Hindawi Publishing Corporation
ISRN Neurology
Volume 2013, Article ID 981070, 6 pages
http://dx.doi.org/10.1155/2013/981070
Clinical Study
Body Mass Index in Multiple Sclerosis: Associations with
CSF Neurotransmitter Metabolite Levels
Manolis Markianos, Maria-Eleftheria Evangelopoulos, Georgios Koutsis,
Panagiota Davaki, and Constantinos Sfagos
Department of Neurology, Eginition Hospital, Athens University Medical School, Vassilissis Sophias 74, 11528 Athens, Greece
Correspondence should be addressed to Manolis Markianos; markian@otenet.gr
Received 11 July 2013; Accepted 19 August 2013
Academic Editors: D. Mathieu, T. Mezaki, D. Schiffer, and E. M. Wassermann
Copyright © 2013 Manolis Markianos et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting
MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212
females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG),
serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for
associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was
found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration
of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in
MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA
and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process
in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in
impairments in food reward capacity and in motivation to eat.
1. Introduction
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. Although viral and genetic
factors have been postulated to trigger the autoimmune
process, the pathogenetic mechanisms regulating the disease
course remain unknown. Increasing amount of evidence
suggests that physical comorbidities as well as adverse health
factors might affect the disease course [1].
The impact of nutrition and diet in the aetiology and
management of MS has been investigated in a large number
of studies [2–6], but with only a limited number reported on
body mass index (BMI) in MS. Ghadirian et al. [3] found
an inverse association between high BMI and the risk of
MS. The difference in BMI was significant for the whole
sample and for female MS patients compared to controls,
while it did not reach significance for males. Formica et al.
[7] reported a lower BMI in women with MS compared to
female controls, and Nortvedt et al. [8] reported significantly
lower BMI of MS patients (75% females) compared to the
general population. Similarly, Alschuler et al. [9] reported
lower BMI in a large number (𝑛 = 597) of patients with MS in
relation to general population. On the other hand, Khurana
et al. [10] reported an increased prevalence of overweight and
obesity in a large sample of older veterans with MS (mean
age 59.6 ± 11.9), predominantly males (86.7%). In their study
of mobility problems in MS patients from five European
countries, Pike et al. [11] reported a mean BMI of 23.9 for
a sample of 3572 patients (36% males) over 18 years of age,
4.6 mean number of years since diagnosis. Munger et al. [12]
found increased risk for MS in females who have been obese
at adolescence but no association of disease risk with adult
BMI. Similarly, Hedstrom et al. [13] reported no differences
in BMI between MS patients and controls, but they found
that subjects who reported body weight at age 20 that gave a
BMI over 25 had higher risk for developing MS. Overweight
in adolescence was considered as a predisposing factor in
developing MS, although at disease onset, patients seem to
have normal weight or even to be underweighted, especially
female patients. This may indicate that not being overweight
2
at adolescence but losing weight after adolescence may be
the predisposing factor. At any case, it is an open question if
BMI is normal at disease onset and reductions develop during
disease course.
Regulation of food intake is a highly complex process
involving many hormonal and neuropeptide pathways,
including monoamine neurotransmitters [14]. Increases in
dopamine (DA) signaling promote feeding, with leptin and
insulin inhibiting and ghrelin activating dopamine neurons,
while too much dopamine signaling seems to inhibit feeding
[15]. Experimental models with dopamine deficient mice
have demonstrated that these animals are aphagic and do not
survive unless DA synthesis is restored [16, 17]. Dopamine
seems to energize feeding and to reinforce food-seeking
behavior, while food reward elevates dopamine levels [18].
In a recent study [19], we reported that subjects in the
upper BMI quartile show higher levels of the serotonin and
dopamine metabolites 5-hydroxyindoleacetic acid (5-HIAA)
and homovanillic acid (HVA) than subjects in the lower and
middle quartiles, indicating an association of higher serotonin and dopamine turnover with overweight. No differences were found in the levels of the noradrenaline metabolite
methoxyhydroxyphenylglycol (MHPG). We had previously
reported changes in CSF MHPG, 5-HIAA, and HVA levels in
MS patients during disease course, possibly relevant regarding BMI [20].
The aim of the present study was (a) to compare BMI of
MS patients presenting to a neurologic clinic, diagnosed as
having clinically isolated syndrome (CIS) or relapsing-remitting MS, to BMI of subjects free from any major neurological
disease and (b) to search for possible associations of the CSF
levels of the main metabolites of noradrenaline, serotonin,
and dopamine in patients who were drug-free at assessment
with BMI.
2. Subjects and Methods
Four hundred and sixty-nine patients (154 males and 315
females) satisfying the revised McDonald criteria for MS or
possible MS [21] and 358 controls (146 males and 212 females),
within the age range of 18 to 60 years, were included in
the study. Two hundred and sixty patients (55.4%), 83 males
and 177 females, were drug-free at assessment. Patients on
medication were included in comparing BMI in order to
have a more representative sample, and possible influences
of drug treatment on BMI were statistically evaluated. Only a
small number of subjects, who at the time of evaluation were
on treatment with atypical neuroleptics that are expected to
strongly influence body weight [22], were not included in the
study.
Two hundred and ten patients (75 males and 135 females)
had clinically isolated syndrome (CIS) suggestive of MS,
and 259 patients (79 males and 180 females) had relapsingremitting MS. Duration of illness ranged from 0.1 to 480
months, and score in the Expanded Disability Status Scale
(EDSS) ranged from zero to 6.0.
A control group in the same age range to the patients
(18 to 60 years) was built from (a) 194 subjects (90 males
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and 104 females), admitted to the hospital for diagnostic
investigations and found not to suffer from any major neurological disease, and (b) 164 healthy subjects (56 males and 108
females). The data of these two subgroups were merged after
it was found that there were no differences in BMI (26.1 ±
4.0 and 26.7 ± 4.2 for males and 25.0 ± 4.5 and 25.8 ± 4.8
for females), to build a control group of 146 males and 212
females. Written informed consent was obtained from all
subjects, and the study was approved by the Ethics Committee
of the hospital.
Lumbar puncture was performed for diagnostic reasons
in the lateral recumbent position between L3 and L4 or L4 and
L5. The CSF fraction from the third to fifth milliliter was used
for estimation of the metabolites. It was centrifuged at 1500 g
for 15 min to remove cells and kept at −30∘ C until analysis,
which was performed within 3 months from sampling.
The levels of the neurotransmitter metabolites were estimated by HPLC with electrochemical detection, all three
in the same run. A 4.6 mm column was used (Spherisorb
ODS2, Waters, Milford, MA, USA), and the mobile phase
consisted of acetate buffer, pH 5.2, with 10% methanol. For
each sample an aliquot of CSF was directly injected into the
HPLC system and subsequently a second aliquot with added
standards corresponding to 5 ng/mL for MHPG, 10 ng/mL
for 5-HIAA, and 20 ng/mL for HVA in the CSF sample. The
concentrations of the metabolites were calculated from the
differences in peak heights between the sample with and the
sample without standards. For this part of the study, we only
included patients who were drug-free for at least two weeks at
the time of lumbar puncture, namely, 89 from the 145 males
and 158 from the 285 females.
Body mass index (weight in kilograms divided by the
square of height in meters) was calculated using self-reported
height and weight. Smoking history and numbers of cigarettes
per day were registered.
A multiple regression analysis was performed in searching for associations of clinical variables with BMI. Patients
were assigned in subgroups regarding smoking (zero, 5–20,
and >20 cigarettes per day), disease phenotype (CIS, RRMS),
duration of illness (duration up to 3 months, 3 months to 3
years, and more than 3 years), and EDSS score (score zero,
1–3, and 3.5–6.5). Regarding treatment at assessment, patients
were assigned in subgroups taking thyroid hormones (𝑛 =
29), steroids (𝑛 = 53), immunomodulatory agents (𝑛 = 20),
antidepressives (𝑛 = 22), other drugs (𝑛 = 34), and drugfree patients (𝑛 = 301). Previous treatments with steroids
(𝑛 = 199) and with immunomodulatory drugs (𝑛 = 58) were
also used as independent variables.
Since there were significant differences in weight, height,
and BMI between genders in MS patients and in control
subjects, the data were further analyzed separately for males
and females.
Quartile limits for weight, height, and BMI were calculated from male and female control subjects, and patients
were thus assigned to defined quartiles. The differences
of frequencies in lower, two middle, and upper quartiles
between controls and patients were evaluated using the chisquare test. The CSF levels of MHPG, 5-HIAA, and HVA of
drug-free patients assigned to BMI quartiles were compared
ISRN Neurology
3
Table 1: Age, weight (kg), height (cm), and body mass index (means ± SD) in male and female control subjects and patients with MS. Duration
of illness (months) and EDSS score are given for patient groups.
Group
Males
Control
CIS + RRMS
CIS
RRMS
Females
Control
CIS + RRMS
CIS
RRMS
𝑁
Age
Weight
Height
BMI
Duration
EDSS
146
154
75
79
35.9 ± 7.5
33.8 ± 9.3
32.9 ± 8.8
34.7 ± 9.9
81.5 ± 14.6
81.6 ± 12.5
81.4 ± 11.9
81.8 ± 13.2
176 ± 8
178 ± 7
179 ± 7∗
177 ± 7
26.3 ± 4.1
25.7 ± 3.3
25.5 ± 3.2
25.9 ± 3.4
43.5 ± 77.0
5.0 ± 10.1
80.0 ± 93.6
1.9 ± 1.1
1.7 ± 1.0
2.2 ± 1.2
212
315
135
180
36.9 ± 9.4
35.2 ± 9.6
36.0 ± 10.1
34.6 ± 9.2
68.0 ± 13.4
64.3 ± 13.7∗
66.1 ± 15.1
63.0 ± 12.4∗
163 ± 6
166 ± 6∗∗
165 ± 5∗
166 ± 6∗∗
25.5 ± 4.6#
23.4 ± 4.8#∗∗
24.2 ± 5.1∗
22.9 ± 4.4∗∗
42.5 ± 58.5
10.2 ± 31.6
66.7 ± 62.7
1.7 ± 1.2
1.3 ± 1.1
1.9 ± 1.2
∗
CIS: clinically isolated syndrome suggesting of MS; RR: Relapsing-Remitting MS. # Significantly lower compared to males. 𝑃 < 0.05 and
compared to same sex control group (ANOVA with age as covariate).
∗∗
𝑃 < 0.01,
Table 2: Number of subjects in BMI quartiles defined from male controls (BMI limits 23.51 and 27.90) and female controls (BMI limits 21.81
and 28.58). Percent of subjects in parentheses.
Controls
CIS
RRMS
CNTR versus CIS
CNTR versus RRMS
CIS versus RRMS
Lower
37 (25.3)
22 (29.3)
20 (25.3)
Males
2nd + 3rd
73 (50.0)
38 (50.7)
42 (53.2)
Chi-square
0.77
0.35
0.32
separately for males and females, using analysis of variance
with age as covariate.
3. Results
A multiple regression analysis was performed for the whole
patient population (459 patients), with dependent variable
BMI and independent variables sex, age, smoking, disease
phenotype, duration of illness, drug treatment, EDSS score,
previous treatment with steroids, and immunomodulatory
drugs. A regression coefficient 𝑅 = .3358 was calculated,
with 𝐹 = 6.34, df = 9, 449, and 𝑃 < .0001. Significant
associations with BMI were found only for sex (beta =
−0.2293, 𝑃 < .0001) and age (beta = 0.2103, 𝑃 < .0001). For
the total patients’ samples, there were no associations of BMI
with smoking, disease phenotype, duration of illness, drug
treatment, previous treatment, or EDSS score. Moreover,
Spearman correlation coefficient tests did not reveal any
significant associations of BMI or weight with duration of
illness, cigarettes smoked per day, or EDSS score.
The data for age, weight, height, and BMI for male and
female control subjects and MS patients and their evaluation
using ANOVA with age as covariate are presented in Table 1.
Body mass index was higher in males than in females, both
in controls (𝑃 = .04) and patients with MS (𝑃 = .0001).
Upper
36 (24.7)
15 (20.0)
17 (21.5)
𝑃
.68
.85
.85
Lower
53 (25.0)
45 (33.3)
92 (51.1)
Females
2nd + 3rd
105 (50.9)
72 (53.3)
71 (39.4)
Chi-square
6.89
32.74
9.93
Upper
51 (24.1)
18 (13.4)
17 (9.4)
𝑃
.032
.0001
.007
Compared to male controls, male patients did not show
any significant difference for weight, height, or BMI (Table 1).
It is worth to mention, though, the near significance differences in height between CIS and controls (𝑃 = .054). The
group of 310 female patients showed, compared to female
controls, near significance (𝑃 = .09) lower body weight,
significantly greater height (𝑃 = .006), and consequently
lower BMI (𝑃 = .005). When disease phenotypes were
compared to those in control subjects, these differences were
found only for patients with RRMS.
The frequencies of control subjects and MS patients in
BMI quartiles are shown in Table 2. Higher frequencies of
patients with lower BMI values compared to controls were
found for female patients with CIS (𝑃 = .032) or with RRMS
(𝑃 = .0001). The difference in frequencies was also significant
when female patients with CIS were compared to RRMS
females (𝑃 = .007).
CSF levels of noradrenaline, serotonin, and dopamine
metabolites in control-defined BMI quartiles for males and
females are shown in Table 3. Analyses of variance with age
as covariate gave significant differences for 5-HIAA and for
HVA for females and near significance for males. Planned
comparisons between quartiles revealed significantly lower
5-HIAA and HVA levels of patients in the lower quartile
compared to patients in the upper quartile, both for males
4
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Table 3: Levels (ng/mL) of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) metabolites in CSF of drug-free multiple
sclerosis patients, grouped in quartiles according to their body mass index. Quartile limits were defined from BMI of control subjects of the
present study, separate for males and for females. Statistical evaluation by analysis of variance with age as covariate.
BMI quartile
Male patients
Lower
Middle (2nd + 3rd)
Upper
𝐹 (2, 79)
𝑃
Female patients
Lower
Middle (2nd + 3rd)
Upper
𝐹 (2, 173)
𝑃
Lower versus upper, 𝑃
𝑁
BMI
Age
MHPG
5-HIAA
HVA
23
46
14
22.3 ± 1.0
25.7 ± 1.2
30.4 ± 2.2
32.2 ± 8.4
34.8 ± 8.5
32.7 ± 5.2
6.64 ± 1.85
6.16 ± 1.97
6.83 ± 2.68
0.67
.52
12.7 ± 5.9
14.6 ± 7.1
15.4 ± 10.5
0.76
.47
22.6 ± 8.3
24.7 ± 11.4
26.0 ± 12.9
0.54
.58
77
79
21
19.9 ± 1.3
24.2 ± 1.6
33.8 ± 4.4
32.2 ± 7.9
36.6 ± 9.8
38.9 ± 11.0
6.37 ± 1.84
6.69 ± 1.93
7.08 ± 2.25
0.85
.43
.21
15.6 ± 5.6
18.3 ± 7.9
21.5 ± 5.9
5.05
.007
.003
25.8 ± 9.1
31.3 ± 11.6
36.6 ± 16.1
9.50
.0001
.0001
(𝑃 = .02 and 𝑃 = .04, resp.) and females (𝑃 = .008 and 𝑃 =
.001). No differences were found regarding the noradrenaline
metabolite MHPG.
4. Discussion
For the female patient population, significantly lower BMI
was found compared to that of sex and age matched controls.
BMI was not related to duration of disease or EDSS score, but
the fact that the difference from controls was not significant
for subjects with CIS indicates that lower BMI is not present at
disease onset but develops later, during disease progression.
This highly significant difference (𝑃 < .005) in BMI is
the result of higher than expected—compared to controls—
numbers of patients with lower weight and also with greater
height. For male patients, the difference in BMI was not
significant. There was, however, a shift towards greater body
height in patients compared to controls.
Our results regarding BMI are in line with those of
Nortvedt et al. [8], who reported for a mixed population of 22
males and 65 females (75% females) a BMI of 23.5 ± 3.6, with
11% of subjects having BMI below 20. In the present study of
149 males and 310 females (69% females), we calculated for
the total sample a BMI of 24.2 ± 4.5, while 13.6% patients had
BMI below 20.
Lower BMI in MS patients compared to age matched
controls was previously reported also by Ghadirian et al.
[3]. In their study, the difference in BMI was significant for
the whole sample of 61 male and 136 female MS patients
compared to 64 male and 138 female controls, but it did not
reach statistical significance for males. Similar results were
found in the present study. While BMI was significantly lower
in female patients than controls, the difference for the male
population did not reach significance.
An intriguing finding of this study is that body height of
patients with MS tends to be greater than that of controls
(Table 1). Similar findings were reported by Ghadirian et al.
[3]. This finding is of specific interest within the context of
the recent rise in the incidence of MS, observed in several
countries. Increases in height over the last decades have been
observed in most industrialized countries presumably as a
result of better nutrition. It is also notable that the incidence
of MS seems to be increasing among women but not men,
with consequent increases in the female to male sex ratio
[23, 24]. Another point that needs further investigation in MS
is the connection of height growth with autoimmunity, as has
been suggested for diabetes in children [25]. Since height is a
highly heritable trait [26], it would be of interest to compare
the height of patients to the target height calculated from
heights of both parents [27], but such data were not collected
in the present study.
A limitation of the current study is the self-reported
weight and height that may not be accurate. This issue
has been thoroughly studied by Stommel and Schoenborn
[28]. They found that deviations of the self-reported from
measured BMI values depend on many sociodemographic
characteristics, among them sex and age. The most accurate
values are obtained from middle-aged subjects, and deviations are greater at the high and low ends of the BMI
scale. Importantly, self-reported and measured height and
weight were highly correlated. The above mentioned factors
are expected to apply for both patients and controls of the
present case-control study and, taking also into account the
high correlation between self-reported and measured values,
are not expected to influence our results. We consider that
the reliability of our results is increased by using as controls
subjects presenting to the same neurology clinic during the
same time period (several years). In addition, the results of
the present study can be better compared to other studies that
used also self-reported data for BMI [3, 9–13].
Male and female patients of the lower quartile for BMI
were found to have lower CSF 5-HIAA and HVA levels
compared to patients of the upper quartile (Table 3). The role
of dopamine in energizing feeding and food-seeking behavior
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through its participation in brain reward circuits has been
recognized [18, 29]. In addition, Kranz et al. [30] reviewing
electrophysiological, pharmacological, genetic, and imaging
studies postulated a role for serotonin in emotional, motivational, and cognitive aspects of reward representation,
possibly as important as that for dopamine. The lower levels
of HVA and 5-HIAA found in the present study in patients
of the lower BMI quartile compared to patients in the
upper quartile indicate that dopamine and serotonin may be
implicated in food-seeking behavior in MS patients. Further
research on motivation to eat and food reward capacity
may show impairments in subjects predisposed to MS. Food
reward elevates dopamine levels [16], and the low CSF HVA
of subjects in the lower BMI quartile may represent an
impaired dopamine reward system in MS patients. It has to
be mentioned that impairments in neurotransmitter activities
that influence eating behavior may exist with no effect on
appearance or intensity of symptoms that are considered in
scales that evaluate disability, for which other neural systems
are responsible.
It is suggested that humoral factors from the periphery
influence the dopaminergic system and affect food intake,
either stimulating, like ghrelin, or inhibiting dopamine signaling, like leptin or insulin [15]. Serum leptin levels correlate
positively to percentage of body fat and to BMI and are
higher in women than in men, both in normal-weight and
obese subjects [31]. Leptin signals nutritional status to other
physiological systems and modulates their function [32].
When administered to animals, it reduces the activation of
dopaminergic neurons and decreases food intake [33].
Increased leptin levels were found in CSF and serum of
treatment-naı̈ve RR MS patients compared to controls
matched for age, gender, and BMI [34]. It can be hypothesized
that in MS patients, especially in females, increased leptin
production reduces dopamine signaling, thus attenuating the
food reward circuits in the brain.
Payne [35] has reviewed the impact of nutrition on the
aetiology and the rate of disease progression in MS. He
concludes that there is no evidence that nutrition is involved
in the aetiology of MS, while it is unclear whether diet may
influence disease progression, although malnutrition may
contribute to disability, since it is related to muscle weakness
and fatigue. In a recent case-control study, Hedstrom et al.
[13] reported no differences in BMI between MS patients and
controls but found that subjects who reported body weight at
age 20 that gave a BMI over 25 had higher risk for developing
MS. This does not necessarily mean that losing weight may be
beneficial, if the weight at disease onset is not known. Deficits
in serotoninergic and dopaminergic turnovers arise during
disease course [20], and this may influence food reward
capacity, facilitating reductions in body weight. The low levels
of serotonin and dopamine metabolites of subjects in the
lower BMI quartile found in the present study support this
assumption. Our results indicate the need for further studies
with information on BMI at adolescence, at first episode, and
later at definite MS before it can be concluded that overweight
at adolescence is a predisposing factor for MS, and losing
weight may be beneficial.
5
Conflict of Interests
The authors declare that they have no conflict of interests.
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