Cervical Artery Dissection And Ischemic Stroke Patients Research Articles

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

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.

Genetic Imbalance in Patients with Cervical Artery Dissection.

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.

Prognostic significance of pulsatile tinnitus in cervical artery dissection.

Our aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. All CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0-1. Sixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22-12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79-0.86), Horner syndrome (OR 1.95, 95% CI 1.16-3.29) and vessel occlusion (OR 0.62, 95% CI 0.40-0.94) and to non-significant predictors age, sex, pain and location of CeAD. The presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.

Clinical import of Horner syndrome in internal carotid and vertebral artery dissection.

To study the prognostic importance of Horner syndrome (HS) in patients with internal carotid artery dissection (ICAD) or vertebral artery dissection (VAD). In this observational study, characteristics and outcome of patients with ICAD or VAD from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) database were analyzed. The presence of HS was systematically assessed using a standardized questionnaire. Patients with HS (HS+) were compared with HS- patients. Crude odds ratios (ORs) with 95% confidence intervals and ORs adjusted for age, sex, center, arterial occlusion, bilateral dissection, stroke severity, and type of antithrombotic treatment were calculated. We analyzed 765 patients (n = 496 with ICAD, n = 269 with VAD, n = 303 prospective, n = 462 retrospective). HS was present in 191 (38.5%) of the patients with ICAD and 36 (13.4%) of the patients with VAD (p < 0.001). HS+ ICAD patients presented less often with stroke or TIA (p < 0.001), less often had bilateral (p = 0.019) or occlusive (p = 0.001) dissections, and had fewer severe strokes (p = 0.041) than HS- ICAD patients. HS+ ICAD patients had a better functional 3-month outcome than those without HS (ORcrude = 4.0 [2.4-6.7]), and also after adjustment for outcome-relevant covariates (ORadjusted = 2.0 [1.1-4.0]). HS+ ICAD patients were less likely to have new strokes than HS- ICAD patients (p = 0.039). HS+ VAD patients more often had vessel occlusion (p = 0.014) than HS- patients but did not differ in any of the other aforementioned variables. In patients with ICAD, HS is an easily assessable marker that might indicate a more benign clinical course. HS had no prognostic meaning in patients with VAD.

Stroke in first‐degree relatives of patients with cervical artery dissection

Patients with ischaemic stroke (IS) caused by a spontaneous cervical artery dissection (CeAD) worry about an increased risk for stroke in their families. The occurrence of stroke in relatives of patients with CeAD and in those with ischaemic stroke attributable to other (non-CeAD) causes were compared. The frequency of stroke in first-degree relatives (family history of stroke, FHS) was studied in IS patients (CeAD patients and age- and sex-matched non-CeAD patients) from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) database. FHS≤50 and FHS>50 were defined as having relatives who suffered stroke at the age of ≤50 or >50years. FHS≤50 and FHS>50 were studied in CeAD and non-CeAD IS patients and related to age, sex, number of siblings, hypertension, hypercholesterolemia, smoking and body mass index (BMI). In all, 1225 patients were analyzed. FHS≤50 was less frequent in CeAD patients (15/598=2.5%) than in non-CeAD IS patients (38/627=6.1%) (P=0.003; odds ratio 0.40, 95% confidence interval 0.22-0.73), also after adjustment for age, sex and number of siblings (P=0.005; odds ratio 0.42, 95% confidence interval 0.23-0.77). The frequency of FHS>50 was similar in both study groups. Vascular risk factors did not differ between patients with positive or negative FHS≤50. However, patients with FHS>50 were more likely to have hypertension and higher BMI. Relatives of CeAD patients had fewer strokes at a young age than relatives of non-CeAD IS stroke patients.

Characteristics and Outcomes of Patients With Multiple Cervical Artery Dissection

Little is known about factors contributing to multiple rather than single cervical artery dissections (CeAD) and their associated prognosis. We compared the baseline characteristics and short-term outcome of patients with multiple to single CeAD included in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. Among the 983 patients with CeAD, 149 (15.2%) presented with multiple CeAD. Multiple CeADs were more often associated with cervical pain at admission (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.10-2.30), a remote history of head or neck surgery (OR, 1.87; 95% CI, 1.16-3.00), a recent infection (OR, 1.71; 95% CI, 1.12-2.61), and cervical manipulation (OR, 2.23; 95% CI, 1.26-3.95). On imaging, cervical fibromuscular dysplasia (OR, 3.97; 95% CI, 2.04-7.74) and the presence of a pseudoaneurysm (OR, 2.91; 95% CI, 1.86-4.57) were more often seen in patients with multiple CeAD. The presence of multiple rather than single CeAD had no effect on functional 3-month outcome (modified Rankin Scale score, ≥3; 12% in multiple CeAD versus 11.9% in single CeAD; OR, 1.20; 95% CI, 0.60-2.41). In the largest published series of patients with CeAD, we highlighted significant differences between multiple and single artery involvement. Features suggestive of an underlying vasculopathy (fibromuscular dysplasia) and environmental triggers (recent infection, cervical manipulation, and a remote history of head or neck surgery) were preferentially associated with multiple CeAD.

Elevated peripheral leukocyte counts in acute cervical artery dissection

It has been suggested that inflammation may play a role in the development of cervical artery dissection (CeAD), but evidence remains scarce. A total of 172 patients were included with acute (<24h) CeAD and 348 patients with acute ischaemic stroke (IS) of other (non-CeAD) causes from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study, and 223 age- and sex-matched healthy control subjects. White blood cell (WBC) counts collected at admission were compared across the three groups. Compared with healthy control subjects, CeAD patients and non-CeAD stroke patients had higher WBC counts (P<0.001). Patients with CeAD had higher WBC counts and were more likely to have WBC>10000/μl than non-CeAD stroke patients (38.4% vs. 23.0%, P<0.001) and healthy controls (38.4% vs. 8.5%, P<0.001). WBC counts were higher in CeAD (9.4±3.3) than in IS of other causes (large artery atherosclerosis, 8.7±2.3; cardioembolism, 8.2±2.8; small vessel disease, 8.4±2.4; undetermined cause, 8.8±3.1; P=0.022). After adjustment for age, sex, stroke severity and vascular risk factors in a multiple regression model, elevated WBC count remained associated with CeAD, as compared with non-CeAD stroke patients [odds ratio (OR)=2.56; 95% CI 1.60-4.11; P<0.001) and healthy controls (OR=6.27; 95% CI 3.39-11.61; P<0.001). Acute CeAD was associated with particularly high WBC counts. Leukocytosis may reflect a pre-existing inflammatory state, supporting the link between inflammation and CeAD.

Migraine in cervical artery dissection and ischemic stroke patients

Several small to medium-sized studies indicated a link between cervical artery dissection (CeAD) and migraine. Migrainous CeAD patients were suggested to have different clinical characteristics compared to nonmigraine CeAD patients. We tested these hypotheses in the large Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) population. A total of 968 CeAD patients and 653 patients with an ischemic stroke of a cause other than CeAD (non-CeAD IS) were recruited. CeAD patients with stroke (CeAD(stroke), n = 635) were compared with non-CeAD IS patients regarding migraine, clinical characteristics, and outcome. CeAD patients with and without migraine were compared in terms of clinical characteristics and outcome. Migraine was more common among CeAD(stroke) patients compared to non-CeAD IS patients (35.7 vs 27.4%, p = 0.003). The difference was mainly due to migraine without aura (20.2 vs 11.2%, p < 0.001). There were no differences in prevalence of strokes, arterial distribution, or other clinical or prognostic features between migrainous and nonmigrainous CeAD patients. Migraine without aura is more common among CeAD(stroke) patients compared to non-CeAD IS patients. The mechanisms and possible causative link remain to be proved. Although CeAD is often complicated by stroke, our data do not support increased risk of stroke in migrainous CeAD patients.

Abstract 3854: Family History Of Cervical Artery Dissection In A Large Multicenter Cohort: The CADISP Study

Background: Little data is available on familial occurrence of cervical artery dissection (CEAD), a major cause of ischemic stroke in young adults. We aimed to examine the prevalence of family history of CEAD in a large multicenter cohort of CEAD patients and compare characteristics of CEAD patients with and without such a family history. Methods: Across 18 neurological departments in 8 countries, consecutive patients with a diagnosis of CEAD were included in the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) cohort study following a standardized protocol and using the same questionnaire. Results: Among 921 consecutive CEAD patients, 11 patients (1.2%, 95%CI:0.5-1.9%) from 9 families (1.0%, 0.3-1.6%) had a family history of CEAD, mostly in a first degree relative (64%). One patient without family history of CEAD had biologically confirmed vascular Ehlers-Danlos syndrome, while none of the patients with a family history of CEAD had a diagnosis of known inherited connective tissue disorder. Risk factors, baseline features, and 3-month outcome did not differ significantly between CEAD patients with and without a family history of CEAD. Conclusion: In the largest series of CEAD patients to date, family history of CEAD was very rare, although slightly higher than expected by chance given the low disease incidence.

Towards understanding seasonal variability in cervical artery dissection (CeAD)

Cervical artery dissection (CeAD) occurs more often in autumn or winter than in spring or summer. We searched for clinical variables associated with this seasonality by comparing CeAD patients with onset of symptoms in autumn–winter (September 22–March 21) versus those with first CeAD symptom in spring–summer (March 22–September 21). We performed a cross-sectional study using data from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) registry. Age- and sex-matched patients with ischemic stroke attributable to a cause other than CeAD (non-CeAD patients) were analyzed to study the specificity of our findings. Autumn–winter CeAD patients had a higher median brachial pulse pressure at admission (55 vs. 52 mmHg; p = 0.01) and more recent infections (22.0% vs. 16.6%; p = 0.047), but prevalence of trauma was not associated with seasonal onset. Multivariable logistic regression analysis revealed that higher pulse pressure was significantly associated with autumn–winter CeAD (p = 0.01), while age, gender, history of hypertension, recent infection, and recent trauma were not. No association between pulse pressure and seasonal occurrence was found in non-CeAD ischemic stroke patients. Increased pulse pressure was associated with the higher frequency of CeAD in autumn or winter.

Gender and cervical artery dissection

To analyze previously established gender differences in cervical artery dissection (CeAD). This case-control study is based on the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) population comprising 983 consecutive CeAD patients (mean age: 44.1 ± 9.9 years) and 658 control patients with a non-CeAD ischemic stroke (IS) (44.5 ± 10.5 years). Cervical artery dissection was more common in men (56.7% vs. 43.3%, P < 0.001) and men were older (46.4 vs. 41.0 years, P < 0.001). We assessed putative risk factors for CeAD including vascular risk factors, recent cervical trauma, pregnancies, and infections. All gender differences in the putative risk factors and outcome were similar in the CeAD and the non-CeAD IS groups. Our analysis of the largest collection of CeAD patients to date confirms male predominance and differences in age at dissection between men and women. Gender differences in putative risk factors may explain the higher frequency of CeAD in men and their older age, but the putative risk factors are probably not specific for CeAD.

Association of Vascular Risk Factors With Cervical Artery Dissection and Ischemic Stroke in Young Adults

Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. The study sample comprised 690 CEAD patients (mean age, 44.2 ± 9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7 ± 10.5 years; 39.9% women), and 1170 referents (45.9 ± 8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥ 30 kg/m²) or overweightness (body mass index ≥ 25 kg/m² and <30 kg/m²) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.

CADISP-Genetics: An International Project Searching for Genetic Risk Factors of Cervical Artery Dissections

Cervical artery dissection (CAD) is a frequent cause of ischemic stroke, and occasionally death, in young adults. Several lines of evidence suggest a genetic predisposition to CAD. However, previous genetic studies have been inconclusive mainly due to insufficient numbers of patients. Our hypothesis is that CAD is a multifactorial disease caused by yet largely unidentified genetic variants and environmental factors, which may interact. Our aim is to identify genetic variants associated with an increased risk of CAD and possibly gene-environment interactions. We organized a multinational European network, Cervical Artery Dissection and Ischemic Stroke Patients (CADISP), which aims at increasing our knowledge of the pathophysiological mechanisms of this disease in a large group of patients. Within this network, we are aiming to perform a de novo genetic association analysis using both a genome-wide and a candidate gene approach. For this purpose, DNA from approximately 1100 patients with CAD, and 2000 healthy controls is being collected. In addition, detailed clinical, laboratory, diagnostic, therapeutic, and outcome data are being collected from all participants applying predefined criteria and definitions in a standardized way. We are expecting to reach the above numbers of subjects by early 2009. We present the strategy of a collaborative project searching for the genetic risk factors of CAD. The CADISP network will provide detailed and novel data on environmental risk factors and genetic susceptibility to CAD.

Response to Letter by Arnold et al

Response: We thank Dr Arnold et al for their interest in our recent article.1 In their Letter,2 Arnold et al suggest that (1) the present data are not sufficient to conclude the safety of anticoagulation in intracranial artery dissection (IAD) patients presenting without subarachnoidal hemorrhage (SAH), and a routine lumbar puncture (LP) is necessary to exclude CT or MRI negative SAH, and (2) a filiform stenosis is not a reliable marker of dissection and more strict diagnostic criteria, ie, pathognomonic signs only, should be used for reliable diagnosis of IAD. Apparently, Arnold and his coauthors themselves2 use anticoagulation treatment in (some) IAD patients after routinely performing a LP to exclude SAH, as some patients may have a normal CT but blood in cerebrospinal fluid. In contrast to their …