Brain-specific biomarkers in urine as a non-invasive approach to monitor neuronal and glial damage.

BACKGROUND AND PURPOSE: This study evaluates the quantitative measurability of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and total tau (t-tau) in urine of patients with acute cerebral damage. METHODS: Serum and urine samples were prospectively collected from patients with an acute ischemic stroke or intracerebral hemorrhage (target group) and compared to healthy subjects (control group); samples were measured using ultrasensitive single-molecule arrays (Simoa®). Glomerular barrier function was assessed based on albumin-creatinine ratio (ACR); biomarker-creatinine ratios were calculated for correction of urine dilution. RESULTS: Ninety-three urine-serum pairs in the target group and 10 urine-serum pairs in the control group were measured. The mean absolute concentration ± standard deviation in urine of the target and control groups were 184.7 ± 362.4 pg/ml and 27.3 ± 24.1 pg/ml for GFAP (r = 0.3 [Wilcoxon effect size], p = 0.007), 17.5 ± 38.6 pg/ml and 0.9 ± 0.3 pg/ml for NfL (r = 0.4, p < 0.005), 320.2 ± 443.3 pg/ml and 109.6 ± 116.8 pg/ml for UCH-L1 (r = 0.26, p = 0.014), and 219.5 ± 255.8 pg/ml and 21.1 ± 27.1 pg/ml for t-tau (r = 0.37, p < 0.005), respectively, whereas biomarker-creatinine ratio was significantly different only for NfL (r = 0.29, p = 0.015) and t-tau (r = 0.32, p < 0.01). In patients with intact glomerular barrier (ACR < 30 mg/g), only NfL in urine was significantly different between the target and control group and showed a significant correlation with the respective serum concentrations (r = 0.58 [Pearson's correlation-coefficient], p < 0.005). CONCLUSION: All four investigated biomarkers could be measured in urine, with NfL and t-tau showing the strongest effect size after correction for urine dilution. NfL revealed the most accurate relation between serum and urine concentrations in patients with intact kidney function.

Moyamoya associated with Turner syndrome in a patient with type 2 spinocerebellar ataxia-Occam's razor or Hickam's dictum: a case report.

BACKGROUND: Turner syndrome (TS) is a rare condition associated with a completely or partially missing X chromosome that affects 1 in 2500 girls. TS increases the risk of autoimmune diseases, including Graves' disease (GD). Moyamoya disease is a rare cerebral arteriopathy of unknown etiology characterized by progressive bilateral stenosis of the internal carotid artery and its branches. Both TS and GD have been associated with Moyamoya. Type 2 spinocerebellar ataxia (SCA2) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in ATXN2. We present the first case of Moyamoya syndrome in a patient with a previous diagnosis of TS and GD who tested positive for SCA2 and had imaging findings compatible with an overlap of SCA2 and Moyamoya. CASE PRESENTATION: A 43-year-old woman presented with mild gait imbalance for 2 years. Her family history was positive for type 2 spinocerebellar ataxia (SCA2). She had been diagnosed with Turner Syndrome (45,X) and Graves disease three years before. Brain MRI revealed bilateral frontal and parietal cystic encephalomalacia in watershed zones, atrophy of pons, middle cerebellar peduncles and cerebellum. MR angiography showed progressive stenosis of both internal carotid arteries with lenticulostriate collaterals, suggestive of Moya-Moya disease. Molecular analysis confirmed the diagnosis of SCA2. CONCLUSIONS: With increased availability of tools for genetic diagnosis, physicians need to be aware of the possibility of a single patient presenting two or more rare diseases. This report underscores the modern dilemmas created by increasingly accurate imaging techniques and available and extensive genetic testing.

Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis.

BACKGROUND AND PURPOSE: Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19. METHODS: We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I2 statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194. RESULTS: Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I2  = 0%, P = 0.82). CONCLUSIONS: Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke.

Recurrent versus first cervical artery dissection - a retrospective study of clinical and vascular characteristics.

BACKGROUND AND PURPOSE: Most recurrent cervical artery dissection (CeAD) events occur shortly after the acute first CeAD. This study compared the characteristics of recurrent and first CeAD events and searched for associations between subsequent events of an individual person. METHODS: Cervical artery dissection patients with a new CeAD event occurring during a 3-6 month follow-up were retrospectively selected in seven specialized stroke centers. Clinical and vascular characteristics of the initial and the recurrent CeADs were compared. RESULTS: The study sample included 76 patients. Recurrent CeADs were occlusive in one (1.3%) patient, caused cerebral ischaemia in 13 (17.1%) and were asymptomatic in 39 (51.3%) patients, compared to 29 (38.2%) occlusive, 42 (55.3%) ischaemic and no asymptomatic first CeAD events. In 52 (68.4%) patients, recurrent dissections affected both internal carotid arteries or both vertebral arteries, whilst 24 (31.6%) patients had subsequent dissections in both types of artery. Twelve (28.6%) of 42 patients with an ischaemic first dissection had ischaemic symptoms due to the recurrent CeADs, too. However, only one (1.3%) of 34 patients with a non-ischaemic first CeAD suffered ischaemia upon recurrence. CONCLUSION: Recurrent CeAD typically affects the same site of artery. It causes ischaemic events less often than the first CeAD. The risk that patients who presented with solely non-ischaemic symptoms of a first CeAD will have ischaemic symptoms in the case of a recurrent CeAD seems very small.

Large vessel occlusion is independently associated with atrial fibrillation detection.

BACKGROUND AND PURPOSE: Covert paroxysmal atrial fibrillation (pAF) is the most frequent cause of cardiac embolism. Our goal was to discover parameters associated with early pAF detection with intensive cardiac monitoring. METHOD: Crypto-AF was a multicentre prospective study (four Comprehensive Stroke Centres) to detect pAF in non-lacunar cryptogenic stroke continuously monitored within the first 28 days. Stroke severity, infarct pattern, large vessel occlusion (LVO) at baseline, electrocardiography analysis, supraventricular extrasystolia in the Holter examination, left atrial volume index and brain natriuretic peptide level were assessed. The percentage of pAF detection and pAF episodes lasting more than 5 h were registered. RESULTS: Out of 296 patients, 264 patients completed the monitoring period with 23.1% (61/264) of pAF detection. Patients with pAF were older [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.08], they had more haemorrhagic infarction (OR 4.03, 95% CI 1.44-11.22), they were more likely to have LVO (OR 4.29, 95% CI 2.31-7.97) (P < 0.0001), they had a larger left atrial volume index (OR 1.03, 95% CI 1.01-1.1) (P = 0.0002) and they had a higher level of brain natriuretic peptide (OR 1.01, 95% CI 1.0-1.1). Age and LVO were independently associated with pAF detection (OR 1.06, 95% CI 1.00-1.16, and OR 4.58, 95% CI 2.27- 21.38, respectively). Patients with LVO had higher cumulative incidence of pAF (log rank P < 0.001) and more percentage of pAF > 5 h [29.6% (21/71) vs. 8.3% (12/144); OR 4.62, 95% CI 2.11-10.08; P < 0.001]. In a mean follow-up of 26.82 months (SD 10.15) the stroke recurrence rate was 4.6% (12/260). CONCLUSIONS: Large vessel occlusion in cryptogenic stroke emerged as an independent marker of pAF.

Fatal intracranial haemorrhage occurring after oral anticoagulant treatment initiation for secondary stroke prevention in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). METHODS: Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed. RESULTS: During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09-1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51-0.95). CONCLUSIONS: Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH.

Statin treatment and accrual of covert cerebral ischaemia on neuroimaging: a systematic review and meta-analysis of randomized trials.

BACKGROUND AND PURPOSE: Prevention of ischaemic stroke and cardiovascular events is an established benefit of statin therapy, but the effects of statin treatment on the accrual of magnetic resonance imaging (MRI) markers of ischaemic cerebral injury remain unknown. A systematic review was performed to identify all studies that randomized patients with cardiovascular risk factors to statin treatment and assessed the effect of statin treatment on covert infarcts (asymptomatic, evident only on neuroimaging) and white matter hyperintensity (WMH) accrual on MRI. METHODS: A systematic review in MEDLINE and Scopus from inception to 23 October 2019 was performed. A random-effects model was used to calculate the pooled estimates of the crude risk ratios and standardized mean differences. RESULTS: Data from three randomized controlled trials (1430 participants) were included evaluating the effect of rosuvastatin (10 mg/day) in 668 hypertensive patients older than 60 years of age over 5 years, pravastatin (40 mg/day) in 554 elderly people more than 70 years of age over 3 years and simvastatin (20 mg/day) in 208 patients with asymptomatic middle cerebral artery stenosis over 2 years. Patients randomized to statin treatment had decreased accrual of new covert infarcts (risk ratio 0.63, 95% confidence interval 0.46-0.88) during a mean follow-up of 2-6 years. Only one study reported WMH decreased volume change in patients randomized to statin treatment compared to patients randomized to non-statin treatment (standardized mean difference -1.17; 95% confidence interval -1.33, -1.00). CONCLUSION: Our findings suggest that, in addition to stroke prevention, statin treatment can reduce the accrual of covert MRI markers of ischaemic cerebral injury.

Colchicine for stroke prevention in patients with coronary artery disease: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Although clinical trials suggest that colchicine may reduce the risk of vascular events in patients with a history of coronary artery disease, its effect on the prevention of cerebrovascular events still remains unclear. METHODS: A systematic review and meta-analysis was performed of all available randomized controlled trials (RCTs) reporting on incident strokes during the follow-up of patients with a history of cardiovascular disease randomized to colchicine treatment or control (placebo or usual care). RESULTS: Four RCTs were identified, including a total of 5553 patients (mean age 61 years, 81% males), with a follow-up ranging from 1 to 36 months. Colchicine treatment was associated with a significantly lower risk of incident stroke during follow-up compared to control (risk ratio 0.31, 95% confidence interval 0.13-0.71), without heterogeneity across included studies (I2  = 0%). Based on the pooled incident stroke rate of control groups (0.9%) in the included RCTs, it was estimated that administration of low-dose colchicine to 161 patients with coronary artery disease would prevent one stroke during a follow-up of 23 months. CONCLUSION: Colchicine treatment decreases stroke risk in patients with a history of coronary artery disease. The effect of colchicine in secondary stroke prevention is currently being evaluated in an ongoing RCT.

CADASIL: yesterday, today, tomorrow.

BACKGROUND AND PURPOSE: In 2019, the Brain Prize crowned the discovery of CADASIL in the 1990s and research efforts on this archetypal small vessel disease of the brain over 40 years. METHODS AND RESULTS: The hereditary origin of this arteriolopathy was discovered from a first clinical case and detailed observation of the patient's family. Thereafter, the role of causative mutations within the NOTCH3 gene were identified, allowing the development of a genetic test and then of an animal model of the disease. These crucial steps led to the discovery progressively that CADASIL is the most common genetic cerebral small vessel disease, to describing for the first time the natural history of a cerebral ischaemic small vessel disease from silent cerebral tissue lesions up to severe motor disability and dementia at the end stage, to demonstrating the central role of matrix proteins in its pathophysiology and to opening the door to the discovery of several other genes involved in monogenic cerebral small vessel diseases. DISCUSSION: Today, CADASIL is known to every neurologist, but the disease has not yet revealed all its secrets. A lot of effort is still needed to understand the intimate mechanisms of the disease and the most efficient targets or approaches for the development of efficient therapeutics. The history of CADASIL will be further enriched by multiple ongoing research projects worldwide, at clinical and preclinical level, and will continue to enlighten research in the field of cerebral small vessel disorders.

Ischaemic stroke.

There are about 25.7 million stroke survivors worldwide. Ischaemic stroke remains the most common type of stroke. Numerous modifiable risk factors have been identified, including behaviors such as cigarette smoking and sedentary lifestyle and treatable medical comorbidities such as hypertension, hyperlipidemia and atrial fibrillation. Once considered irreversible, acute ischaemic stroke is now amenable to acute medical and endovascular therapies to reduce infarct volume. Many advances are expected in the years to come, particularly in the areas of prevention and recovery.

Intracranial pressure and cerebral perfusion pressure during apnoea testing for the diagnosis of brain death - an observational study.

BACKGROUND AND PURPOSE: Some authors have suggested a rise of intracranial pressure (ICP) during apnoea testing and the possibility of harm to patients. Data, however, have yet to be obtained. METHODS: Between October 2012 and May 2014 an observational study was performed on patients who received ICP measurements and who underwent brain death diagnosis. ICP, cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP) and heart rate were recorded continuously from 15 min before the start of brain death diagnosis (baseline), during clinical examination including apnoea testing, until 15 min after this procedure. RESULTS: A total of 16 clinical examinations for brain death including apnoea testing were performed on 13 patients. All patients had primary brain lesions. Mean ICP and mean CPP during the examination were 95 ± 27.7 mmHg and 13.5 ± 20.7 mmHg, respectively. ICP and MAP showed a strong and statistically significant correlation, with Pearson's correlation coefficients of more than +0.6 or less than -0.6 in 13 of the 15 examinations. CONCLUSION: Mean ICP even before brain death determination is increased excessively. Changes of ICP during apnoea show a clear correlation to the changes of MAP. Furthermore, CPP during the condition of brain death may not equal zero but may be positive thereby indicating some minor net influx of blood into the brain in some patients.

Outcomes of intravenous tissue plasminogen activator for acute ischaemic stroke in HIV-infected adults.

BACKGROUND AND PURPOSE: To our knowledge there are no studies reporting the use and short-term outcomes of intravenous tissue plasminogen activator (IV-TPA) for the treatment of acute ischaemic stroke (AIS) in people living with HIV. METHODS: The US Nationwide Inpatient Sample (NIS) (2006-2010) was searched for HIV-infected AIS patients treated with IV-TPA. RESULTS: In the NIS, 2.2% (62/2877) of HIV-infected AIS cases were thrombolyzed with IV-TPA (median age 52 years, range 27-78, 32% female, 22% Caucasian) vs. 2.1% (19 335/937 896) of HIV-uninfected cases (median age 72 years, range 17-102 years, 50% female, 74% Caucasian; P = 0.77). There were more deaths in HIV-infected versus uninfected patients with stroke (220/2877, 7.6% vs. 49 089/937 547, 5.2%, P < 0.001) but no difference in the proportion of deaths amongst IV-TPA-treated patients. The age- and sex-adjusted odds ratio for death following IV-TPA administration in HIV-infected versus uninfected patients was 2.26 (95% CI 1.12, 4.58), but the interaction on mortality between HIV and IV-TPA use was not statistically significant, indicating no difference in risk of in-hospital death by HIV serostatus with IV-TPA use. A higher number of HIV-infected patients remained in hospital versus died or were discharged at both 10 and 30 days (P < 0.01 at 10 and 30 days). No difference in the proportion of intracerebral hemorrhage in the two groups was found (P = 0.362). CONCLUSIONS: The in-hospital mortality is higher amongst HIV-infected AIS patients than HIV-uninfected patients. However, the risk of death amongst HIV-infected patients treated with IV-TPA is similar to HIV-uninfected groups.

Borderzone Infarction and Small Vessel Disease in a Sample of Egyptian Stroke Patients: Differences and Similarities.

BACKGROUND: The anatomical location of white matter hyperintense lesions in small vessel disease are apparently similar to those of borderzone infarction. The objective of this study is to find clinical and radiological points of differentiation between the two vascular disorders in a sample of Egyptian patients which might have an impact on primary and secondary prevention. METHODS: Ischemic stroke patients with white matter lesions were categorized into two groups: small vessel disease and borderzone infarctions. NIHSS was done on admission. Risk factor profile was reported, and investigations done including: HbA1C, lipid profile, CRP, ECG, echocardiography, carotid duplex, brain MRI, MRA and MR perfusion study. RESULTS: 46 patients completed the study, 29 with SVD and 17 with BZI. Smoking, hypertension and recurrent stroke were more common in borderzone infarctions, but only diabetes was significantly higher (p = 0.047). Limb shaking was more observed in borderzone infarctions (p = 0.049). Radiologically: lacunar pattern was observed more in small vessel disease, while rosary pattern was more in borderzone infarctions (p = 0.04). FLAIR symmetrical lesions and microbleeds were more significant in small vessel disease (p = <0.001; 0.048, respectively). Perfusion study time to peak denoted evidence of significant hypoperfusion in all regions of interest in borderzone infarctions. CONCLUSION: Limb shaking, retinal claudication or syncope, with MRI showing rosary pattern of white matter hyperintensity, few microbleeds and markedly impaired perfusion favor the diagnosis of borderzone infarctions. On the other hand, presence of lacunae, FLAIR showing symmetrical WMH and microbleeds with minimal or no perfusion deficit suggests the diagnosis of small vessel disease.