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Introduction There is limited knowledge of the effects of blood pressure (BP) lowering on cerebral haemodynamics after transient ischaemic attack (TIA) and non-disabling stroke, particularly at older ages. We aimed to evaluate changes in transcranial Doppler (TCD) haemodynamic indices in patients undergoing early blood pressure lowering after TIA/non-disabling stroke, irrespective of age. Patients and methods Among consecutive eligible patients attending a rapid-access clinic with suspected TIA/non-disabling stroke and no evidence of extra/intracranial stenosis, hypertensive ones underwent intensive BP-lowering guided by daily home telemetric blood pressure monitoring (HBPM). Clinic-based BP, HBPM, End-tidal CO2 and bilateral middle cerebral artery (MCA) velocity on TCD were compared in the acute setting versus one-month follow-up; changes were stratified by baseline hypertension (clinic-BP≥140/90) and by age (Results In 697 patients with repeated TCD measures, mean/SD baseline systolic-BP (145.0/21.3 mmHg) was reduced by an average of 11.3/19.9 mmHg ( p < 0.0001) at one-month (133.7/17.4 mmHg), driven by patients hypertensive at baseline (systolic-BP change = −19.0/19.2 mmHg, p < 0.001; vs −0.5/15.4, p = 0.62 in normotensives). Compared with baseline, a significant change was observed at one-month only in mean/SD MCA end diastolic velocity (EDV) (0.77/7.26 cm/s, p = 0.005) and in resistance index (RI) (−0.005/0.051, p = 0.016), driven by hypertensive patients (mean/SD EDV change: 1.145/6.96 cm/s p = 0.001, RI change −0.007/0.06, p = 0.014). Findings were similar at all ages (EDV change – ptrend=0.357; RI change – ptrend=0.225), including 117 patients aged ≥80. EDV and RI changes were largest in 100 patients with clinic systolic-BP decrease ≥30 mmHg (mean/SD EDV change = 2.49/7.47 cm/s, p = 0.001; RI change −0.024/0.063, p < 0.0001). Conclusion There was no evidence of worsening of TCD haemodynamic indices associated with BP-lowering soon after TIA/non-disabling stroke, irrespective of age and degree of BP reduction. In fact, EDV increase and RI decrease observed after treatment of hypertensive patients suggest a decrease in distal vascular resistance.

Background and Purpose: Blood pressure variability (BPV) from beat to beat is associated with an increased risk of cardiovascular events and enables rapid assessment of BPV, but the underlying causes of elevated BPV are unclear. Methods: In consecutive patients within 4 to 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), continuous noninvasive blood pressure was measured beat to beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). After automated and manual data cleaning, associations between BPV (residual coefficient of variation), demographic factors, and arterial stiffness were determined for both systolic and diastolic blood pressure, by ANOVA and linear models. Relationships between demographic factors and arterial stiffness were determined by interaction terms and mediation. Results: Among 1013 patients, 54 (5.3%) were in AF, and 51 (5%) had low-quality recordings. In a general linear model including the remaining 908 participants, systolic BPV (SBPV) was most strongly associated with age ( P =0.00003), body mass index (BMI; P =0.003), and arterial stiffness ( P =0.008), with weaker independent associations with current smoking ( P =0.01) and a low diastolic blood pressure ( P =0.046). However, while there was a linear increase in SBPV with BMI in men, in women, SBPV was lowest for a BMI in the normal range but was greater below 20 or above 30 (ANOVA, P =0.012; BMI-sex interaction, P =0.03). Although BMI and pulse wave velocity were partially independent, increased pulse wave velocity mediated ≈32% of the relationship between increased BMI and SBPV ( P Conclusions: Vascular aging, manifest as arterial stiffness, was a strong determinant of increased SBPV and partially mediated the effect of increased BMI. However, although high BMI was independently associated with SBPV in both sexes, a low BMI was associated with increased SBPV only in women. SBPV may partially mediate the relationship between BMI and cardiovascular events, while obesity may provide a modifiable target to reduce SBPV and cardiovascular events.

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4–6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling’s pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.

Background: Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. Methods: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. Results: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P P P =0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P P P =0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP ( P Conclusions: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Supplemental Digital Content is available in the text., Background and Purpose— Breath holding (BH) and hyperventilation are used to assess abnormal cerebrovascular reactivity, often in relation to severity of small vessel disease and risk of stroke with carotid stenosis, but responses may be confounded by blood pressure (BP) changes. We compared effects of BP and end-tidal carbon dioxide (etCO2) on middle cerebral artery mean flow velocity (MFV) in consecutive transient ischemic attack and minor stroke patients. Methods— In the population-based, prospective OXVASC (Oxford Vascular Study) phenotyped cohort, change in MFV on transcranial Doppler ultrasound (ΔMFV, DWL-DopplerBox), beat-to-beat BP (Finometer), and etCO2 was measured during 30 seconds of BH or hyperventilation. Two blinded reviewers independently assessed recording quality. Dependence of ΔMFV on ΔBP and ΔetCO2 was determined by general linear models, stratified by quartiles. Results— Four hundred eighty-eight of 602 (81%) patients with adequate bone windows had high-quality recordings, more often in younger participants (64.6 versus 68.7 years; P

Supplemental Digital Content is available in the text., Beat-to-beat variability in blood pressure (BP) is associated with recurrent stroke despite good control of hypertension. However, no study has identified rates of progression of beat-to-beat BP variability (BPV), its determinants, or which patient groups are particularly affected, limiting understanding of its potential as a treatment target. In consecutive patients one month after a transient ischaemic attack or nondisabling stroke (Oxford Vascular Study), continuous noninvasive BP was measured beat-to-beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). Repeat assessments were performed at the 5-year follow-up visit and agreement determined by intraclass correlation coefficient. Rates of progression of systolic BPV (SBPV) and diastolic BPV (DBPV) and their determinants were estimated by mixed-effect linear models, adjusted for age, sex, and cardiovascular risk factors. One hundred eighty-eight of 310 surviving, eligible patients had repeat assessments after a median of 5.8 years. Pulse wave velocity was highly reproducible but SBPV and DBPV were not (intraclass correlation coefficient: 0.71, 0.10, and 0.16, respectively), however, all 3 progressed significantly (pulse wave velocity, 2.39%, P

Importance Patent foramen ovale (PFO) closure may prevent recurrent stroke after cryptogenic transient ischemic attack (TIA) or stroke (TIA/stroke) in patients aged 60 years or younger. Patent foramen ovale is associated with cryptogenic stroke in the older population, but risk of recurrence is unknown. Data on prognosis of patients receiving medical treatment at older ages (≥60 years) are essential to justify trials of PFO closure. Objective To examine the age-specific risk of recurrence in patients with cryptogenic TIA/stroke with PFO. Design, Setting, and Participants A prospective study was nested in the population-based Oxford Vascular Study between September 1, 2014, and March 31, 2019, with face-to-face follow-up for 5 years. A total of 416 consecutive patients with a diagnosis of cryptogenic TIA or nondisabling stroke, screened for PFO at a rapid-access TIA/stroke clinic, were included. A systematic review and meta-analysis of cohort studies reporting on ischemic stroke recurrence after cryptogenic TIA/stroke in patients with PFO who were receiving medical therapy alone, or with PFO vs no-PFO was conducted. Sample size calculation for future trials on PFO closure was performed for patients aged 60 years or older. Exposures Patent foramen ovale and age as modifiers of risk of recurrent stroke after cryptogenic TIA/stroke in patients receiving only medical therapy. Main Outcomes and Measures Risk of ischemic stroke recurrence in patients with cryptogenic TIA/stroke and PFO receiving medical therapy only, and in patients with vs without PFO, stratified by age ( Results Among the 153 Oxford Vascular Study patients with PFO (mean [SD] age, 66.7 [13.7] years; 80 [52.3%] men), recurrent ischemic stroke risk (2.05 per 100 patient-years) was similar to the pooled estimate from a systematic review of 23 other studies (9 trials and 14 observational studies) (2.00 per 100 patient-years; 95% CI, 1.55-2.58). However, there was heterogeneity between studies (P Conclusions and Relevance The findings of this study suggest that age is a determinant of risk of ischemic stroke after cryptogenic TIA/stroke in patients with PFO, such that trials of PFO closure at older ages are justified; however, projected sample sizes are large.

Background Although large artery stiffness has been implicated in the pathogenesis of cerebral small vessel disease, whether carotid pulsatility, a convenient surrogate marker of arterial stiffness, is similarly associated with global burden of small vessel disease is unknown. Aims To determine the age and sex-specific associations of carotid pulsatility with global burden of small vessel disease. Methods We studied consecutive patients with transient ischemic attack or non-disabling ischemic stroke from the Oxford Vascular Study who had a brain MRI and carotid duplex ultrasound during 2002–2014. We determined clinical correlates of common carotid artery (CCA) and internal carotid artery (ICA) pulsatility index (PI) and their associations with the total small vessel disease score on MRI, stratified by age (median = 72). Results In 587 patients, correlates of CCA and ICA-PI were both independently associated with age, diabetes, and premorbid mean pulse pressure after adjustment for age, sex, and cardiovascular risk factors (all p 0.05). No associations between CCA-PI with small vessel disease score were noted at any age. In 94 consecutive patients who also received transcranial Doppler ultrasound, strong associations between middle cerebral artery (MCA)-PI and an increasing small vessel disease score were noted (unadjusted OR–MCA: 4.26, 1.45–12.55, p = 0.009; ICA: 2.37, 0.81–6.87, p = 0.11; CCA: 1.33, 0.45–3.96, p=0.61). Conclusions ICA and MCA-PI are associated with global small vessel disease burden, especially in individuals aged

Aims: To prospectively assess the incidence and etiology (ie, primary vs symptomatic) of headache in women during the first month postdelivery, with particular emphasis on the type of presentation as a clue for identifying potentially harmful etiologies. A secondary aim was to evaluate the relative frequency of migraine- vs tension-type headache in cases of primary headache. Methods: A total of 900 consecutive women were enrolled in the study and examined within 3 days of delivery, both clinically and with transcranial color-coded sonography (TCCS). During the course of follow-up, all subjects presenting with headache suspected of being secondary to intracranial pathology underwent a complete clinical and instrumental assessment with TCCS and magnetic resonance imaging (MRI) and angiography. A telephone interview was administered to all subjects 1 month after delivery. Two-tailed t test, Mann-Whitney test, Pearson chi-square test, and multiple logistic regression were used to analyze the data. Results: At the end of the follow-up period, 241 women (26.8% of the sample) reported at least one headache attack. In 88 of these 241 cases (9.8%), the headache attack occurred soon after delivery and was already recorded at the first visit. Thunderclap headache occurred in 34 (3.8%) of the subjects. In all but one of these subjects, the course was spontaneously benign. None of the recorded variables allowed discrimination of the subjects with thunderclap headache from those without headache. Three subjects had thunderclap headache following dural anesthesia, and one subject was found to have reversible cerebral vasoconstriction syndrome. Headache with gradual onset was recorded in 207 subjects (23%). Three of these subjects fulfilled the criteria for pre-eclampsia, and 13 had postural headache after dural anesthesia. Migraine history and urinary protein were independent predictors of gradual onset headache, and migraine history and parity were significant independent predictors of pulsating pain with gradual onset headache. Conclusion: Headache appeared early in the first days postdelivery, and its incidence increased in the first month thereafter. Predictors were different according to whether the headache had a gradual onset or a thunderclap presentation. Primary headache accounted for the overwhelming majority of the recorded cases.

Rationale: Docosahexaenoic acid (DHA) in cell membrane may influence breast cancer (BC) patients' prognosis, affecting tumor cells sensitivity to chemo- and radio-therapy and likely modulating inflammation. The possibility of identifying BC patients presenting with low DHA levels and/or low ability of DHA incorporation into cell membrane might help to treat this condition.Methods: We enrolled BC patients and healthy controls, recording their seafood dietary intake. DHA in form of algal oil was administered for 10 consecutive days (2 g/day). Blood samples were collected at baseline (T0) and after 10 days of supplementation (T1) to assess DHA, omega-3 index, as the sum of DHA + eicosapentaenoic acid (EPA), in red blood cells (RBC) membranes and plasma tumor necrosis factor-alpha and interleukin-6 levels. Pre- and post-treatment fatty acid profiles were obtained by gas-chromatography. Parametric and non-parametric tests were performed, as appropriate, and P-value < 0.05 was considered statistically significant.Results: Forty-three women were studied, divided into 4 groups: 11 patients with BRCA1/2 gene mutation (M group), 12 patients with familiar positive history for BC (F group), 10 patients with sporadic BC (S group), and 10 healthy controls (C group). DHA and omega-3 index increased from T0 to T1 in the 3 groups of BC patients and in controls (P < 0.001). No difference was found in DHA incorporation between each group of BC patients and between patients and controls, except for M group, which incorporated higher DHA levels with respect to controls (β = 0.42; P = 0.03). No association was documented between cytokines levels and DHA and omega-3 index at baseline and after DHA supplementation. Independent of the presence of BC, women considered as “good seafood consumers” showed at baseline DHA and omega-3 index higher with respect to “low seafood consumers” (P = 0.04; P = 0.007, respectively). After supplementation, the increase in DHA levels was greater in “low seafood consumers” with respect to “good seafood consumers” (P < 0.0001).Conclusion: DHA supplementation was associated with increased DHA levels and omega-3 index in RBC membranes of BC cancer patients, independent of the type of BC presentation, and in controls. BRCA1/2 mutation, as well as low seafood consuming habits in both BC patients and healthy controls, seem to be associated with greater ability of DHA incorporation. Larger samples of BC patients are necessary to confirm our observation.

Stroke is a major cause of dysphagia. Few studies to date have reported on standardized multidisciplinary protocolized approaches to the management of post-stroke dysphagia. The aim of this retrospective cohort study was to evaluate the impact of a standardized multidisciplinary protocol on clinical outcomes in patients with post-stroke dysphagia. We performed retrospective chart reviews of patients with post-stroke dysphagia admitted to the neurological ward of Verona University Hospital from 2004 to 2008. Outcomes after usual treatment for dysphagia (T- group) were compared versus outcomes after treatment under a standardized diagnostic and rehabilitative multidisciplinary protocol (T+ group). Outcome measures were death, pneumonia on X-ray, need for respiratory support, and proportion of patients on tube feeding at discharge. Of the 378 patients admitted with stroke, 84 had dysphagia and were enrolled in the study. A significantly lower risk of in-hospital death (odds ratio [OR] 0.20 [0.53-0.78]), pneumonia (OR 0.33 [0.10-1.03]), need for respiratory support (OR 0.48 [0.14-1.66]), and tube feeding at discharge (OR 0.30 [0.09-0.91]) was recorded for the T+ group (N = 39) as compared to the T- group (N = 45). The adjusted OR showed no difference between the two groups for in-hospital death and tube feeding at discharge. Use of a standardized multidisciplinary protocolized approach to the management of post-stroke dysphagia may significantly reduce rates of aspiration pneumonia, in-hospital mortality, and tube feeding in dysphagic stroke survivors. Consistent with the study's exploratory purposes, our findings suggest that the multidisciplinary protocol applied in this study offers an effective model of management of post-stroke dysphagia.

Background Sickle cell disease (SCD) is one of the most common causes of stroke in children worldwide. Based on the results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP), annual transcranial Doppler ultrasound (TCD) screening for affected children is standard practice. However, the need for TCD surveillance programs could override the accuracy of the screening, affecting the correct stratification of stroke risk and subsequent clinical management of the target population. Aims To shed light on this issue, a systematic review of the literature on TCD screening for children and adolescents with SCD was carried out (CRD42016050549), according to a list of clinically relevant questions, with a particular focus on screening practices in European countries. Quality of the evidence was rated using the grading of recommendations assessment, development and evaluation. Summary of review Thirty-three studies published in English or French were included (5 randomized controlled trials, 8 experimental non-randomized, and 20 observational studies). The quality of the retrieved evidence ranged between low and high, but was rated as moderate or high most of the times. TCD is effective as a screening tool for the primary prevention of stroke in SCD children. There is no high-quality evidence on the effectiveness of alternative screening methods, such as imaging-TCD with or without angle correction or magnetic resonance angiography. No evidence was found on effectiveness of the screening on children on hydroxyurea and with genotypes other than HbSS and HbS/β0. No European data were found on screening rates or adherence of screening practices to the STOP protocol. Conclusions High-quality studies on alternative screening methods that are currently used in real-world practice, and on screening applicability to specific subgroups of patients are urgently needed. Considering the low awareness of the disease in European countries and the lack of data on screening practices and adherence, clinicians need up-to-date guidelines for more uniform and evidence-based surveillance of children with SCD.

Background and Aim of the Study Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe “thunderclap” headache, with or without associated neurological symptoms and neuroimaging findings of reversible vasoconstriction of cerebral arteries. Puerperium is a recognized precipitant, but the incidence of puerperal RCVS is unknown. We conducted a prospective study to assess incidence, risk factors and clinical features of RCVS. Material and Method Nine-hundred consecutive puerperae were prospectively enrolled within three days of delivery. Past medical history, basal demographic, anthropometric and biological variables were recorded. Transcranial Colour Coded Sonography (TCCS) was performed to assess early signs of vasospasm in brain vessels. A structured telephone interview was planned in all subjects one month post delivery. Results Thunderclap headache was recorded in 8 subjects (0.9%) on the first visit. At the one month follow-up interview 27 more patients reported having had at least one episode of thunderclap headache. In these 33 (3.8%) patients the course was spontaneously benign. One patient presented to the Emergency ward with throbbing thunderclap headache three weeks after delivery. Diagnostic work-up ended up in the diagnosis of RCVS, the outcome was favorable Conclusion In normally coursing pregnancies and after uncomplicated delivery the risk of puerperal RCVS is negligible (0.1%). On the other way thunderclap headache may occur in a measurable proportion of (3.4%), although in the vast majority of cases ( 33/34 = 97%) it is of benign course. Transcranial Doppler sonography may be helpful to pick up those cases in whom further neuroradiological investigation is warranted.

Background and Purpose— Among screening tools for cognitive impairment in large cohorts, the Montreal Cognitive Assessment (MoCA) seems to be more sensitive to early cognitive impairment than the Mini-Mental State Examination (MMSE), particularly after transient ischemic attack or minor stroke. We reasoned that if MoCA-detected early cognitive impairment is pathologically significant, then it should be specifically associated with the presence of white matter hyperintensities (WMHs) and reduced fractional anisotropy (FA) on magnetic resonance imaging. Methods— Consecutive eligible patients with transient ischemic attack or minor stroke (Oxford Vascular Study) underwent magnetic resonance imaging and cognitive assessment. We correlated MoCA and MMSE scores with WMH and FA, then specifically studied patients with low MoCA and normal MMSE. Results— Among 400 patients, MoCA and MMSE scores were significantly correlated (all P r MoCA =−0.336; r MMSE =−0.297) and FA ( r MoCA =0.409; r MMSE =0.369) and—on voxel-wise analyses—with WMH in frontal white matter and reduced FA in almost all white matter tracts. However, only the MoCA was independently correlated with WMH volumes ( r =−0.183; P r =0.218; P t =3.1; P =0.002), lower average FA ( t =−4.0; P Conclusions— In patients with transient ischemic attack or minor stroke, early cognitive impairment detected with the MoCA but not with the MMSE was independently associated with white matter damage on magnetic resonance imaging, particularly reduced FA.

Background and Purpose— Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. Methods— Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Gosling's index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). Results— In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, P 2 =0.39, MCA-PI P =0.01, aortic pulse wave velocity P =0.06; age-related white matter change: χ 2 =0.38, MCA-PI P =0.015; aortic pulse wave velocity P =0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model ( r 2 =0.68, P P =0.016) and aortic pulse pressure ( P P P =0.001). Conclusions— MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis.

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.

Pharmacological studies highlighted pleiotropic effects of statins, that seem to influence atherogenesis not only by increasing atherosclerotic plaque stability but also by modulating endothelial function and inflammation and acting on platelet aggregation and thrombosis. Despite a strong association between increased levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of coronary heart disease (CHD) has been well proven, it not yet established whether serum LDL-C levels are related to stroke incidence. The major aim of this paper is to perform a comprehensive up-to-date review of research papers, meta-analyses and randomized controlled clinical trials reporting the effects of statins in primary and secondary stroke prevention strategies. In addition, our work provides an overview on statin chemical structure, mechanism of action and pharmacological properties, investigating also most common adverse effects and relationship between statin therapy and haemorrhagic stroke risk, in order to assess drugs safety. Although studies are heterogeneous, our analysis shows that statins reduce the risk of stroke occurrence in high risk patients and seem also to reduce stroke recurrence. Moreover, the low incidence and reversibility of adverse effects, and the unclear association with hemorrhagic events, support the safe use of these drugs.

Recently, Canadian, US and European health regulatory agencies issued warnings about an increased risk of stroke and death in elderly patients with dementia receiving atypical antipsychotics. Assessing both randomised and non-randomised evidence, this systematic review found conflicting findings, particularly for risperidone. More research is needed to better inform clinical practice.

In 2004 a new condition called ‘‘hereditary hemorrhagic telangiectasia–juvenile polyposis’’ (HHT–JP) was described, in which symptoms of the autosomal dominant diseases HHT (Osler–Rendu disease) and JP overlap, both genetically and clinically. In this syndrome, juvenile polyps and anemia are the predominant clinical features, although affected patients display symptoms of both diseases, and a high prevalence of visceral arteriovenous malformations (AVMs) has been reported [1]. Stroke secondary to pulmonary AVMs (PAVMs) is one of the possible neurological manifestations of HHT [2]. Interestingly, the underlying pathophysiological mechanism of stroke in this rare disease is exemplary of strokes due to paradoxical embolism [3]. To our knowledge, only two patients with HHT–JP syndrome presenting with stroke have been reported, but no details of the related clinical picture can be found in the literature [1]. We therefore report on a case of juvenile stroke associated with PAVMs as the clinical presentation of HHT–JP overlap syndrome.

The ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy (ataxic-CIDP) has been recently described as a subtype of chronic ataxic neuropathy, distinguished by steroid responsiveness and relative preservation of myelinated fibres at sural nerve biopsy. We report on a case of progressive, predominantly sensory, steroid-responsive neuropathy with clinical, laboratory, electrophysiological and pathological features of this uncommon form of CIDP. Moreover, the present case displays peculiar hyperpyrexia-triggered relapses leading to transitory severe tetraparesis, bilateral facial drooping, dysphonia, dysphagia and dyspnoea, which leave clinicians with some unresolved questions.

We herein report a case of ischemic stroke due to paradoxical brain embolism in a young man, a trumpet player. Extensive diagnostic investigations revealed the presence of an isolated pulmonary arteriovenous fistula as the only risk factor for stroke. The peculiarity of this case is the early onset of neurological symptoms in the absence of Hereditary Hemorrhagic Teleangiectasia. The Authors suppose the repeated Valsalva maneuvers as a possible factor promoting fistula enlargement and symptoms development.

Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.

A case of a 79-year-old man, affected by persistent right eye blindness after multiple episodes of transient left hemiparesis and right eye amaurosis. Brain computed tomography (Angio CT) well documented right internal carotid artery (ICA) plaque with a 8-mm thrombus extending from ICA origin to the ophthalmic artery, in progressive lysis in the next days.

To the Editor: With regard to the article from Zigari et al,1 we would like to add some comments to the authors’ reply2 to our letter.3 The authors are very welcome to …

Background /Aims: Up to more than 50% of cryptogenetic stroke patients and patients with migraine with aura (MA) are found to have a right-to-left shunt (RLS), which is usually due to a patent foramen ovale. Moreover, both MA and stroke are cardinal features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Notch3 mutations have been suggested to induce an abnormally high incidence of atrial septal defects in a family harbouring an Arg141Cys pathogenetic mutation. We sought to determine the prevalence of RLS in CADASIL patients with different Notch3 mutations, both with and without migraine as a clinical feature. Methods: Subjects with a molecular diagnosis of CADASIL were tested for the presence of an RLS by means of contrast-enhanced transcranial Doppler (TCD). The diagnosis of migraine was made according to the 2004 International Headache Classification. Results: Sixteen CADASIL patients were tested; 6 had MA. Four patients displayed an RLS on contrast-enhanced TCD examination. Three of these patients had MA. Both patients with Arg141Cys displayed a large RLS. Conclusion: We conclude that RLS is not necessarily linked to CADASIL as a comorbidity factor. Nevertheless, there could be a relation between RLS and specific Notch3 mutations, such as Arg141Cys.

In the last ten years a considerable bulk of evidence has accumulated on the relationship between migraine, particularly migraine with aura, and atrial septal defects, particularly patent foramen ovale (PFO). The increased frequency of PFO in migraine with aura, which almost parallels that found in stroke of unknown cause, the fact that in migraine patients PFO tends to be larger than in non-migraine controls and some positive results on migraine severity obtained after PFO closure have spurred speculation on a possible causal relationship. By applying the criteria proposed by Bradford-Hill to establish causality between associated phenomena, we try to demonstrate that PFO is not just a further example of migraine comorbidity but exerts a causal effect at least in the triggering of aura.

To the Editor: In 2001 Angeli et al1 reported a remarkably high prevalence of right to left shunt (RLS) in a single CADASIL pedigree, suggesting “a possible association between CADASIL and RLS”. Surprisingly, and notwithstanding the large volume of data building up on CADASIL pathogenesis and diagnosis, no further data has followed this first and only publication on this topic up to now. This is why we read with much interest the article from Zicari et al,2 reporting on a very high prevalence of RLS (71%) in a sample of 21 patients with CADASIL. However, some concerns have to be issued. …

Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are sporadic and genetic neurodegenerative conditions characterized by brain accumulation and deposition of protein aggregates. In AD, the key pathogenic event is linked to the formation of a 4-kDa amyloid beta (Abeta) peptide, generated by sequential cleavages of the amyloid precursor protein (APP). In CJD and other prion diseases, the process is initiated by conformational changes of the cellular prion protein, or PrP(C), into a beta-sheet rich isoform, named PrP(Sc), which acquires protease-resistance and detergent insolubility. Once generated, Abeta and PrP(Sc) are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Abeta and PrP(Sc) is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Abeta, PrP(Sc) is also infectious, and this feature poses public health concerns, as in the case of iatrogenic and variant CJD (vCJD). Several lines of evidence suggest that Abeta and PrP(Sc) are the main factors responsible for death of selected neuronal populations in brains of AD and prion disease's victims. Therefore, in addition to symptomatic treatment of dementia, therapeutic efforts are currently aimed at testing the efficacy of disease-modifying, anti-amyloid therapies. Experimental and clinical therapeutic interventions include passive and active immunization against amyloidogenic peptides, non immunological strategies, as well as drugs enhancing the nonamyloidogenic protein processing. In this review, we focus on molecular mechanisms of AD and prion diseases, and on novel treatment approaches.

A few hours after a motorcycle accident with multiple rib and right wrist fractures, a 37-year-old man developed transient dysphasia and right hemiparesis associated with left Horner syndrome (figure A). Brain …

Watershed infarcts (WI) evolve in hemodynamic risk zones. Clinical picture of WI can be associated to partial epileptic seizures. Diffusion weighted brain magnetic resonance imaging (MRI) allows a clear diagnosis. WI pathogenesis involves either embolic or hemodynamic mechanism. A 69-year old patient presented with sub-acute occurrence of right hemiparesis and partial epileptic seizures of the right arm. Carotid ultrasounds demonstrated occlusion of the right extra-cranial internal carotid artery (ICA) and tight stenosis of the contralateral ICA. Brain Diffusion-Weighted magnetic resonance revealed acute ischemic lesions within the watershed area of the left hemisphere. Our case supports the hypothesis of impaired washout of emboli in low-perfusion brain areas as the mechanism underlying cortical WI.

ObjectivesAn inflammatory process following stroke in human brains and systemic inflammatory responses after stroke in humans have been reported by numerous investigators. The aim of the study was to investigate if genes involved in the cyclooxygenase 2 (COX-2) pathway are upregulated at peripheral level in patients after transient ischaemic attack (TIA) and stroke.Design of StudyBlood samples were obtained from two groups of patients undergoing carotid endarterectomy. The first group included 25 patients who presented TIA or ischaemic stroke. The second group included 35 patients who had an asymptomatic internal carotid artery stenosis. Total RNA was isolated and the expression of Toll-like Receptor 4 (TLR4), COX-2, membrane-associated Prostaglandin E synthase (mPGES-1), Prostaglandin E2 receptors (EP3 and EP4) was analysed by real time RT-PCR.ResultsExpression of COX-2 and TLR4 were significantly increased in symptomatic patients (p