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Presents a letter to the editor about the genetic analysis of cervical artery dissection in a group of patients under chiropractic care in Italy.

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., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH., Methods: Multicenter, retrospective, case-control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 -). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression., Results: A total of 33 COV19 + patients and 321 COV19 - controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026)., Conclusions: ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To standardize assessment and coordinate processes in stroke rehabilitation, an integrated care pathway (ICP) was developed in an Italian Rehabilitation and Research Institution by a knowledge-translation interdisciplinary process, from evidence-based guidelines to rehabilitation practice. The ICP was implemented in two pilot Tuscan rehabilitation Centers., Aim: The purpose of this study was to describe ICP development and assess the ICP effects on postacute stroke inpatient rehabilitation outcomes., Design: Prospective observational study, before and after comparison., Setting: Two Tuscan inpatient rehabilitation centers., Population: Patients accessing either centers for intensive rehabilitation after acute stroke., Methods: Two cohorts were prospectively recruited before (2015-2017) and after (2018) implementation of the pathway. The primary outcome was change in activities of daily living disability, assessed by the modified Barthel Index (mBI) from admission to discharge. Secondary outcomes included length of stay (LOS), adverse outcomes, and changes in communication ability, trunk control, pain, ambulation, bladder catheter (Y/N), bedsores (Y/N)., Results: In 2015-2017, 443 postacute stroke patients (mean age 77±11 years, 47% women), while in 2018, 84 patients (mean age 76±13 years, 61% women) were admitted to the two facilities. Comparing the 2018 vs. the 2015-17 cohort, the mean mBI increase was not substantially different (26 vs. 24 points), nor were LOS (37±18 vs. 36±16 days), adverse outcomes, discharge destination, and improvement of ambulation, pain, and communication (P>0.05). Instead, a significantly higher improvement of trunk control (trunk control test: 69.6±33.2 vs. 79.0±31.3, P=0.019), and a higher percentage of bedsore resolution (13% vs. 5%, P=0.033), and bladder catheter removal (37% vs. 17% P<0.001) were observed in 2018 vs. 2015-2017., Conclusions: Compared to prior practice, ICP was associated to improvement of trunk control recovery, bladder catheter removal, and bedsores resolution. Further ICP implementation on a larger scale is needed to verify improvements of stroke inpatient rehabilitation outcomes., Clinical Rehabilitation Impact: An evidence-based stroke rehabilitation ICP was interdisciplinary developed and implemented in two rehabilitation centers of a multicenter Italian health group. ICP implementation as to inpatient intensive postacute stroke rehabilitation was associated to improved trunk control recovery, bladder catheter removal, and bedsore resolution. Further ICP implementation will allow multicenter studies and quality benchmarking.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

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.

Background: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107)., Conclusion: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.

Objective: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated., Methods: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH., Results: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones., Conclusions: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: We sought to compare the benefit of percutaneous closure to that of medical therapy alone for the secondary prevention of embolism in patients with patent foramen ovale (PFO) and otherwise unexplained ischemic stroke, in a propensity scored study., Methods and Results: Between 2000 and 2012, we selected consecutive first-ever ischemic stroke patients aged 18 to 45 years with PFO and no other cause of brain ischemia, as part of the IPSYS registry (Italian Project on Stroke in Young Adults), who underwent either percutaneous PFO closure or medical therapy for comparative analysis. Primary end point was a composite of ischemic stroke, transient ischemic attack, or peripheral embolism. Secondary end point was brain ischemia. Five hundred and twenty-one patients qualified for the analysis. The primary end point occurred in 15 patients treated with percutaneous PFO closure (7.3%) versus 33 patients medically treated (10.5%; hazard ratio, 0.72; 95% confidence interval, 0.39-1.32; P=0.285). The rates of the secondary end point brain ischemia were also similar in the 2 treatment groups (6.3% in the PFO closure group versus 10.2% in the medically treated group; hazard ratio, 0.64; 95% confidence interval, 0.33-1.21; P=0.168). Closure provided a benefit in patients aged 18 to 36 years (hazard ratio, 0.19; 95% confidence interval, 0.04-0.81; P=0.026) and in those with a substantial right-to-left shunt size (hazard ratio, 0.19; 95% confidence interval, 0.05-0.68; P=0.011)., Conclusions: PFO closure seems as effective as medical therapy for secondary prevention of cryptogenic ischemic stroke. Whether device treatment might be more effective in selected cases, such as in patients younger than 37 years and in those with a substantial right-to-left shunt size, deserves further investigation., (© 2016 American Heart Association, Inc.)

Background and Purpose: Although lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent acute manifestations of the same pathological process involving cerebral small vessels (small vessel disease), it remains unclear what factors predispose to one phenotype rather than the other at individual level., Methods: Consecutive patients with either acute symptomatic LS or dICH were prospectively enrolled as part of a multicenter Italian study. We compared the risk factor profile of the 2 subgroups using multivariable logistic regression., Results: During a time course of 9.5 years, 1931 subjects (1434 LS and 497 dICH; mean age, 71.3±13.3 years; males, 55.5%) qualified for the analysis. Current smoking was associated with LS (odds ratio [OR], 2.17; P<0.001). Conversely, dICH cases were more likely to be hypertensive (OR, 1.87; P<0.001), excessive alcohol consumers (OR, 1.70; P=0.001), and more frequently under treatment with warfarin (OR, 2.05; P=0.010) and statins (OR, 3.10; P<0.001). Hypercholesterolemia, diabetes mellitus, and antiplatelet treatment were not associated with a specific small vessel disease manifestation., Conclusions: The risk factor profile of dICH differs from that associated with LS. This might be used for disease risk stratification at individual level., (© 2016 American Heart Association, Inc.)

Factors predicting family history (FH) of premature arterial thrombosis in young patients with ischaemic stroke (IS) have not been extensively investigated, and whether they might influence the risk of post-stroke recurrence is still unknown. In the present study we analysed 1,881 consecutive first-ever IS patients aged 18-45 years recruited from January 2000 to January 2012 as part of the Italian Project on Stroke in Young Adults (IPSYS). FH of premature arterial thrombosis was any thrombotic event [IS, myocardial infarction or other arterial events event] < 45 years in proband's first-degree relatives. Compared with patients without FH of premature arterial thrombosis, those with FH (n = 85) were more often smokers (odds ratio [OR], 1.94; 95 % confidence interval [CI], 1.21-3.09) and carriers of procoagulant abnormalities (OR, 3.66; 95 % CI, 2.21-6.06). Smoking (OR, 2.48; 95 % CI, 1.20-5.15), the A1691 mutation in factor V gene (OR, 3.64; 95 % CI, 1.31-10.10), and the A20210 mutation in the prothrombin gene (OR, 8.40; 95 % CI 3.35-21.05) were associated with FH of premature stroke (n = 33), while circulating anti-phospholipids to FH of premature myocardial infarction (n = 45; OR, 3.48; 95 % CI, 1.61-7.51). Mean follow-up time was 46.6 ± 38.6 months. Recurrent events occurred more frequently in the subgroup of patients with FH of premature stroke [19.4 %); p = 0.051] compared to patients without such a FH. In conclusion, young IS patients with FH of premature arterial thrombosis exhibit a distinct risk-factor profile, an underlying procoagulant state and have worse vascular prognosis than those with no FH of juvenile thrombotic events.

Background: Seizures are common neurological consequences of stroke. Although a number of factors including stroke severity on admission, cortical involvement, and stroke subtype have been consistently associated with post-stroke seizures, the effect that medical and neurological complications of stroke, occurring in the very acute phase, might have on such a risk has never been adequately explored. In the present study we aimed at determining the extent to which complications within the first week of stroke influence the risk of early seizures (ES)., Methods: Data of consecutive patients with first-ever acute stroke included in the Brescia Stroke Registry were analyzed. ES (≤7 days) were recorded and correlated with demographic data, disease characteristics, risk factors, and prespecified medical and neurological stroke complications in a multivariate path analysis model., Results: 516 patients with first-ever acute stroke were eligible for inclusion in the present study. Of them, 436 patients had ischemic stroke (IS) [64 (14.6%) with hemorrhagic transformation (HT)] and 80 had intracerebral hemorrhage (ICH). Twenty patients (3.9%) developed ES. Patients with ES had a higher burden of complications compared with those without (30 vs. 4.2%, for patients with >6 complications). Lesion type, stroke complications, and lesion site were directly related to the risk of seizure occurrence (OR, 0.24; 95% CI, 0.07-0.80 for IS vs. ICH; OR, 1.57; 95% CI, 1.21-2.01 for any increase of 1 in the number of complications; OR, 0.15; 95% CI, 0.04-0.56 for subcortical lesions vs. cortical lesions). Complications appeared also to mediate the indirect effect of lesion type on the occurrence of ES (OR, 0.75; 95% CI, 0.60-0.94). No significant difference on the risk of ES was observed when HT and ICH were compared. The total effect of lesion type was 0.25 × 0.75 = 0.18, corresponding to (1-0.18) = 82% lower risk of ES for IS as compared to ICH., Conclusion: Although major determinants of ES are nonmodifiable, preventable and treatable medical and neurologic complications within the first week of stroke increase the risk of ES and mediate the effect of established predictors on the propensity to post-stroke epilepsy. Future epidemiologic studies aimed at investigating post-stroke seizures should include precise information on these complications., (Copyright © 2013 S. Karger AG, Basel.)

Cerebral vein thrombosis (CVT) is a rare complication of spontaneous intracranial hypotension (SIH). When to suspect a thrombotic disorder during the course of intracranial hypotension is not fully elucidated. A 48-year-old woman was admitted because of SIH with no signs of CVT on neuroimaging. The occurrence of diplopia and blurred vision 12 days later led to the performance of further investigations, which revealed thrombosis of the left lateral sinus, in the absence of variations in the headache characteristics. Among the other 4 cases of SIH clearly preceding the occurrence of CVT reported so far, only one had a change in the headache pattern related to CVT development. Although a change in the characteristics of headache is considered a marker of CVT in patients with SIH, this is not invariably part of the clinical scenario. Any new neurologic finding on exam in the disease course should raise a suspicion of venous thrombosis, thus prompting further specific investigations., (© 2012 American Headache Society.)

Grange syndrome is a disorder characterized by arterial occlusive disease, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities. It was first described in four members of the same family and in two sporadic cases thereafter, suggesting the possibility of various patterns of inheritance. We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome. Although rare and not fully characterized, Grange syndrome should be included in the differential diagnosis of stroke at young age., (Copyright © 2012 Wiley Periodicals, Inc.)

Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin therapy which can be responsible for thrombotic events with embolic consequences. Although ischemic stroke is a well known consequence of HIT, few cases of cerebral ischemia of arterial origin have been reported so far. A 38-year-old man was admitted because of acute multiple ischemic strokes and pulmonary embolism which occurred during treatment with low molecular weight heparin as prophylactic therapy for orthopedic surgery. Neuroimaging showed occlusion of the right common carotid artery with multiple acute cerebral infarcts. Testing for anti-platelet factor 4 antibodies confirmed the diagnosis. Systematic review of the literature revealed 55 cases of arterial stroke and three cases of carotid artery occlusion caused by HIT. Although arterial ischemic stroke is a rare complication of HIT, a high level of suspicion and a prompt diagnosis of this coagulation disorder are necessary to avoid life-threatening thromboembolic complications.

Large middle cerebral artery (MCA) and panhemispheric stroke represent a minority of cerebral ischemic events, yet they are responsible for a disproportionate share of morbidity and mortality. Malignant infarction with formation of cerebral edema is a common cause for secondary neurologic deterioration. Despite intensive medical and surgical care, prognosis is often poor and mortality may be as high as 60-80%. Surgical intervention can reduce that mortality compared to medical therapy alone, but necessitates a careful exploration of patient characteristics for acceptable outcomes., (Copyright © 2012 S. Karger AG, Basel.)

The optimal management of blood pressure (BP) during acute stroke is controversial. We aimed to investigate whether (1) acute BP has differential impact on clinical outcome of ischemic stroke (IS) and spontaneous intracerebral hemorrhage (ICH), and (2) the magnitude of such an effect varies from the very acute phase to the postacute phase of the two diseases. BP values were automatically recorded at 15-min intervals within the first 48 h in consecutive patients with stroke onset less than 24 h before Stroke Unit admission. Growth mixture models were applied to evaluate the association between binary outcome measures [(1) early neurological deterioration (defined as a ≥4-point increase in 48-h National Institutes of Health Stroke Scale [NIHSS] score), (2) 90-day unfavorable functional status (modified Rankin Scale [mRS] 3-6), and (3) 90-day mortality] and the latent heterogeneity of maximum BP trajectories over time, expressed by two (high/low) BP latent classes within stroke groups. After exclusions, 264 patients (198 IS, 66 ICH) were included. High systolic BP (sBP) class was associated with (1) a direct ~15% increased risk of early neurological deterioration [risk difference (RD), +0.151; 95% confidence interval (CI) +0.039 to +0.263] and ~4% worse 48-h outcome for ICH with respect to IS (RD, +0.038; 95% CI +0.005 to +0.071), (2) a ~28% increased risk of 90-day unfavorable outcome in the group of patients with ICH with respect to IS [IRD = RD(ICH) - RD(IS), +0.289; 95% CI +0.010 to +0.571], and (3) no significant effect on 90-day mortality. The influence of acute BP values on mid-term stroke outcome varies depending on the stroke subtype.

Ischemic stroke during pregnancy and puerperium represents a rare occurrence but it could be a serious and stressful event for mothers, infants, and also families. Whenever it does occur, many concerns arise about the safety of the mother and the fetus in relation to common diagnostic tests and therapies leading to a more conservative approach. The physiological adaptations in the cardiovascular system and in the coagulability that accompany the pregnant state, which are more significant around delivery and in the postpartum period, likely contribute to increasing the risk of an ischemic stroke. Most of the causes of an ischemic stroke in the young may also occur in pregnant patients. Despite this, there are specific conditions related to pregnancy which may be considered when assessing this particular group of patients such as pre-eclampsia-eclampsia, choriocarcinoma, peripartum cardiomiopathy, amniotic fluid embolization, and postpartum cerebral angiopathy. This article will consider several questions related to pregnancy-associated ischemic stroke, dwelling on epidemiological and specific etiological aspects, diagnostic issue concerning the use of neuroimaging, and the related potential risks to the embryo and fetus. Therapeutic issues surrounding the use of anticoagulant and antiplatelets agents will be discussed along with the few available reports regarding the use of thrombolytic therapy during pregnancy.

In spite of the strong epidemiologic evidence linking migraine and ischemic stroke in young adults, the mechanisms explaining this association remain poorly understood. The observation that stroke occurs more frequently during the interictal phase of migraine prompts to speculation that an indirect relation between the two diseases might exist. In this regard, four major issues might be considered which may be summarized as follows: (1) the migraine-ischemic stroke relation is influenced by specific risk factors such as patent foramen ovale or endothelial dysfunction and more frequent in particular conditions like spontaneous cervical artery dissection; (2) migraine is associated with an increased prevalence of cardiovascular risk factors; (3) the link is caused by migraine-specific drugs; (4) migraine and ischemic vascular events are linked via a genetic component. In the present paper, we will review epidemiological studies, discuss potential mechanisms of migraine-induced stroke and comorbid ischemic stroke, and pose new research questions.

Thrombus formation at a site of arterial injury (eg, rupture of an atherosclerotic plaque in a carotid artery), a crucial step in the pathogenesis of cerebral ischemia, is initiated by the adhesion of platelets to the arterial wall. In vivo, activated platelets release adenosine diphosphate (ADP), whose binding to the platelet P2Y12 receptor elicits progressive and sustained platelet aggregation. As a result, this receptor has been a target for the development of clinically effective antiplatelet agents, such as the thienopyridines ticlopidine and, more recently, clopidogrel, the only two currently FDA-approved P2Y12 antagonists. Clopidogrel has a well-established role as an antithrombotic agent in the setting of ischemic stroke. However, several challenges remain, including the relatively slow onset of action of this drug and the phenomenon of clopidogrel response variability or "resistance". A number of novel P2Y12 antagonists are therefore under investigation to determine whether they can result in better or more rapid antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic (or other) side effects. These include 1) prasugrel, an orally-administered thienopyridine prodrug, 2) ticagrelor (AZD6140), an ATP analog reversible P2Y12 antagonist, 3) cangrelor, an intravenously-administered reversible P2Y12 antagonist, and 4) PRT060128. Whether the promising pharmacological profile of these drugs will be translated into clinical benefit for stroke patients will be determined by the results of clinical trials.

There is compelling evidence that treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors - "statins" - the most important class of lipid lowering agents, reduces ischemic stroke incidence independent on their effect on serum cholesterol levels. In this review, the non-lipid-mediated - "pleiotropic" - effects of statins as well as their potential implication in developing new treatment strategies for stroke prevention will be discussed.

Strong epidemiological evidence indicates that migraine, especially migraine with aura, is associated with increased risk of ischemic stroke. However, the precise mechanisms of such a relation are currently not fully elucidated and are still a matter of speculation. Migraine may directly cause an ischemic event (i.e, migrainous infarct), by inducing cerebral microcirculatory vasoconstriction (cortical spreading depression-related oligemia), intracerebral large vessels spasm, and vascular endothelium-related hypercoagulability. On the other hand, migraine may predispose to cerebral ischemia outside of a migraine attack by affecting endothelial function, alone or in combination with traditional vascular risk factors, or by interacting with pre-existent stroke susceptibility conditions (i.e, patent foramen ovale). At least theoretically, the migraine-stroke link may be the consequence of the unfavourable effect of migraine-specific drugs (i.e, triptans or ergot alkaloids). Finally, migraine and ischemic vascular events may be linked via genetic pathways, certain genes playing a role on both diseases and influencing their relation. The coexistence of ischemic stroke and migraine in the context of specific syndromes (i.e, CADASIL) characterized by peculiar phenotype, proven inherited background and chronic alterations of the wall of cerebral small vessel arteries suggests that migraine and ischemic stroke may be the end phenotype of common pathogenic mechanisms. How to identify those migraineurs at highest risk of ischemic stroke and whether stroke can be prevented by specific therapeutic strategies are the goals of future research.

Numerous epidemiologic observations reporting high prevalence of migraine among young individuals with stroke as well as dysfunction of cerebral arteries during migraine attacks prompt speculation on the existence of a comorbidity between the two disorders. The recent finding of silent infarct-like brain lesions in migraineurs reinforced this hypothesis and raised questions on whether migraine may be a progressive disorder rather than simply an episodic disorder. Stroke can occur during the course of migraine attacks with aura, supporting the assumption of a causal relation between the two diseases. Migraine may accentuate other existing risk factors for stroke, and both jointly increase the risk of cerebral ischemia outside of migraine attacks. In this regard, the role of migraine might be that of predisposing condition for cerebral ischemia. Migraine and ischemic stroke may be the end phenotype of common pathogenic mechanisms. Evidence of a migraine-stroke relation in cases of specific disorders, such as CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), strongly supports this concept. Finally, acute focal cerebral ischemia can trigger migraine attacks, and, thus, migraine may be the consequence of stroke. In this paper, we will review contemporary epidemiologic studies, discuss potential mechanisms of migraine-induced stroke and comorbid ischemic stroke, and pose new research questions.

Background and Purpose: The objective was to investigate the role of C677T MTHFR polymorphism in migraine pathogenesis and in the migraine-ischemic stroke pathway., Methods: A first genotype-migraine association study was conducted on 100 patients with migraine with aura (MA), 106 with migraine without aura (MO), and 105 subjects without migraine, which provided evidence in favor of association of the TT677 MTHFR genotype with increased risk of MA compared with both control subjects (OR, 2.48; 95% CI, 1.11 to 5.58) and patients with MO (OR, 2.21; 95% CI, 1.01 to 4.82). Based on these findings, mediational models of the genotype-migraine-stroke pathway were fitted on a group of 106 patients with spontaneous cervical artery dissection, 227 young patients whose ischemic stroke was unrelated to a spontaneous cervical artery dissection (noncervical artery dissection), and 187 control subjects, and a genotype-migraine partial mediation model was selected., Results: Both migraine and the TT genotype were more strongly associated to the subgroup of patients with spontaneous cervical artery dissection (OR, 4.06; 95% CI, 1.63 to 10.02 for MA; OR, 5.45; 95% CI, 3.03 to 9.79 for MO; OR, 2.87; 95% CI, 1.45 to 5.68 for TT genotype) than to the subgroup of patients with noncervical artery dissection ischemic stroke (OR, 2.22; 95% CI, 1.00 to 4.96 for MA; OR, 1.81; 95% CI, 1.02 to 3.22 for TT genotype) as compared with controls., Conclusions: Migraine may act as mediator in the methylenetetrahydrofolate reductase-ischemic stroke pathway with a more prominent effect in the subgroup of patients with spontaneous artery dissection.

Homocysteine is a thiol aminoacid synthesized during the metabolism of methionine. Increased plasma levels of homocysteine can be the result of mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine-beta synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR). Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or vitamin B12 (methylcobalamin), can induce hyperhomocysteinemia. Over the last decade, following in vitro and in vivo observations of a homocysteine-associated vascular pathology, convincing epidemiological evidence has been gathered on the relation between moderate elevation of plasma homocysteine and vascular disease, including cerebral ischemia. However, causality has yet to be established. The association between homocysteine and ischemic stroke might be a spurious epidemiological finding because of confounding or it might reflect reverse causality. If this is the case, elevated levels of plasma homocysteine should be interpreted as an epiphenomenon secondary to the vascular disease itself. Thus, whether lowering homocysteine concentration prevents cerebral ischemia remains to be determined. The only method to answer the question of the causal relation between homocysteine and ischemic stroke is by intervention trials in which patients at high vascular risk, such as those who have had a recent cerebral ischemic event are randomly allocated to placebo or homocysteine-lowering multivitamin therapy, and followed prospectively. Some of these randomized controlled trials are currently ongoing. Their results should hopefully resolve the issue in the next future.

Background and Purpose: Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on the risk of ischemic stroke. These mechanisms are more likely to play a relevant role in younger individuals., Methods: The cumulative effect of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene, and the epsilon4-carriership of the apolipoprotein (APOE) gene, as well as their interactions with modifiable predisposing factors, were determined in a series of 163 stroke patients aged younger than 45 years and 158 controls., Results: Odds ratios (ORs) for stroke were 1.73 (95% confidence interval [CI], 1.20 to 2.51) in subjects with 1 polymorphism and 3.00 (95% CI, 1.43 to 6.30) in those with > or =2. Compared with nonsmokers with none of the studied polymorphisms, ORs for stroke were 1.88 (95% CI, 1.18 to 3.00) and 3.55 (95% CI, 1.40 to 8.98) for nonsmokers with 1 and 2 polymorphisms, respectively, and 3.99 (95% CI, 2.00 to 7.96) and 15.99 (95% CI, 4.01 to 63.3) for smokers. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 1.91 (95% CI, 1.28 to 2.87) and 3.68 (95% CI, 1.64 to 8.26) for nonhypertensive subjects with 1 and 2 polymorphisms, 3.28 (95% CI, 1.01 to 10.7) and 10.79 (95% CI, 1.01 to 115.4) for hypertensive., Conclusions: These data suggest a gene-dose effect of the examined prothrombotic and proatherogenic gene variants and a synergistic effect of these polymorphisms and modifiable risk factors in the pathogenesis of cerebral ischemia in young adults.

Background and Purpose: The effect of apolipoprotein E (APOE) polymorphisms on stroke risk may be influenced by the coexistence of modifiable predisposing conditions. We explored the interactions of APOE genotypes and conventional risk factors in a case-control study of young adults with cerebral infarct., Methods: We analyzed 124 consecutive patients (age, 34.7+/-7.3 years) and 147 age- and sex-matched controls. APOE genotypes were determined by restriction fragment-length polymorphism analysis., Results: The prevalence of the epsilon4 allele and epsilon34 genotype was slightly higher in cases than in controls (0.125 versus 0.071 and 0.242 versus 0.136, respectively). Carriers of the epsilon34 genotype and epsilon4 allele were associated with an increased risk of stroke on multivariate analysis compared with the epsilon33 genotype and non-epsilon4 carriers, respectively (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.10 to 4.76; and OR, 2.27; 95% CI, 1.13 to 4.56). ORs for stroke were 2.99 (95% CI, 1.64 to 5.45), 2.69 (95% CI, 1.25 to 5.77), and 5.39 (95% CI, 1.59 to 18.30) for smokers with the epsilon33 genotype, nonsmokers with the epsilon34 genotype, and smokers with the epsilon34 genotype, respectively, compared with nonsmokers with the epsilon33 genotype. Similar results were obtained when epsilon4 carriers and non-epsilon4 carriers were compared in the same interaction model. No significant interaction between APOE and hypertension was found., Conclusions: In young adults, the APOE epsilon4 allele and cigarette smoking act synergistically, increasing an individual's propensity to have a cerebral ischemic event. This finding may help in determining an individual's predisposition to stroke and more targeted preventive interventions.

Background and Purpose: The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study., Methods: We investigated 125 consecutive subjects (age, 34.7+/-7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV)(G1691A) mutation, the prothrombin (PT)(G20210A) variant, and the TT677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects., Results: A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO-). The PT(G20210A) variant was more frequent in the PFO+ group compared with control subjects and the PFO- group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO-, 11% versus 1.1%; 95% CI, 1.09 to 109; P=0.047). A similar distribution was observed for subjects carrying either the PT(G20210A) variant or the FV(G1691A) mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO-, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1; P=0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66; P=0.015), and in 0 subjects in the PFO- group. A trend toward a difference in the frequency of the FV(G1691A) mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%; P=0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the TT MTHFR genotype in the 3 groups., Conclusions: In young adults, the PT(G20210A) variant and, to a lesser extent, the FV(G1691A) mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.

Despite the increasing incidence of cervical artery dissection (CAD) due to chiropractic manipulation of the cervical spine, risk factors predisposing to vascular damage are still unknown. In the present study we measured fasting total plasma homocysteine (tHcy) concentration in 4 subjects with manipulation-related CAD selected from a larger series of patients with spontaneous dissection of the neck arteries (sCAD) and in a group of 36 control subjects. C677T MTHFR genotypes and 844ins68bp CBS genotypes were also determined. Median tHcy levels were significantly (P = 0.002) higher in patients with manipulation-related CAD (18.2 micromol/l, range 14.3 to 30.0) compared with controls (8.9 micromol/l, range 5 to 17.3) and not significantly different (P = 0.129) from those observed in patients with sCAD (13.9 micromol/l, range 7 to 32.8). No significant difference in the distribution of genotypes was observed in the three groups. Hyperhomocysteinemia may represent a potential risk factor for manipulation-related CAD, leading to structural abnormalities of the arterial wall and increasing the susceptibility to mechanical stress.

Background and Purpose: The role of mild hyperhomocysteinemia as a risk factor for cerebral ischemia may depend on stroke subtype. To test this hypothesis, we undertook a prospective case-control study of a group of patients with spontaneous cervical artery dissection (sCAD), a group of patients with atherothrombotic stroke (non-CAD), and a group of control subjects., Methods: Fasting total plasma homocysteine (tHcy) concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype were determined in 25 patients with sCAD, 31 patients <45 years of age with non-CAD ischemic stroke, and 36 control subjects. Biochemical data in the patient groups were obtained within the first 72 hours of stroke onset., Results: Median tHcy levels were significantly higher in patients with sCAD (13.2 micromol/L; range, 7 to 32.8 micromol/L) compared with control subjects (8.9 micromol/L; range, 5 to 17.3 micromol/L; 95% CI, 1.05 to 1.52; P=0.006). Cases with tHcy concentration above the cutoff level of 12 micromol/L were significantly more represented in the group of patients with sCAD compared with control subjects (64% versus 13.9%; 95% CI, 2.25 to 44.23; P=0.003); a significant association between the MTHFR TT genotype and sCAD was also observed (36% versus 11.1%; 95% CI, 1.10 to 19.23; P=0.045). No significant difference in tHcy levels and in the prevalence of thermolabile MTHFR was found between patients with non-CAD ischemic stroke and control subjects and between patients with sCAD and non-CAD ischemic stroke. The distribution of the 844ins68bp CBS genotype and the prevalence of subjects carrying both the TT MTHFR and 844ins68bp CBS genotypes were not significantly different among the 3 groups., Conclusions: Our results are consistent with the hypothesis that increased plasma homocysteine levels and the TT MTHFR genotype may represent risk factors for sCAD. In contrast, their role in atherothrombotic strokes remains a contentious issue.

Background: Most reports on thalamic infarcts have focused on clinicoanatomical correlations while the mechanisms of stroke have rarely been investigated. Moreover, most series have included mainly elderly stroke patients, whereas scarce information is available about the etiology of thalamic infarcts in the young., Objective: To investigate the mechanisms of thalamic infarcts according to vascular territory in a series of young adults., Methods: A sample of 24 consecutive patients with thalamic infarcts were found in an unselected series of 129 patients with cerebral infarction aged 18-45 years. Diagnostic investigation included computed tomography and magnetic resonance imaging scans, ultrasonic scanning of the extracranial and intracranial arteries, conventional angiography and magnetic resonance angiography, transthoracic and transesophageal echocardiography and extensive thrombophilic studies. The affected vascular territory within the thalamus was determined using standard templates., Results: Thalamic infarcts constituted almost one fifth of the ischemic strokes in our series. Ten patients (42%) had infarct in the territory of the thalamogeniculate pedicle (group 1), 10 (42%) in the territory of the paramedian thalamosubthalamic artery (group 2) and 3 (12%) in the territory of the tuberothalamic artery (group 3). In 1 patient (4%), the lesion involved more than one vascular thalamic territory. A significant association between cardioembolism and paramedian infarcts was found when comparing the mechanisms of stroke of group 2 with those of the group including infarcts in other thalamic territories (p = 0.002) and with those of group 1 (p = 0.02)., Conclusions: Our findings provide information about the epidemiology of thalamic infarcts in young adults and point to a differential association between the distribution of infarcts in specific vascular territories and the mechanism of stroke., (Copyright 2002 S. Karger AG, Basel)

The prevalence and pattern of cognitive impairment in systemic lupus erythematosus (SLE) patients with (NPSLE) and without (nSLE) overt neuropsychiatric manifestations were investigated. Fifty-two nSLE patients, 23 NPSLE patients and 27 healthy controls were evaluated with a battery of standardized neuropsychological and psychological tests. Disease duration, disease activity index, and current corticosteroid therapy were collected. Cognitive impairment was identified in 14 (26.9%) and in 12 (52.2%) of subjects with nSLE and NPSLE, respectively. Both SLE groups showed a significant impairment compared with controls on tasks assessing verbal and non-verbal long-term memory, and visuoconstructional abilities. In addition, NPSLE patients reported worse performances than both nSLE patients and controls on task evaluating short-term visuospatial memory. NPSLE subjects were significantly more anxious and depressed compared to both nSLE subjects and controls. By multivariate analysis, only depression levels, among clinical variables, significantly predicted cognitive performance. This study shows that cognitive impairment occurs frequently in both nSLE and NPSLE subjects. The higher frequency in NPSLE may be related to coexisting depressive disturbances.

We report the case of a 62-year-old man with no past CNS history who for some weeks had had fits of weeping that lasted from 30" to 3', precede by any aura; sensorium was clear; there were no symptoms of any kind after the paroxysm; in the course of them his facial expression was that of weeping with sobbing and tears, but no corresponding affective-emotional content, as reported by the patient, who was able to converse during these episodes. The fits were easily triggered by speaking. EEG during an episode showed a slight flattening of the trace, high voltage sharp waves at 4-6 c/s appeared, especially over the left hemisphere. CT brainscan and cerebral angiogram revealed a large space-occupying lesion of cystic-necrotic appearance with considerable mass effect and characteristics of glioblastoma. Treatment with barbiturates ended the paroxysmal weeping. We consider that these episodes were simple partial epileptic seizure according to the WHO classification of 1981.

Case history of a 20-year old man with Hodgkin's disease, clinical stage I, lymphocytic predominance, complicated by a subacute cerebellar degeneration, which was diagnosed by computed tomography scan. Following local radiotherapy, cerebellar and brain stem symptoms and signs had a complete regression. Two months later, a recurrence of the neurological picture was recorded: polychemotherapy (MOPP) was then administered and after 5 courses the symptoms improved considerably. The association of subacute cerebellar degeneration with Hodgkin's disease is rare: only 10 cases have previously been described. Pathogenesis of cerebellar atrophy complicating tumors is undetermined.