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Background Small vessel disease (SVD), and most specifically hereditary forms like CADASIL and cerebral amyloid angiopathy (hCAA), are conditions of increasing clinical importance. We report a rare case of hCAA in a Greek family that presented with a CADASIL clinical and neuroimaging phenotype. Methods A 65-year-old man was admitted with recurrent transient episodes of right leg numbness. The patient's medical history started at the age of 50 years with depression and behavioral disorders. His family history was positive for stroke (father), dementia (father and brother), migraine (daughter) and depression (father and daughter). Results Neurological examination disclosed anomic aphasia with severely impaired cognitive status, and brisk reflexes. Brain computed tomography and magnetic resonance imaging showed CADASIL-like leukoencephalopathy (hyperintense lesions in bilateral temporopolar area, external capsule, thalami, centrum semiovale and superior frontal regions) with occipital calcifications and cerebral microbleeds. Screen for variants in NOTCH3 gene was negative. Exome sequencing revealed a novel pathogenic mutation for hCAA. Conclusions We report a novel amyloid precursor protein mutation which results in a CADASIL-like clinical phenotype (progressive cognitive and motor decline, stroke, migraine and behavioral disorders) and CADASIL-leukoencephalopathy coupled with occipital calcifications. Earlier recognition and swift hCAA diagnosis may prompt rational preventive and potential disease-modifying interventions.

Emerging studies highlight high on-treatment of platelet reactivity (HTPR) as a major hindrance to the secondary prevention of cardiovascular ischemic events. The aim of this systematic review and meta-analysis is to assess the prevalence of HTPR in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and reveal a possible relation with a higher risk of cerebrovascular event recurrence. Studies were selected if they reported absolute numbers or percentages of HTPR with ASA or clopidogrel in IS/TIA patients at any time point after the cerebrovascular event onset and assessed with any type of platelet function tests. We included 52 full-text studies with a total of 8364 patients. Overall, the pooled prevalence of HTPR was 24% (95%CI: 20-27%). In subgroup analyses, the prevalence of HTPR on ASA was 23% (95%CI: 20-28%), on clopidogrel 27% (95%CI: 22-32%) and on dual antiplatelet treatment (DAPT) 7% (95%CI: 5-10%). The overall analysis of all studies providing data on the risk of IS/TIA recurrence, indicates that the patients with HTPR had a significantly higher risk for IS/TIA recurrence (RR=1.81, 95%CI: 1.30-2.52; p

Objective We performed a systematic review and meta-analysis to evaluate the proposed association of restless legs syndrome (RLS) with cerebrovascular/cardiovascular outcomes. Methods We calculated the corresponding odds ratios on the prevalence of cerebrovascular/cardiovascular risk factors and standardized mean differences on the reported mean age at baseline between RLS patients and controls. We also calculated the corresponding risk ratios and adjusted for potential confounders hazard ratios (HRsadjusted) on the reported outcomes of interest between RLS patients and controls. Results We identified 8 eligible studies (644 506 patients, mean age: 60.2 years, 36.2% males; 3.3% with RLS). RLS patients were found to have significantly higher prevalence of hypertension (P = .002), diabetes (P = .003) and hyperlipidemia (P = .010) compared to controls. In the unadjusted analyses of prospective observational studies, RLS patients were found to have significantly higher risk for cerebrovascular ischaemia (P = .01) and all-cause mortality (P = .04) compared to controls during follow-up, while in the adjusted for potential confounders analyses RLS patients were only found to have a higher risk of all-cause mortality (HR adjusted=1.52, 95% CI: 1.17-1.97, P = .002). Conclusions The present report does not provide evidence for an increased risk of cerebrovascular and cardiovascular events in RLS patients, which highlights the vast presence of confounding factors.

Dear Editor, A 44 year-old female patient was admitted via the emergency room with an acute-onset left-sided frontal-temporal headache. The patient's medical history of migraines and superficial venous thrombosis was significant, but she did not take any regular medications. No history of smoking, excessive alcohol consumption, or drug use was reported, nor any family history of stroke/myocardial infarction or angiopathy. The patient did not complain of other symptoms. A neurological examination revealed no focal deficits or other findings. There were no pathological findings in a brain CT scan performed at admission. However, a MRI scan performed 24 hours later produced findings consistent with acute infarction of the temporal branch of the left middle cerebral artery (Supplementary Fig. 1 in the online-only Data Supplement). The patient was put on dual antiplatelet therapy (aspirin and clopidogrel), in accordance with current American Heart Association/American Stroke Association guidelines, pending further diagnostic workup. Blood screening did not identify any vascular risk factors, including hypercholesterolemia, diabetes mellitus, coagulation disorders, or autoimmune diseases. The results of a cardiologic evaluation, including transthoracic echocardiography and 24-hour Holter monitoring, were normal. CT angiography revealed no stenoses in either extracranial or intracranial vessels. Transesophageal echocardiography (TEE) revealed the presence of a patent foramen ovale (PFO) with a large right-to-left shunt during the Valsalva maneuver (Fig. 1), and so the antiplatelet treatment was switched to oral anticoagulation with acenocoumarol due to the history of superficial venous thrombosis.1 The patient remained asymptomatic during the hospital stay and was discharged with no deficit. At the 3-month after stroke onset re-evaluation the patient remained asymptomatic with no cerebrovascular incident recurrence. Fig. 1 Patent foramen ovale with a large right-to-left shunt during the Valsalva maneuver (>20 microbubbles) identified using transesophageal echocardiography. There is increasing skepticism about the diagnostic utility of TEE in patients with cryptogenic cerebral ischemia, due to both the high intrarater variability for the method and the low prevalence of identified cardiac conditions that are finally considered to be causally associated with the ischemic event.2 This controversy led to the currently proposed criteria for the definition of embolic strokes of undetermined source (ESUS), which do not include TEE in the mandatory diagnostic workup for an ESUS diagnosis.3 In the present case report, all of the results obtained in the routine diagnostic stroke workup were normal, whereas TEE finally not only uncovered the missing link between superficial venous thrombosis, migraine,4 and cerebral ischemia and the possible underlying pathophysiological mechanism, but also had a crucial impact on secondary prophylaxis and prognosis.5 Because of the patient's young age, the absence of conventional vascular risk factors, the presence of a superficially located lesion (risk of paradoxical embolism score=8/10), and the history of lower limb phlebothrombosis, the discovered PFO was considered to be stroke-related rather than incidental.6 This case report suggests that patients with cerebral ischemia in the absence of conventional risk factors should undergo investigation with TEE to search for potential cardiogenic or aortogenic embolic sources. It also demonstrates that examining single cases can lead to important observations with significant clinical applications.7 Not all of the important clinical answers can be answered by large-scale analyses of possibly heterogeneous patients. In cases of ESUS, we should continue the thorough search of the locations, from which embolic material arrise.8