Iatrogenic cerebral amyloid angiopathy: A multinational case series and individual patient data analysis of the literature.

BACKGROUND: The transmission of amyloid ß (Aß) in humans leading to iatrogenic cerebral amyloid angiopathy (iCAA) is a novel concept with analogies to prion diseases. However, the number of published cases is low, and larger international studies are missing. AIMS: We aimed to build a large multinational collaboration on iCAA to better understand the clinical spectrum of affected patients. METHODS: We collected clinical data on patients with iCAA from Austria, Croatia, Italy, Slovenia, and Spain. Patients were included if they met the proposed Queen Square diagnostic criteria (QSC) for iCAA. In addition, we pooled data on disease onset, latency, and cerebrospinal fluid (CSF) biomarkers from previously published iCAA cases based on a systematic literature review. RESULTS: Twenty-seven patients (22% women) were included in this study. Of these, 19 (70%) met the criteria for probable and 8 (30%) for possible iCAA. Prior neurosurgical procedures were performed in all patients (93% brain surgery, 7% spinal surgery) at median age of 8 (interquartile range (IQR) = 4-18, range = 0-26 years) years. The median symptom latency was 39 years (IQR = 34-41, range = 28-49). The median age at symptom onset was 49 years (IQR = 43-55, range = 32-70). Twenty-one patients (78%) presented with intracranial hemorrhage and 3 (11%) with seizures. CONCLUSIONS: Our large international case series of patients with iCAA confirms a wide age boundary for the diagnosis of iCAA. Dissemination of awareness of this rare condition will help to identify more affected patients.

Subclinical atherosclerosis in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory disorder of the central nervous system. Inflammation may create high susceptibility to subclinical atherosclerosis. The purpose of this study was to compare subclinical atherosclerosis and the role of inflammatory cytokines between the group of patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls matched for age and sex. METHODS: The study group consisted of 112 non-diabetic and non-hypertensive RRMS patients treated with disease modifying drugs (DMD) and the control group was composed of 51 healthy subjects. The common carotid artery (CCA) intima media thickness (IMT) was investigated. Serum levels of risk factors for atherosclerosis and inflammatory cytokines were also determined. RESULTS: The mean CCA IMT (0.572 ± 0.131 mm vs. 0.571 ± 0.114 mm) did not differ (p > 0.05) between patients and controls. The RRMS patients' CCA IMT was significantly correlated with serum interleukin 6 (IL-6) (p = 0.027), high-sensitivity C-reactive protein (hs-CRP) (p = 0.027), cystatin C (p < 0.0005), glucose (p = 0.031), cholesterol (p = 0.008), LDL (p = 0.021), erythrocyte sedimentation rate (p = 0.001) and triglyceride (p = 0.018) level. We fitted generalized linear models in order to assess the relationship between CCA IMT and IL­6 with adjustment for sex and age. The obtained results showed that adjusted for age (p < 0.001) and sex (p = 0.048) IL­6 serum levels statistically significantly (p = 0.009) predict CCA IMT only in the RRMS group. CONCLUSION: The findings of the present study suggest that when treated with DMD RRMS might not be an independent risk factor for early atherosclerosis presenting with arterial wall thickening; however, the results suggest a significant association of IL­6 serum levels with CCA IMT only in the RRMS group.

Intracranial Vertebrobasilar Calcification in Patients with Ischemic Stroke is a Predictor of Recurrent Stroke, Vascular Disease, and Death: A Case-Control Study.

Intracranial artery calcification can be detected on nonenhanced brain computer tomography (NECT) and is a predictor of early vascular events. Here, we assessed the impact of vertebrobasilar artery calcification (VBC) on the long-term risk for recurrent stroke and vascular events. We performed a case-control trial of all consecutive stroke patients admitted to the University Hospital of Maribor, Slovenia over a period of 14 months. VBC was defined as presence of a hyperdense area within vertebrobasilar arteries that exceeds > 90 Hounsfield units as seen on NECT. Clinical follow-up information was obtained from the hospital documentation system and mortality registry of the district and included recurrent stroke, subsequent vascular events (myocardial infarction, heart failure, peripheral arterial occlusive disease), and death. We followed a total of 448 patients for a median of 1505 days (interquartile range, IQR 188-2479). Evidence for VBC was present in 243 (54.2%) patients. Median age was 76 years, recurrent stroke occurred in 33 (7.4%), any vascular events in 71 (15.8%), and death in 276 (61.6%). VBC was associated with a higher risk of recurrent stroke (hazard ratio, HR 3.13, 95% confidence interval (CI 1.35-7.20)) and vascular events (HR 2.05, 95% CI 1.21-3.47). Advanced age, male gender, and ischemic stroke involving the entire anterior circulation raised the likelihood for death. We conclude that the presence of VBC in patients with ischemic stroke is a short- and long-term prognostic factor for stroke recurrence and subsequent manifestation of acute vascular disease. Further understanding of the pathophysiology of VBC is warranted.

Endovascular Therapy for Tandem Occlusion in Acute Ischemic Stroke: Intravenous Thrombolysis Improves Outcomes.

Ischemic stroke related to tandem internal carotid and middle cerebral artery (TIM) occlusion is a challenging condition where endovascular treatment (EVT) is an emerging revascularization option. The identification of factors influencing clinical outcomes can assist in creating appropriate therapeutic algorithms for such patients. This study aimed to evaluate prognostic factors in the context of EVT for TIM occlusion. We performed a retrospective study of consecutive patients with TIM occlusion admitted within 6 h from symptom onset to two tertiary stroke centers. We recorded the etiology of stroke, clinical deficits at stroke onset and discharge, details of EVT, final infarct volume (FIV), in-hospital mortality, and outcome at three months. Among 73 patients with TIM occlusion, 53 were treated with EVT. The median age was 75.9 years (interquartile range (IQR) 64.6⁻82.6), with the most common etiology of cardioembolism (51.9%). Intravenous thrombolysis with tissue-plasminogen activator (t-PA) was performed in the majority (69.8%) of cases. EVT achieved successful recanalization with a thrombolysis in cerebral infarction (TICI) grade of 2b or 3 in 67.9%. A good outcome (modified Rankin score of 0⁻2 at three months) was observed in 37.7%. After adjustment for age, the National Institutes of Health Stroke Scale (NIHSS) at admission, and success of recanalization, smaller final infarct volume (odds ratio (OR) 0.021 for FIV above 25th percentile (95% CI 0.001⁻0.332, p = 0.005)) and administration of intravenous t-PA (OR 12.04 (95% CI 1.004⁻144.392, p = 0.049)) were associated with a good outcome at three months. Our study demonstrates that bridging with t-PA is associated with improved outcomes in the setting of tandem ICA and MCA occlusions treated with EVT and should therefore not be withheld in eligible patients.

Prolonged-release fampridine in multiple sclerosis: clinical data and real-world experience. Report of an expert meeting.

Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4-7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and re-treatment, and stopping criteria. This article summarizes the experts' opinions on how PR-fampridine can be used in real-world clinical practice to optimize the benefits to people with MS with impaired walking ability.

Proximal flow to middle cerebral artery is associated with higher thrombus density in terminal internal carotid artery occlusion.

Proximal collaterals may determine the composition of occluding thrombi in acute ischemic stroke (AIS) in addition to source, hematocrit, time, and medication. Here, we performed a retrospective study of 39 consecutive patients with radiological evidence of I-, L-, and T-type terminal internal carotid artery occlusion. Middle cerebral artery (MCA) thrombus density was assessed on noncontrast enhanced CT and proximal collaterals on CT angiography. In patients with presence of proximal collaterals to the MCA we detected more hyperdense clots (P = 0.003) and a higher frequency of leptomeningeal collaterals (P = 0.008). We expand the spectrum of factors that potentially determine clot perviousness and evolution of ischemic stroke.

Sigmoid Sinus Characteristics Correlate with Early Clinical and Imaging Surrogates in Anterior Circulation Ischemic Stroke.

Cerebral venous outflow may play a decisive role in acute ischemic stroke. Here, we assessed the relation of cerebral sinus vein characteristics with clinical and imaging surrogates of early outcome in acute ischemic stroke. We evaluated cerebral vein characteristics in 212 patients with the middle cerebral artery (MCA) occlusive stroke confirmed by CT angiography CTA within 6 h from symptom onset. Readout parameters included volume and density of the sigmoid sinus (SS) and density of the superior sagittal sinus (SupSagS). These were correlated with early clinical outcome defined as hospital death (HD), final infarct volume (FIV), and National Institute of Health Stroke Scale (NIHSS) at discharge. We found a correlation for the volume of the right SS and the FIV when the M1 segment of the MCA of either side was occluded (p = 0.002, Rho = 0.206, n = 134). A decrease in SS density was more pronounced in the subgroup with unfavorable outcome (NIHSS > 15 + HD) but only when the left hemisphere was affected (p = 0.026, n = 101). On stepwise logistic regression analysis, adjusted for on-admission NIHSS, age at presentation, and FIV, smaller SS volume was independently associated with lower odds for hospital death (n = 183, OR 0.13, 95 % CI 0.02-0.94, p = 0.043). A larger right SS and a decrease in density increase the risk of unfavorable early clinical and imaging outcome in AIS. This finding of an outflow pattern independent of the stroke site implicates an involvement of the cerebral venous drainage system in the pathophysiology of ischemic stroke.

Intracranial Thrombus Morphology and Composition Undergoes Time-Dependent Changes in Acute Ischemic Stroke: A CT Densitometry Study.

The aim of our study was to assess whether cerebral artery clots undergo time-dependent morphological and compositional changes in acute ischemic stroke. We performed a retrospective chart review of patients admitted within 5 h from symptom onset to three European stroke centers and evaluated non-contrast-enhanced CT (NECT) for hyperdense artery signs (HAS) in 2565 scans. The occlusion site, density of HAS expressed in Hounsfield units (HU), area of HAS, and relative density (rHU) (HU clot/HU non-affected artery) were studied and related to time from symptom onset, clinical severity, stroke etiology, and laboratory parameters. A HAS was present in the middle cerebral artery (MCA) in 185 (7.2%) and further explored. The mean time from symptom onset to CT was 100 min (range 17-300). We found a time-dependent loss of density in the occluded M1 segment within the first 5 h (N = 118, 95% CI [-15, -2], p = 0.01). Further, the thrombus area in the M2 segment decreased with time (cubic trend N = 67, 95% CI [-63, -8], p = 0.02). Overall, and especially in the M2 segment, a lower clot area was associated with higher fibrinogen (-21.7%, 95% CI [-34.8, -5.8], p = 0.009). In conclusion, our results disclosed time-dependent changes of intracranial thrombi with regard to occlusion site, density and area.

Antiplatelet Usage Impacts Clot Density in Acute Anterior Circulation Ischemic Stroke.

We explored whether clot density in middle cerebral artery (MCA) occlusion is related to clinical variables, stroke etiology, blood constituents, and prestroke medication. We performed a retrospective chart review of patients with acute ischemic stroke of the anterior circulation admitted to two Central European stroke centers. The acquisition of non-contrast enhanced CT (NECT) and CT angiography (CTA) within 4.5 h of symptom onset was obligatory. We assessed the site of MCA occlusion as well as density, area, and length of the clot in 150 patients. The Hounsfield unit values for the clot were divided with contralateral MCA segment to yield relative Hounsfield Unit ratio (rHU). The site of the vessel occlusion (M1 vs. M2) and antiplatelet usage, but not stroke etiology, significantly influenced rHU. We found an inverse correlation of rHU with erythrocyte count (p < 0.001). The multivariate analysis revealed that a higher rHU (i.e., clot being more hyperdense) was more likely with the use of antiplatelets (OR 4.24, CI 1.10-16.31, p = 0.036). Erythrocyte (OR 0.18, CI 0.05-0.55, p = 0.003), and thrombocyte counts (OR 0.99, CI 0.98-0.99, p = 0.029) were associated with odds for more hypodense clots (lower rHU). Our study disclosed that antiplatelet therapy impacts the composition of intracranial clots of the anterior circulation.

Are arterial calcifications a marker of remodeling in vertebrobasilar territory?

BACKGROUND AND PURPOSE: Intracranial atherosclerosis is responsible for a substantial proportion of stroke, and vessel calcifications as seen on native computed tomographic scans could be an estimate of its burden. The presence of vertebrobasilar artery calcifications is associated with risk factors. METHODS: This study is a retrospective clinical study on 449 consecutive patients with stroke. Native computed tomographic scans were assessed for the presence of calcification in the intracranial segment of vertebrobasilar artery, and the area of each vessel was calculated from 2 perpendicular diameters. A comprehensive assessment of standard risk factors was recorded. RESULTS: A total of 245 (54.6%) patients had visible calcifications in vertebrobasilar artery. Calcifications were positively associated with advanced age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06; P<0.001), larger total vessel area (odds ratio, 1.01; 95% confidence interval, 1.00-1.01; P<0.001), and history of previous transient ischemic attack/stroke (odds ratio, 1.82; 95% confidence interval, 1.08-3.07; P=0.024). CONCLUSIONS: Higher prevalence of calcifications in vertebrobasilar artery territory of patients with stroke is associated with advanced age, larger arterial area, and history of previous transient ischemic attack/stroke.

Calcifications of vertebrobasilar arteries on CT: detailed distribution and relation to risk factors in 245 ischemic stroke patients.

INTRODUCTION: Intracranial atherosclerosis is responsible for a substantial proportion of strokes worldwide but its detailed morphology in the vertebrobasilar arteries (VBA) is unknown. SUBJECT AND METHODS: Cases with ischemic strokes were retrospectively sought from the hospital database. Native CT scans were assessed for vessel area and intracranial artery calcifications (ICACs) in VBA. The calcifications were classified as focal (FCs), crescent, and circular. RESULTS: 245 patients (mean age: 77.1 ± 10.2 years, 57.6% females) had visible ICACs. Calcifications were found in 75.9%, 63.3%, and 17.1% in the left vertebral artery (LVA), the right vertebral artery (RVA), and the basilar artery (BA), respectively. FCs were present in 91.0%, 90.3%, and 100.0%; crescents in 30.3%, 29.0%, and 7.1%, and circulars in 6.4%, 4.8%, and 0.0% ) and 46 (27.4%) for RVA and LVA, respectively. Risk factors associated with vertical dispersion of ICACs were male gender (OR : 2.69, 1.38-5.28) and diabetes of the RVA, LVA, and BA, respectively. FCs in dorsolateral quadrant were least prevalent in both vertebral arteries (VAs): 46 (29.8%(OR : 2.28, 1.04-4.99). CONCLUSIONS: FCs in VAs are least prevalent in dorsolateral quadrants. The vertical dispersion of ICACs seems to be associated with the male gender and diabetes.