female. The IRR was acceptable over 33 cases (κ=0.855, SD 0.078, p<0.001) with 81.8% being concordant. There were 15 patients (10.9%) with Grade 0, 50 (36.2%) with Grade 1, 61 (44.2%) with Grade 2, 12 (8.7%) with Grade 3, and none with Grade 4. Patients with a lower severity grade (grade 0 vs 3) tended to be younger (49.5 vs. 61.9 years) and had a lower prevalence of hypertension (50% vs. 20%, p = 0.027) and diabetes mellitus (0% vs. 25%, p = 0.018). A higher severity grade was associated with an increased number of vascular risk factors (p = 0.02) and independently associated with hypertension and diabetes (p<0.05). Comparing Grade 0 vs. 3, cortical thickness tended to be greater (2.06 vs. 1.87 mm; p = 0.06) and white matter hyperintensity volume tended to be lower (54.7 vs. 72.5 ml; p = 0.73), but the differences did not reach significance. Conclusion: The CADASIL severity grading system is a pragmatic, reliable system for characterizing CADASIL phenotype that does not require testing beyond that done in standard clinical practice. Higher severity grades tended to have a higher vascular risk factor burden. This system offers a simple method of categorizing CADASIL patients which may help to describe populations in observational and interventional studies.

Malignant ischemic stroke revealing a spontaneous carotid dissection in a young patient: Rare case report.

Ischemic stroke remains today a major health problem that requires adequate management and etiological research. The prevalence in young people has increased. This article is a case report of a 37-year-old female diabetic patient who had an acute ischemic stroke due to spontaneous dissection of the right internal carotid artery. The article discusses the epidemiology, pathophysiology, diagnosis, and treatment of cervical artery dissection, which is a common cause of stroke in young patients. The use of antiplatelet and anticoagulant therapy, as well as endovascular and surgical interventions, is also discussed. Spontaneous carotid bulb dissection is an emergency in ischemic stroke in young people. The prognosis depends on the severity of the initial injury and the extent of collateral circulation, with successful recovery in 75% of cases.

Balamuthia mandrillaris Encephalitis Presenting as a Symptomatic Focal Hypodensity in an Immunocompromised Patient.

We present the case of a 61-year-old woman with a history of orthotopic heart transplant who was hospitalized with new-onset headache. Magnetic resonance imaging (MRI) of the brain revealed T2 hyperintense signal involving the left occipital lobe with leptomeningeal enhancement and mild vasogenic edema. Initial neurologic examination was normal; however, after 7 days she developed imbalance, visual disturbances, night sweats, bradyphrenia, alexia without agraphia, and right hemianopsia. Brain MRI showed enlargement of the left occipital mass and worsening edema. Stereotactic needle biopsy showed nondiagnostic necrosis. The patient continued to deteriorate despite dexamethasone. Cerebrospinal fluid (CSF) suggested infection, and cytomegalovirus CSF polymerase chain reaction (PCR) was positive. The patient received vancomycin, imipenem, and ganciclovir. After obtaining a positive serum beta-D-glucan (Fungitell), amphotericin was added. Despite best medical efforts, the patient died. Postmortem broad-range PCR sequencing of the brain tissue was positive for rare amoeba Balamuthia mandrillaris.

CGRP, Migraine, and Brain MRI in CADASIL: A Pilot Study.

BACKGROUND: Migraine is associated with neuroimaging differences in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, it is unknown if migraine-related disability (MRD) or if calcitonin gene-related peptide (CGRP), a vasoactive peptide important in migraine pathology, have radiographic implications. The aims of this study were to identify whether MRD or interictal serum CGRP levels impacted neuroimaging findings for those with CADASIL. MATERIALS AND METHODS: A cross-sectional analysis was performed. The primary outcomes were neuroimaging differences associated with MRD among those with migraine or interictal serum CGRP levels of those with and without migraine. MRD was defined by 2 migraine disability scales (Migraine Disability Assessment, Headache Impact Test-6). Retrospective brain magnetic resonance imaging was reviewed (average 1.7 ± 2.0 y before enrollment). Rank-sum and χ 2 tests were used. RESULTS: Those with migraine (n=25, vs. n=14 without) were younger [median 49 (25 to 82) y vs. 60 (31 to 82) y, P <0.007], had fewer cerebral microbleeds (0 to 31 vs. 0 to 50, P =0.02) and less frequently had anterior temporal lobe T2 hyperintensities [68% (17/25) vs 100% (14/14), P =0.02]. MRD scale outcomes had no significant radiographic associations. Interictal serum CGRP did not differ (migraine: n=18, 27.0±9.6 pg/mL vs. no migraine: n=10, 26.8±15.7 pg/mL, P =0.965). CONCLUSIONS: Migraine may forestall microangiopathy in CADASIL, though possibly independent of severity as measured by MRD. Interictal serum CGRP did not differ in our cohort suggesting CGRP may not be vital to migraine pathophysiology in CADASIL. Larger studies are needed to account for age differences.

Yield of Head Imaging in Ambulatory and Hospitalized Patients With SARS-CoV-2: A Multi-Center Study of 8675 Patients.

BACKGROUND AND PURPOSE: To describe the neurological and cerebrovascular findings in patients who tested positive for SARS-CoV-2 and underwent head imaging in ambulatory and inpatient settings. METHODS: Consecutive patients aged ≥18 years with SARS-CoV-2 infection diagnosed or treated at Mayo Clinic sites from 3/11/2020 to 7/23/2020 with head CT or brain MRI within 30 days of SARS-CoV-2 diagnosis were included. Demographics, medical history, indication for SARS-CoV-2 testing, neurologic symptoms, indication for brain imaging, neuroimaging findings, etiology of cerebrovascular events, and hospital course were abstracted from medical records. RESULTS: Of 8,675 patients with SARS-CoV-2, 180 (2.07%) had head imaging. Mean age of the entire cohort was 42 ± 18 years, whereas mean age of those with head imaging was 62 ± 19 years. Common indications for imaging were headache (34.4%), encephalopathy (33.4%), focal neurologic symptom (16.7%), and trauma (13.9%). While 86.1% of patients who underwent head imaging had normal exams, cerebrovascular events occurred in 18 patients (0.21% of the total cohort). Of patients with cerebrovascular events, 8 (44.5%) had acute infarct; 6 (33.3%), acute intracranial hemorrhage; 5 (2.8%), subacute infarct; and 1 (0.6%) posterior reversible encephalopathy syndrome. In the thirteen patients with ischemic stroke, 6 (46.2%) had cryptogenic stroke; 3 (23.1%), other defined causes; 2 (15.4%), small vessel stroke; 1 (7.7%), large vessel stroke; and 1 (7.7%) cardioembolic stroke. CONCLUSION: In ambulatory and hospitalized patients with SARS-CoV-2 infection, the rate of head imaging is low, with common indications of encephalopathy and headache. Cerebrovascular events occurred rarely, and cryptogenic stroke was the most common stroke mechanism.

Plasma neurofilament light predicts mortality in patients with stroke.

Given the heterogeneity of stroke brain injury, there is a clear need for a biomarker that determines the degree of neuroaxonal injury across stroke types. We evaluated whether blood neurofilament light (NFL) would fulfill this purpose for patients with acute cerebral infarction (ACI; N = 227), aneurysmal subarachnoid hemorrhage (aSAH; N = 58), or nontraumatic intracerebral hemorrhage (ICH; N = 29). We additionally validated our findings in two independent cohorts of patients with ICH (N = 96 and N = 54) given the scarcity of blood biomarker studies for this deadliest stroke type. Compared to healthy individuals (N = 79 and N = 48 for the discovery and validation cohorts, respectively), NFL was higher for all stroke types. NFL associated with radiographic markers of brain tissue damage. It correlated with the extent of early ischemic injury in patients with ACI, hemorrhage severity in patients with aSAH, and intracranial hemorrhage volume in patients with ICH. In all patients, NFL independently correlated with scores from the NIH Stroke Scale, the modified Rankin Scale, and the Mini-Mental State Examination at blood draw, which respectively assess neurological, functional, and cognitive status. Furthermore, higher NFL concentrations independently associated with 3- or 6-month functional disability and higher all-cause mortality. These data support NFL as a uniform method to estimate neuroaxonal injury and forecast mortality regardless of stroke mechanism. As a prognostic biomarker, blood NFL has the potential to assist with planning supportive and rehabilitation services and improving clinical trial efficiency for stroke therapeutics and devices.

Treatment of migraine in patients with CADASIL: A systematic review and meta-analysis.

BACKGROUND: Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) without consensus guidelines for treatment. Migraine treatment poses a theoretical risk within this unique population with precarious cerebrovascular autoregulation, given the vasomodulatory influence of many antimigraine medications. In this systematic review and meta-analysis, we evaluate the frequency and efficacy of treatments for migraine in individuals with CADASIL. METHODS: A search protocol was designed to include all available publications reporting antimigraine therapies for CADASIL. Individual responses to medications were categorized as unfavorable, neutral, or favorable. Responses across medication classes were compared using the Mann-Whitney U test. RESULTS: Thirteen studies were included, yielding a cohort of 123 individuals with a median age of 53 years (range: 23-83 years), with 61% (75/123) being women. No controlled trials were identified. Simple analgesics (35.8%, 44/123) and beta-blockers (22.0%, 27/123) were the most common abortive and prophylactic strategies, respectively. Over half (54.4%) of all patients had used more than 1 medication sequentially or concomitantly. Beta-blockers were significantly associated with a neutral or unfavorable response (13.5%, 22/163, p = 0.004). We found no significant associations among other medication categories. CONCLUSIONS: Migraine in CADASIL remains a formidable therapeutic challenge, with patients often tried on several medications. Antimigraine prophylaxis with beta-blockers may be contraindicated relative to other common therapies in CADASIL. Controlled studies are needed to rigorously evaluate the safety and efficacy of antimigraine therapies in this population.

Cerebral Small Vessel Disease Burden and All-Cause Mortality: Mayo Clinic Florida Familial Cerebrovascular Diseases Registry.

GOAL: Cerebral small vessel disease (CSVD) leads to cognitive decline, gait disturbances, mood changes, and an increased risk of stroke. The goal of this study is to describe the relationship between a composite radiographic CSVD score and all-cause mortality. MATERIALS AND METHODS: Data were collected from a prospective registry of patients with and without cerebrovascular disease from November 2010 through April 2018. The radiographic Total CSVD Score (tSVD) ranges from 0 (minimal disease) to 4 (severe disease), based on detection of lacunar infarcts, cerebral microbleeds, perivascular spaces, and subcortical or periventricular white matter hyperintensities. All-cause mortality served as the primary endpoint. The independent relationship between CSVD burden and all-cause mortality was assessed using Cox regression models with significance being P < .05. FINDINGS: Four hundred and forty-nine patients were included (mean age, 63 years; 50.1% [225 of 449] women). The hazard ratio for mortality significantly increased with advancing score (1.92, P = .014 score 1; 2.92, P < .001 score 2; 4.23, P < .001 combined scores 3 and 4). Significance remained despite adjustment for coexistent cerebrovascular risk factors aside from age. CONCLUSIONS: The clinically practical tSVD score may serve as a predictor for all-cause mortality in populations with high disease prevalence. Continued investigations are needed to better understand the effects of risk factor modification on mortality and pathogenesis with the goal of developing disease modifying therapies.

A Cross-Sectional Analysis of Migraine-Related Disability in CADASIL: A Mayo Clinic Cohort.

OBJECTIVES: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is inherited microangiopathy characterized by recurrent subcortical infarcts. A majority of those with CADASIL report coexistent migraine with aura. The authors aim to quantitatively describe migraine-related disability within a CADASIL cohort. METHODS: A cross-sectional analysis was performed in a cohort of CADASIL. The Migraine Disability Assessment (MIDAS) quantified migraine-related disability. Further metrics obtained include first and last migraine, aura semiology, and therapeutic measures. RESULTS: Twenty-four individuals were included [63% (15/24) female individuals; mean age, 56 y; range, 34 to 81 y]. Fifty-four percent (13/24) reported migraine, whereas 46% (11/24) reporting varying degrees of migraine-related disability. MIDAS Questionnaire scores appeared bimodal: 58% (14/24) scored 0 to 5, 7% (1/24) scored 6 to 10, 7% (1/24) scored 11 to 20 and 33% (8/24) scored over 20. Severe disability was associated with the multiplicity of aura semiologies and poor response to pharmacologic prophylaxis. CONCLUSIONS: A bimodal distribution of migraine-related disability was observed. A third of individuals had a severe disability and appeared medically refractory to medical migraine prophylactic measures. This study may serve as a reference point for future trials quantitatively gauging response of novel migraine treatment strategies within this unique population.

Pharmacotherapy for Patients with Atrial Fibrillation and Cerebral Microbleeds.

BACKGROUND: Patients with cerebral microbleeds have increased risk of intracranial hemorrhage and ischemic stroke. No trial specifically informs antithrombotic therapy for patients with cerebral microbleeds and atrial fibrillation. We investigated the safety of anticoagulation versus no anticoagulation with regard to cerebrovascular outcomes and mortality. METHODS: All consecutive atrial fibrillation patients from 2015 to 2018 with MRI evidence of ≥1 cerebral microbleed at time of imaging were reviewed. Patients were treated with warfarin, direct oral anticoagulants, or neither. Primary outcome was all-cause mortality informed by National Death Registry and the composite of ischemic and hemorrhagic stroke. All statistical tests were 2-sided and significant at P < .05. RESULTS: The median interval from patient identification until the end of electronic health record surveillance was 9.93 months (interquartile range, 2.83-19.17 months). We identified 308 atrial fibrillation patients with cerebral microbleeds; 128(41.6%) were on warfarin, 88(28.6%) on direct oral anticoagulants, and 92(29.9%) on neither. Over the surveillance interval, 87 deaths, 51 ischemic strokes, and 14 hemorrhagic strokes occurred. The estimated likelihoods of the composite stroke outcome and ischemic stroke only did not differ significantly among the 3 groups. However, patients taking direct oral anticoagulants had a significantly smaller likelihood of all-cause mortality than patients who were not anticoagulated (adjusted hazard ratio: .44[.23, .83], P=.012). CONCLUSIONS: In patients with coprevalent atrial fibrillation and cerebral microbleeds, we did not detect differences in subsequent ischemic stroke, hemorrhagic stroke, or both, comparing warfarin, direct oral anticoagulants, or neither. Patients treated with direct oral anticoagulants had better survival than nonanticoagulated patients.

CNS small vessel disease: A clinical review.

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.

Severity of White Matter Hyperintensities and Effects on All-Cause Mortality in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry.

OBJECTIVE: To compare all-cause mortality rates across the severity range of white matter hyperintensities (WMH). PATIENTS AND METHODS: Between October 26, 2010, and October 5, 2017, the ongoing Mayo Clinic Florida Familial Cerebrovascular Diseases Registry prospectively enrolled 1011 diverse participants with and without cerebrovascular disease. T2-weighted magnetic resonance imaging of the brain was used to evaluate WMH in 455 participants using the Fazekas scale. Fazekas deep WMH (FD) and periventricular WMH (FPV) scores (0-3 points) were assigned on the basis of WMH severity. Kaplan-Meier survival analyses, Cox proportional hazards models, and estimated hazard ratios compared survival rates across FD and FPV categories. The Fisher exact and χ2 tests evaluated the relationship of categorical variables, and the Kruskal-Wallis test measured the relationship of continuous variables across FD and FPV categories. All tests were performed at a P<.05 significance level. RESULTS: Over a median follow-up of 3.06 years (range, 0.00-6.96 years), 96 deaths occurred. Higher FD scores corresponded to a higher likelihood of mortality (P<.001). Participants with an FD score of 3 were 4.69 (95% CI, 2.60-8.46) times more likely to die compared with those with an FD score of 0. Participants with higher FPV scores had a higher likelihood of mortality (P<.001). Participants with an FPV score of 3 were 7.04 (95% CI, 3.39-14.62) times more likely to die compared with those with an FPV score of 0. Once adjusted, age and baseline functional status explained most of the survival differences among the FD scores. CONCLUSION: Associations between all-cause mortality rates across the severity range of WMH were observed in the Registry. Further studies are warranted to understand the clinical importance of WMH in other clinical populations.