Clinical and neuroimaging correlates among cohorts of cerebral arteriostenosis, venostenosis and arterio-venous stenosis

The purpose of this study was to discriminate the clinical and imaging correlates of cerebral arterial stenosis (CAS), venous stenosis (CVS) and arterio-venous stenosis (CAVS) in the clinical setting. Patients were classified into three groups: CAS (n = 75), CVS (n=74) and CAVS (n=67). Focal neurological deficits were the prominent presenting symptoms in CAS group, while venous turbulence related symptoms were common in both CVS and CAVS group. Risk factor analysis showed the OR (95%CI) for diabetes, male gender and age in CAS vs. CVS group were 13.67(2.71, 68.85), 6.69(2.39, 18.67) and 1.07(1.03, 1.12) respectively. Male gender, diabetes and age in CAVS vs. CAS groups were 0.27(0.11, 0.63), 0.26(0.10, 0.67) and 1.09(1.04, 1.14) respectively, while age in CAVS vs. CVS group was 1.11(1.07, 1.15). The white matter lesions (WMLs) in CAS group varied in size, with clear boundaries asymmetrically distributed in bilateral hemispheres. CVS-induced WMLs revealed a bilaterally symmetric, cloudy-like appearance. The cerebral perfusion was asymmetrically reduced in CAS but symmetrically reduced in CVS group. The clinical characteristics and neuroimaging presentations were different among patients with CAS, CVS and CAVS. We recommended for aged patients, both arterial and venous imaging should be considered in diagnosis of cerebral stenotic vascular disorders.


INTRODUCTION
Cerebral arterial stenosis (CAS) plays an important role in chronic cerebral circulation insufficiency (CCCI) [1][2][3]. Persistent reduced cerebral blood volume and flow cause ischemia and hypoxia in the brain tissue, leading to various brain dysfunctions [1]. Chronic cerebrospinal venous insufficiency (CCSVI) has also been confirmed to contribute to neurological deficits and impose a significant impact on cerebral arterial circulation to some extent [4][5][6][7][8][9]. In theory, CCSVI plays a causative role in pathogenesis of CCCI as well. Venous outflow disturbance may raise the pressure in arterio-venous anastomoses and affect the blood flow AGING (CBF) and volume (CBV) in the arterial system subsequently [4][5][6]. Advanced neuroimaging can confirm vasculopathic diagnoses, but clinicians often neglect to further explore the disorders as they related to venous vasculopathy. This leaves many patients with rather severe venous stenosis-related ailment untreated and in a great deal of suffering.
Cerebral venous stenosis (CVS) mainly results from extracranial venostenosis (internal jugular vein stenosis, IJVS) and intracranial venostenosis (cerebral venous sinus stenosis, CVSS) [4][5][6][7]. Previous publications have described its typical clinical manifestations such as headache, noise, visual impair, sleep disorder and dysphrenia [4,8]. It can be confirmed by magnetic resonance venography (MRV), computed tomography venography (CTV) and digital subtraction venography (DSV) generally, however, the presentations of brain tissue and perfusion-metabolism status are not fully known. Furthermore, since covered by CAS, some venous stenosis may be misdiagnosed. As for these patients, only treating on arterial stenosis is far from adequate, in contrast, restoring the patency of venous outflow is the key to relieve the refractory neurological symptoms. The aim of this study is to describe the clinical characteristics and imaging findings in CAS, CVS and CAVS, in attempt to further aid the differentiation of these disorders in the clinical settings.

Population demographics
According to the inclusion and exclusion criteria, a total of 216 subjects who had an average age of 55.0±13.5 years, with 112 male and 104 female, were consecutively enrolled in this study. Seventy five out of 216 patients who had CAS alone were classified into CAS group, 74 patients who had CVS alone were into CVS group, and 67 patients who were confirmed as CAVS made up the CAVS group. The average age of patients was 56.00±9.30, 46.50±14.96 and 63.22±9.87 years respectively (p<0.001). Male gender accounted for 74.7%, 39.2% and 40.3% in each group with a statistical significance as well (p<0.001). The details aforementioned are presented in Table 1 and the representative vascular images are shown in Figure 1.

Clinical features and history
The clinical symptoms differed among the three groups. Focal neurological deficits (hemiplegia, aphasia, dysarthria, etc.), parethesia and vertigo were prominent in CAS group, followed by CAVS and CVS group. On the contrary, other neurological impairments including sleep disturbance, hearing disorder, visual disorder, headache, tinnitus, tinnitus cerebri, dry or puffy eyes, neck discomfort, dizziness, anxiety or depression and nausea or vomiting were commonly seen in CVS and CAVS group. The incidences of subjective memory decline were almost same among three groups.
A history of diabetes, hypertension and smoking was more common in CAS group, when compared with CVS and CAVS groups (all p≤0.001). Other recorded history such as dyslipidaemia, hyperhomocysteinaemia, hyperuricaemia and drinking did not reach a significant difference among three groups (all p>0.05). See Table 1 for complete data entries.

Risk factor analysis
A pairwise comparison for risk factors using univariate, multivariate and Lasso regression model is shown in  analysis. Lasso regression rejected variable 'hypertension' and OR (95%CI) for age in this model was 1.11(1.07, 1.15), while the remaining variable 'diabetes' did not reach significance.

Imaging measurement
The features of WMLs in CAS group were nonsymmetrical, point shape, clear boundaries, and varying size lesions, on the contrary, venostenosis-induced WMLs showed bilateral and symmetrical cloudy-like appearance surrounding bilateral ventricles and centrum semiovale. The median (IQR) of Scheltans scales for WMLs were 0.0 (0.0, 0.0) in CVS group, 5.0 (2.0, 8.0) in CAS group, 3.0 (2.0, 4.0) in CAVS group respectively. The scale in CAS group was significantly higher than that in both CAVS and CVS group (p=0.004 and <0.001). Likewise, WMLs in CAVS group were more severe than that in CVS group (p<0.001). The representative images of WMLs in three groups are shown in Figure 2.
A total of 37 patients completed SPECT assessment, including 12 in CAS group, 12 in CVS group and 13 in CAVS group. The frontal and parietal lobe were regarded as ROI in this study because all of the involved patients had profound perfusion reduction in these areas. The perfusion and metabolic status were abnormal in these patients. The perfusion and metabolism mismatch was always noticed in CVS group (68.3%), followed by CAS group (41.6%) and CAVS group (30.8%). The radio difference of regional perfusion between two sides of ROI on SPECT was substantially higher in CAS group than that in CVS group [median (IQR), 0.18 (0.12, 0.25) vs. 0.0 (0.0, 0.14), p=0.003], while no statistical differences were AGING seen between CAVS group [0.11 (0.0, 0.24)] and any other two groups (all p>0.05). There was a tendency for higher radio difference of glucose metabolism in ROI in CAS group than CVS group [0.26 (0.15, 0.75) vs. 0.18 (0.10, 0.23), p=0.089], while when compared with CAVS group [0.25 (0.13, 0.31)], the difference was small (all p>0.05). A typical presentation of perfusion and metabolism difference among three groups is shown in Figure 3.

DISCUSSION
A total of 216 patients were enrolled in this study with nearly even sample size among the three groups. We selected the subjects from two prospective registered trials rather than one cohort, therefore, this study is not a cross-sectional epidemiological investigation, but a nested case-control study. Only patients with NIHSS≤3 or TIA were involved in order to be well matched for the presentations of CCCI [4,8,10]. Minor disability induced by CAS can be confused with the symptoms from CVS, whereby this cohort is warranted to be distinguished.
In this study, patients with CAS alone commonly presented with focal neurological deficits (hemiplegia, aphasia, dysarthria, etc.), parethesia and vertigo, in contrast to those with CVS alone and CAVS, in whom non-specific whole brain symptoms and venous turbulence related symptoms dominated the clinical presentation. Venous outflow obstruction does not destroy focal brain tissue, rather rendering the whole brain to a low-perfusion background through the indirect impact on CBF and CBV on capillary pressures [4][5][6][7][8].
On the contrary, arterial stenosis often reduces the regional perfusion leading to focal brain tissue impairment [11][12][13]. When the functional area is invaded, the focal symptoms occur finally [13]. Given most of the patients in CAVS group were derived from the cohort whose primary diagnosis was venous disorders (82%), this seemed to impart a significant selection bias into the results toward a low prevalence of focal deficits in these participants. Intracranial hypertension induced by venous stenosis may cause headache, visual disorder and vomiting, and the outflow turbulence is associated with tinnitus and abnormal noise, all of which are the specific presentations in CCSVI entities [4][5][6][7][8].   Multivariate analysis showed patients in CAVS group had the highest age, followed by CAS group and CVS group. In order to remove the multi-collinearity function, Lasso regression was used and to the same conclusion, that is, elderly patients should be considered of having arterial comorbid with venous stenosis pictures. Young people are vulnerable to cerebral venous disorders due to the high possibility of immune disease, genetic disease, gestation and so forth, and aged people tend to be more prone to CAS due to atherosclerosis formation [13,14]. Patients with CAVS have a higher age than those with CAS or CVS alone, possibly suggesting a time dependent process or later manifestation of the disease. Degenerative cervical spondylosis and severe atherosclerosis inducing arterial dilation may compress venous outflow patterns in these population [4,8,15,16]. The ratio of patients with male gender and diabetes were significantly higher in CAS group than the other two groups after Lasso regression analysis. Females were more susceptible to cerebral venous system diseases due to the specific physiological status [14].
Previous studies report CCSVI is associated with severe WMLs is to some degree at odds with our findings [17,18]. The ischemia-induced demyelination derived from CAS displays non-symmetrical multiple round, ovoid, patch or even fused lesions while CVS typically presents with symmetrical cloudy-like appearance surrounding bilateral ventricles and centrum semiovale [4,7,19,20]. CAVS has the concomitant imaging characteristics of arterial and venous stenosis. Multiple sclerosis (MS) was considered a relative of CCSVI, however, in this study, none of patients had convincing evidence to support an MS diagnosis [21][22][23]. Through SPECT imaging, we noted a perfusion-metabolism mismatch could be seen more frequently in the CVS group, followed by CAVS group and finally the CAS group. Long-term low-perfusion induced by CCCI is implicated in the propensity of the brain tissue metabolism rate to increase so as to suffice the cellular basic need [1]. As perfusion decreases further, the compensatory mechanisms cannot protect cells from ischemia, and as a result, the necrose or appoptose ultimately reducing metabolism. Our results indicated that both CAS and CVS can contribute to CCCI status. Regional circulation disturbances lead to focal perfusion-metabolism anomalies while venous outflow obstruction may cause the whole brain perfusionmetabolism deficiency [9]. This explains why focal signs typically occurred in the CAS group, and nonfocal symptoms were more often seen in the CVS group.
Currently CVS can be corrected by stenting. Venous stenting is conducted for patients with a pressure gradient >8mmHg after failed conservative treatment (weight loss, antithrombosis, diamox) and balloon dilation. A large number of studies have demonstrated the safety and efficacy of stenting in cerebral venous outflow disturbance. Hence, as for CAVS, especially in patients with intractable non-focal neurological symptoms, stenting in stenotic venous segments may be a plausible therapy [24,25].
There are some limitations to this study. (1) We enrolled patients from two cohorts that one is with primary diagnosis of CAS and one is with CVS. Most of the patients (82%) with CAVS were from the second cohort, which means, despite with arterial and venous disorders concurrently, the initial diagnosis of CVS indicated venous disorder symptoms dominated the majority of clinical presentations in these patients. (2) As aforementioned, this is a nested case-control study rather than cross-section study. The presentation percentage cannot be used as epidemic data for these populations due to high selection bias. (3) DSA is confirmed as the gold standard for vascular stenosis. Although the imaging techniques in this study can

Participants
This study was designed as a nested case-control study utilizing a prospectively maintained data set and has been approved by the   [15,[26][27][28]. Magnetic resonance imaging (MRI), including axial T1-, T2-weighted sequence, diffuse weighted image (DWI) and fluid attenuated inversion recovery (FLAIR) weighted sequence were performed in each enrolled patient. Single-photon emission computed tomography (SPECT) was conducted in a portion of patients to assess the perfusion and glucose metabolism status as well. According to the invaded vessels, the enrolled patients were divided into the groups of CAS, CVS and CAVS.
All of the patients in the database were screened according to inclusion and exclusion criteria presented as following.

Assessment
The demographics, clinical manifestations and history were recorded entirely at admission. Meanwhile, the detailed angiography presentations on MRA, CTA, MRV and CTV were depicted. The white matter lesions (WMLs) were evaluated on MRI through semiquantitative Scheltans scales with a range from 0-84, where scores 0-6 were given in the periventricular regions, 0-24 in the deep white matter, 0-24 in the infratentorial regions and 0-30 in the basal ganglia [29]. We set region of interest (ROI) to describe the regional change of perfusion and metabolism on SPECT maps. The degree of cerebral perfusion and metabolism were categorized on a 6-point scale according; to the chromatic aberration change (white 100%, red 80%, yellow 60%, green 40%, blue 20% and black 0%) [4]. The white and red represented normality, yellow and green were reduction while blue and black indicated robust reduction or even disappearance. Both regional perfusion and metabolism status on SPECT were also represented as R/L, a radio of right ROI radionuclide uptake versus left ( 99m Tc-ECD for perfusion and 18 F-FDG for metabolism) [30,31]. The degree of symmetry of right and left perfusion or metabolism for ROI was evaluated by radio difference [the absolute value of (R/L minus 1)], that is, the closer to 0 it was, the more symmetrical the bilateral perfusion or metabolism was. A perfusion and metabolism mismatch indicated regions with decreased 99m Tc-ECD uptake indexes in combination with elevated or normal 18 F-FDG uptake indexes. Two senior neuro-radiologists who were blinded to the clinical database evaluated all of the images in a side-by-side fashion. A third assessor would re-examined the images if inconsistencies occurred between the two assessors. The final decision was in accordance with the ratings that had the majority, at least two thirds votes.

Statistical analysis
R software (http://www.r-project.org) was used to perform the analysis. Continuous data was complied with a Gaussian distribution and was presented as mean±standard deviation (SD), otherwise as median (interquartile range, IQR). Categorical data was expressed as counts (percents, %). Student's t test and Mann-Whitney U tests were used to compare continuous variables, and the Pearson χ 2 test or Fisher's exact tests were used to compare categorical variables among these groups. Only risk factors that are closely related to the dependent variables (with p<0.05) were enrolled as variates in the logistic regression model to assess independent risk factors. However, high multicollinearity may amplify the regression co-efficiency, leading to inaccurate results. In order to prevent multi-collinearity, a Lasso regression model was used to remove the independent variables that had high multi-collinearity with other independent variables. A 2-side p value<0.05 was indicative of statistical significance.