Serum Neurofilament Light Chain Levels Are Associated with Clinical Characteristics and Outcome in Patients with Cervical Artery Dissection.

BACKGROUND: Serum neurofilament light chain (sNfL) levels represent a promising marker of neuroaxonal injury. They are elevated in several neurological conditions, but their importance in cerebrovascular diseases remains unclear. In a proof of concept study, we compared sNfL levels with clinical characteristics and outcome in patients with cervical artery dissection (CeAD). METHODS: A total of 49 non-traumatic CeAD patients were included. sNfL levels were measured by high-sensitivity electrochemiluminescence immunoassay. Levels were compared with regard to (i) type of presenting symptoms (local symptoms only (n = 8), transient ischemic attack (TIA; n = 10) or ischemic stroke (n = 31)), (ii) stroke severity quantified by National Institute of Health Stroke Scale (NIHSS), (iii) time interval between onset of symptoms and blood sampling and (iv) 3-month outcome as measured by the modified Rankin Scale score. Analyses were performed using univariate and multivariate linear and ordinal regression models. RESULTS: CeAD patients presenting with stroke had significantly higher sNfL levels (median 108.9 pg/ml, interquartile range (37.8-427.7)) than patients with TIA (16.4 pg/ml (8.7-36.3), p = 0.002) or local symptoms (23.4 pg/ml (17.8-30.8), p = 0.0007). Among stroke patients, sNfL levels were positively associated with both NIHSS (p = 0.0002) and time between stroke onset and serum sampling (p = 1.9 × 10-6). Higher sNfL levels were associated with unfavorable outcome at 3 months (OR 4.67, 95% CI 1.69-12.95, p = 0.003). However, this association lost significance after adjustment for NIHSS. The highest sNfL level was observed in a TIA patient who had ischemic stroke 1 day after serum sampling for sNfL measurement. CONCLUSION: sNfL levels were increased in CeAD patients presenting with stroke, correlated with clinical severity and were influenced by the time point of blood sampling. The prognostic meaning of sNfL in CeAD deserves further testing.

Efficacy and safety of novel oral anticoagulants in patients with cervical artery dissections.

BACKGROUND: American and European guidelines support antiplatelet agents and anticoagulants as reasonable treatments of cervical artery dissection (CAD), though randomized clinical trials are lacking. The utility of novel oral anticoagulants (NOAC), effective in reducing embolic stroke risk in non-valvular atrial fibrillation (NVAF), has not been reported in patients with CAD. We report on the use, safety, and efficacy of NOACs in the treatment of CAD. METHODS: We retrospectively identified patients diagnosed with CAD at a single academic center between January 2010 and August 2013. Patients were categorized by their antithrombotic treatment at hospital discharge with a NOAC (dabigatran, rivaroxaban, or apixaban), traditional anticoagulant (AC: warfarin or treatment dose low-molecular weight heparin), or antiplatelet agent (AP: aspirin, clopidogrel, or aspirin/extended-release dypyridamole). Using appropriate tests, we compared the baseline medical history, presenting clinical symptoms and initial radiographic characteristics among patients in the 3 treatment groups. We then evaluated for the following outcomes: recurrent stroke, vessel recanalization, and bleeding complications. p values <0.05 were considered significant. RESULTS: Of the 149 included patients (mean age 43.4 years; 63.1% female; 70.5% vertebral artery CAD), 39 (26.2%), 70 (47.0%), and 40 (26.8%) were treated with a NOAC, AC, and AP, respectively. More patients with severe stenosis or occlusion were treated with NOAC than with AC or AP (61.8 vs. 60.0 vs. 22.5%, p = 0.002). Other baseline clinical and radiographic findings, including the presence of acute infarction and hematoma, did not differ between the 3 treatment groups. One hundred and thirty-five (90.6%) patients had clinical follow-up (median time 7.5 months) and 125 (83.9%) had radiographic follow-up (median time 5 months) information. There were 2 recurrent strokes in the NOAC group and 1 in each of the AC and AP groups (p = 0.822). There were more major hemorrhagic events in the AC group (11.4%) compared to the NOAC (0.0%) and AP (2.5%) groups (p = 0.034). Three patients treated with NOAC and none treated with AC or AP had a worsened degree of stenosis on follow-up imaging (8.6 vs. 0.0 vs. 0.0%, p = 0.019). CONCLUSION: Compared to traditional anticoagulants for CAD, treatment with NOACs is associated with similar rates of recurrent stroke, fewer hemorrhagic complications, but greater rates of radiographic worsening. These data suggest that NOACs may be a reasonable alternative in the management of CAD. Prospective validation of these findings is needed.

Continuous brain tissue oxygenation monitoring in the management of pediatric stroke.

BACKGROUND: Direct invasive monitoring of brain tissue oxygenation (PbtO(2)) has been routinely utilized to predict cerebral ischemia and to prevent secondary injury in patients with traumatic brain injury (TBI) and vasospasm secondary to subarachnoid hemorrhage (SAH). The safety and utility of these devices in the pediatric population have been examined in a few small studies. No studies, however, have examined the use of PbtO(2) monitoring in stroke patients. METHODS: Retrospective chart review of the first two consecutive, critically ill pediatric patients in the pediatric intensive care unit requiring brain tissue oxygen monitoring for newly diagnosed cerebral ischemia. ICP, CPP, PbtO(2), SaO(2), BP, and RR were all continually monitored during their care and were retrospectively collected and reviewed. RESULTS: We present two pediatric stroke patients managed in a critical care setting with PbtO(2) monitoring in addition to ICP, MAP, CPP, and SaO(2). Both patients had multiple events of low brain tissue oxygen (PbtO(2) <20 torr), independent of abnormal values in other monitoring parameters, which required physician intervention. No new ischemic damage occurred after PbtO(2) monitoring began in either patient. CONCLUSIONS: There is currently inadequate data to support the application of PbtO(2) monitoring in children with stroke to prevent progressive ischemia and to improve outcome. However, the positive results for these two patients support the need for further study in this area.

Internal carotid artery dissection and ischemic cerebral infarction in the setting of essential thrombocythemia.

Cervical artery dissection (CAD) is an important etiology of stroke in young adults. Its etiology is incompletely understood. Here, we report a young woman who presented with acute ischemic stroke in the setting of internal carotid artery (ICA) dissection and essential thrombocythemia (ET). We present a review of previous cases with comorbidity of CAD and ET and discuss the pathophysiological implications of this co-occurrence. In particular, we speculate that ET may increase the susceptibility of cervical vessels to spontaneous dissection, for example, by disturbing the microcirculation within the vessel wall.

Functional polymorphisms in matrix metalloproteinases -1, -3, -9 and -12 in relation to cervical artery dissection.

BACKGROUND: Cervical artery dissection is a leading cause of cerebral ischemia in young adults. Morphological investigations have shown alterations in the extracellular matrix (ECM) of affected vessel walls. As matrix metalloproteinases (MMP) play a central role in the regulation of the ECM, an increased expression of these enzymes might lead to the endothelial damage in spontaneous cervical artery dissection (sCAD). Five different DNA polymorphisms in MMP-1, -3, -9 and -12 were tested for their frequency in patients with sCAD and compared with those of a control population. METHODS: Blood was sampled from 70 unrelated patients presenting consecutively in the department of neurology of the Aachen University Medical School with sCAD and from 87 control subjects living in the same area as the patients. The MMP polymorphisms were analyzed with hybridization probes using the LightCycler (Roche Diagnostics), by sequencing using the ABI 310 Genetic Analyzer (Applied Biosystems) and with the GeneScan program on a ABI 310 Genetic Analyzer. RESULTS: No statistically significant differences in the allelic distribution were found between sCAD patients and the controls. CONCLUSION: Alleles of these 5 functional polymorphisms of MMPs seem not to be associated with structural alterations in the blood vessel wall of sCAD patients. However, this does not exclude a pathogenetic role for MMPs in sCAD via secondary factors such as cytokines that are able to induce these enzymes in cervical blood vessel walls.

Mild hyperhomocysteinemia and low folate concentrations as risk factors for cervical arterial dissection.

BACKGROUND AND PURPOSE: Elevated homocysteine (Hcy) plasma levels are associated with an increased risk of spontaneous cervical artery dissection (sCAD). We examined the potential association between Hcy, folate, vitamin B(12) levels and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms in patients with cerebral infarct caused by sCAD. PATIENTS AND METHODS: 39 patients who survived a cerebral infarct caused by sCAD [20 (51%) women; 24 (61.5%) vertebral and 15 (38.5%) internal carotid arteries], and 76 healthy control subjects were included. Hcy plasma levels (fasting and after methionine load), folate and vitamin B(12) levels were measured. We also performed polymorphisms of MTHFR. Hcy, vitamin B(12), folates and polymorphisms of MTHFR were assessed and any associations were analyzed using multivariate statistics. RESULTS: Mean plasma fasting Hcy level was 9.81 mumol/l for cases and 6.38 for controls (p = 0.001). The occurrence of sCAD was associated with elevated fasting Hcy levels (>95th percentile over the control group) with an adjusted odds ratio of 7.9 (95% CI 1.66-35). The association between low plasma folate values (<5th percentile) and the presence of CAD was 7.9 (95% CI 1.6-31) after adjusting for confounding variables. The distribution of the MTHFR genotype showed a higher TT mutant frequency among CAD patients (p = 0.034). CONCLUSIONS: High plasma concentrations of Hcy and low plasma levels of folate were associated with an increased risk of sCAD in the sample studied. We conclude that deficiencies in nutritional status may contribute to the relatively high incidence of CAD in Mexico.

Protease inhibitors in spontaneous cervical artery dissections.

BACKGROUND AND PURPOSE: Observations in patients with arterial aneurysms, fibromuscular dysplasia, and spontaneous cervical artery dissection (sCAD) indicate that protease inhibitor deficiency might boost the enzymatic destruction of arterial tissue and increase the risk of these arterial wall diseases. Here we present the first large investigation of the protease inhibitor hypothesis in patients with sCAD. METHODS: Eighty patients with sCAD were compared with 80 age- and sex-matched healthy individuals. Alpha1-antitrypsin (alpha1-AT) and alpha2-macroglobulin (alpha2-MG) levels, and alpha1-AT genotypes were assessed and compared between groups. RESULTS: alpha1-AT and alpha2-MG levels as well as alpha1-AT genotypes did not differ significantly between patients and controls. The frequency of Z alleles in the patient group was higher than in the control group and than in other cohorts from Europe; however, the difference remained nonsignificant. All patients with Z alleles had internal carotid artery dissections. CONCLUSIONS: Overall, this data does not support the hypothesis that protease inhibitor levels or alpha1-AT genotypes play an important role in the etiology of sCAD. The present data does not exclude that the Pi-Z allele might have an influence on subgroups of sCAD, such as internal carotid artery dissections.

Levels of alpha1-antitrypsin in plasma and risk of spontaneous cervical artery dissections: a case-control study.

BACKGROUND AND PURPOSE: Abnormalities of dermal connective tissue have been detected in patients with spontaneous cervical artery dissections (sCAD), suggesting an underlying structural defect of the arterial wall. Alpha1-antitrypsin (A1-AT) is a circulating serine proteinase inhibitor of proteolytic enzymes that helps to maintain the integrity of elastic and collagen fibers. METHODS: To test the hypothesis that moderate deficiency of A1-AT may be a risk factor for sCAD, 22 cases with sCAD and 113 controls were included in the study. RESULTS: Patients with sCAD had significantly mean lower levels of A1-AT compared with controls (116.0+/-24.9 versus 141.1+/-31.7 mg/dL; P<0.01). Low levels of A1-AT (<90 mg/dL) were more frequently observed in patients with sCAD compared with controls (27.3% versus 2.7%; P<0.001). A positive correlation between age and plasma levels of A1-AT was found (r=0.22; P<0.01). A1-AT levels were not affected by sex or vascular risk factors, including smoking habit. On multivariate analysis, A1-AT <90 mg/dL was associated with sCAD independently of age, sex, or vascular risk factors (odds ratio, 17.7; 95% confidence interval, 2.9 to 105.6). CONCLUSIONS: Low plasma levels of A1-AT may be a risk factor for sCAD.

Mild hyperhomocyst(e)inemia: a possible risk factor for cervical artery dissection.

BACKGROUND AND PURPOSE: The pathogenesis of cervical artery dissection (CAD) remains unknown in most cases. Hyperhomocyst(e)inemia [hyperH(e)], an independent risk factor for cerebrovascular disease, induces damage in endothelial cells in animal cell culture. Consecutive patients with CAD and age-matched control subjects have been studied by serum levels of homocyst(e)ine and the genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR). METHODS: Twenty-six patients with CAD, admitted to our Stroke Unit (15 men and 11 women; 16 vertebral arteries, 10 internal carotid arteries), were compared with age-matched control subjects. All patients underwent duplex ultrasound, MR angiography, and/or conventional angiography. RESULTS: Mean plasma homocyst(e)ine level was 17.88 micromol/L (range 5.95 to 40.0 micromol/L) for patients with CAD and 6.0+/-0.99 micromol/L for controls (P:<0.001). The genetic analysis for the thermolabile form of MTHFR in CAD patients showed heterozygosity in 54% and homozygosity in 27%; comparable figures for controls were 40% (P:=0.4) and 10% (P:=0.1), respectively. CONCLUSIONS: Mild hyperH(e) might represent a risk factor for cervical artery dissection. The MTHFR mutation is not significantly associated with CAD. An interaction between different genetic and environmental factors probably takes place in the cascade of pathogenetic events leading to arterial wall damage.