Prevalence of abnormal bloodflow Patterns and effects of biochemistry and lifestyle factors on the major neck vessels in Patients with multiPle sclerosis in the western caPe, south africa

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Objectives The purpose of this study was to investigate the prevalence of vascular dysfunction (chronic cerebrospinal venous insuf-ficiency; CCSVI) and the effects of biochemical and lifestyle factors on carotid arteries and internal jugular veins
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  ISSN 1011 5528 | www.smltsa.org.za   43 Volume 28 No. 1 | June 2014 Medical Technology SA Peer reviewed ORIGINAL ARTICLE Prevalence of abnormal bloodflow Patterns and effects of biochemistry and lifestyle factors on the major neck vessels in Patients with multiPle sclerosis in the western caPe, south africa MC Nelson 1   (MTech Radiography)   | F Isaacs 1   (MTech Radiography)   | MS Hassan 1   (M.Pharm) | M Kidd 2   (PhD Statistics)  FJ Cronje 3   (MBChB, MSc Aerospace Medicine)   | SJ Van Rensburg 4   (PhD Medical Sciences)  1 Department of Nursing and Radiography, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa 2 Centre for Statistical Consultation, Stellenbosch University, Cape Town, South Africa 3 Baromedical Facility, University of Stellenbosch, South Africa 4 Division of Chemical Pathology, National Health Laboratory Service and Stellenbosch University, Cape Town, South AfricaCorresponding author: M Nelson   | Email: merlisacnelson@gmail.com  ABSTRACT Objectives  The purpose of this study was to investigate the prevalence of vascular dysfunction (chronic cerebrospinal venous insuf-ficiency; CCSVI) and the effects of biochemical and lifestyle factors on carotid arteries and internal jugular veins (IJVs) in patients diagnosed with multiple sclerosis (MS). Methods  A B-Mode and Doppler ultrasound examination was done on 29 MS patients assessing the vasculature to identify pat-ency, stenosis, occlusion and/or abnormal bloodflow patterns. Lifestyle (smoking, exercise and diet), Expanded Disability Status Scale (EDSS) and biochemistry (fibrinogen, plasma homocysteine and serum total cholesterol) data were available for 20 patients. Results  No evidence was found for CCSVI or deep vein thrombosis. Smokers displayed significantly smaller cross-sectional di-ameters of the proximal (p=0.03) and mid left IJV (p=0.02) than non-smokers. There was an inverse association (p=0.03) between physical activity and the intima media thickness (IMT) of the left common carotid artery (CCA). The EDSS showed a direct as-sociation with the IMT (p<0.0001) and an inverse association with adherence to a lifestyle/dietary program (p=0.03). Fibrinogen was associated with the peak systolic velocity of the left External Carotid Artery (p=0.03) and homocysteine showed an inverse association with the cross sectional diameter of the proximal left IJV (p=0.045). No significant associations were found between ultrasound measuments and total cholesterol. Conclusions  This pilot study supports previous findings that there is no association between CCSVI and MS, but rather a detrimen-tal effect of smoking and a sedentary lifestyle on MS disabilty. This may indicate that people diagnosed with MS may improve their disability status by avoiding risk factors that would adversely affect the vasculature. KEYWORDS multiple sclerosis, ultrasound, CCSVI, smoking, physical activity, IMT, cerebral perfusion, reflux, fibrinogen INTRODUCTION Multiple Sclerosis (MS) is characterised by demyelination within the central nervous system (CNS), which may result in neuro-logical disabilities over time, causing considerable hardship to patients and their families, in addition to being costly to treat. [1]  There are indications that vascular factors may play a role in demyelination since myelin production and maintenance in the brain is dependent on the delivery of nutrients and removal of toxic waste products by the blood. [2]  Studies have described three types of vascular dysfunction in MS [3] : first, endothelial dys-function due to inflammation and increased homocysteine con-centrations; second, global cerebral hypoperfusion and third, impaired cerebral venous outflow with reported rapid improve-ment of MS symptoms with surgical correction thereof. [4]  Singh and Zamboni [5]  described altered cerebral venous drainage in patients with MS, a condition they called chronic cerebrospinal venous insufficiency (CCSVI). Their research suggested that this condition may be a major risk factor for MS. Subsequent studies have not consistently confirmed Zamboni’s srcinal findings [6] , and have found the prevalence of venous occlusions to differ in different populations. In the present study, ultrasound imaging was used to determine the prevalence of abnormal extracranial venous outflow pat-terns and carotid artery disease in MS patients within the region of the Western Cape, South Africa. The parameters measured included intima media thickness (IMT) of the common carotid artery (CCA); the peak systolic velocity (PSV) and end diastolic velocity (EDV) of the CCA, internal carotid artery (ICA) and ex-ternal carotid artery (ECA); as well as the cross-sectional diam-eter (CSD) and reflux of the internal jugular veins. Lifestyle factors such as smoking, exercise and diet have sig-nificant effects on the vascular system. Biochemical factors also have an effect on blood flow due to altered hemostasis involving the clotting cascade, including blood proteins such as fibrinogen. With the catalytic action of thrombin, fibrinogen is converted into molecules of the insoluble protein fibrin, which link together to form clots. When these clots are enzymatically digested D-dimers are produced. According to Aksungar [7]  there is a significant correlation between D-dimer and homocysteine levels in MS patients. Increased levels of fibrinogen and ho-mocysteine are associated with vascular damage. Wakefield et al. [8]  showed that the earliest evidence of microvascular  44 www.smltsa.org.za | ISSN 1011 5528Volume 28 No. 1 | June 2014 Medical Technology SA injury in acute MS was endothelial activation with associated fibrin deposition, even in areas in which myelin was preserved, as well as occlusion of vessels by reticulated fibrin clots. In-creased IMT of the CCA is widely accepted to be a surrogate marker for early atherosclerosis, and risk factors include in-creased hypertension, body mass index (BMI), LDL cholesterol, homocysteiene and fibrinogen. IMT also increases with age. [9]  In contrast, a diet which is high in fruits, wholegrains, fibre and olive oil and low in saturated fat may reduce IMT and the devel-opment and progression of carotid atherosclerosis. [10] The aims of the present study were to investigate the effects of biochemical and lifestyle factors on vascular outcomes using ultrasound B-Mode and Doppler ultrasound imaging in patients diagnosed with MS. METHODS This investigation was an ethically approved collaborative study between the Cape Peninsula University of Technology, the Na-tional Health Laboratory Service (NHLS) and the University of Stellenbosch in the Western Cape, South Africa. The study was granted ethical approval by the Faculty Ethics Research Com-mittee of the Cape Peninsula University of Technology (CPUT) and was done according to the ethical guidelines provided by the Declaration of Helsinki. [11]  Written and signed informed consent was obtained from all participants. Ultrasound exami-nations of these patients were performed at a private radiology practice in Cape Town. Study participants The study population consisted of 29 MS patients, 26 females and 3 males (Table 1). Patients were diagnosed with MS ac-cording to the criteria of McDonald et al. [12] , by their neurolo-gists. Exclusion criteria were other neurological diseases (neu-romyelitis optica and acute disseminated encephalomyelitis) as well as a previous diagnosis of carotid artery and extracranial venous disease. Ultrasound examination GE Logiq 9 and GE Logiq E9 ultrasound machines with Dop-pler software (B-mode imaging, Colour Doppler, Power Dop-pler and pulsed-wave Doppler) and 9-12 MHz multifrequency linear transducer were used to image the carotid arteries and extracranial venous system. B-mode imaging was used to inter-rogate the major neck vessels for tortuosity, anatomical varia-tion, plaque formation in the carotid arteries, and to measure IMT of the CCA (Figure 1) and cross-sectional diameter of the internal jugular veins (Figure 2). Colour Doppler was used to assess the vessels for patency, direction of blood flow within the vessel and detect an occlusion if present. An automated average IMT, on the far side of the vessel wall, over a 2 cm segment of the mid CCA (3 cm distal to the carotid bulb) was determined in the longitudinal plane. An IMT of 0.8 mm is regarded as the upper limit of normal. Pulsed-wave (PW) Doppler was used to detect carotid stenosis by measuring the speed (velocity) of blood flow in systole and diastole within the carotid vessel being sampled; as well as to detect reflux within the IJV. A value of >0.88s was considered to be indicative of significant IJV reflux. The Pulsed Repetition Frequency for this study was set as 150 cm/s for assessment of the carotid vessels. The North American Symptomatic Carotid Endarterectomy Trials (NASCET) criteria were used to grade in-ternal carotid artery stenosis, where a stenosis ≥ 70% is regarded as significant. [13] Biochemical and Lifestyle data Of the 29 MS patients who underwent ultrasonography, bio-chemical and lifestyle data were available for 20 patients (17 females and 3 males). Their disability status was assessed by participating clinicians using the Expanded Disability Status Scale (EDSS). [14]  The EDSS ranges from 0 to 10, with higher scores indicating higher disability. The patients were in remis-sion when their EDSS scores were measured, so that the scores reflected the residual disability when patients were not in a relapse. The patients completed a questionnaire developed by a regis-tered dietician (Gknowmix Medical History and Lifestyle Ques-tionnaire, available at www.gknowmix.com). [2]  Smoking status, BMI and physical activity were also recorded. The physical activity was self-reported and categorised into: 1 = Recreational sport occasionally or complete lack of exercise; 2 = Recrea-tional sport once a week; 3 = Exercise 2-3 times a week; 4 = Exercise 4 or more times a week. Individualised reports were given to the patients with recommendations for mitigating lifestyle risk factors, including moderate exercise and dietary advice. This included intake of at least 5 portions of fruit and vegetables per day and lower intake of saturated compared to unsaturated fat, as well as a recommended nutritional program (the Rapha Regimen), which includes amino acids, vitamins, minerals, antioxidants and essential fatty acids. Iron is taken in addition if biochemical testing reveals iron deficiency. The total list of nutrients was published by van Rensburg et al. [15]  However, the srcinal nutrient combination has been modified by the addition of 500 IU vitamin D per day.Eight of the patients subsequently followed the recommenda-tions of the diet and lifestyle intervention program, 6 of them for more than 5 years while the other two had been on the program for less than 5 years. Twelve patients did not follow the program of whom four were on MS medication (Interferon beta). One of the patients who opted to follow the program was on Interferon beta as well. Biochemical determinations Blood was drawn for biochemistry testing in the morning be-tween 9h00 and 10h30 to standardise for diurnal variation. Plasma homocysteine was measured using a Siemens Centaur XP auto-analyser. Serum total cholesterol was determined us-ing a Siemens Advia 1800 auto-analyser. Fibrinogen was de-termined by the Hemos IL-Fibrinogen C method using an ACL TOP (Beckman Coulter SA). Statistical analysis Mixed model repeated measures ANOVA was used to compare left and right vessel measurements. One way ANOVA was used for comparison of measurements between groups (on lifestyle/ nutritional program and not on program, smoking and non-smoking). ANOVA F-test and the Mann-Whitney U test were used to test the same hypothesis. Spearman correlations were used in addition for testing relationships between biochemical variables and ultrasound measurements. RESULTS Twenty-nine patients with MS with a mean age of 47.72 were assessed, with a disease duration of 0.83-27 years. The clinical characteristics of the patients are shown in Table 1.B-mode, pulsed-wave (PW) and Colour Doppler ultrasound demonstrated no thrombus within the proximal-, mid- and dis-tal segments of the right and left IJVs. Colour and PW Doppler ultrasound imaging demonstrated reversed flow of >0.88s in IJV in (four) 13.79% of MS subjects as seen in Figure 3.No stenosis in IJVs was demonstrated on B-mode, Colour or PW Doppler ultrasound imaging. However, significnatly larger  ISSN 1011 5528 | www.smltsa.org.za   45 Volume 28 No. 1 | June 2014 Medical Technology SA Figure 1:  B-mode image of a normal Right Common Carotid Artery (CCA) in the longitudinal plane.  Average IMT=0.42mm (upper limit of normal=0.8mm). Figure 2:  Cross-sectional Diameter (CSD) of the mid right Internal Jugular Vein (IJV). CSD measures 1.25cm. (normal) Figure 3:  Reversed flow of 1.416sec (block arrow) noted in the right IJV on Colour and Pulsed-wave (PW) Doppler. proximal and mid cross-sectional diameters (CSD) of the right IJV compared to the left were demon-strated (proximal p=0.026 and mid p=0.023). The mean CSD of the right IJV was 8.79mm +/-1.67 and the left IJV was 7.96mm +/-1.26 in the 26 female subjects. In the 3 male subjects (10.34%) the mean CSD of the right IJV was 11.05mm +/-2.27 and of the left IJV was 7.36mm +/-1.78 as seen in Figure 4. A larger CSD of the right IJV compared to the left was demonstrated in this study, which supports previous studies. [16] The right and left CCA appeared patent and dis-played no stenosis, occlusion or plaque formation on B-mode, Colour and PW Doppler ultrasound imaging. No blood flow disturbances were identi-fied. Four (13.79%) subjects with MS displayed an increased CCA IMT of >0.8mm on B-mode ultrasound imaging. The increased IMT ranged between 0.9 -1.0mm. No evidence of vessel narrowing or increased peak systolic velocity (PSV) and end-diastolic velocity (EDV) of the ICA (PSV>125cm/s, EDV>100cm/s) and ECA (PSV>200cm/s) were identified on B-mode, Colour and PW Doppler imaging. Echogenic plaque in the ICA was identified in two (6.89%) of the 29 subjects with MS on B-mode ultrasound imaging. This small amount of plaque did not cause disturbances to blood flow. No plaque formation was noted in the External Carotid arteries (ECAs).Biochemical and lifestyle assessments, available for 20 subjects with MS, were evaluated statistically for associations with ultra-sound measurements. Significant differences were found between smokers and non-smokers in the CSD of the mid left IJV (Mann-Whitney U test; p=0.02; Figure 5a) and proximal left IJV (p=0.03; Fig 5b). Smok-ers had significantly smaller IJV diameters than non-smokers. The maximum CSD of the proximal mid IJV was 1.00 cm in non-smoking MS patients, and 0.80 cm in smoking MS patients.The maximum CSD of the proximal left IJV was 1.20 cm in non-smoking MS patients, and 0.95 cm in smoking MS patients. Homocysteine concentration also had an inverse association with the CSD of the proximal left IJV (p=0.045). Inverse non-significant associations were also seen between homocysteine and the CSDs of the proximal-, mid- and distal right IJVs. A significant direct association was seen between fibrinogen and the left ECA PSV (p=0.03). No as-sociations of fibrinogen with CSDs of the carotid arteries or the IMT were recorded; however, a trend towards associations of fibrinogen with di-ameters of the IJVs could be detected, although these effects were not significant (PROX R IJV CSD r=-0.38, p=0.08; MID R IJV CSD r=-0.36, p=0.08; DIST L IJV CSD r=-0.19, p=0.05). A significant inverse association between homocysteine and the right ECA PSV was found (p<0.01); however, similar inverse associations were not observed for homocysteine with PSV measurements in other vessels. No significant associations were found between ultrasound measuments and total cho-lesterol.A novel finding of this study was that the disabil-ity status, assessed with the EDSS, correlated sig-nificantly with the IMT of the R CCA (p<0.0001; Figure 6). A similar direct association was found  46 www.smltsa.org.za | ISSN 1011 5528Volume 28 No. 1 | June 2014 Medical Technology SA with the lMT of the L CCA (p=0.02; Spearman p=0.09). Age also correlated significantly with IMT of the L and R CCA (p<0.001 in both cases). The Sobel test for mediation was used to test the hypothesis that age was a mediator between the IMT and the EDSS. The test was not significant (p=0.58 for the L CCA, and p=0.82 for the R CCA), indicating that a direct relationship between the IMT and the EDSS was found. Age was not signifi-cantly associated with the EDSS: of people over 50 years of age, 5 had an EDSS of 1.5 - 3 (considered a benign outcome) while 5 had an EDSS of 4 - 7.5 (more disabled). Figure 7 demonstrates a significant inverse association (Spear-man p=0.03) between physical activity and the IMT of the L CCA. The IMT of the R CCA was inversely related to physical activity, and was thicker in smokers compared to non-smokers; however the differences were not significant. The EDSS did not correlate with physical activity (Spearman R=-0.32; p=0.20). Patients on the dietary and lifestyle program had a lower mean BMI (26.1 ± 2.8; 95% CI 19.9 - 32.3) than patients not on the program (31.6 ± 2.1; 95% CI 27.0 - 36.2). However, the BMI did not correlate with the R CCA IMT (p=0.5) or the L CCA IMT (p=0.8).Figures 8a and 8b illustrate significant differences (Mann-Whitney U test, p=0.03 and p<0.01) respectively for the PSV and the EDV of the R CCA in subjects with MS on the dietary and lifestyle program (NUTR PROG) versus those not on the program, which may indicate narrower carotid arteries in the latter group. [17]  Figure 8c shows significantly lower EDSS scores in patients on the program versus those not on the program (p=0.03). The EDSS was not associated with disease duration (p=0.46) or medication use (p=0.52). DISCUSSION The internal jugular veins (IJV) are considered to be the main outflow pathway for intracranial venous blood. [18]  The present study demonstrated patency of the IJVs in 29 subjects with MS sampled with no evidence of thrombus on B-mode and Col-our Doppler ultrasound imaging. This can be regarded as a new finding as no literature is available on the prevalence of internal jugular vein thrombus in subjects with MS. Previous research studies, however, have demonstrated IJV intraluminal defects such as webs, septa and/or malformed valves which affects the venous outflow patterns. [19]  No IJV intraluminal de-fects were demonstrated in this study. According to Zamboni et al. [20] , reflux of flow directed towards the brain for a duration of >0.88s is regarded as significant. They defined this abnormal cerebrospinal venous drainage in subjects with MS as chronic cerebrospinal venous insufficiency (CCSVI) and hypothesised that CCSVI is strongly associated with MS and could play a causative role in the development of the disease. Zamboni’s theory generated great interest in patients with MS, who have communicated on social media, expressing their desire to have ultrasound tests done. This enhanced interest was also experi-enced by the researchers during this study. A larger CSD of the right IJV compared to the left was dem-  ISSN 1011 5528 | www.smltsa.org.za   47 Volume 28 No. 1 | June 2014 Medical Technology SA Figure 4:  Cross-sectional Diameters of the Internal Jugular Veins. Figure 5a:  Cross-sectional diameter (CSD) of the mid left internal jugular vein (IJV) of smoking MS patients versus non-smoking MS patients. IJV=internal Jugular Vein, L=left, CSD=cross-sectional diameter, no=non-smoking MS patients, yes=smoking MS patients. There is a significant difference between the 2 groups (Mann-Whitney U test, p=0.02). The maximum CSD of the left mid IJV in non-smoking MS patients (n=16) is ~10mm (1.00cm). The maximum CSD of the left mid IJV in smoking MS patients (n=4) is <8mm (0.80cm). Figure 5b:  Cross-sectional diameter (CSD) of the proximal left internal jugular vein (IJV) of smoking MS patients versus non-smoking MS patients.IJV=internal Jugular Vein, L=left, CSD=cross-sectional diameter, no=non-smoking MS patients, yes=smoking MS patients. There is a significant difference between the 2 groups (Mann-Whitney U test, p=0.03). The maximum CSD of the left proxi-mal IJV in non-smoking MS (n=16) patients is ~12mm (1.20cm). The maximum CSD of the left proximal IJV in smoking MS patients (n=4) is ~9.5mm (0.95cm). Figure 6: Significant association between the EDSS and the IMT of the R CCA (p<0.0001). R CCA=right common carotid artery, IMT=intima media thickness. EDSS=Expanded Disability Status Scale. Figure 7:  Significant inverse association between Physical Activity and the IMT of the L CCA (Spearman p=0.03). L CCA=left common carotid artery, IMT=intima media thickness. onstrated, which supports previous studies. [16]  Reversed flow in the internal jugular veins during valsalva was demonstrated in 13.79% of subjects with MS. Reflux in the IJV could be due to valve incompetence or stenosis. A reduction of ≥ 50% of the CSD of the IJV was considered stenotic. However, no stenosis of the IJV was identified. The reflux identified in the 13.79% of subjects with MS was due to valve incompetence and not stenosis. Thus, this study does not support Zamboni’s CCSVI theory. Other published studies could also not reproduce the findings published by Zamboni and his colleagues. Mayer et al. [21]  found no supportive evidence for the presence of CCSVI in patients with MS. Awad et al. [22]  also states that there is no conclusive evidence to support CCSVI and its association with MS. Gever [23]  wrote a report on the “Largest CCSVI study fails to support theory” where approximately 2000 subjects with blinded central imaging analysis found CCSVI in approximately
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