Italian symptomatic intracranial atherosclerosis study (ISIDE) : A multicenter transcranial ultrasound evaluation.

There are currently no data available on the prevalence of symptomatic intracranial atherosclerosis (ICAS) in Italy. The aim of this prospective, multicenter, hospital-based, transcranial ultrasound study was to establish the prevalence of ICAS among patients hospitalized with acute ischemic stroke. At 11 stroke centers across Italy, patients consecutively admitted for their first ever acute ischemic stroke were assessed prospectively over a 24-month period either with transcranial color-coded Doppler sonography (TCCS) or transcranial Doppler (TCD) according to validated criteria. ICAS was diagnosed when there was an evidence of a cerebral infarction in the territory of a ≥50 % stenosis detected by TCCS/TCD and confirmed by magnetic resonance angiography or computed tomography angiography. A total of 1134 patients were enrolled, 665 of them (58.6 %) men, with a mean age of 71.2 ± 13.3 years. ICAS was recorded in 99 patients (8.7 % of the whole sample, 8.9 % among Caucasians), most commonly located in the anterior circulation (63 of 99, 5.5 %). After adjusting for potential confounders, multivariate analysis identified carotid/vertebral ≥50 % stenosis [odds ratio (OR) 2.59, 95 % (confidence interval) CI 1.77-6.33; P = 0.02] and hypercholesterolemia (OR 1.38, 95 % CI 1.02-1.89; P = 0.02) as being independently associated with ICAS. ICAS is a surprisingly relevant cause of ischemic stroke in Italy, identified in almost 9 % of first-ever stroke patients. It is more prevalent in the anterior circulation and independently associated with hemodynamically significant cervical vessel atherosclerosis and hypercholesterolemia. These findings support the systematic use of transcranial ultrasound to identify ICAS in patients presenting with acute ischemic stroke and in cases with ≥50 % cervical vessel stenoses.

Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper.

OBJECTIVES: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. BACKGROUND: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. METHODS: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. RESULTS: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow-up evaluation was appraised. CONCLUSIONS: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.

Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper: executive summary.

OBJECTIVES: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. BACKGROUND: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. METHODS: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. RESULTS: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow-up evaluation was appraised. CONCLUSIONS: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.

Residual shunt after patent foramen ovale closure: preliminary results from Italian patent foramen ovale survey.

BACKGROUND: Percutaneous patent foramen ovale (PFO) closure is accepted as treatment for cryptogenic ischemic stroke/transient ischemic attack in young subjects. However, a thorough evaluation of residual right-to-left shunt (rRLS) after PFO closure is needed. Our aims were to analyze the characteristics related to PFO diagnosis and closure, focusing on rRLS and clinical recurrences until 24-month follow-up. Data were extrapolated from the 12-month Italian PFO Survey. METHODS: In all, 1035 patients were included. PFO diagnosis and right-to-left shunt (RLS) were assessed by contrast-enhanced transesophageal and/or transthoracic echocardiography and/or transcranial Doppler. RESULTS: PFO diagnosis with RLS data were available in 894 of 1035 (86.4%) patients. rRLS was investigated in 49.6% (6 months), 27.1% (12 months), and 3.5% (24 months), and observed in 19.5% (6 months) and 18.2% (12 months) of subjects. Large permanent rRLS was observed in less than 3% of RLS-positive patients after 1 year. Eleven of 14 and 3 of 14 neurological recurrences were observed in 10 of 444 (2.25%) and 2 of 243 (0.8%) patients within the 6- and 12-month follow-up, respectively. Among these, no large rRLS was reported. There were no neurological events at 2-year follow-up. Forty of 444 subjects had non-neurological complications, mostly cardiac arrhythmias within the sixth month. CONCLUSIONS: PFO closure is a safe procedure. rRLS is not uncommon but large rRLS is rare. Clinical complications, mostly related to cardiac arrhythmias, are not unusual. Evaluation of the data of the whole survey is underway.

A model of multi-disciplinary approach to the diagnosis and treatment of young patients with cryptogenic stroke and patent foramen ovale.

BACKGROUND: Treatment of patent foramen ovale in young patients with stroke is not supported by robust scientific evidence. In clinical practice, a pragmatic approach is needed to guide such therapeutic decisions. This study aims at standardising the diagnostic pathway for stroke patients younger than 55 years of age with a patent foramen ovale; elaborating a therapeutic algorithm; discussing every case in regular interdisciplinary counselling meeting; and setting up a follow-up schedule to assess clinical outcomes. METHODS: This is a cohort study on the effect of a standardised treatment of stroke patients with a patent foramen ovale. The primary endpoints include occurrence of recurrent ischaemic events, major bleeding, and device-related complications. The secondary endpoints include drug- or procedure-related side effects, persistence of right-to-left shunt, and persistent cardiac arrhythmia of new onset. RESULTS: A total of 103 patients have been enrolled. In all, 51 patients underwent percutaneous atrial septal repair; of these, one had minor post-procedural bleeding. At 12 months, 25% of this group of patients showed a latent I grade shunt, one patient a latent II degree shunt, and none had a persistent shunt. The remaining 52 patients were addressed to medical therapy; one of them experienced stroke recurrences while on medical therapy. CONCLUSIONS: This model of implementation of available evidence to clinical practice via a group-based, multi-disciplinary counselling provides a shared and coherent decision pathway and yielded a very low rate of recurrent events and therapy-related complications. This approach could be replicated in specific protocols for other complex or neglected clinical problems.

Can aura migraine be elicited by isolated pulmonary arteriovenous fistula?-A case report.

A pulmonary arteriovenous fistula (PAVM) is an abnormal blood vessel that creates a direct connection between a pulmonary artery and its tributary vein bypassing capillary filter, establishing as a consequence of a low-resistance right-to-left shunting (RLS). The vast majority of PAVMs are congenital appearing more often in females than in males. A great number of patients with PAVMs is suffering concurrently from hereditary hemorrhagic telangiectasia (HHT) whose incidence is around 1 in 5,000. Very few cases of acquired PAVMs have been described in the literature. Paradoxical embolism through PAVMs can cause systemic desaturation, cyanosis, and serious cerebrovascular ischemic events (transient ischemic attacks, strokes, and intracranial abscess), even when the abnormal blood vessel is small (diameter <3 mm). Notably, it has been reported a high prevalence of aura migraine (MHA) symptoms in patients with PAVMs and concomitant HHT. We described in this study the case of a young aura migraineur female patient without HHT in whom isolated PAVM below the detection limit of pulmonary angiography and chest computed tomography angiography (CTA) has been documented by contrast Transthoracic and Transesophageal Echocardiography (cTTE/TEE) showing a delayed (>17 s) RLS coming from left pulmonary veins to left atrium while a patent foramen ovale (PFO), small atrial septal defects or septum primum fenestration could not be detected despite several attempts. Contrast Transcranial Doppler (cTCD) confirmed a delayed (>16 s) RLS with two short "shower" patterns corroborating the diagnosis of an extra-cardiac RLS. During the right heart catheterization and pulmonary angiography, it was impossible to cross the interatrial septum with a multipurpose catheter. The patient was finally discharged with off-label thienopyridine agents (clopidogrel 75 mg die) in terms of primary prophylaxis for paradoxical right-to-left embolization of thrombotic material ultimately. Aura migraine symptoms were nearly abolished by P2Y12 platelet inhibition, suggesting a platelet-based mechanism. During 2 years of clinical follow-up on thienopyridine therapy, the resolution of aura migraine episodes was definitively accomplished with significant improvement in her quality of life.

Neither ACEIs nor ARBs are associated with respiratory distress or mortality in COVID-19 results of a prospective study on a hospital-based cohort.

Considerable concern has emerged for the potential harm in the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) in COVID-19 patients, given that ACEIs and ARBs may increase the expression of ACE2 receptors that represent the way for coronavirus 2 to entry into the cell and cause severe acute respiratory syndrome. Assess the effect of ACEI/ARBs on outcome in COVID-19 patients. Hospital-based prospective study. A total of 431 patients consecutively presenting at the Emergency Department and found to be affected by COVID-19 were assessed. Relevant clinical and laboratory variables were recorded, focusing on the type of current anti hypertensive treatment. Outcome variables were NO, MILD, SEVERE respiratory distress (RD) operationally defined and DEATH. Hypertension was the single most frequent comorbidity (221/431 = 51%). Distribution of antihypertensive treatment was: ACEIs 77/221 (35%), ARBs 63/221 (28%), OTHER than ACEIs or ARBs 64/221 (29%). In 17/221 (8%) antihypertensive medication was unknown. The proportion of patients taking ACEIs, ARBs or OTHERs who developed MILD or SEVERE RD was 43/77 (56%), 33/53 (52%), 39/64 (61%) and 19/77 (25%), 16/63 (25%) and 16/64 (25%), respectively, with no statistical difference between groups. Despite producing a RR for SEVERE RD of 2.59 (95% CI 1.93-3.49), hypertension was no longer significant in a logistic regression analysis that identified age, CRP and creatinine as the sole independent predictors of SEVERE RD and DEATH. ACEIs and ARBs do not promote a more severe outcome of COVID-19. There is no reason why they should be withheld in affected patients.

Transcranial Doppler and transesophageal echocardiography: comparison of both techniques and prospective clinical relevance of transcranial Doppler in patent foramen ovale detection.

BACKGROUND: Patent foramen ovale (PFO) has been investigated in several conditions apart from cryptogenic ischemic stroke. Contrast transesophageal echocardiography (cTEE) is the gold standard for the diagnosis, although it has some known limitations. Contrast transcranial Doppler (cTCD) allows a semiquantitative estimation of right-to-left shunt (RLS) volume. The aims of our study were to confirm the diagnostic accuracy of cTCD in PFO diagnosis and to compare the abilities of cTCD and cTEE to detect a RLS and PFO, respectively, under normal breathing. The latter could represent an important feature for its clinical significance. METHODS: A total of 100 consecutive patients (59 women and 41 men, age 46 +/- 12 years) were evaluated after stabilized ischemic stroke/transient ischemic attack, migraine, and lacunae, and before neurosurgery in sitting position. All patients undertook cTEE and cTCD, at rest and under Valsalva maneuver (VM). cTEE under VM was the reference standard. A categorization of patients and a semiquantitative cTCD classification were proposed. RESULTS: In all, 63 of 100 patients had PFO diagnosed by cTEE. A general concordance of up to 90% between both techniques was found. cTCD sensitivity and specificity were 96.8% and 78.4%, respectively. In 17 of 100 patients with cTEE-proven PFO under VM, cTCD and cTEE detected RLS at rest in 75% (95% confidence interval [CI] 62%-85%) and 48% (95% CI 35%-61%) of cases, respectively (P < .001). cTEE disclosed RLS at rest in about 71% (95% CI 9%-42%) of cTCDs showing a "shower-curtain" pattern and only in about 22% (95% CI 52%-85%) of those cTCDs without that pattern. CONCLUSIONS: In diagnosing PFO, cTCD has a good accuracy compared with cTEE. To detect a RLS at rest, cTCD appears to be more sensitive than cTEE. The latter resulted positive under normal breathing, mostly in cases of significant RLS at cTCD. Our results point out the impact of cTCD in the evaluation of RLS volume, thus aiding, in association with the anatomic details by cTEE, in the prevention of the occurrence or recurrence of paradoxical embolism in individuals with and without cerebrovascular diseases. The combination of cTEE and cTCD could be considered the real gold standard for PFO in the near future.

Postural dependency of right to left shunt: role of contrast-enhanced transcranial Doppler and its potential clinical implications.

BACKGROUND AND PURPOSE: Right to left shunt is involved in conditions in which postural changes may be pathogenically relevant. The aim of this work was to assess the frequency of posturally dependent right to left shunt. METHODS: In 109 consecutive right to left shunt-positive subjects (male/female=40/69, age 43+/-12 years), we assessed with contrast-enhanced transcranial Doppler the bubble load during normal breathing and after the Valsalva maneuver in both standing and recumbent position randomizing the order of testing. RESULTS: During normal breathing, the average bubble count was 11+/-20 in the recumbent and 26+/-60 in the standing position. After the Valsalva maneuver, it was 40+/-38 and 42+/-37, respectively. The increase of bubble load in standing position occurred in 42% of patients and was independent of the order of testing. CONCLUSIONS: The amount of permanent right to left shunt is posture-dependent in 40% of patients. Testing in the sitting position may thus be warranted in doubtful or inconclusive results obtained with the subject in the horizontal position.

Postpartum Headache: A Prospective Study.

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.

Reversible cerebral vasoconstriction syndrome in puerperium: A prospective study.

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 postdelivery. 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 favourable 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.

Cerebrovascular reactivity by quantitative magnetic resonance angiography with a Co2 challenge. Validation as a new imaging biomarker.

Assessment of cerebrovascular reactivity (CVR) is essential in cerebrovascular diseases, as exhausted CVR may enhance the risk of cerebral ischemic events. Transcranial Doppler (TCD) with a vasodilatory stimulus is currently used for CVR evaluation. Scanty data are available for Quantitative Magnetic Resonance Angiography (QMRA), which supplies higher spatial resolution and quantitative cerebral blood flow values. Aims of our pilot study were: (a) to assess safety and feasibility of CO2 administration during QMRA, (b) evaluation of CVR under QMRA compared to TCD, and (c) quantitative evaluation of blood flow from the major intracranial arterial vessels both at rest and after CO2. CVR during 5% CO2 air breathing was measured with TCD as a reference method and compared with QMRA. Fifteen healthy subjects (age 60.47 ± 2.24; male 11/15) were evaluated at rest and during CO2 challenge. Feasibility and safety of QMRA under CO2 were ensured in all subjects. CVR from middle cerebral artery territory was not statistically different between TCD and MRI (p>0.05). Mean arterial pressure (MAP) and heart rate (HR) increased during QMRA and TCD (MAP p=0.007 and p=0.001; HR p=0.043 and p=0.068, respectively). Blood flow values from all intracranial vessels increased after CO2 inhalation (p<0.001). CO2 administration during QMRA sessions is safe and feasible. Good correlation in terms of CVR was obtained comparing TCD and QMRA. Blood flow values significantly increased from all intracranial arterial vessels after CO2. Studies regarding CVR in physiopathological conditions might consider the utilization of QMRA both in routine clinical settings and in research projects.

[Multidisciplinary position paper on the management of patent foramen ovale in the presence of cryptogenic cerebral ischemia - Italian version 2013]. / Documento di posizione multidisciplinare sulla gestione del forame ovale pervio in presenza di ischemia cerebrale criptogenica - versione 2013.

There is no generally accepted consensus on the management of patent foramen ovale (PFO) in the presence of cryptogenic cerebral ischemia, because of the lack of conclusive evidence. The aim of this position paper was to develop and promote a joint approach based on available data that may be shared by different specialists, while waiting for definite results from randomized controlled trials. A position statement was produced involving the major national scientific societies. The task force members were nominated by the presidents and/or executive boards of each society or working group, as appropriate, based on their previous work in relevant topic areas. Specific task force working groups prepared the drafts. In order to achieve maximum agreement, these drafts were merged and distributed to the scientific societies for local evaluation. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by all scientific societies. The following issues were addressed: definitions of transient ischemic attack (TIA) and both symptomatic and asymptomatic cryptogenic stroke; formulation of a diagnostic workup for patients with clinical event(s) and PFO; recommendations regarding medical and interventional treatment options considering individual risk factors based on the three available randomized trials and other observational studies; recommendations regarding requirements for operators and centers in Italy; definition of a follow-up evaluation protocol. In conclusion, available data provided the basis for the first multi-society position paper on the management of cryptogenic stroke/TIA and PFO.