Multiple Sclerosis Resource Centre

Welcome to the Multiple Sclerosis Resource Centre. This website is intended for international healthcare professionals with an interest in Multiple Sclerosis. By clicking the link below you are declaring and confirming that you are a healthcare professional

You are here

Vascular comorbidities in the onset and progression of multiple sclerosis

Journal of the Neurological Sciences, 1-2, 347, pages 23 - 33

Abstract

Vascular comorbidities are common in the general population and are associated with adverse health outcomes. In people with multiple sclerosis (MS), an increasing amount of evidence suggests that vascular comorbidities are also common, but an association with MS risk and disability has not been conclusively established. This review aims to critically examine published data on the relationship between vascular comorbidities (including vascular risk factors) and MS. The evidence suggests an increased risk of MS in people with a high BMI during childhood or adolescence but not adulthood. People with established MS appear to have a slightly increased risk of cardiovascular disease and a greater proportion of people with MS die from cardiovascular disease, which has important implications for clinicians trying to identify risk factors for cardiovascular disease and reviewing treatment options. In relation to whether vascular comorbidities influence MS clinical disability or other aspects of the disease course, the key finding was that having type-2-diabetes, hypertension, dyslipidaemia or peripheral vascular disease at any point in the disease course may be associated with a greater progression in disability. Additionally, a negative effect of high cholesterol and triglycerides and a positive effect of higher HDL (high density lipoprotein) levels on acute inflammatory activity were observed on magnetic resonance imaging. The results of the published clinical trials of statins as an intervention in MS were however conflicting and care needs to be taken when treating people with MS with statins. Taken together, the literature seems to indicate a potential association of vascular comorbidities with MS risk and disability, but the number of prospective studies was sparse, thus precluding ascription of causality. We therefore recommend that future studies of the frequency and effects of vascular comorbidities on MS risk and disability should be prospective and objective where relevant.

Highlights

 

  • We reviewed published data on the relationship between vascular comorbidities and MS.
  • The evidence suggests an increased risk of MS in people with a high BMI.
  • MS patients appear to have a slightly increased risk and death due to cardiovascular disease.
  • Vascular comorbidities may be associated with greater progression in disability.
  • Clinical trials of statins as an intervention in MS were conflicting.

Keywords: Multiple sclerosis, Comorbidities, Disability, Obesity, Lipids, Statins.

1. Introduction

Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) with autoimmune, inflammatory and neurodegenerative components which may influence each other or alternatively may have independent natural histories. Although the typical age of onset of MS is in the third and fourth decades of life, the burden of disease is most marked in the fifth to seventh decades [1] . MS affects more than 2.5 million individuals worldwide [2] , with higher incidence and prevalence in women than men [3] . MS has a highly variable inter and intra-personal clinical course, both in pattern and rate of deterioration [1] .

In relation to aetiology, MS is a complex disease in which multiple environmental and lifestyle risk factors act together in a genetically susceptible individual to cause the disease [4] . Environmental and lifestyle risk factors include low sunlight exposure and vitamin D, cigarette smoking and exposure to Epstein–Barr virus[3], [4], and [5]. However it is not entirely clear whether the same factors also modulate disease progression and whether the putative factors that modulate the inflammatory components of the disease are the same as those that potentially modulate the neurodegenerative components. In the last several years, vascular risk factors and vascular comorbidities such as obesity, dyslipidaemia, type-2 diabetes and cardiovascular disease have been associated with MS onset and disease progression[4] and [6]. In line with this background, MS has been proposed to have, in part, a vascular basis due to its shared pathophysiology with these comorbidities, including endothelial dysfunction [7] , inflammation [8] , and cardiovascular autonomic dysfunction [9] .

In this review, we examine the current literature on the relationship between cardiovascular risk factors including obesity, hypertension, dyslipidaemia, type-2 diabetes, and cardiovascular disease with MS risk, disability progression and mortality. Throughout the text, the term vascular comorbidity refers to cardiovascular risk factors and diseases.

2. Obesity and MS

2.1. Prevalence of obesity in people with MS and comparison with healthy populations

The prevalence of obesity in people with MS has been investigated in several studies. For example, in a large study of persons with MS (n = 8983), 31.3% of participants were classified as overweight and 25% as obese [10] . A study of 123 women with MS from Oregon found 47.5% of participants to be overweight and 25.8% were obese [11] . In a study of by Pilutti and colleagues [12] , 36.3% of the 168 MS patients were overweight and 32.7% were obese. In a 24-month longitudinal study of 269 individuals with relapsing–remitting MS (RRMS), 24.0% and 28.3% were classified as overweight and obese respectively [13] . Similarly, a study by Marrie and colleagues [14] reported that nearly half had high BMI at MS onset, with 26.4% being overweight and 23.8% being obese.

A number of studies compared the prevalence of high BMI to a control population. A study by Khurana and colleagues [15] found that 4339 veterans with MS had a slightly higher age and sex-adjusted prevalence of overweight than veterans in general (42.3% vs. 39.6%, respectively) but a lower adjusted prevalence of obesity (20.1% vs. 33.1%). In contrast, other case–control studies were not able to detect any difference in BMI between MS cases and controls, though these studies were relatively small (sample size ranging from 16 to 68) compared to that of Khurana and colleagues[16], [17], and [18]. Two other studies even reported a lower BMI in MS cases than controls[16] and [19]. Overall, there is currently no evidence that the prevalence of overweight and obesity in MS is higher than that of the general population. The use of self-reported height and weight may have led to underestimation of overweight and obesity in these investigations.

2.2. Obesity and MS risk

Table 1 provides an overview of the studies that have examined the association between BMI and MS risk. It shows that a number of prospective and case–control studies have observed an association between BMI in childhood[20] and [21]and adolescence[22] and [23]and MS risk; however no associations have been found between BMI in adulthood and MS risk[22] and [23]. Interestingly, the two studies that examined childhood BMI both found that the association was only present in females and not in males, both showing a clear dose-dependent relationship between childhood BMI in females and subsequent MS risk[20] and [21]. In addition, two studies found a dose–response relationship between BMI and MS when BMI was measured at ages 18 and 20[22] and [23]but no association was observed when BMI was measured in adulthood[22] and [23]. Certainly having an association with exposure prior to disease onset is potentially supportive of a causal directionality, but it is interesting and perhaps disruptive to a causal interpretation that the BMI–MS association does not track forward to later adulthood. It may be that by this age other factors that occur among all adults in their later decades of life nullify any appreciable differences in BMI between MS cases and other adults.

Table 1 Studies examining obesity and risk of multiple sclerosis.

Author (year) Study information Number of MS patients/total cohort Age BMI measured Main findings
Munger and colleagues, (2013) [20] Cohort study (1930–1983) 774/302,043 7 years 1. Girls: BMI z-score (HR = 1.20, (95% CI: 1.10–1.30), p < 0.001)

2. Boys: BMI z-score (HR = 1.12, (95% CI: 0.99–1.28), p > 0.05)
13 years 1. Girls: BMI z-score (HR = 1.18, (95% CI: 1.08–1.28), p < 0.001)

2. Boys: BMI z-score (HR = 1.10, (95% CI: 0.97–1.25), p > 0.05)
Langer-Gould and colleagues, (2013) [21] Cohort study (2007–2009) 75/913,097 2–18 years Girls: Normal weight: OR = 1 (ref), Overweight: OR = 1.58 (95% CI: 0.71–3.50), Moderate obesity: OR = 1.78 (95% CI: 0.70–4.49), Extreme obesity: OR = 3.76 (95% CI: 1.54–9.16), p-trend = 0.005
Boys: Normal weight: OR = 1 (ref), Overweight: OR = 1.80 (95% CI: 0.83–3.93), Moderate obesity: OR = 0.89 (95% CI: 0.30–2.64), Extreme obesity: OR = 0.82 (95% CI: 0.19–3.56),

p-trend = 0.93
Hedstrom

and colleagues, (2012) [23]
Case–control study (2005–2011) 1571/3371 20 years Normal weight (BMI): 18.5–21, OR = 1 (ref); 21–23, OR = 1.1 (95% CI: 0.9–1.2), p = 0.5;

23–25, OR = 1.2 (95% CI: 1.0–1.5), p = 0.03

Overweight (BMI): 25–27, OR = 1.4 (95% CI: 1.1–1.8), p = 0.2; 27–29, OR = 2.2 (95% CI: 1.6–3.0), p = 1 × 10–6

Obese (BMI):>30, OR = 2.2 (95% CI: 1.5–3.0), p = 9 × 10− 6; p-trend = 2 × 10− 10
> 20 years No association between current/adult BMI and MS risk (data not shown)
Munger and colleagues, (2009) [22] Cohort study (1976–2003) 593/238,371 18 years Normal weight (BMI): 18.5–21, RR = 1 (ref); 21–23, RR = 1.13 (95% CI: 0.91–1.40);

23–25, RR = 0.97 (95% CI: 0.72–1.31)

Overweight (BMI): 25–27, RR = 1.44 (95% CI: 0.87–2.39); 27–29, RR = 1.40 (95% CI: 0.92–2.14)

Obese (BMI): > 30, RR = 2.25 (95% CI: 1.50–3.37); p-trend < 0.001
25–55 years Normal weight (BMI): 18.5–21, RR = 1 (ref); 21–23, RR = 0.87 (95% CI: 0.69–1.10);

23–25, RR = 1.00 (95% CI: 0.78–1.29)

Overweight (BMI): 25–27, RR = 1.23 (95% CI: 0.93–1.62); 27–29, RR = 0.79 (95% CI: 0.30–2.12)

Obese (BMI): > 30, RR = 0.91 (95% CI: 0.46–1.79); p-trend = 0.88

Normal: 18.5 to 24.9 kg/m2, Overweight: 25 to 29.9 kg/m2, Obese: ≥ 30 kg/m2.

A substantial limitation of these studies was the fact that they were unable to adjust for sun exposure and/or 25-hydroxyvitamin D serum levels. It is well known that individuals with high BMI have less sun exposure and lower vitamin D levels[24] and [25]. In part, this may be due to changes in behaviour and the effects of increased adiposity on systemic vitamin D availability. Low sun exposure and vitamin D levels are now established risk factors for MS.[26], [27], and [28]It is therefore feasible that the observed associations between childhood/adolescence BMI and MS may be explained by the fact that cases had less sun exposure and lower serum vitamin D levels. That said, there are a number of deleterious effects of obesity that might independently contribute to MS risk, such as increased oxidation and dyslipidaemia, so both BMI and sun/vitamin D are worthy covariates to assess in studies of MS risk and disability progression. Importantly, the absence of association between adult BMI and the risk of MS is interesting and seems to suggest that some aspects of early life or adolescence may be critical in determining the risk of MS.

2.3. Obesity and MS disability

Three studies examined the association between BMI and disability. In the first study, 269 individuals with RRMS were prospectively followed for 24 months and participants reported information about their BMI and level of disability as measured by the Patient Determine Disease Steps (PDDS), a self-reported variant of EDSS [13] . Higher BMI at baseline was associated with a higher PDDS at 12 months (β: + 0.06, p < 0.05), but BMI at 12 months was not significantly associated with PDDS at 24 months (β: -0.04, p > 0.05). In the second study by Marrie and colleagues [10] , PDDS was grouped into mild (EDSS ≤ 3; n = 1318), moderate (EDSS 4.5–5.5; n = 350) and severe (EDSS ≥ 6; n = 707) disability. No significant association was observed between BMI and disability, because among those with mild, moderate and severe disability, 24.0%, 27.7% and 25.6% were obese, respectively (OR = 1.09 (95% CI: 0.90–1.33) for moderate vs. mild disability; OR = 0.99 (95% CI: 0.86–1.14) for severe vs. mild disability; ptrend= 0.11). In our own work [29] , BMI was measured objectively and disability assessed by EDSS. We found that BMI was independently associated with higher EDSS (p = 0.013). In another study where we investigated the associations between BMI and relapse in MS in cohort of 141 participants with relapsing–remitting MS, BMI was not associated with the hazard of relapse [30] .

The fact that two studies used self-reported height and weight to calculate BMI is a potential limitation, because it is well known that those who are more overweight are more likely to under-report their weight [31] . This under-reporting could bias an association towards the null, though the fact that the Pilutti study found a significant effect of baseline BMI and disability at 12 months despite a self-reported BMI may just indicate the absence of effect. Regardless, additional studies are needed to assess any association, ideally measuring BMI objectively.

We could not identify any studies that examined disability longitudinally to determine whether obesity could be related to a more rapid change in disability. Certainly such an analysis would greatly improve upon the capacity to assess the veracity of the associations demonstrated with previous retrospective and cross-sectional designs, though the logistics required do complicate implementation. A blended method, prospectively collecting data on early and mid-adulthood BMI and making use of medical records for childhood BMI may allow a more feasible design without being too logistically onerous.

2.4. Potential biological mechanisms

The mechanisms by which obesity might impact upon MS risk are not yet known. As mentioned, part or all of the association between childhood/adolescence BMI and MS risk could be confounded by other factors such as sun exposure and vitamin D. If there were to be an independent effect of obesity, then the mechanism may be related to the lipid pathway, as obese people are known to have a more adverse lipid profile compared to those of normal weight[32] and [33],

It is also possible that there is a shared pathway between vitamin D and lipids[34] and [35]. While serum lipids are prone to oxidation and inflammation in the vascular endothelium, vitamin D is known to exert immunomodulatory and antioxidant effects on the immune system [36] . The connection between vitamin D and lipids is not unexpected, as vitamin D synthesis starts in the skin from a cholesterol precursor, 7-dehydrocholesterol, and it is thought that higher serum vitamin D levels may improve the plasma lipid profile [17] . In line with these findings, patients that began using statins in order to improve their cholesterol profile experienced an increase in serum vitamin D levels [37] .

An alternative hypothesis is that the effects of obesity are mediated by a low-grade chronic inflammatory state. There is evidence that adipose tissue secretes inflammatory factors collectively known as adipokines that influence immune system functioning, including leptin [38] and interleukin-6 [39] , which has been shown to reduce regulatory T-cell activity [40] and [41]and promote an inflammatory T helper 1 cell response [42] thought to be responsible for the autoimmune inflammation, development and progression of MS. [43]

2.5. Summary: obesity and MS

Collectively, the results from the studies on BMI and MS suggest that weight status during early life may be important in determining subsequent MS risk. In relation to the question of whether obesity is associated with disability or a change in disability, studies are required that measure BMI objectively and prospectively.

3. Type-2 diabetes and MS

3.1. Prevalence of type-2 diabetes in people with MS and comparison with healthy populations

We could not identify any studies that examined T2D and the risk of MS to determine whether T2D is more prevalent prior to the onset of MS. However a number of studies compared T2D frequencies in people with MS and healthy controls. In a study by Hussein and Reddy [44] , the prevalence of T2D among a cohort of 1206 MS patients was significantly higher (prevalence: 6.75%; 95% CI: 6.74–6.76), p = 0.005) than in the general population. A study by Kang and colleagues reported that the prevalence of T2D in a group of 898 MS patients was 8.6%, this was 1.5-times higher than that of the 4490 randomly matched controls without MS (OR: 1.5; 95% CI: 1.1–1.2; p < 0.01) [45] . However, in a study by Marrie and colleagues, the age-adjusted prevalence of T2D in patients with MS was similar to that of the general population (7.62 vs. 8.31%; prevalence ratio 0.91; 95% CI: 0.81–1.03) [46] . Fleming and Blake compared T2D frequencies among MS and non-MS cases admitted to the hospital, finding the prevalence of T2D was lower in MS cases (3.08 per 100 discharges) compared to controls (6 per 100 discharges) [47] .

A retrospective study by Sternberg and colleague also showed no difference in the prevalence of T2D between MS patients and non-MS patients indicated by the lack of difference in the use of anti-diabetic drugs between the two groups[8] and [48]. Plasma glucose level was however significantly lower in MS patients compared to non-MS patients [8] and also lower in disease modifying therapies naive (DMTs-naive) MS patients compared to MS patients on disease modifying therapies [48] , showing that the chronic use of pharmacological agents by MS patients could increase plasma glucose levels and also modulate the risk of T2D in MS patients.

The heterogeneity of the findings reported could also be due to differences in study design used in these investigations that is, hospital-based versus population-based studies. From these inconsistent results, there is no convincing evidence that the prevalence of T2D is higher among people with MS compared to the general population, and thus no evidence indicative of an association between T2D and MS risk.

3.2. Type-2 diabetes and MS disability

The relationship between T2D and disability in MS was investigated by Marrie and colleagues. In this study [6] , they examined whether T2D was associated with the time to different ambulatory disability endpoints in a large population of 8983 MS patients enrolled in the North American Research Committee on MS Registry (NARCOMS). Compared with MS patients who did not report T2D, individuals with MS who developed T2D at any point during their disease course had a 29% increased risk of early gait disability (hazard ratio (HR): 1.29; 95% CI: 1.13–1.48), a 28% increased risk of requiring unilateral assistance (HR: 1.28; 95% CI: 1.11–1.49) and a 56% increased risk of requiring bilateral assistance (HR: 1.56; 95% CI: 1.30–1.88).

In another study using the NARCOMS registry, Marrie and Cutter [49] also assessed the effect of T2D on the development of visual disability using the Vision subscale of Performance Scales (PSV) which is scored ordinally as 0 (normal), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (total disability). They reported that developing T2D at any point in the disease course was associated with a 35% (HR: 1.35 (1.15–1.58) increased risk of mild visual disability, a 41% (HR: 1.41 (1.12–1.78) increased risk of moderate visual disability and a 54% increased risk of visual disability (HR: 1.54 (1.04–2.28).

These results are in line with a non-MS systematic review and meta-analysis by Wong et al reporting that diabetes is associated with increased physical disability compared to people without diabetes in the general population [50] which in part, may be due to the complications of diabetic neuropathy which is characterised by muscle weakness and significant autonomic dysfunction [51] . These results are suggesting that T2D comorbidity is associated with a worse progression in disability. The lack of consistently higher prevalence of T2D in people with MS does not preclude any potential association with disability progression, given the distinct pathways for inflammatory and neurodegenerative mechanisms.

3.3. Summary: type-2 diabetes and MS

Data on the prevalence of T2D in MS patients is limited and the findings are inconsistent. The result on the relationship between T2D and disability suggest that people with MS who also have T2D may have a worse progression in disability compared to people with MS without T2D. Further studies are required to confirm this finding, however.

4. Hypertension and MS

4.1. Prevalence of hypertension in people with MS and comparison with healthy populations

The frequency of hypertension in MS patients has been investigated by a number of studies. For instance, in a study of 898 MS patients by Kang and colleagues, the prevalence of hypertension was higher in the MS patients compared to the control group (OR: 1.40; 95% CI: 1.10–1.70) [45] . In a cross-sectional study of 1142 male veteran MS patients, LaVela and colleagues reported higher prevalence of hypertension in MS patients compared to general veteran population (46.7% versus 41.2%, p < 0.001) and the general population (46.7% versus 20.9%, p < 0.001) [52] . However, in a study using the NACORMS registry, Marrie and colleagues reported that 30.1% of 8983 MS participants reported being hypertensive which was similar to the rate expected for the general population [6] . In another study of 430 MS patients by Marrie and colleagues, the age-adjusted prevalence of hypertension in the MS patients was similar to that of the general population (MS: 20.8% versus general population: 22.5% [PR: 0.9; 95% CI: 0.78–1.06]). Studies reporting actual blood pressure values recorded similar values in MS patients compared to controls[8], [48], and [53]. Sternberg and colleagues also reported that there was no significant difference in the use of antihypertensive drugs between MS and non-MS patients. Lower prevalence of hypertension was also reported by some studies[19] and [54]. For example, in study of 8281 MS patients by Jadidi and his colleagues, the frequency of hypertension was lower in MS patients compared to the matched controls (0.42% versus 0.68%) [54] . Similarly, Allen and colleagues reported lower prevalence of hypertension in 9949 hospitalised MS patients compared to non-MS hospitalised controls (18.3% versus 29.3%, p < 0.05) [19] . Lower prevalence of hypertension in MS patients compared to controls have been reported in other studies[8] and [47].

The data available on the prevalence of hypertension in MS is inconsistent and there is no convincing trend of evidence that the prevalence of hypertension is higher in MS patients compared to the general population or healthy controls. This may be due to differences in demographic and clinical characteristic between studies, including differences in exposure to pharmacological agents in MS.

4.2. Hypertension and MS disability

Marrie and colleague investigated the relationship between hypertension and disability in MS. [6] They examined whether hypertension was associated with the time to different ambulatory disability endpoints using the NARCOMS registry. Compared with MS patients who did not report hypertension, individuals with MS who developed hypertension at any point during their disease course had a 29% increased risk of early gait disability (HR: 1.29; 95% CI: 1.20–1.39), a 25% increased risk of requiring unilateral assistance (HR: 1.25; 95% CI: 1.15–1.36) and a 17% increased risk of requiring bilateral assistance (HR: 1.56; 95% CI: 1.05–1.31).

Using the NARCOMS registry, Marrie and Cutter [49] also assessed the effect of hypertension on the development of visual disability using the Vision subscale of Performance Scales (PSV). Developing hypertension at any point in the disease course was associated with 32% (HR: 1.32 (1.20–1.46) increased risk of mild visual disability, 31% (HR: 1.31 (1.13–1.51) increased risk of moderate visual disability and 16% increased risk of visual disability (HR: 1.16 (0.89–1.51).

These results suggest that hypertension as comorbidity in MS patients may be associated with a worse progression in disability. These findings are consistent with data from non-MS studies which have reported significant association between hypertension and disability in the general population[55] and [56].

4.3. Summary: hypertension and MS

We found no convincing evidence of higher prevalence of hypertension in MS patients compared to matched controls. However, there is some evidence to suggest that MS patients who develop hypertension at any point in the disease course may experience faster progression in clinical disability.

5. Cardiovascular diseases and MS

Cardiovascular diseases are common in the general population [57] and are associated with many adverse health outcomes, including reduced functional status [58] , severity of the primary disease[57] and [59], reduced quality of life[59] and [60]and increased mortality [60] . If cardiovascular diseases were also common in MS and were associated with disability, then this could partly explain the highly variable inter and intra-personal clinical course observed in MS. Despite their potential importance, little information exists about the prevalence of cardiovascular diseases in MS, how the prevalence is changing over time, and how they affect treatment decisions, treatment responses or health outcomes in MS.

5.1. Cardiovascular diseases and mortality in people with MS and comparison with healthy populations

To the best of our knowledge, no study has been conducted that examined whether the occurrence of cardiovascular disease prior to MS onset was associated with MS risk. However, mortality due to cardiovascular disease in individuals with MS has been investigated by a number of studies. In Denmark, Koch-Henriksen and colleagues [61] reported that individuals with MS had a 34% increased risk of death from cardiac and vascular disease compared to the general population (standardised mortality ratio [SMR]:1.34; 95% CI: 1.02–1.71). In another Danish study, Bronnum-Hansen and colleagues [62] reported a 32% increased risk for MS patients of dying from cardiovascular disease compared to the general population (SMR: 1.32; 95% CI: 1.22–1.43). Lalmohamed and colleagues reported a stronger effect, with a 2.4-fold increased risk of death from cardiovascular disease compared to gender-matched referent subjects. However Hirst and colleagues [63] reported that MS patients had a 6% increased risk of death from cardiovascular diseases which was not statistically different from the general population (p = 0.22).

These studies collectively suggest an association between cardiovascular diseases and mortality in people with MS.

5.2. MS and risk of cardiovascular diseases

Table 2 provides a summary of the studies that have examined the association between MS and risk of cardiovascular disease. Two studies reported a higher risk of myocardial infarction in MS cases than matched controls[54] and [64]. However a third study reported a lower prevalence of myocardial infarction in MS cases than controls [19] . MS cases have been found to have a higher risk of heart failure[54] and [64], stroke[19], [54], and [64]or cerebrovascular disease [45] and peripheral vascular disease[6] and [45]when compared to matched controls. Coronary heart disease has also been found to be more frequent in MS cases compared to controls[45] and [54]. The prevalence of ischemic heart disease was higher in MS cases compared to controls [65] in some studies but lower in others [19] . In a study by Fleming and Blake [47] , the frequencies of acute myocardial infarction, heart failure, atrial fibrillation and cerebrovascular disease were lower in MS cases than matched hospitalised controls.

Table 2 Studies examining occurrence of cardiovascular diseases in people with multiple sclerosis.

Author (year) Study information MS patients Control group Main findings
Jadidi and colleagues, (2013) [54] Case–control (1987–2009) 8281 76,640 matched

Controls
1. Myocardial infarction: IRR = 1.85 (95% CI: 1.59–2.15)

2. Heart failure: IRR = 1.97 (95% CI: 1.52–2.56)

3. Atrial fibrillation: IRR = 0.63 (95% CI: 0.46–0.87)

4. Stroke: IRR = 1.71 (95% CI: 1.46–2.00)
Kang and colleagues, (2010) [45] Case–control (2007) 898 4490 matched

controls
1. Hypertension: OR = 1.40 (95% CI: 1.1–1.7)

2. Peripheral vascular disease: OR = 6.60 (95% CI: 4.00–11.00)

3. Cerebrovascular disease: OR = 3.70 (95% CI: 2.90–4.10)
Christiansen

and colleagues, (2010) [64]
Case–control (1977–2006) 13,963 66,407 matched

controls
One year follow-up:

1. Myocardial infarction: IRR = 1.84 (95% CI: 1.28–2.65),

2. Heart failure: IRR = 1.92 (95% CI: 1.27!–2.90)

3. Stroke: IRR = 1.69 (95% CI: 1.42, 2.71)

2–30 year follow-up:

1. Myocardial infarction: IRR = 1.10 (95% CI: 0.97–1.24)

2. Heart failure: IRR = 1.53 (95% CI: 1.37–1.71)

3. Stroke: IRR = 1.23 (95% CI: 1.10–1.38)
Allen and colleagues, (2008) [19] Case–control (2005–2011) 9949 19,898 matched controls 1. Myocardial infarction: OR = 0.78 (95% CI: 0.64–0.96)

2. Ischemic stroke: OR = 1.66 (95% CI: 1.33–2.09)

3. Haemorrhagic stroke: OR = 1.14 (95% CI: 0.76–2.32)

4. Ischemic heart disease: OR = 0.58 (95% CI: 0.51–0.66)
Fleming & Blake,(1994) [47] Case–control (1989) 7168 7168 matched controls 1. Coronary heart disease: 3.81% in MS and 10.69% in control group (p < 0.05)

2. Atrial fibrillation: 2.66% in MS and 6.60% in control group (p < 0.05)

3. Cerebrovascular disease: 1.86% in MS and 2.58% in control group (p < 0.05)

4. Hypertension: 7.42% in MS and 15.95% in control group (p < 0.05)
Marrie and colleagues, (2010) [6] Cohort study (2006) 8983   Bilateral assistance to walk

1. Hypertension: HR = 1.17 (95% CI: 1.05–1.31)

2. Coronary heart disease: HR = 0.99 (95% CI: 0.80–1.23)

3. Peripheral vascular disease: HR = 1.87 (95% CI: 1.35–2.60)
Marrie and colleagues, (2011) [49]       Severe visual disability

1. Hypertension: HR = 1.16 (95% CI: 0.89–1.51)

2. Coronary heart disease: HR = 1.20 (95% CI: 0.80–1.80)

3. Peripheral vascular disease: HR = 1.90 (95% CI: 1.11–3.23)
Marrie and colleagues, (2013) [65] Case–control (1984–2005) 2366 11,786 matched controls Ischemic heart disease

1. Aged 20–44 years: Prevalence ratio (PR) = 1.87 (95% CI: 1.65–2.12)

2. Aged 45–59 years: PR = 1.21 (95% CI: 1.08–1.35)

3. Aged ≥ 60 years: PR = 0.81 (95% CI: 0.70–0.92)
1. Aged 20–44 years: Incidence ratio (IRR) = 2.01 (95% CI: 0.94–4.30)

2. Aged 45–59 years: IRR = 1.33 (95% CI: 0.95–1.86)

3. Aged ≥ 60 years: IRR = 1.04 (95% CI: 0.69–1.56)

Differences in patients' demographic and clinical characteristics between studies could contribute to the inconsistencies in the results. For instance, in the studies by Jadidi and colleagues [54] and that of Christiansen et al. [64] , they used newly diagnosed MS patients and reported higher incidence of cardiovascular disease in MS patients compared to matched controls. One of the factors that may account for this is the activation of the sympathetic autonomic nervous system which is potentiated by heightened inflammation at the initial stages of the disease[9], [66], and [67]. However, the study by Fleming and Blake [47] reported contrasting results, since it was conducted in elderly MS patients (≥ 65 years of age), where inflammation is low, and the sympathetic autonomic function is severely dysfunctional. Secondly, differences in the use or exposure to DMTs of MS and other pharmacological agents between studies may also contribute to the varied results since studies have shown that the use of pharmacological agents in MS may be associated with increased risk of cardiovascular diseases[68] and [69].

In summary, current evidence suggests that people with MS may be at a slightly increased risk of cardiovascular diseases than matched controls. To what extent this is reflective of any causal mechanisms or just a common set of predictors for MS and cardiovascular disease can't be discerned from these study methods.

5.3. Cardiovascular disease and MS disability

Marrie and colleagues evaluated the association between the presence of vascular comorbidities and the time to different ambulatory disability endpoints in 8983 MS patients from the NARCOMS Registry [6] . Participants reporting one or more vascular comorbidities at MS diagnosis had an increased risk of ambulatory disability, and the risk increased with the number of vascular comorbidities reported. A single vascular comorbidity at diagnosis was associated with 51% increased risk of early gait disability (HR: 1.51; 95% CI: 1.41–1.61) while two vascular comorbidities were associated with a 228% increased risk of early gait disability. A single vascular comorbidity at any point in the disease course was also associated with 58% increased risk of early gait disability (HR: 1.58; 95% CI: 1.48–1.68). Similarly, compared with MS patients who did not report peripheral vascular disease, individuals with MS who developed peripheral vascular disease at any point in the disease course had a 29% increased risk of early gait disability (hazard ratio (HR): 1.29; 95% CI: 1.20–1.39), a 25% increased risk of requiring unilateral assistance (HR: 1.25; 95% CI: 1.15–1.36) and a 17% increased risk of requiring bilateral assistance (HR: 1.56; 95% CI: 1.05–1.31). However, compared with MS patients who did not report coronary heart disease, individuals with MS who developed coronary heart disease had similar ambulatory disability.

Using the NARCOMS registry, Marrie and Cutter also assessed the effect of vascular comorbidities on the development of visual disability [49] . They reported that developing peripheral vascular disease at any point in the disease course was associated with 45% (HR: 1.45 (1.14–1.80) increased risk of mild visual disability, 63% (HR: 1.63 (1.17–2.27) increased risk of moderate visual disability and 90% increased risk of visual disability (HR: 1.90 (1.11–3.23). Similarly, coronary heart disease was associated with 27% (HR: 1.27 (1.09–1.46) increased risk of mild visual disability, 45% (HR: 1.45 (1.16–1.80) increased risk of moderate visual disability and 20% increased risk of visual disability (HR: 1.20 (0.80–1.80).

Another study using the NARCOMS Registry assessed the association between pre-existing comorbidity and the severity of disability at diagnosis [70] . Using PDDS, participants were classified as having mild, moderate or severe disability. Among participants enrolled within two years of diagnosis, the adjusted odds ratio of moderate vs. mild disability at diagnosis increased in participants with a vascular comorbidity (OR: 1.51; 95% CI: 1.12–2.05). However, the odds ratio of severe vs. mild disability was not statistically different for participants with a vascular comorbidity (OR: 1.06; 95% CI: 0.77–1.44).

Taken together, this data suggests that having a cardiovascular disease at diagnosis or at any point in the disease course may be associated with a worse progression in disability compared to those without a cardiovascular comorbidity. As with MS risk, however, whether this reflects a causal mechanism or just shared predictors is unclear.

5.4. Potential biological mechanisms

There are some potential hypotheses for the biological mechanisms underlying the relationship between cardiovascular disease and progression in disability. Firstly, vascular comorbidities are associated with increased peripheral inflammation and could act to increase disease progression by activating the inflammatory cascade. Elevated levels of inflammatory markers in MS are associated with an excess activation of cellular and humoral components of the immune system which may increase inflammatory demyelination and neurodegeneration. The neurodegeneration which manifests in disability progression in MS evokes neuronal and axonal loss which leads to brain atrophy and cognitive decline[71], [72], and [73]. Secondly, it has been proposed that the chronic inflammatory process that characterises MS pathogenesis may contribute to the aetiogenesis and dysfunction of the cerebral endothelium[7] and [72]. Serum proinflammatory cytokines such as TNF-α and IFN-γ, which are elevated before clinical exacerbations of MS, can activate the cerebral endothelial cells (CECs) and alter their anatomical distribution and activity leading to the disruption of the blood–brain barrier as evidenced by a decrease expression of endothelial tight junction proteins of the CECs. Dysfunction of the CECs and permeability of the blood–brain barrier causes adherence and trans-endothelial migration of T-lymphocytes and monocytes to the CNS with destructive and often neurodegenerative consequences[7] and [74].

5.5. Summary: cardiovascular disease and MS

On the whole, the prevalence of cardiovascular disease and the risk of death from cardiovascular disease appear to be higher in people with MS compared to the general population. Whether comorbidities are already frequent prior to the onset of MS is unknown and case–control or ideally prospective study designs are needed to assess this. Importantly, whether present at diagnosis or later in the disease course, cardiovascular diseases may be associated with a faster accumulation of disability. Having two or more cardiovascular diseases, which independently cause impairment, could act in concert to increase disability in MS patients [70] .

While MS in itself may not cause cardiovascular disease, patients with MS may be subject to the risk of cardiovascular diseases because of co-occurring conditions such as dyslipidaemia, depression, neurological impairment or physical disability, which make them less physically active than the general population. Physical inactivity would be expected to increase the risk of cardiovascular diseases. Consequently some MS patients may die from cardiovascular diseases even without a direct relation to the disease.

6. Lipids and MS

Apart from adipose tissue, the brain is the most cholesterol-rich organ in the body [75] , with cholesterol forming about 80% of the intact myelin [76] . Lipids play important roles in the central nervous system and their transport through the blood-brain barrier have been demonstrated in normal physiological conditions [77] and [78]and during breakdown of the blood-brain barrier in MS. [79] To maintain cholesterol homeostasis in the body [80] and the CNS[81] and [82]there are antioxidant defence systems and mechanisms to regulate lipid metabolism. Notwithstanding, the brain is believed to be particularly susceptible to oxidative damage and lipid dysregulation[83], [84], and [85]due to its high content of lipids and high oxygen consumption, as well as a less effective antioxidant defence system compared with other tissues [85] . Dysregulation and oxidation of lipids are closely linked to the development of several neurodegenerative disorders including Alzheimer's and Parkinson's disease[86] and [87].

6.1. Lipids in people with MS and comparison with healthy populations

We could not identify any studies that examined the risk of MS in people with dyslipidaemia (HDL below 1.3 mmol/L, LDL above 4.1 mmol/L, triglycerides above 2.3 mmol/L). However a number of studies were found which compared lipid profiles between MS cases and controls. Table 3 provides a summary of the studies that examined the lipid profile in people with MS compared with healthy populations. Generally, a more adverse lipid profile among MS cases was observed in some studies, but this was not consistently found. For example, some studies have shown significantly elevated total cholesterol in people with MS compared to healthy controls[8], [88], and [89], while other studies found no difference in total cholesterol levels[18], [90], and [91]. Similarly some studies reported higher LDL levels in people with MS compared with healthy controls [89] while other studies did not find any significant difference in LDL levels[8], [18], and [88]. Likewise, HDL concentrations have been found to be higher in MS cases compared with controls[8], [88], and [91], but other studies did not find any significant differences[18] and [89]. Triglycerides levels were also higher in MS cases compared to healthy control in some studies but did not find any significant differences[18], [88], [89], [90], and [91]. A study by Sternberg and colleagues which compared the lipid profile difference between MS patients who were on disease modifying therapies (DMTs-users) and DMTs-naïve demonstrated a significantly higher HDL in DMTs-users compared to DMTs-naïve. The level of TC and LDL were higher in DMTs-users but not significantly different [48] .

Table 3 Studies examining the serum lipid profile in people with multiple sclerosis.

Author Study information Outcome measure of interest Main findings
Guibilei and colleagues, (2002) [88] Case–control, 18 MS cases & 18 controls Lipid profile differences between cases and controls & Correlation between lipid profile and CEL 1. TC significantly higher in cases than controls

2. LDL, Trig & ApoE higher in cases than controls but the difference not significant.

3. TC and LDL correlated significantly with CEL number
Salemi and colleagues, (2010) [91] Case–control, 40 MS cases & 80 controls Lipid profile differences between cases and controls 1. HDL significantly higher in cases than controls

2. TC & Trig higher in cases than controls but differences not significant
Jamroz-Wisniewska and colleagues, (2009) [89] Case–control, 82 RRMS, 55 progressive MS & 40 controls Lipid profile differences between cases and controls 1. TC significantly higher in cases than controls.

2. LDL significantly higher in RRMS in remission and progressive MS than controls

3. HDL higher in cases than controls but difference not significant
Sternberg and colleagues, (2013) [8] Case–control, 206 MS cases & 142 controls Lipid profile differences between cases and controls 1. TC and HDL significantly higher in cases than non-MS patients used us controls.

2. LDL & Trig higher in MS cases than controls but difference not significant
Palavra and colleagues, (2013) [90] Case–control, 30 MS cases & 66 controls Lipid profile differences between cases and controls & Correlation between lipid profile and EDSS 1. Trig, Ox-LDL & small HDL particles higher in MS cases than control

2. LDL significantly lower in MS cases than controls

3. TC, LDL & Ox-LDL significantly correlated positively with EDSS
Çomoğlu and colleagues, (2004) Case–control, 22 MS cases & 16 healthy controls Lipid profile differences between cases and controls 1. Trig & VLDL were significantly higher in MS cases than the healthy controls

2. TC & LDL higher in cases than controls but difference not significant.

3. LDL/HDL significantly higher in cases (male) than the controls (males)
Weinstock-Guttman and colleagues, (2011) [34] Cohort study, 178 CDMS patients EDSS and MSSS 1. EDSS associated with TC/HDL ratio

2. No association between EDSS & MSSS and the other lipid variables
Weinstock-Guttman and colleagues, (2011) [92] Cohort study, 492 CDMS patients EDSS, MSSS CHEDSS, CHMSSS, and T1-LV, T2-LV lesions, CEL, CE-LV and BPF. 1. Trend of association between lipid variables and EDSS, MSSS, CHEDSS and CHMSSS

3. Associations between lipids variables and CEL, CE-LV and BPF

5. No association between lipid variables, BMI and T1-LV & T2-LV
Weinstock-Guttman and colleagues, (2013) [93] Cohort study, 135 CIS patients Relapse, MRI measures 1. TC & LDL associated with increased cumulative number of new T2 lesions.

2. Trend of association of TC & LDL with lower baseline whole brain volume.

3. Trend of association between TC and CEL. Other lipids were not associated with CEL

Abbreviations: TC: total cholesterol; LDL: low density lipoprotein; Ox-LDL: oxidised LDL; HDL; high density lipoprotein; Trig: triglycerides; VLDL: very low density lipoprotein; EDSS: expanded disability status scale; CHEDSS: change in EDSS; MSSS: multiple sclerosis severity score; CHMSSS: change in MSSS; CDMS: clinically definite MS; CIS: clinical isolated syndrome CEL: contrast enhancing lesions; T1-LV: T1 lesion volume; T2-LV: T2 lesion volume; BPF: brain parenchyma fraction.

Further to this, contrasting results also exist showing that dyslipidaemia is more frequent in people with MS compared with healthy controls. Lavela and colleagues [52] reported a significantly higher prevalence of dyslipidaemia in 1142 male veterans with MS (48.5%) compared to 31,500 non-MS veterans (44.6%). Similarly Kang and colleagues [45] reported significantly higher (p < 0.001) dyslipidaemia in 898 MS cases (14%) compared to 4490 controls (6.9%). However, significantly (p < 0.05) lower prevalence of dyslipidaemia was reported in 9949 MS cases (3.0%) compared to 19,898 controls (5.1%) by Allen and colleagues [19] .

The disparities in the lipid profile could stem from differences in the [49] use of DMTs and other unrelated MS pharmacological agents which has been shown to modulate the lipid profiles [48] . The disparity in dyslipidaemia and lipid profile between the studies examined above could also be due to difference in what constitute a dyslipidaemia (cut off point), difference in population and age of MS patients recruited in the various studies.

6.2. Lipids and MS disability

A number of studies have been conducted to determine the impact of serum lipids on disability and disease progression. Using a time-to-event analysis model in the large NARCOMS registry, Marrie and colleagues reported that the presence of hypercholesterolemia (higher LDL and lower HDL) at any time during the disease course was associated with 35% increased risk of early gait disability (HR: 1.35; 95% CI: 1.26-1.45), 33% increased risk of unilateral walking assistance (HR: 1.33; 95% CI: 1.23-1.44) and 24% increased risk of bilateral walking assistance (HR: 1.24; 95% CI: 1.11-1.39) [6] . Similarly, hypercholesterolemia was associated with 83% (HR: 1.83 (1.67-2.01) increased risk of mild visual disability, 75% (HR: 1.75 (1.52-2.01) increased risk of moderate visual disability and 59% increased risk of visual disability (HR: 1.59 (1.23-2.06) [49] .

In a study by Palavra and colleagues [90] , total cholesterol (r = 0.40, p = 0.027), LDL (r = 0.37, p = 0.05) and oxidised-LDL (r = 0.46, p = 0.01) were positively correlated with EDSS. In a study [34] looking at the association between vitamin D and serum lipid profiles in a population of 178 MS patients, total cholesterol/HDL ratio was associated with higher EDSS (r = 0.21, p = 0.008). In our own work [29] , TC (p = 0.037), apolipoprotein B (ApoB) (p = 0.003), and the apolipoprotein B to apolipoprotein A-I ratio (ApoB/ApoA-I ratio) (p = 0.018) were independently associated with a higher EDSS.

In terms of measuring progression of disability as an outcome, Weinstock-Guttman and colleagues [92] assessed the associations of baseline lipid profile with subsequent disability progression. A cohort of 492 participants were followed for an average of 2.2 years and data on EDSS and serum lipids were collected at baseline and after a mean period of 2.2 ± 1.0 years follow-up. They found that higher baseline total cholesterol (partial correlation coefficient (rp) = 0.15, p = 0.001), LDL (rp = 0.13, p = 0.006), triglycerides (rp = 0.10, p = 0.025), total cholesterol/HDL ratio (rp = 0.091, p = 0.005) were significantly associated with a greater increase in EDSS. We [29] also investigated the relationship between the lipid profile and disability progression and reported that TC to HDL ratio (TC/HDL ratio) was prospectively associated with progression in clinical disability (p = 0.029) as measured by annual change in EDSS.

Results from these studies suggest a possible relationship between adverse lipid profile, disability and disease progression. However, data on these relationships, particularly the prospective data, are limited and requires further investigation.

6.3. Serum lipids and inflammatory activity in MS

Studies have been conducted to determine whether any relationship exists between serum lipid profile and inflammatory activity as evidenced by MRI. Weinstock-Guttman and colleagues [92] found that higher levels of HDL were associated with a reduced likelihood of having contrast-enhancing lesions (p = 0.01) and with a reduced lesion volume when they did occur (p < 0.001). Higher levels of triglyceride and total cholesterol/HDL ratio were associated with a greater likelihood of having contrast-enhancing lesions (p = 0.038) and lesion volume (p = 0.023). Giubilei and colleagues [88] also reported that higher levels of total cholesterol (r = 0.59, p = 0.01) and LDL (r = 0.54, p = 0.02) were associated with a greater number of contrast-enhancing lesions. In a cohort of participants with clinically isolated syndromes, Weinstock-Guttman and colleagues [93] also observed that higher LDL (p = 0.006) and total cholesterol (p = 0.001) levels were associated with increased cumulative number of new T2 lesions over 2 years. From the MRI studies examined above, individuals with an adverse lipid profile had higher number of inflammatory lesions on MRI in clinically isolated syndromes or clinically definite MS. Since contrast-enhancing lesions represent recent inflammatory activity, their association with serum lipid profile in both early and established MS may be an indication of a causal relationship. However, whether maintaining the lipid profile within a normal range will modulate inflammatory activity is not clear and needs further investigation.

6.4. Clinical trials of statins in MS

Statins are a class of lipid-lowering drugs which inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the main rate-limiting enzyme in cholesterol biosynthesis. In addition to their lipid-lowering effects, statins have been found to have anti-inflammatory and immunomodulatory properties  [94] . A number of small randomised controlled trials using statins have been conducted in MS patients, though with contradictory results. The first single-arm trial (simvastatin 80 mg/day) in 30 RRMS cases found a decrease in gadolinium-enhancing lesion number (44%) and volume (41%) compared to pre-treatment [95] . A recent double-blind placebo-controlled trial in secondary-progressive MS cases with simvastatin found that those on simvastatin had a 43% reduction in brain atrophy compared to the placebo group and a 40% reduction in the rate of disability progression between the active and control arms. [96] The ACTIVE study [97] and others[98] and [99]reported a protective effect of statin.

However, others found no evidence of a protective effect of statin therapy. A post-hoc analysis of the SENTINEL trial in RRMS patients (natalizumab plus interferon-beta-1a (n = 40) vs. placebo plus interferon-beta (n = 542)) found no differences in relapse rate, disability progression or number of gadolinium-enhancing lesions between those using statins and those not [100] . The SIMCOMBIN trial [101] , STAyCIS study [102] , and others[103] and [104]found no evidence of therapeutic effect of statin.

The inconsistencies in the trial results calls for further research into the role of serum lipids in the pathogenesis of MS and obtaining a mechanistic understanding of cholesterol metabolism and the role of these pathways in MS. Understanding these mechanisms can inform as to the potential benefits of lipid-lowering drugs for MS in the future, which may be critical in designing future randomised controlled trials.

6.5. Summary: lipid profile and MS

Results from the case–control studies examined above were largely inconsistent but the best-designed studies showed slightly elevated total cholesterol and HDL in MS cases compared to the controls. In the longitudinal and cross-sectional studies, higher levels of HDL were associated with lower acute inflammatory activity on MRI and lower MS disability, which is consistent with the antioxidant and anti-inflammatory properties of HDL. While MS cases may be expected to have lower levels of HDL than controls, the high concentrations observed may be due to their increased role in the antioxidant and anti-inflammatory activities and reverse cholesterol transfer in MS. This contradiction therefore calls for further investigation to provide a consistent body of knowledge on the relationship between serum lipids and MS in both longitudinal and case–control studies.

On the whole, evidence from the studies examined above suggest a negative impact of high LDL and triglycerides on acute inflammatory activity and disease course in MS patients and a beneficial effect of higher HDL levels on MS. Holistically, the prevalence of dyslipidaemia and its association with disability may be an indication that the serum lipid profile could be a potential target for reducing or modulating the rate of disability progression. However, the results of the statin clinical trials on MS have been contradictory and needs further investigation to explore their potential benefits.

7. Conclusions, implications and recommendations

There is a growing body of evidence to indicate that MS is associated with vascular comorbidities such as obesity, type-2 diabetes, cardiovascular diseases and dyslipidaemia in a number of different ways. In relation to MS risk, there is evidence that high childhood/adolescent BMI, but not adult BMI is associated with MS, but it is unclear whether this is due to confounding by other factors like sun and/or vitamin D. The other factors show some indirect evidence of an association with MS, but the directionality of these associations, if any, is unclear. There is no data on whether type-2 diabetes, cardiovascular disease and dyslipidaemia are more common prior to the disease onset in people with MS compared to controls.

Comparing people with established MS to healthy controls, there is insufficient evidence to suggest that the prevalence of obesity, hypertension or T2D is higher in people with MS, and there is inconsistent evidence around the association with lipids. However, people with MS appear to have a slightly increased risk of cardiovascular disease and they also die more often of cardiovascular disease. The question still remains whether this cardiovascular disease risk develops prior to the MS onset or after. Regardless, it is important from a clinical perspective, as the awareness by neurologists of this issue may assist with the prevention of cardiovascular disease or mortality in people with MS. At a patient level, the identification of personal risk factors of cardiovascular disease, including high BMI, dyslipidaemia, adverse diet, and low physical activity, can inform individual lifestyle modifications or drug treatments.

The presence of vascular comorbidities could increase and complicate the MS disease burden. These comorbidities may be partly responsible for the highly variable inter and intra-personal clinical course of MS. In relation to whether vascular comorbidities influence MS disability and the progression of disability or other aspects of the disease course, the key finding was that having a vascular comorbidity at diagnosis or at any point in the disease course may be associated with a worse progression in disability. In addition, a negative effect of high cholesterol and triglycerides and positive effect of higher HDL levels was observed on acute inflammatory activity, measured by MRI. Little data was available on BMI or T2D and progression. In general, it was clear from our review that prospective studies are sparse.

There are important therapeutic opportunities for lipid lowering drugs. The use of these may be justified when the aim is to reduce a patient's risk of cardiovascular disease. However, the use of these is not yet justified as an intervention in MS. Importantly, that statin trials have produced inconsistent evidence, including negative effects, is critical and may indicate that previous observational studies demonstrating associations may have been confounded. Adverse effects in people with MS are possibly explained by laboratory evidence showing negative impacts of statins on oligodendrocytes and myelin formation. Thus, care needs to be taken when considering the use of statins in the treatment of MS.

We recommend that future studies of the prevalence and effects of vascular comorbidities on MS risk and disability progression should be prospective where relevant and using sufficiently validated means of assessing outcomes and vascular comorbidities, and where possible objectively assessed (e.g. BMI). Studies must separately investigate vascular comorbidities which occur before the onset of MS and those that occur during the course of MS in order to determine those that may be important in the onset or progression of MS and those that merely co-vary with age, decreased physical activity and subsequent increased BMI. This research will hopefully lead to potential interventions that may improve outcomes for persons with MS.

Conflict of interest statement

None of the authors have any financial conflicts to report.

References

  • [1] B.G. Weinshenker, B. Bass, G.P. Rice, J. Noseworthy, W. Carriere, J. Baskerville, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133-146
  • [2] I.S. Haussleiter, M. Brune, G. Juckel. Psychopathology in multiple sclerosis: diagnosis, prevalence and treatment. Ther Adv Neurol Disord. 2009;2:13-29
  • [3] C.A. Young. Factors predisposing to the development of multiple sclerosis. QJM. 2011;104:383-386
  • [4] R.A. Marrie. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol. 2004;3:709-718
  • [5] I.A. van der Mei, S. Simpson Jr., J. Stankovich, B.V. Taylor. Individual and joint action of environmental factors and risk of MS. Neurol Clin. 2011;29:233-255
  • [6] R.A. Marrie, R. Rudick, R. Horwitz, G. Cutter, T. Tyry, D. Campagnolo, et al. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology. 2010;74(13):1041-1047
  • [7] A. Minagar, W. Jy, J.J. Jimenez, J.S. Alexander. Multiple sclerosis as a vascular disease. Neurol Res. 2006;28:230-235
  • [8] Z. Sternberg, C. Leung, D. Sternberg, F. Li, Y. Karmon, K. Chadha, et al. The prevalence of the classical and non-classical cardiovascular risk factors in multiple sclerosis patients. CNS Neurol Disord Drug Targets. 2013;12(1):104-111
  • [9] P. Flachenecker, A. Wolf, M. Krauser, H.P. Hartung, K. Reiners. Cardiovascular autonomic dysfunction in multiple sclerosis: correlation with orthostatic intolerance. J Neurol. 1999;246:578-586
  • [10] R. Marrie, R. Horwitz, G. Cutter, T. Tyry, D. Campagnolo, T. Vollmer. High frequency of adverse health behaviors in multiple sclerosis. Mult Scler. 2009;15:105-113
  • [11] J.N. Slawta, A.R. Wilcox, J.A. McCubbin, D.J. Nalle, S.D. Fox, G. Anderson. Health behaviors, body composition, and coronary heart disease risk in women with multiple sclerosis. Arch Phys Med Rehabil. 2003;84:1823-1830
  • [12] L.A. Pilutti, D. Dlugonski, J.H. Pula, R.W. Motl. Weight status in persons with multiple sclerosis: implications for mobility outcomes. J Obes. 2012;2012:868256
  • [13] L.A. Pilutti, E. McAuley, R.W. Motl. Weight status and disability in multiple sclerosis: an examination of bi-directional associations over a 24-month period. Mult Scler Relat Disord. 2012;1(3):139-144
  • [14] R.A. Marrie, R.I. Horwitz, G. Cutter, T. Tyry, T. Vollmer. Association between comorbidity and clinical characteristics of MS. Acta Neurol Scand. 2011;124:135-141
  • [15] S.R. Khurana, A.M. Bamer, A.P. Turner, R.V. Wadhwani, J.D. Bowen, S.L. Leipertz, et al. The prevalence of overweight and obesity in veterans with multiple sclerosis. Am J Phys Med Rehabil. 2009;88(2):83-91
  • [16] C. Sioka, A. Fotopoulos, A. Georgiou, S. Papakonstantinou, S.-H. Pelidou, A.P. Kyritsis, et al. Body composition in ambulatory patients with multiple sclerosis. J Clin Densitom. 2011;14(4):465-470
  • [17] A. Mähler, J. Steiniger, M. Bock, A.U. Brandt, V. Haas, M. Boschmann, et al. Is metabolic flexibility altered in multiple sclerosis patients?. PLoS ONE. 2012;7(8):e43675
  • [18] S. Çomoğlu, S. Yardimci, Z. Okçu. Body fat distribution and plasma lipid profiles of patients with multiple sclerosis. Turk J Med Sci. 2004;34:43-48
  • [19] N.B. Allen, J.H. Lichtman, H.W. Cohen, J. Fang, L.M. Brass, M.H. Alderman. Vascular disease among hospitalized multiple sclerosis patients. Neuroepidemiology. 2008;30:234-238
  • [20] K.L. Munger, J. Bentzen, B. Laursen, E. Stenager, N. Koch-Henriksen, T. Sorensen, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler. 2013;19(10):1323-1329
  • [21] A. Langer-Gould, S.M. Brara, B.E. Beaber, C. Koebnick. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80:548-552
  • [22] K.L. Munger, T. Chitnis, A. Ascherio. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73:1543-1550
  • [23] A.K. Hedstrom, T. Olsson, L. Alfredsson. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler. 2012;18:1334-1336
  • [24] I. Sioen, T. Mouratidou, J.M. Kaufman, K. Bammann, N. Michels, I. Pigeot, et al. Determinants of vitamin D status in young children: results from the Belgian arm of the IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants) Study. Public Health Nutr. 2012;15(6):1093-1099
  • [25] R.M. Daly, C. Gagnon, Z.X. Lu, D.J. Magliano, D.W. Dunstan, K.A. Sikaris, et al. Prevalence of vitamin D deficiency and its determinants in Australian adults aged 25 years and older: a national, population-based study. Clin Endocrinol (Oxf). 2012;77(1):26-35
  • [26] R.M. Lucas, A.L. Ponsonby, K. Dear, P.C. Valery, M.P. Pender, B.V. Taylor, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76(6):540-548
  • [27] K.L. Munger, L.I. Levin, B.W. Hollis, N.S. Howard, A. Ascherio. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832-2838
  • [28] I.A. van der Mei, A.L. Ponsonby, T. Dwyer, L. Blizzard, R. Simmons, B.V. Taylor, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case–control study. BMJ. 2003;327(7410):316
  • [29] P. Tettey, S. Simpson Jr., B. Taylor, L. Blizzard, A.L. Ponsonby, T. Dwyer, et al. An adverse lipid profile is associated with disability and progression in disability, in people with MS. Mult Scler. 2014;
  • [30] P. Tettey, S. Simpson Jr., B. Taylor, L. Blizzard, A.L. Ponsonby, T. Dwyer, et al. Adverse lipid profile is not associated with relapse risk in MS: results from an observational cohort study. J Neurol Sci. 2014;340(1–2):230-232
  • [31] F.J. Elgar, J.M. Stewart. Validity of self-report screening for overweight and obesity. Evidence from the Canadian Community Health Survey. Can J Public Health. 2008;99:423-427
  • [32] U. Korsten-Reck, K. Kromeyer-Hauschild, K. Korsten, M.W. Baumstark, H.H. Dickhuth, A. Berg. Frequency of secondary dyslipidemia in obese children. Vasc Health Risk Manag. 2008;4:1089-1094
  • [33] B. Klop, J.W. Elte, M.C. Cabezas. Dyslipidemia in obesity: mechanisms and potential targets. Nutrients. 2013;5:1218-1240
  • [34] B. Weinstock-Guttman, R. Zivadinov, M. Ramanathan. Inter-dependence of vitamin D levels with serum lipid profiles in multiple sclerosis. J Neurol Sci. 2011;311:86-91
  • [35] B. Weinstock-Guttman, R. Zivadinov, D. Horakova, et al. Lipid profiles are associated with lesion formation over 24 months in interferon-beta treated patients following the first demyelinating event. J Neurol Neurosurg Psychiatry. 2013;84:1186-1191
  • [36] J.M. Lemire. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 1995;53:599-602
  • [37] T. Sathyapalan, J. Shepherd, C. Arnett, A.M. Coady, E.S. Kilpatrick, S.L. Atkin. Atorvastatin increases 25-hydroxy vitamin D concentrations in patients with polycystic ovary syndrome. Clin Chem. 2010;56:1696-1700
  • [38] M. Maffei, J. Halaas, E. Ravussin, R.E. Pratley, G.H. Lee, Y. Zhang, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1(11):1155-1161
  • [39] V. Mohamed-Ali, S. Goodrick, A. Rawesh, D.R. Katz, J.M. Miles, J.S. Yudkin, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82(12):4196-4200
  • [40] V. De Rosa, C. Procaccini, G. Cali, G. Pirozzi, S. Fontana, S. Zappacosta, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007;26(2):241-255
  • [41] G. Matarese, P.B. Carrieri, A. La Cava, F. Perna, V. Sanna, V. De Rosa, et al. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25 + regulatory T cells. Proc Natl Acad Sci U S A. 2005;102(14):5150-5155
  • [42] G.M. Lord, G. Matarese, J.K. Howard, R.J. Baker, S.R. Bloom, R.I. Lechler. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998;394:897-901
  • [43] J.M. Fletcher, S.J. Lalor, C.M. Sweeney, N. Tubridy, K.H. Mills. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162:1-11
  • [44] W.I. Hussein, S.S. Reddy. Prevalence of diabetes in patients with multiple sclerosis. Diabetes Care. 2006;29:1984-1985
  • [45] J.H. Kang, Y.H. Chen, H.C. Lin. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. Eur J Neurol. 2010;17:1215-1219
  • [46] R.A. Marrie, B.N. Yu, S. Leung, L. Elliott, P. Caetano, S. Warren, et al. Rising prevalence of vascular comorbidities in multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and hyperlipidemia. Mult Scler. 2012;18(9):1310-1319
  • [47] S.T. Fleming, R.L. Blake Jr. Patterns of comorbidity in elderly patients with multiple sclerosis. J Clin Epidemiol. 1994;47:1127-1132
  • [48] Z. Sternberg, C. Leung, D. Sternberg, J. Yu, D. Hojnacki. Disease modifying therapies modulate cardiovascular risk factors in patients with multiple sclerosis. Cardiovasc Ther. 2014;32:33-39
  • [49] R.A. Marrie, G. Cutter, T. Tyry. Substantial adverse association of visual and vascular comorbidities on visual disability in multiple sclerosis. Mult Scler. 2011;17:1464-1471
  • [50] E. Wong, K. Backholer, E. Gearon, J. Harding, R. Freak-Poli, C. Stevenson, et al. Diabetes and risk of physical disability in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013;1(2):106-114
  • [51] S. Tesfaye, D. Selvarajah. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2012;28(Suppl. 1):8-14
  • [52] S.L. Lavela, T.R. Prohaska, S. Furner, F.M. Weaver. Chronic diseases in male veterans with multiple sclerosis. Prev Chronic Dis. 2012;9:E55
  • [53] E.O. Sanya, M. Tutaj, C.M. Brown, N. Goel, B. Neundorfer, M.J. Hilz. Abnormal heart rate and blood pressure responses to baroreflex stimulation in multiple sclerosis patients. Clin Auton Res. 2005;15:213-218
  • [54] E. Jadidi, M. Mohammadi, T. Moradi. High risk of cardiovascular diseases after diagnosis of multiple sclerosis. Mult Scler. 2013;
  • [55] I. Hajjar, L. Quach, F. Yang, P.H. Chaves, A.B. Newman, K. Mukamal, et al. Hypertension, white matter hyperintensities, and concurrent impairments in mobility, cognition, and mood: the Cardiovascular Health Study. Circulation. 2011;123(8):858-865
  • [56] C. Rosano, W.T. Longstreth Jr., R. Boudreau, C.A. Taylor, Y. Du, L.H. Kuller, et al. High blood pressure accelerates gait slowing in well-functioning older adults over 18-years of follow-up. J Am Geriatr Soc. 2011;59(3):390-397
  • [57] K.R. Merikangas, M. Ames, L. Cui, P.E. Stang, T.B. Ustun, M. Von Korff, et al. The impact of comorbidity of mental and physical conditions on role disability in the US adult household population. Arch Gen Psychiatry. 2007;64(10):1180-1188
  • [58] D.D. Dunlop, L.M. Manheim, M.W. Sohn, X. Liu, R.W. Chang. Incidence of functional limitation in older adults: the impact of gender, race, and chronic conditions. Arch Phys Med Rehabil. 2002;83:964-971
  • [59] O. McDaid, M.J. Hanly, K. Richardson, F. Kee, R.A. Kenny, G.M. Savva. The effect of multiple chronic conditions on self-rated health, disability and quality of life among the older populations of Northern Ireland and the Republic of Ireland: a comparison of two nationally representative cross-sectional surveys. BMJ Open. 2013;3
  • [60] R. Gijsen, N. Hoeymans, F.G. Schellevis, D. Ruwaard, W.A. Satariano, G.A. van den Bos. Causes and consequences of comorbidity: a review. J Clin Epidemiol. 2001;54:661-674
  • [61] N. Koch-Henriksen, H. Bronnum-Hansen, E. Stenager. Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish Multiple Sclerosis Registry. J Neurol Neurosurg Psychiatry. 1998;65:56-59
  • [62] H. Bronnum-Hansen, N. Koch-Henriksen, E. Stenager. Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain. 2004;127:844-850
  • [63] C. Hirst, R. Swingler, D.A. Compston, Y. Ben-Shlomo, N.P. Robertson. Survival and cause of death in multiple sclerosis: a prospective population-based study. J Neurol Neurosurg Psychiatry. 2008;79:1016-1021
  • [64] C.F. Christiansen, S. Christensen, D.K. Farkas, M. Miret, H.T. Sorensen, L. Pedersen. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology. 2010;35:267-274
  • [65] R.A. Marrie, B.N. Yu, S. Leung, L. Elliott, P. Caetano, S. Warren, et al. Prevalence and incidence of ischemic heart disease in multiple sclerosis: a population-based validation study. Mult Scler Relat Disord. 2013;2(4):355-361
  • [66] I. Adamec, M. Habek. Autonomic dysfunction in multiple sclerosis. Clin Neurol Neurosurg. 2013;115(Suppl. 1):S73-S78
  • [67] A. Saari, U. Tolonen, E. Paakko, et al. Cardiovascular autonomic dysfunction correlates with brain MRI lesion load in MS. Clin Neurophysiol. 2004;115:1473-1478
  • [68] L. Wei, T.M. MacDonald, B.R. Walker. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004;141:764-770
  • [69] T.J. Murray. The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks?. Expert Opin Drug Saf. 2006;5:265-274
  • [70] R.A. Marrie, R. Horwitz, G. Cutter, T. Tyry, D. Campagnolo, T. Vollmer. Comorbidity delays diagnosis and increases disability at diagnosis in MS. Neurology. 2009;72:117-124
  • [71] A.L. Jefferson, J.M. Massaro, P.A. Wolf, et al. Inflammatory biomarkers are associated with total brain volume: the Framingham Heart Study. Neurology. 2007;68:1032-1038
  • [72] J.S. Alexander, R. Zivadinov, A.H. Maghzi, V.C. Ganta, M.K. Harris, A. Minagar. Multiple sclerosis and cerebral endothelial dysfunction: mechanisms. Pathophysiology. 2011;18:3-12
  • [73] J.J. Geurts, P.K. Stys, A. Minagar, S. Amor, R. Zivadinov. Gray matter pathology in (chronic) MS: modern views on an early observation. J Neurol Sci. 2009;282:12-20
  • [74] A. Minagar, J.S. Alexander. Blood–brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9:540-549
  • [75] M. Orth, S. Bellosta. Cholesterol: its regulation and role in central nervous system disorders. Cholesterol. 2012;2012:292598
  • [76] G. Saher, S. Quintes, K.A. Nave. Cholesterol: a novel regulatory role in myelin formation. Neuroscientist. 2011;17:79-93
  • [77] Z. Balazs, U. Panzenboeck, A. Hammer, et al. Uptake and transport of high-density lipoprotein (HDL) and HDL-associated alpha-tocopherol by an in vitro blood–brain barrier model. J Neurochem. 2004;89:939-950
  • [78] I. Borghini, F. Barja, D. Pometta, R.W. James. Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid. Biochim Biophys Acta. 1995;1255:192-200
  • [79] J. Newcombe, H. Li, M.L. Cuzner. Low density lipoprotein uptake by macrophages in multiple sclerosis plaques: implications for pathogenesis. Neuropathol Appl Neurobiol. 1994;20:152-162
  • [80] L. Goedeke, C. Fernandez-Hernando. Regulation of cholesterol homeostasis. Cell Mol Life Sci. 2012;69:915-930
  • [81] I. Bjorkhem, D. Lutjohann, U. Diczfalusy, L. Stahle, G. Ahlborg, J. Wahren. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res. 1998;39:1594-1600
  • [82] D. Lutjohann, O. Breuer, G. Ahlborg, et al. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A. 1996;93:9799-9804
  • [83] A.I. Bush. Metals and neuroscience. Curr Opin Chem Biol. 2000;4:184-191
  • [84] H.T. Besler, S. Comoglu. Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis. Nutr Neurosci. 2003;6:189-196
  • [85] R.M. Adibhatla, J.F. Hatcher. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2010;12:125-169
  • [86] R.M. Adibhatla, J.F. Hatcher. Role of lipids in brain injury and diseases. Futur Lipidol. 2007;2:403-422
  • [87] S. Tsimikas, Y.I. Miller. Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des. 2011;17:27-37
  • [88] F. Giubilei, G. Antonini, S. Di Legge, et al. Blood cholesterol and MRI activity in first clinical episode suggestive of multiple sclerosis. Acta Neurol Scand. 2002;106:109-112
  • [89] A. Jamroz-Wisniewska, J. Beltowski, Z. Stelmasiak, H. Bartosik-Psujek. Paraoxonase 1 activity in different types of multiple sclerosis. Mult Scler. 2009;15:399-402
  • [90] F. Palavra, D. Marado, F. Mascarenhas-Melo, et al. New markers of early cardiovascular risk in multiple sclerosis patients: oxidized-LDL correlates with clinical staging. Dis Markers. 2013;34:341-348
  • [91] G. Salemi, M. Gueli, F. Vitale, et al. Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients. Lipids Health Dis. 2010;9:19
  • [92] B. Weinstock-Guttman, R. Zivadinov, N. Mahfooz, et al. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J Neuroinflammation. 2011;8:127
  • [93] B. Weinstock-Guttman, R. Zivadinov, D. Horakova, E. Havrdova, J. Qu, G. Shyh, et al. Lipid profiles are associated with lesion formation over 24 months in interferon-beta treated patients following the first demyelinating event. J Neurol Neurosurg Psychiatry. 2013;
  • [94] S. Bhardwaj, C.I. Coleman, D.M. Sobieraj. Efficacy of statins in combination with interferon therapy in multiple sclerosis: a meta-analysis. Am J Health Syst Pharm. 2012;69:1494-1499
  • [95] T. Vollmer, L. Key, V. Durkalski, et al. Oral simvastatin treatment in relapsing–remitting multiple sclerosis. Lancet. 2004;363:1607-1608
  • [96] J. Chataway, N. Schuerer, A. Alsanousi, et al. THE MS-STAT TRIAL: high dose simvastatin slows brain atrophy and delays disability in secondary progressive multiple sclerosis: a Phase II placebo-controlled trial [abstract]. Neurology. 2013;80:PL02.001
  • [97] R. Lanzillo, G. Orefice, M. Quarantelli, et al. Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing–remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy. Mult Scler. 2010;16:450-454
  • [98] F. Paul, S. Waiczies, J. Wuerfel, et al. Oral high-dose atorvastatin treatment in relapsing–remitting multiple sclerosis. PLoS ONE. 2008;3:e1928
  • [99] M. Togha, S.A. Karvigh, M. Nabavi, et al. Simvastatin treatment in patients with relapsing–remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial. Mult Scler. 2010;16:848-854
  • [100] R.A. Rudick, A. Pace, M.R. Rani, et al. Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a. Neurology. 2009;72:1989-1993
  • [101] P.S. Sorensen, J. Lycke, J.P. Eralinna, et al. Simvastatin as add-on therapy to interferon beta-1a for relapsing–remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10:691-701
  • [102] E. Waubant, D. Pelletier, M. Mass, et al. Randomized controlled trial of atorvastatin in clinically isolated syndrome: the STAyCIS study. Neurology. 2012;78:1171-1178
  • [103] C.P. Kamm, M. El-Koussy, S. Humpert, et al. Atorvastatin added to interferon beta for relapsing multiple sclerosis: a randomized controlled trial. J Neurol. 2012;259:2401-2413
  • [104] G. Birnbaum, B. Cree, I. Altafullah, M. Zinser, A.T. Reder. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology. 2008;71:1390-1395

Footnotes

Menzies Research Institute Tasmania, University of Tasmania, Australia

lowast Corresponding author at: Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS, Australia. Tel.: + 61 03 6226 7710; fax: + 61 03 6226 7704.