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Nutritional Neuroscience
An International Journal on Nutrition, Diet and Nervous System
ISSN: 1028-415X (Print) 1476-8305 (Online) Journal homepage: https://www.tandfonline.com/loi/ynns20
Effect of omega-3 fatty acids and fish oil
supplementation on multiple sclerosis: a
systematic review
Welayah Ali AlAmmar, Fatima Hassan Albeesh, Layla Makki Ibrahim, Yasmin
Yussuf Algindan, Lamya Zohair Yamani & Rabie Yousif Khattab
To cite this article: Welayah Ali AlAmmar, Fatima Hassan Albeesh, Layla Makki Ibrahim, Yasmin
Yussuf Algindan, Lamya Zohair Yamani & Rabie Yousif Khattab (2019): Effect of omega-3
fatty acids and fish oil supplementation on multiple sclerosis: a systematic review, Nutritional
Neuroscience, DOI: 10.1080/1028415X.2019.1659560
To link to this article: https://doi.org/10.1080/1028415X.2019.1659560
Published online: 28 Aug 2019.
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REVIEW
Effect of omega-3 fatty acids and fish oil supplementation on multiple sclerosis: a
systematic review
Welayah Ali AlAmmar
a
, Fatima Hassan Albeesh
a
, Layla Makki Ibrahim
a
, Yasmin Yussuf Algindan
a
, Lamya
Zohair Yamani
b
and Rabie Yousif Khattab
a
a
Clinical Nutrition Department, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia;
b
Department of Clinical Laboratory Sciences,
Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
ABSTRACT
Background: Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous
system, resulting in the degradation of the myelin sheath. Diet especially fish oils and omega-3
has been found to play an important role in MS. This work aimed to review the literature
systematically for evidence on the effect of omega-3 fatty acids (EPA, DPA and DHA) on MS
progression in adults.
Methods: The literature search was conducted in PubMed, Oxford, Cochrane, Embase, International
pharmaceutical abstract, PsychINFO, and clinical trials government. The inclusions were studies
performed on humans both male and female, aged 18 years at minimum, diagnosed with MS
according to McDonald 2010 criteria. Otherwise, all studies were excluded.
Results: A total of 5554 studies were screened and seven were thoroughly focused on as they
typically met the inclusion criteria. These studies showed the beneficial roles of fish oil
supplementation and omega-3 fatty acids in improving the quality of life of MS patients. These
roles were attributed to their beneficial effects on inflammatory markers, glutathione reductase,
reducing the relapsing rate, and achieving balanced omega-6 to omega-3 ratios.
Conclusion: Omega-3 and fish oils supplementations have beneficial effects on reducing the
relapsing rate, inflammatory markers, and improving the quality of life for MS patients.
KEYWORDS
Multiple sclerosis; diet;
omega-3; fish oil;
inflammation
List of abbreviations
Definition Abbreviation
α-Linolenic Acid ALA
Annualized Relapse Rate ARR
Arachidonic acid AA
Central Nervous System CNS
Cerebrospinal Fluid CSF
Cyclooxygenase-2 COX-2
Disseminated in Space DIS
Disseminated in Time DIT
Docosahexaenoic Acid DHA
Docosapentaenoic Acid DPA
Eicosapentaenoic Acid EPA
Food Frequency Questionnaire FFQ
Health-Related Quality of Life HRQOL
Interferon Gamma IFN-ϒ
Interleukin-1 Beta IL-1β
Interleukin-10 Il-10
Interleukin-6 IL-6
Linoleic Acid LA
Lipooxygenases LOXs
Magnetic Resonance Imaging MRI
Matrix Metalloproteinase MMP-9
Multiple Sclerosis MS
Not Available N/A
Fatty Acids FAs
Omega 6 n-6
Omega 3 n-3
Poly Unsaturated Fatty Acid PUFA
Glutathione Reductase GR
Primary Progressive Multiple Sclerosis PPMS
Quality of Life QOL
Relapsing Remitting Multiple Sclerosis RRMS
Rheumatoid Arthritis RA
Secondary Progressive Multiple Sclerosis SPMS
Systemic Lupus Erythematosus SLE
Tumor Necrosis Factor-Alpha TNF-α
Introduction
Immune system defenses human body from foreign anti-
gens that may cause infections and diseases. This protec-
tion manages and controls these foreign antigens by
eliminating them in order to restore homeostasis [1]. If
this protective mechanism is unable to distinguish
between self and foreign antigens, the immune system
might initiate an attack against its own cells and tissues
leading to autoimmunity. Autoimmune diseases can be
categorized into two types either being systemic or
organ specific. There are many examples related to auto-
immune disease as type 1 diabetes, rheumatoid arthritis
(RA), celiac disease, systemic lupus erythematosus (SLE)
and multiple sclerosis (MS) [2]. Multiple sclerosis (MS)
is a chronic, neurological, inflammatory, and progressive
© 2019 Informa UK Limited, trading as Taylor & Francis Group
CONTACT Rabie Yousif Khattab rykhattab@iau.edu.sa, khattabry@gmail.com Clinical Nutrition Department, Imam Abdulrahman Bin Faisal University,
Dammam 34212, Saudi Arabia
NUTRITIONAL NEUROSCIENCE
https://doi.org/10.1080/1028415X.2019.1659560
autoimmune disorder that typically affects the central
nervous system of adults in their reproductive years
causing major disabilities that can cause disorganize of
the flow of information within the brain and between
the brain and the body. It is considered the most com-
mon progressive neurologic disease of young adults
worldwide [3,4]. According to the Atlas of MS, 2.3
million people were diagnosed with MS globally in
2013. The incidence may be higher as many people
with MS remain undiagnosed in some regions [5]. The
precise cause of MS remains unknown [6]. However,
research has shown that there are risk factors that may
increase the incidence of MS such as genetics and gender.
Gender is a biological variable that plays a significant role
in immune defense [7]. Men and women differ in their
innate and adaptive immunological responses to foreign
and self-antigens [8]. This can be explained by the hor-
monal changes during puberty, pregnancy, and meno-
pause including estrogen, progesterone and prolactin in
females and androgens in males. Females are at higher
risk of developing MS than males [2]. MS ultimately
affects the neurons. Neurons are surrounded by a fatty
layer known as the myelin sheath. MS leads to demyeli-
nation which is a degradation of the myelin sheath and
transection of neuron axons in patches throughout the
brain and spinal cord resulting in axonal and neuronal
death [9]. MS has different types including relapsing
remitting multiple sclerosis (RRMS) which is the most
common type of MS, the secondary progressive multiple
sclerosis (SPMS) and the primary progressive multiple
sclerosis (PPMS). Symptoms of MS vary from weakness
of the limbs, dysfunction of organs such as bowel or
bladder, mental changes, diplopia, and ataxia [6].
Risk factors that can contribute to neurodegenerative
diseases have been described by the gut-brain axis hypoth-
esis: stress, unbalanced diet, and drugs impact altering
microbiota composition which contributes to dysbiosis
[10,11]. Recent work underlines that diet can positively
change microbiota composition and increase anti-inflam-
matory immune responses [12]. The promising effect of
omega-3 supplementation in shifting gut microbiota bal-
ance towards an eubiosis status has been reported [13].
Studies showed that dietary habits have a predominant
influence on the progression of MS [14]. Proper diet can
improve the health and nutritional status of MS patients
and control the disease or reduce its progression [15].
The effect of diet depends on the amount and type of
food intake. Some nutrients have positive or negative
effects. A healthy diet can help MS patients by positively
affecting gut microbiota [16]. Whole grains and other
high-fiber foods such as vegetables and fruits have protec-
tive effects and can delay the symptoms of MS and
improve bowel movement [17,18]. Moreover, the
consumption of low-fat dairy products containing high
amounts of vitamin D and calcium decreases the risk of
MS. Despite its high amount of heme iron that may help
MS patients through regulating blood hemoglobin levels,
red meat contains the omega-6 poly unsaturated fatty
acid (n-6 PUFA) arachidonic which is the precursor of
inflammatory eicosanoids that can negatively affect MS
progression [14]. A Mediterranean diet, including unpro-
cessed red meat, was associated with reduced risk of a first
clinical diagnosis of central nervous system demyelination
(FCD) in Australian adults. The addition of unprocessed
red meat to a Mediterranean diet may be beneficial for
those at high risk of MS [19]. PUFAs play a key role in
the homeostasis of the immune system in which n-3
PUFAs have anti-inflammatory effect [20,21]. There is a
lot of evidence that confirm the protective and beneficial
effects of omega-3 FAs in inflammatory diseases including
MS [22]. Figure 1 shows the pathway for producing eico-
sanoids of varied properties in the human body from the
two types of fatty acids (n-6 and n-3) [23]. Both linoleic
acid (LA) and α-linolenic acid (ALA) are considered the
primary precursors for this pathway. The body is unable
to convert n-6 into n-3 PUFAs and, therefore, the tissue
levels of these fatty acids and their corresponding eicosa-
noid metabolites link directly to the amount of their diet-
ary consumption [24].
Certain n-6 and n-3 PUFA metabolites have opposing
physiological and pathological activities. Studies suggest
that consuming more PUFAs, especially fish oil and n-3
PUFAs reduces the progression of MS. Increased dietary
intake of n-3 PUFAs (mainly EPA and DHA) has been
associated with a lower production of tumor necrosis
factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and
interleukin-6 (IL-6) and on the other hand, increased
level of the anti-inflammatory cytokine interleukin-10
(il-10) [25–27]. In addition, consumption of omega-3
FAs was highly linked with improving quality of life
(QOL) for MS patients [25]. Oils of certain plants and
nuts, such as flaxseed oil are considered rich dietary
sources for ALA, while fatty fish (e.g. salmon and mack-
erel) are rich dietary sources for EPA, DPA and DHA
[20]. Sorto-Gomez et al. [28]reported the effectiveness
of fish oil supplementation on increasing the glutathione
reductase (GR) which is an important enzyme in MS sta-
tus balance. Various studies suggest consuming more
polyunsaturated fatty acid (PUFAs) especially fish oil
and omega-3 fatty acids to reduce the progression of
MS [25]. This systematic review was conducted to
study the role of omega-3 fatty acids as a potentially pre-
ventive intervention against MS progression in adults. It
was also aimed to investigate how much and which kind
of these components would be protective against MS and
to evaluate the quality of available evidence.
2W. A. ALAMMAR ET AL.
Methodology
Literature search
Different reviewers independently searched the data-
bases covering the literature from 2009 up to 2018.
Search engines that were used included PubMed, Oxford,
Cochrane, Embase, International pharmaceutical
abstract, PsychINFO, and clinical trials government.
Key words and specific terms used in the search along
with the number of studies found are listed in (Table
1). Combination of these terms and filters regarding
study design and type (ie, randomized controlled trial,
cohort study, follow-up study, and controlled clinical
trial) were used to obtain the search results.
Criteria for inclusion and validation of study
sample
In order to provide a focused systematic review,
inclusion and exclusion criteria were developed. Studies
with longitudinal, prospective observational or interven-
tional designs were considered. Studies included were
those performed on humans both male and female
aged 18 years or older, diagnosed with MS according
to McDonald 2010 criteria [29](Figure 2). These studies
were all written in the English language. The excluded
studies, however, were those involving MS patients hav-
ing other issues as chronic diseases, pregnancy, lactation,
physical or mental disabilities, patients with other auto-
immune diseases, or any study that did not particularly
represent the relationship between MS and omega-3
fatty acids.
In April 2001 an international panel recommended
new diagnostic criteria for MS [30]. The McDonald cri-
teria were revised in 2005 [31], in 2010 [29] and recently
in 2017 [32]. Since this review was intended to cover the
work published during the period from 2009 to 2018, the
inclusion criteria of this systematic review were to
include the studies conducted on adults aged 18 years
and over who were diagnosed with MS according to
McDonald 2010 criteria [29] as the latest published revi-
sion of McDonald criteria in the respective period. The
last revision of McDonald criteria [32] was published
only in 2018 after the included studies had been done
and published. The McDonald Criteria incorporate clini-
cal evaluation with magnetic resonance imaging (MRI)
scans in establishing MS. Like an earlier approach, it
also requires evidence of damage to the central nervous
system (CNS; the brain, spinal cord and optic nerves)
that is disseminated in time (occurs on different dates)
Figure 1. Role of n-6 and n-3 fatty acids in the production of eicosanoids in the human body. *COX-2 = cyclooxygenase-2; LOXs =
lipooxygenases; AA = arachidonic acid; EPA = eicosapentaenoic acid; DPA = docosapentaenoic acid; DHA = docosahexaenoic acid.
Adapted from Hidaka et al. [23].
NUTRITIONAL NEUROSCIENCE 3
and space (found on two or more parts of the CNS). The
2010 revision of McDonald criteria [29]reflected the
need to simplify whether myelin damage seen on an
MRI according to DIS and/or DIT was distinctive of
MS. The revision also improved the criteria’s applica-
bility to other populations (pediatric, Asian and Latin
Americans), since it was developed using a white and
Western patient population. The last revision of McDo-
nald criteria was done in 2017 [32] when the
International Panel on Diagnosis of Multiple Sclerosis
reviewed the 2010 McDonald criteria and introduced
some updates. They stated that the presence of CSF-
specific oligoclonal bands allows a diagnosis of multiple
sclerosis in patients with a typical clinically isolated syn-
drome and clinical or MRI demonstration of dissemina-
tion in space. Furthermore, symptomatic lesions may be
used to prove dissemination in space or time in patients
with supratentorial, infratentorial, or spinal cord
Table 1. Source of reviewed articles for potential inclusion in the current study.
Terms PubMed Oxford Cochrane library Embase International pharmaceutical abstract Psych INFO
Clinical
Trials
Gov Total
Multiple sclerosis 2300 91 68 51 60 79 1766 4415
MS and diet 274 3 2 0 8 0 41 328
MS and nutrition 295 3 0 0 1 0 4 303
Dietary patterns and MS 10 0 0 0 0 0 0 10
MS and omega-3 10 0 2 0 0 0 2 14
MS and oils used 5 0 0 0 19 0 0 24
MS and fish oils 4 0 5 0 1 0 4 14
MS and PUFA 6 1 1 0 5 0 1 14
MS and linolenic A 4 0 2 0 0 0 0 6
MS and EPA 1 1 0 0 0 0 1 3
MS and DHA 7 1 0 0 0 0 1 9
T cell and MS 297 6 0 0 43 0 10 356
T cell and omega-3 28 0 6 0 23 0 1 58
Total 3241 106 86 51 160 79 1831 5554
Figure 2. Guidelines for MS diagnosis: 2010 McDonald Criteria [29].
4W. A. ALAMMAR ET AL.
syndrome. The cortical lesions can be further used to
demonstrate dissemination in space.
Study selection
The total articles retrieved were 5554 (3241 from
PubMed, 106 from Oxford, 86 from Cochrane, 51 from
Embase, 160 from international pharmaceutical abstract,
79 from psych INFO, and 1831 from clinical trial) (Table
1). The primary selection was made by reading the title
or abstract. The articles were then thoroughly screened
as per detailed criteria where the most appropriate
ones (n= 7) have been selected and the rest were
excluded (n= 5547). The study selection process is
described in Figure 3.
Systematic evaluation
The included studies were assessed for design, setting,
and study population. The definition of MS was evalu-
ated systematically according to McDonald 2010 criteria
[29] taking into account assessment methods, assess-
ment period, and intensity. Adequate diagnostic evalu-
ation and the use of appropriate diagnostic criteria
were checked from each study. To assess the quality of
reviewed studies, an applicable measure was adopted
based on the validated methods of Shamliyan et al.
[33,34] and the Cochrane collaboration’s tool for asses-
sing risk of bias in randomized trials [35] according to
the research aims of this review. This measure assessed
the evidence in three domains of bias including the
population representativeness, valid outcome assess-
ment, and participants’drop-out or attrition. Good
population representatives were those aged ≥18 years
who have been diagnosed with MS according to McDo-
nald 2010 criteria [29]. There were no specifically defined
cutoffs for sample sizes, but a general rule was to have a
sample size large enough to detect a clinically significant
difference of 5% in event rates or an odds ratio or risk
ratio increase of ≥1.5. Moreover, cohort studies typically
require larger sample sizes to have the same power as a
case–control study [36]. The limitations for age were
defined because the prevalence of MS is high in young
adults who tend to have their first symptoms between
the ages of 20 and 40 [3,4]. The good or valid outcome
assessment considered the definition of MS according
to McDonald 2010 criteria [29]. Whenever reported in
the study under selection, good attrition rate was
defined as <20% loss or no response of participants.
Thirty percent drop-out over a period of 5 years was con-
sidered as poor attrition rate, while 60% attrition rate
over 20 years was not much [37,38]. The quality of evi-
dence of the included studies was assessed based on
the categories described earlier. Quality of evidence was
defined as ‘good’or low risk of bias if the study was
rated as ‘good’in the three domains.
Results
The main analyzed studies in this review (n=7)
[25,26,28,39–42] included a total of 240,914 subjects
from both genders. Based on the population representa-
tiveness, outcome assessments, and attrition rate, the
overall quality of evidence was good for these seven
studies. They all included participants in the intended
age group (≥18 years) with valid outcome assessments
based on McDonald 2010 criteria [29] for MS diagnosis.
In addition to the inclusion criteria described in the
‘Methods’section, the quality of these studies has been
further assessed scientifically by assessing the risk of
bias as well as the overall strength taking the study pur-
pose, design, outcomes, statistical analysis, limitation
reporting, bias reporting and providing appropriate con-
clusion into account (Table 2) and technically (Table 3).
The study was considered ‘good’if it scored an overall
quality of ≥75%. The seven selected studies scored
good quality in different aspects. All of them had a
clear purpose and research question, an extensive litera-
ture review and a proper conclusion. The results were
statistically analyzed in five studies and the limitations
and bias were reported in six studies. All the studies
reviewed referred to omga-3 fatty acids and their
effects on MS, relapses, symptoms, and disability pro-
gression time (Table 4).
Discussion
In cohort study conducted on 2303 participants (1896
females and 407 males), Jelinek et al [25]. investigated
the effect of fish consummation and omega-3 sup-
plementation on the quality of Life of MS patients
using the MS quality of Life-54, diet habits questionnaire
and dietary assessment tools. Patients who consumed
fish three or more times weekly or those taking high
doses of omega-3 FAs have lower levels of disability
and are almost living with normal mobility (ρ< 0.001).
In addition, the health-related quality of life (HRQOL)
was better and showed a stronger association for those
using omega-3 supplements of 1–20 ml/d or consuming
fish more frequently. In contrast, the relapsing rate was
not improved by consumption of fish or taking the sup-
plements, but there was little improvement among
patients who consumed both fish and flaxseed oils (ρ<
0.005). Similar to relapsing rate, both fish and flaxseed
oils increased the stability of the disease. The study had
some limitations from which self-reporting of the data
NUTRITIONAL NEUROSCIENCE 5
was an important factor limiting the possibility to verify
the reported data or to provide recommendation regard-
ing the dose of fish, omega-3 or flaxseed oil. On the other
hand, Wergeland et al. [43] found no difference in relap-
sing rate as well as on fatigue and QOL score between the
group who consumed omega-3 and the placebo group. In
Figure 3. Screening of articles for potential inclusion in the present review.
Table 2. Quality assessment of the studies included in the current review.
Quality Assessments
Pantzaris et al.
[40]
Jelinek et al.
[25]
Shinto et al.
[39]
Bjørnevik et al.
[41]
Zandi-Esfahan
et al. [42]
Ramirez-Ramirez
et al. [26]
Sorto-Gomez
et al. [28]
1- Study purpose Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
2- Literature review Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
3- Clear design Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
4- Sample (described) Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
No
(0)
No
(0)
5- Outcomes (reliable) No
(0)
Yes
(1)
No
(0)
No
(1)
Yes
(1)
Yes
(1)
Yes
(1)
6- Outcomes (validated) Yes
(1)
No
(0)
Yes
(1)
No
(0)
No
(0)
No
(0)
No
(0)
7- Prediction equation
described
Yes
(1)
Yes
(1)
Yes
(1)
No
(0)
No
(0)
Yes
(1)
Yes
(1)
8- Results statistically
analyzed
Yes
(1)
Yes
(1)
Yes
(1)
No
(1)
Yes
(1)
Yes
(1)
No
(1)
9- Limitation and bias
reported
Yes
(1)
Yes
(1)
No
(0)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
10- Appropriate
conclusion
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Overall quality (out of 13) 9 (90%) 9 (90%) 8 (80%) 8 (80%) 8 (80%) 8 (80%) 8 (80%)
Yes = 1, No = 0, N/A = 0.5.
6W. A. ALAMMAR ET AL.
a study on 175,431 females from Nurses’Health Studies
(1984–2004 and 1991–2009) women reported on diet
using a validated FFQ every 4 years and 479 incident
MS cases were identified during follow-up [41]. It was
found that higher intake of total PUFAs at baseline
was associated with a lower risk of MS (ρ< 0.001).
Among PUFAs, only α-linolenic acid (ALA) was inver-
sely associated with MS risk, however both EPA and
DHA were not associated with MS risk. ALA may con-
tribute to the immune pathway which controls the
pathogenesis of MS by decreasing the inflammation mar-
kers. EPA and DHA, however, may have a role in
decreasing the Matrix Metalloproteinase (MMP-9) levels
in both the control and MS patients’groups (ρ< 0.001).
This protein is one of the dangerous markers for
immune cell migration. It is responsible for migration
of immune cells towards the central nervous system by
inducing the disruption of the blood brain barrier, so
when it increases, the brain barrier will degrade.
In line with the preceding results, Shinto et al. [39]
conducted a study on 10 participants who received 9.6
g/d of fish oil to determine the effect of fish oil and
omega 3 on MMP-9 and Quality of life (QOL). The
results showed that omega-3 FAs decreased the immune
cell secretion of MMP-9 by 58% after 3 months of sup-
plementation significantly (p< 0.01), and no improve-
ment or deference in the QOL. Moreover, this effect
was coupled with a significant increase in omega-3 FAs
levels in red blood cell membranes. These results are in
accordance with Riccio and Rossano [14] who reported
that fish oil supplementation have a beneficial effect in
inhibiting the expression of MMP-9, and that omega-3
supplementation can reduce the MMP-9 level in MS
patients. In another study by Cunnane et al. [44] through
the intervention with LCFA, the omega-3 FAs were
reduced in plasma from MS patients and LA was reduced
in erythrocyte ghosts from MS patients (p< 0.0 1).
A randomized double-blind placebo control study
with 80 subjects [40] showed the effect of a novel oral
nutraceutical formula of 1:1 omega-3 (DHA and EPA
3:1) and omega-6 (linoleic acid and γ-linolenic acid
2:1) fatty acids (PLP10) in relapsing remitting multiple
sclerosis. The treatment significantly reduced the
annualized relapse rate (ARR) and the risk of sustained
Table 3. Technical assessment of the studies included in the current review.
Technical Assessments
Pantzaris
et al. [40]
Jelinek
et al. [25]
Shinto
et al. [39]
Bjørnevik
et al. [41]
Zandi-
Esfahan
et al. [42]
Ramirez-
Ramirez et al.
[26]
Sorto-
Gomez
et al. [28]
1- Was the spectrum of participant’s representative of
the patients who will receive the test in practice?
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
2- Were selection criteria clearly described? Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
3- Was the reference standard likely to classify the
target condition correctly?
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
4- Was the period between performing the reference
standard and the index test short enough so that the
target condition did not change between the two
tests?
No
(0)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
5- Was the selection of the sample verified using the
reference standard?
Yes
(1)
Yes
(1)
Yes
(1)
N/A (0.5) Yes
(1)
Yes
(1)
Yes
(1)
6- Did participants receive the same reference standard
regardless of the index test result?
No
(0)
Yes
(1)
Yes
(1)
Yes
(1)
No
(0)
No
(0)
No
(0)
7- Was the reference standard independent of the index
test? (that is, the index test did not form part of the
reference standard)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
N/A (0.5) Yes
(1)
Yes
(1)
8- Was the execution of the index test described in
sufficient detail to permit its replication?
Yes
(1)
Yes
(1)
Yes
(1)
No
(0)
Yes
(1)
Yes
(1)
Yes
(1)
9- Was the execution of the reference standard
described in sufficient detail to permit its replication?
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
10-Were the index test results interpreted without
knowledge of the results of the reference standard?
N/A (0.5) N/A (0.5) N/A (0.5) N/A (0.5) N/A (0.5) Yes
(1)
N/A (0.5)
11- Were the reference standard results interpreted
without knowledge of the results of the reference
standard?
N/A (0.5) N/A (0.5) N/A (0.5) N/A (0.5) N/A (0.5) Yes
(1)
N/A (0.5)
12- Were the same clinical data avilable when the test
results were interpreted as would be avilable when
the test is used in practice?
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
13- Were un-interpertable, indeterminate, or
intermediat test results reported?
N/A (0.5) Yes
(1)
Yes
(1)
Yes
(1)
N/A (0.5) Yes
(1)
Yes
(1)
14- Were withdrawals from the study explained? Yes
(1)
N/A (0.5) N/A (0.5) N/A (0.5) Yes
(1)
Yes
(1)
Yes
(1)
Overall technical quality (out of 14) 10.5 (75%) 12.5
(89%)
12.5
(89%)
11 (79%) 11 (79%) 13 (93%) 12 (86%)
Yes = 1, No = 0, N/A = 0.5.
NUTRITIONAL NEUROSCIENCE 7
Table 4. Comparing the main studies investigated in the current review.
Reference Country
Type
of MS Assessment
Dose of
supplementation
(if applicable)
Study
duration
Participants Age
Range
(Y) Outcome
Study type &
Statistical test
applied Main resultF M total
Pantzaris
et al. [40]
N/A RRMS Supplements of omega-3 (EPA.DHA,
LA), vitamin E, and A.
Daily:
1650 mg EPA
4650 mg DHA
2000mg GLA
3850 mg LA
600 mg Other n-3
FAs
0.6 mg Vitamin A
22 mg Vitamin E
30 M 80 ––18–65
Y
Effect of fish oil
supplement and
vitamin PLP10 on
QOF
Randomized
double-blind,
placebo-
controlled,
clinical trial
rank test,
Kruskal-Wallis
rank test and
Fisher’s exact
test
PLP10 reduce annualized relapse rate
and disability with p= 0.006
Jelinek
et al. [25]
US, UK,
Austria
and
others
N/A Used MS Quality of Life-54 (MSQOL-54)-
52, EDSS, diet habits Questionnaire
and dietary assessment tools with 22
items, assessed the average fish
consummation weekly and omega-3
supplementation.
•1–10 g/d
•More than 11 g /d
of fish oil or flaxseed
oil or both or
unspecified
12 M 1896 407 2303 18 and
over
Effect the quality of
life, disease activity
and disability
Cohort study
ANOVA, Fisher’s
exact test, and
chi square test
Consummation of fish for more than 3
time a week can increase the quality
of life, physical health and mental
health (p< 0.001), take 1–20 ml /d
of omega-3 lead to improve health
related quality of life (p<0.001)
Shinto et al.
[39]
USA RRMS Omega-3 fatty acid (fish oil)
supplementation and measuring:
1. Matrix metalloproteinase-9(MMP-
9), 2. Peripheral blood mononuclear
cell (PBMC) and 3. Red blood cell
(RBC), and assess MS Quality of life
inventory (MSQLI).
9.6 g/d of fish oil 6 M ––10 18–65
Y
Effect the Matrix
Metalloproteinase-9
Intervention Omega-3 FA significantly decreased
MMP-9 (p< 0.01)
Bjørnevik
et al. [41]
N/A N/A Food frequency questionnaire
and questionnaire on medical history
and health related behavior.
–1980–
2007
238,371 ––25–50
Y
PUFA intake and risk
of MS
Nurse health study
Tow tailed
High intake of PUFA reduce MS risk (p
= 0.001)
Zandi-
Esfahan
et al. [42]
Iran RRMS Fish oil supplementation
Assess the EDSS and level of TNF-α, IL-
Iβ, IFN-ϒand IL-6.
1 g/d 12 M ––50 18–45
Y
Effect of fish oil and
inflammatory
markers
Case control study
t-test and Mann-
Whitney U
test, Chi-squared
test and sample
t-test or
Wilcoxon signed
rank test
Consummation of fish oil
supplementation have no potential
effect in lowering the serum levels of
TNF-α,IL1β, IL6, and IFN-γ(p>0.05)
and the change of EDSS level (p=
0.08)
Ramirez-
Ramirez
et al. [26]
Mexico RRMS Fish oil supplementation.
Assess the EDSS and level of TNF-α, IL-
Iβ, il-6, nitric oxide catabolites,
lipoperoxide and number of relapses.
4 g/d of fish oil 12 M ––50 18–55
Y
Effect of fish oil and
inflammatory
markers
Case control study,
use ANOVA and
Mann-Whitney U
test.
Fish oil have potential effect in lower
the serum levels of TNF-α, IL1β, IL6
and nitric oxide (P< 0.001)
Sorto-
Gomez
et al. [28]
Mexico RRMS Fish oil supplementation.
Assess the level of glutathione
reductase and GSH/ GSSG ratio, lipid
profile.
4 g/d of fish oil 12 M ––50 18–55
Y
Effect of fish oil on
fatty acid profile
Case control study
Mann-Whitney U
test
fish oil supplementation, increase the
level of EPA and DHA and reduce AA
and ratio of n-6/n-3, AA/ EPA
8W. A. ALAMMAR ET AL.
disability progression without any reported serious
adverse events. The authors reported a shortage in the
sample size because of the patients who dropped out
from their project. Ramirez-Ramirez et al. [26] found
that fish oil containing high amount of omega-3
PUFAs EPA and DHA had anti-inflammatory, antioxi-
dant and neurologic effect. A daily supplement of 4
grams of fish oil had a significant effect in reduction
the level of tumor necrosis factor alpha (TNF-α)(ρ<
0.001) which acts to increase the inflammation in the
human body. It also reduces the level of Interleukin 1
beta (IL1β) part of cytokine which is a mediator of the
inflammatory response Interleukin 6 (IL6) that stimu-
lates the inflammatory and auto-immune processes and
Interferon gamma (IFN-γ). The sample size, however,
was not large enough to ensure the results and the out-
come about the relapses duration and the duration itself
between each relapse. These results are in line with Seda-
ghat et al. [18] who stated that diet low in omega-3 poly-
unsaturated fats and high in animal fats or saturated fats
may increase the risk of MS.
Controversial results were reported by Zandi-Esfa-
han et al. [42] in a double-blind randomized pla-
cebo-controlled trial carried out with 74 participants
who took 1g/day of fish oil as a dietary supplement.
Administration of fish oil did not reduce the serum
levels of TNF-α, IL1β, IL6, and IFN-γcompared to
placebo. Similarly, it did not improve the disability in
patients. Similar results were reported by Wergeland
et al. [43] who determined the effect of PUFAs by ran-
domized controlled trials and found no evidence of
PUFAs as beneficial in relapsing rate and state of MS
disease. Moreover, Sorto-Gomez et al. [28] conducted
a study on 50 of MS patients who received 4 g/d of
fish oil for one year. The results showed a significant
change in glutathione reductase activity in fish oil
group after 12 months of intervention (ρ< 0.0001),
while the placebo groups had no changes during the
study period. These results suggest the positive effect
of fish oil on the antioxidant defense mechanisms of
the cell. This effect is attributed to the immune-modu-
latory and antioxidant actions of n-3 PUFAs in redu-
cing the production of pro-inflammatory mediators
and increasing the production of anti-inflammatory
mediators. Omega-3 FAs supplementation can decrease
the level of pro-inflammatory eicosanoid formation
leading to decrease the free radical which can improve
the MS patient’s health and decrease the relapsing rates
[14]. The limited number of cases, the shortage in the
study duration, and the inclusion of tocopherols in the
placebo capsules given to the control group are the
limitations that may confounded the outcome of the
results as reported by the authors.
Strengths, limitations and recommendations
of the study
This review summarizes the relationship between the
supplementation of omega-3 fatty acids and MS. It
handles a number of studies with large sample size to
evaluate the relationship. On the other hand, the study
has some limitations. It is not easy to find updated,
clear and straightforward evidence and articles regarding
the relationship between multiple sclerosis and omega-3
fatty acids. In most of the studies reviewed, the sample
size taken in predominating studies was insufficient
which may affect the finding. The duration of the inter-
vention was usually not enough to evaluate the effect of
fish oils or omega-3 supplementation on MS status.
There is no systematic review on the link between fish
oil and omega-3 supplementation with MS done before.
Because of the lack of recent studies, further research is
needed in this regard.
Conclusion
Omega-3 fatty acids and fish oil supplementation have
many beneficial effects regarding to MS patients specifi-
cally and human body in general. Consumption of
omega-3 fatty acids and fish oils supplementation can
affect the level of inflammatory markers such as: TNF-
Α, IL-Iβ, IFN-ϒAnd IL-6, relapsing rate, quality of life
and the progression of MS disease as seen in the recent
reviewed studies. The studies showed that 4 gm of
daily omega-3 supplementation or fish oil is rec-
ommended. However, the effectiveness of this dose or
supplementation varies depending on many factors
especially the progression and disease status before start-
ing the supplementation. Further studies are needed to
determine the effectiveness of omega-3 fatty acids on
MS health status.
Disclosure statement
No potential conflict of interest was reported by the authors.
Notes on contributors
Ms. Welayah Ali AlAmmar is a B.Sc. Graduate from the Clini-
cal Nutrition Department at Imam Abdulrahman University,
Dammam, Saudi Arabia.
Ms. Fatima Hassan Albeesh is a B.Sc. Graduate from the
Clinical Nutrition Department at Imam Abdulrahman Univer-
sity, Dammam, Saudi Arabia.
Ms. Layla Makki Ibrahim is a B.Sc. Graduate from the Clinical
Nutrition Department at Imam Abdulrahman University,
Dammam, Saudi Arabia.
NUTRITIONAL NEUROSCIENCE 9
Dr. Yasmin Yussuf Algindan got her bachelor’s degree from
the King Faisal university in Dammam, Saudi Arabia in
1996. She obtained her masters and Ph.D. degrees in 2007
and 2016 from University of Manitoba, Canada and University
of Glasgow, UK, respectively. She is currently working as
assistant professor and chairperson for the Clinical Nutrition
Department at Imam Abdulrahman University, Dammam,
Saudi Arabia.
Dr. Lamya Zohair Yamani is an assistant professor at the
department of Clinical Laboratory Sciences, Imam Abdulrah-
man University, Dammam, Saudi Arabia.
Dr. Rabie Yousif Khattab obtained his Ph.D. degree in Food
Chemistry from Alexandria University, Egypt in 2004. From
2007 to 2010 he worked as a post-doctoral research fellow in
the Department of Food and Human Nutritional Sciences at
the University of Manitoba, Canada. He joined the Depart-
ment of Process Engineering and Applied Science at Dalhousie
University, Canada as a research associate in 2014. Dr. Khattab
is currently working as associate professor at the department of
Clinical Nutrition at Imam Abdulrahman University, Dam-
mam, Saudi Arabia.
ORCID
Rabie Yousif Khattab http://orcid.org/0000-0002-1715-
970X
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NUTRITIONAL NEUROSCIENCE 11
