Risk Profile of Patients with Spontaneous Cervical Artery Dissection.

OBJECTIVE: Epidemiological data to characterize the individual risk profile of patients with spontaneous cervical artery dissection (sCeAD) are rather inconsistent. METHODS AND RESULTS: In the setting of the Italian Project on Stroke in Young Adults Cervical Artery Dissection (IPSYS CeAD), we compared the characteristics of 1,468 patients with sCeAD (mean age = 47.3 ± 11.3 years, men = 56.7%) prospectively recruited at 39 Italian centers with those of 2 control groups, composed of (1) patients whose ischemic stroke was caused by mechanisms other than dissection (non-CeAD IS) selected from the prospective IPSYS registry and Brescia Stroke Registry and (2) stroke-free individuals selected from the staff members of participating hospitals, matched 1:1:1 by sex, age, and race. Compared to stroke-free subjects, patients with sCeAD were more likely to be hypertensive (odds ratio [OR] = 1.65, 95% confidence interval [CI] = 1.37-1.98), to have personal history of migraine with aura (OR = 2.45, 95% CI = 1.74-3.34), without aura (OR = 2.67, 95% CI = 2.15-3.32), and family history of vascular disease in first-degree relatives (OR = 1.69, 95% CI = 1.39-2.05), and less likely to be diabetic (OR = 0.65, 95% CI = 0.47-0.91), hypercholesterolemic (OR = 0.75, 95% CI = 0.62-0.91), and obese (OR = 0.41, 95% CI = 0.31-0.54). Migraine without aura was also associated with sCeAD (OR = 1.81, 95% CI = 1.47-2.22) in comparison with patients with non-CeAD IS. In the subgroup of patients with migraine, patients with sCeAD had higher frequency of migraine attacks and were less likely to take anti-migraine preventive medications, especially beta-blockers, compared with the other groups. INTERPRETATION: The risk of sCeAD is influenced by migraine, especially migraine without aura, more than by other factors, increases with increasing frequency of attacks, and seems to be reduced by migraine preventive medications, namely beta-blockers. ANN NEUROL 2023;94:585-595.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

BACKGROUND: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. METHODS: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. RESULTS: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]). CONCLUSIONS: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Antithrombotic therapy in the postacute phase of cervical artery dissection: the Italian Project on Stroke in Young Adults Cervical Artery Dissection.

OBJECTIVE: To explore the impact of antithrombotic therapy discontinuation in the postacute phase of cervical artery dissection (CeAD) on the mid-term outcome of these patients. METHODS: In a cohort of consecutive patients with first-ever CeAD, enrolled in the setting of the multicentre Italian Project on Stroke in Young Adults Cervical Artery Dissection, we compared postacute (beyond 6 months since the index CeAD) outcomes between patients who discontinued antithrombotic therapy and patients who continued taking antithrombotic agents during follow-up. Primary outcome was a composite of ischaemic stroke and transient ischaemic attack. Secondary outcomes were (1) Brain ischaemia ipsilateral to the dissected vessel and (2) Recurrent CeAD. Associations with the outcome of interest were assessed by the propensity score (PS) method. RESULTS: Of the 1390 patients whose data were available for the outcome analysis (median follow-up time in patients who did not experience outcome events, 36.0 months (25th-75th percentile, 62.0)), 201 (14.4%) discontinued antithrombotic treatment. Primary outcome occurred in 48 patients in the postacute phase of CeAD. In PS-matched samples (201 vs 201), the incidence of primary outcomes among patients taking antithrombotics was comparable with that among patients who discontinued antithrombotics during follow-up (5.0% vs 4.5%; p(log rank test)=0.526), and so was the incidence of the secondary outcomes ipsilateral brain ischaemia (4.5% vs 2.5%; p(log rank test)=0.132) and recurrent CeAD (1.0% vs 1.5%; p(log rank test)=0.798). CONCLUSIONS: Discontinuation of antithrombotic therapy in the postacute phase of CeAD does not appear to increase the risk of brain ischaemia during follow-up.

Association of the careggi collateral score with radiological outcomes after thrombectomy for stroke with an occlusion of the middle cerebral artery.

We aimed to examine the association between Careggi Collateral Score (CCS) and radiological outcomes in a large multicenter cohort of patients receiving thrombectomy for stroke with occlusion of middle cerebral artery (MCA). We conducted a study on prospectively collected data from 1785 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. According to the extension of the retrograde reperfusion in the cortical anterior cerebral artery-MCA territories, CCS ranges from 0 (absence of retrograde filling) to 4 (visualization of collaterals until the alar segment of the MCA). Radiological outcomes at 24 h were the presence and severity of infarct growth defined by the absolute change in ASPECTS from baseline to 24 h; presence and severity of cerebral bleeding defined as no ICH, HI-1, HI-2, PH-1, or PH-2; presence and severity of cerebral edema (CED) defined as no CED, CED-1, CED-2, or CED-3. Using CCS = 0 as reference, ORs of CCS grades were significantly associated in the direction of better radiological outcome on infarct growth (0.517 for CCS = 1, 0.413 for CCS = 2, 0.358 for CCS = 3, 0.236 for CCS = 4), cerebral bleeding grading (0.485 for CCS = 1, 0.445 for CCS = 2, 0.400 for CCS = 3, 0.379 for CCS = 4), and CED grading (0.734 for CCS = 1, 0.301 for CCS = 2, 0.295 for CCS = 3, 0.255 for CSS = 4) shift in ordinal regression analysis after adjustment for pre-defined variables (age, NIHSS score, ASPECTS, occlusion site, onset-to-groin puncture time, procedure time, and TICI score). Using CCS = 4 as reference, ORs of CCS grades were significantly associated in the direction of worse radiological outcome on infarct growth (1.521 for CCS = 3, 1.754 for CCS = 2, 2.193 for CCS = 1, 4.244 for CCS = 0), cerebral bleeding grading (2.498 for CCS = 0), and CED grading (1.365 for CCS = 2, 2.876 for CCS = 1, 3.916 for CCS = 0) shift. The CCS could improve the prognostic estimate of radiological outcomes in patients receiving thrombectomy for stroke with MCA occlusion.

Clinical Features of Patients With Cervical Artery Dissection and Fibromuscular Dysplasia.

BACKGROUND AND PURPOSE: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. METHODS: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD-). RESULTS: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13-2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06-18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26-0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58-7.31] and 2.07 [95% CI, 1.06-4.03], respectively) in multivariable Cox proportional hazards analysis. CONCLUSIONS: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Reperfusion strategies in stroke due to isolated cervical internal carotid artery occlusion: systematic review and treatment comparison.

INTRODUCTION: Despite intravenous thrombolysis (IVT) and endovascular treatment (EVT) have been demonstrated effective in acute ischemic stroke (AIS) due to large vessel occlusions, there are still no conclusive data to guide treatment in stroke due to cervical internal carotid artery (ICA) occlusion. We systematically reviewed available literature to compare IVT, EVT, and bridging (IVT + EVT) and define optimal treatment. METHODS: Systematic review followed predefined protocol (Open-Science-Framework osf.io/bfykj ). MEDLINE, EMBASE, and Cochrane CENTRAL were searched. Results were restricted to studies in English, with sample size ≥ 10 and follow-up ≥30 days. Primary outcomes were favorable outcome (mRS ≤ 2), mortality, and symptomatic intracerebral hemorrhage(sICH), defined according to study original report. Newcastle-Ottawa scale was used for bias assessment. RESULTS: Seven records of 930 screened were included in meta-analysis. Quality of studies was low-to-fair in 5, good in 2. IVT (n = 450) did not differ for favorable outcome and mortality compared to EVT (n = 150), though having lower rate of sICH (OR = 0.4, 95% CI 0.2-0.8). Compared to IVT, bridging (IVT + EVT) was associated with higher rate of favorable outcome (OR = 2.2, 95% CI 1.3-3.7). Compared to EVT, bridging (IVT + EVT) provided higher rate of favorable outcome (OR = 1.9, 95% CI 1.1-3.4), with a marginally increased risk of sICH (OR = 2.1, 95% CI 1-4.4) but similar mortality rates. CONCLUSIONS: Our systematic review highlights that, in acute ischemic stroke associated with isolated cervical ICA occlusion, bridging (IVT + EVT) might lead to higher rate of functional independence at follow-up, without increasing mortality. The low quality of available studies prevents from drawing firm conclusions, and randomized-controlled clinical trials are critically needed to define optimal treatment in this AIS subgroup.

Impact of COVID-19 pandemic on acute stroke care: facing an epidemiological paradox with a paradigm shift.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) outbreak, a decrease of stroke's hospital admissions and reperfusion therapy has been reported worldwide. This retrospective observational study assessed the volume of stroke cases managed in the Emergency Department (ED) and reperfusion therapies in an Italian stroke network with a high incidence of COVID-19, particularly to evaluate if the in-hospital rerouting and the switch from a drip-and-ship to a mothership model could assure an adequate volume of acute treatments. METHODS: We compared data from March 2020 with those from previous years and formulated five PICO questions regarding (1) incidence of stroke cases in the ED; (2) relation between stroke cases and COVID-19; (3) differences in the number of reperfusion therapies, (4) in the call-to-needle and door-to-needle times for intravenous thrombolysis, and (5) in the call-to-groin and door-to-groin times for thrombectomy. RESULTS: We found (1) a 28% decreased of confirmed stroke cases managed in the ED, (2) a negative correlation between stroke cases in ED and COVID-19 progression (rs = - .390, p = .030), and (3) a similar number of treatments in March 2020 and March 2019. The adoption of the mothership model (4) did not delay alteplase infusion (median call-to-needle p = .126, median door-to-needle p = .142) but led to (5) a significant reduction in median call-to-groin (p = .018) and door-to-groin times (p = .010). CONCLUSION: The "hospital avoidance" of stroke patients during the "stay-at-home" appeals needs to be considered for future public health campaigns. A prompt reorganization of the stroke network can guarantee optimal performances at times of crisis.

Long-term outcome of cervical artery dissection : IPSYS CeAD: study protocol, rationale, and baseline data of an Italian multicenter research collaboration.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t1) and then annually (t2 at 1 year, t3 at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.

Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.

Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.

Migraine improvement after spontaneous cervical artery dissection the Italian Project on Stroke in Young Adults (IPSYS).

OBJECTIVE: Whether migraine modifies after spontaneous cervical artery dissection (sCeAD) more than after other stroke etiologic subtypes has never been adequately investigated. METHODS: In the setting of the Italian Project on Stroke in Young Adults (IPSYS), we compared the course of migraine before and after acute brain infarct in a group of migraine patients with sCeAD and a group of migraine patients whose ischemia was due to a cause other than CeAD (non-CeAD IS), matched by sex, age (± 3 years), and migraine subtype.We applied linear mixed models to evaluate pre-event vs post-event changes and differences between sCeAD and non-CeAD IS patients. RESULTS: Eighty-seven patients per group (migraine without aura/migraine with aura, 67/20) qualified for the analysis. After the acute event, migraine headaches disappeared in 14.0% of CeAD patients vs 0.0% of non-CeAD IS patients (p ≤ 0.001). Migraine frequency (patients suffering at least 1 attack, from 93.1 to 80.5%, p = 0.001), pain intensity (from 6.7 ± 1.7 to 4.6 ± 2.6 in a 0 to 10 pain scale, p ≤ 0.001), and use of acute anti-migraine medications (patients taking at least 1 preparation, from 81.6 to 64.4%, p = 0.007) also improved significantly after CeAD as opposed to that observed after non-CeAD IS. CONCLUSION: The spontaneous improvement of migraine after sCeAD reinforces the hypothesis of a pathogenic link between the two conditions.

Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults.

Importance: Although sparse observational studies have suggested a link between migraine and cervical artery dissection (CEAD), any association between the 2 disorders is still unconfirmed. This lack of a definitive conclusion might have implications in understanding the pathogenesis of both conditions and the complex relationship between migraine and ischemic stroke (IS). Objective: To investigate whether a history of migraine and its subtypes is associated with the occurrence of CEAD. Design, Setting, and Participants: A prospective cohort study of consecutive patients aged 18 to 45 years with first-ever acute ischemic stroke enrolled in the multicenter Italian Project on Stroke in Young Adults was conducted between January 1, 2000, and June 30, 2015. In a case-control design, the study assessed whether the frequency of migraine and its subtypes (presence or absence of an aura) differs between patients whose IS was due to CEAD (CEAD IS) and those whose IS was due to a cause other than CEAD (non-CEAD IS) and compared the characteristics of patients with CEAD IS with and without migraine. Main Outcomes and Measures: Frequency of migraine and its subtypes in patients with CEAD IS vs non-CEAD IS. Results: Of the 2485 patients (mean [SD] age, 36.8 [7.1] years; women, 1163 [46.8%]) included in the registry, 334 (13.4%) had CEAD IS and 2151 (86.6%) had non-CEAD IS. Migraine was more common in the CEAD IS group (103 [30.8%] vs 525 [24.4%], P = .01), and the difference was mainly due to migraine without aura (80 [24.0%] vs 335 [15.6%], P < .001). Compared with migraine with aura, migraine without aura was independently associated with CEAD IS (OR, 1.74; 95% CI, 1.30-2.33). The strength of this association was higher in men (OR, 1.99; 95% CI, 1.31-3.04) and in patients 39.0 years or younger (OR, 1.82; 95% CI, 1.22-2.71). The risk factor profile was similar in migrainous and non-migrainous patients with CEAD IS (eg, hypertension, 20 [19.4%] vs 57 [24.7%], P = .29; diabetes, 1 [1.0%] vs 3 [1.3%], P > .99). Conclusions and Relevance: In patients with IS aged 18 to 45 years, migraine, especially migraine without aura, is consistently associated with CEAD. This finding suggests common features and warrants further analyses to elucidate the underlying biologic mechanisms.

Severe familial ALS with a novel exon 4 mutation (L106F) in the SOD1 gene.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease associated with a positive familial history in 5-10% of ALS cases. Mutations in the superoxide dismutase-1 (SOD1) gene have been found in 12%-23% of patients diagnosed with familial ALS. Here we report a novel mutation in exon 4 of SOD1 gene in a 55-year-old ALS patient belonging to a large Italian family with ALS first clinically described in 1968. In the family the clinical presentation was characterized by relatively early age of onset, spinal onset with proximal distribution weakness, bulbar involvement and a rapid disease course. Molecular analysis showed a heterozygous mutation at codon 106 resulting in a substitution of phenylalanine for leucine in the SOD1 protein (L106F). In analogy with the previously reported L106V mutation, we propose that the L106F causes a relevant destabilization of the protein chain around the mutation site, able to affect the SOD1 monomer and dimer structures suggesting a pathogenic role for this novel mutation.