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Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20

Omega-3 fatty acids (ῳ-3 fatty acids) in epilepsy:


animal models and human clinical trials

Christopher M DeGiorgio & Ameer Taha

To cite this article: Christopher M DeGiorgio & Ameer Taha (2016): Omega-3 fatty acids
(ῳ-3 fatty acids) in epilepsy: animal models and human clinical trials, Expert Review of
Neurotherapeutics, DOI: 10.1080/14737175.2016.1226135

To link to this article: http://dx.doi.org/10.1080/14737175.2016.1226135

Accepted author version posted online: 18


Aug 2016.
Published online: 18 Aug 2016.

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Download by: [Cornell University Library] Date: 21 August 2016, At: 03:48
Publisher: Taylor & Francis

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2016.1226135
Special report

Omega-3 fatty acids ( -3 fatty acids) in epilepsy: animal models and human

clinical trials

DeGiorgio, Christopher M

Corresponding Author - cmd@mednet.ucla.edu

Professor and Vice Chairman

University of California Los Angeles David Geffen School of Medicine Ringgold standard

institution - Neurology

Los Angeles, California 90095

United States

Taha, Ameer

University of California, Davis - Department of Food Science and Technology, College of

Agriculture and Environmental Sciences, University of California, Davis

Davis, Connecticut

United States

1
Key words: Fish Oil, -3 fatty acids, omega-3 fatty acids, Epilepsy, Seizures, Animal

Models, Clinical Trials

2
Abstract
Introduction: There is growing interest in alternative and nutritional therapies for drug

resistant epilepsy. -3 fatty acids as fish or krill oil are widely available supplements

used to lower triglycerides and enhance cardiovascular health. -3 fatty acids have

been studied extensively in animal models of epilepsy. Yet, evidence from randomized

controlled clinical trials in epilepsy is at an early stage.

Areas covered: This report focuses on the key -3 fatty acids DHA and EP, their

incorporation into the lipid bilayer, modulation of ion channels, and mechanisms of

action in reducing excitability within the central nervous system. This paper presents

pre-clinical evidence from mouse, rat, and canine models, and reports the efficacy of n-3

fatty acids in randomized controlled clinical trials. An English language search of

PubMed and Google scholar for the years 1981-2016 was performed for animal studies

and human randomized controlled clinical trials.

Expert commentary: Basic science and animal models provide a cogent rationale and

substantial evidence for a role of -3 fatty acids in reducing seizures. Results in humans

are limited. Recent Phase II RCT evidence suggests that low to moderate dose -3 fatty

acids reduce seizures; however, larger multicenter randomized trials are needed to

confirm or refute the evidence. The safety, health effects, low cost, and ease of use

make -3 fatty acids an intriguing alternative therapy for drug resistant epilepsy. Though

safety of profile is excellent, the human data is not yet sufficient to support efficacy in

drug resistant epilepsy at this time.

3
1. Introduction

Interest in dietary and alternative interventions for epilepsy (i.e. ketogenic diet,

modified Atkins diet, cannabinoids, and n-3 fatty acids) is exploding. To date, four

randomized controlled trials (RCTs) for the ketogenic diet and one RCT for the modified

Atkins diet have been published [1]. Efficacy is promising, with reductions of up to 85%

for the ketogenic diet, and 60% for the modified Atkins diet [1]. Cannabinoids have also

received significant attention [2]. The evidence is still limited pending completion of

multiple ongoing clinical trials [2]. Interest in -3 fatty acids is also growing. The primary

goal of this review is to present the basic science data supporting or refuting the role of

-3 fatty acids in mechanistic and animal models of epilepsy. A second goal is to review

results from randomized human clinical trials of -3 fatty acids for epilepsy.

2. Methods

The PubMed and Google scholar English language databases were searched for

publications with the following keywords: -3 fatty acids, omega-3 fatty acids, EPA,

DHA, PUFA, seizures, epilepsy. Preclinical studies (including basic science and animal

models), randomized controlled clinical trials (RCTs), and Cochrane database

publications were included. For human studies, non-randomized or open label human

studies were excluded. For background, basic science and clinical data for heart

disease, infant development, and aging were also included. The database search

ranged from 1981 to 2016.

4
3. Overview Of Omega-3 ( -3) Fatty Acids

-3 fatty acids are essential long-chain polyunsaturated fatty acids which play an

important role in health and disease prevention. -3 fatty acids are incorporated into

lipids and cell membranes, modulate ion flux across myocytes and neurons, reduce

excitability, and lower the risk of cardiovascular disease [3-9]. The term “Omega-3” or

“ -3” refers to the presence of a double-bond at the third carbon from the methyl

terminus of the molecule [19]. Humans and other mammals cannot synthesize -3 fatty

acids, because they lack delta-12 and delta-15 desaturase enzymes, which remove

hydrogen atoms and create double bonds, necessary to create polyunsaturated fatty

acids [20].

The three major -3 fatty acids are linolenic acid (ALA), eicosopentaenoic acid

(EPA), and docosohexaenoic acid (DHA). ALA is an essential 18-carbon fatty acid found

in walnuts, flaxseed, soybean oil and canola oil. EPA and DHA are essential -3 fatty

acids found in marine sources, including salmon, tuna, mackerel, anchovies, and krill.

EPA and DHA are the primary ingredients in Fish oil or Krill oil.

4. -3 Fatty Acids and the Brain

DHA, a 22 carbon -3 fatty acid is the principle fatty acid in the brain. DHA

accumulates in lipid and synaptic membranes in cortex and retina, accounting for up to

35% of synaptic membrane content [20]. DHA is critical for brain maturation,

development, and aging. [20, 21] DHA regulates the neurogenesis of stem cells to

neurons, and promotes cell growth and differentiation. [20, 21]. Maternal DHA deficiency

5
may have a negative effect on infant brain development. Since -3 fatty acids are

transferred from mother to infant via the placenta, infants are solely dependent on

maternal dietary intake. Higher DHA concentrations in infants are positively correlated

with better visual acuity, cognition, and motor development in infants. [20] As a result,

prenatal vitamins now routinely include DHA.

In the aging, fish oil supplementation in Alzheimer’s disease or mild cognitive

impairment has not been proven to slow disease progression, but high levels of w-3 fatty

acids are associated with reduced rates of cerebral atrophy [12, 13]. Interventional

studies have demonstrated that -3 fatty acid supplementation reduces the rate of grey

matter atrophy. In one longitudinal study, healthy elderly subjects randomized to 2.2

grams of -3 fatty acids over a 26 week period demonstrated significantly better grey

matter volumes than controls n hippocampus, temporal, and parietal cortex [22]. In

another randomized controlled trial, vitamin B supplementation reduced was associated

with improved brain volumes only when -3 fatty acid levels were normal, indicating a

protective effect of -3 fatty acids on brain atrophy [12].

Relevant to epilepsy, -3 fatty acids reduce neuronal excitability. Reduction in

excitability is heavily dependent on sodium and calcium ion channels, which can be

modulated by EPA and DHA. Xiao et el made the seminal observation that EPA

suppresses voltage-activated Na+ currents in cultured rat myocytes, and found that both

EPA and DHA reduce inward calcium currents, prolonging the inactivation state

[23,24,25]. Leaf and el proposed that inhibition of sodium and calcium channels may

occur via juxtaposition of essential fatty acids adjacent to trans-membrane sodium and

calcium channels [26]. It is hypothesized that EPA and DHA are incorporated into the

6
lipid bi-layer, and the negatively-charged carboxyl terminal of EPA and DHA come into

proximity with the positively-charged region of the alpha subunit of the ion channel [26].

This leads to de-activation and stabilization. In the brain, EPA inhibits action potentials in

mouse hippocampus, while EPA and DHA reduce firing rates of CA1 pyramidal neurons

by 40-50% [27].

In animal models of epilepsy, the experience with -3 fatty acids has been highly

variable. Several animal studies reported that -3 fatty acids reduce seizure frequency

or prolong the latency to the onset of seizures, while some have found no effect. In a

mouse model of epilepsy, Taha et al. reported a 45% non-significant increase in time to

the onset of seizures (prolonged seizure latency) in fat-1 mice, which synthesize EPA

and DHA endogenously from Arachidonic Acid [28]. Willis et al. found no anticonvulsant

effect of EPA or DHA administration for 1-month at a low dose of 6 mg/kg. [29] However,

El-Mowafy et al. and Abdel-Dayem et al. found that high dose EPA (125-200 mg/kg) or

DHA (120-250 mg/kg) administration delayed the onset of seizures by 49%, and

synergistically enhanced the anticonvulsant activity of Valproic acid by 3-fold [30,31].

Mutso et al. demonstrated that the DHA-metabolite, neuroprotection D1 (NPD-1),

reduced frequency and amplitude of pilocarpine-induced epileptiform activity by more

than 50% when given intra-peritoneal to mice for 5 days at 0.57 mg/kg [32]. This

suggests that the anticonvulsant effects of DHA may be mediated by one of its

lipoxygenase-derived metabolites. In contrast, arachidonic acid (AA) increases seizure

frequency > 50% in the electroconvulsive shock seizure model, but decreases latency to

PTZ-induced seizures by 20%, suggesting differential effects of acute AA depending on

the seizure model [33].

7
5. Rat models of -3 fatty acids in epilepsy

In rat studies, fish oil containing EPA and DHA was reported to raise seizure

threshold in most studies when given over a longer term of at least 3 months [34-36].

When administered for only one month, two studies did not find an anticonvulsant effect

[37, 38]. However, a time-course study by Taha et al. showed that at least 3 months are

required for fish oil to raise seizure threshold in rats [39]. The delayed effect of dietary

fish oil may be due to the delay in formation of unesterifed EPA and DHA or their

bioactive metabolites (such as NPD1) within the brain. Since fish oil high in EPA and

DHA raises seizure thresholds in rats, studies have tested the anticonvulsant effects of

injected unesterified EPA or DHA. Voskuyl et al. reported that EPA or DHA injected

intravenously (IV) at 60-69 mg/kg over 30 minutes increased focal and generalized

seizure thresholds up to 6-16 fold in a cortical stimulation model [40]. Taha et al. found

that high dose (400 mg/kg), but not low dose, DHA administered subcutaneously

delayed the onset of seizures using a PTZ-induced seizure model [41]. DHA at 300-400

mg/kg raised PTZ-induced seizure threshold one-hour after subcutaneous

administration and within minutes after 25-200 mg/kg IV administration [41]. The

anticonvulsant effects of DHA may be related to its metabolite, neuroprotectin 1 [42].

Interestingly, Taha et al. and Trepanier et al both found that high doses of DHA were not

as effective as lower doses, an interesting finding that is consistent with recent clinical

trials in epilepsy indicating lower dose w-3 fatty acids may be more effective than higher

doses [41, 43].

6. Canine models of -3 fatty acids and epilepsy

8
In canines, two studies tested the anticonvulsant effects of -3 fatty acids in

dogs. Scorza et al. reported a reduction in seizure incidence from 3 per month to 1 per 3

months in a dog supplemented with 2 g/ day of -3 fatty acids for at least 18 months

[44]. However, in a double-blind randomized control study involving 15 dogs, Matthews

et al found no effect of EPA (40 mg/kg) and DHA (25 mg/kg) supplementation for 12

weeks, except in one German shepherd dog which showed a 10-fold reduction in

seizure frequency during fish oil supplementation phase [45]. Overall, the data in canine

models is incomplete, and more evidence is needed. We can conclude that efficacy of

EPA and DHA on seizures is species specific, and dependent on dose and duration of

exposure. The greatest efficacy has been identified in mouse and rat models, with little

evidence in canine models. The evidence supports that acute administration of -3 fatty

acids requires high doses for acute efficacy. Chronic dosing for 3-months or longer is

more effective than short term exposure (1-month).

7. Other -3 fatty acids and synergy with antiepileptic drugs

Other -3 fatty acids like ALA acid have anti-seizure effects, and are synergistic

when administered with antiepileptic drugs. This synergistic effect of ALA has been

reported by multiple authors [46-48]. ALA from flaxseed or canola oil decreases

convulsions by 50%, and by 63% when co-administered with carbamazepine in a model

of audiogenic seizures [46]. By itself, EPA 300 mg/kg increased latency to PTZ-induced

tonic-clonic seizures by 49%. However, when co-administered with valproate (175

mg/kg), EPA further increased latency by more than 300% compared with EPA alone

[47]. EPA did not increase seizure latency in a PTZ model of tonic-clonic seizures,

however Levetiracetam co-administration with 200 mg/kg -3 fatty acids increased

9
latency and decreased severity up to 59% compared to -3 fatty acids alone [48]. This

animal data suggests that -3 fatty acids are best administered as adjunctive therapy to

standard anti-epileptic drugs, rather than as a stand-alone therapy. This would need to

be confirmed in add-on RCT’s.

8. Human clinical trials of -3 fatty acids, fish oil, and epilepsy

Fish Oil is safe and well tolerated. Mild gastrointestinal side effects such as

burping, fishy after-taste or diarrhea may occur [18, 49, and 50]. Independent laboratory

tests found that most brands of Fish Oil contained little or no heavy metals or PCB [51].

In preparation for one of the author’s recent clinical trial, independent testing of fish oil

capsules showed no evidence of PCB’s or mercury [17].

Three major randomized controlled trials (RCT) of -3 fatty acids in epilepsy have

been reported to date [15-17]. All have been performed in subjects with severe drug

resistant focal-onset (partial) epilepsy with or without tonic-clonic seizures. The first and

largest was reported by Yuen et al in 2005. The primary intervention was 6 capsules of

fish-oil/day, containing a total of 1700 mg/day of EPA+DHA. The primary outcome

measure was 50% or greater reduction in seizures during the 12-week treatment period.

58 subjects with drug resistant epilepsy were randomized to fish oil or placebo. Fish oil

was well tolerated. Side effects were few, and diarrhea was reported in only 1/30 (3%) of

patients on active treatment. Within the first 6-weeks of treatment, seizure frequency

was significantly reduced in the active treatment fish-oil group. At 6-weeks, 17% of fish

oil group experienced a 50% reduction in seizures, versus none (0%) in the control

10
group. [15]. Five of twenty-nine had at least a 50% reduction in seizures (compared with

0/27) [15]. However, at 12-weeks, there was no difference in efficacy between the fish

oil group and controls [15]. Though this study did not demonstrate sustained efficacy

over the 12-month treatment period, it did establish the overall safety of fish oil in people

with epilepsy [15].

A second RCT of -3 fatty acids was reported by Bromfield et al at in 2008 [16].

The dose of -3 fatty acids was higher than the Yuen et al study, at 2200 mg/day

EPA+DHA. The primary outcome was similar, a > 50% reduction in seizure frequency.

27 subjects with four or more seizures/month were randomized. 21 subjects completed

the trial [16]. The study cohort was highly drug resistant, averaging 14.9/month

(treatment) versus 21.4/month (control). After a 4-week baseline, active subjects were

titrated to 2200 mg/day, and no changes in AED’s were allowed. EPA+DHA 2200 m/day

was well tolerated. At 12-weeks, the -3 supplemented group experienced a 6%

increase in seizures, versus a 12% reduction for controls. (Not significant, p =0.17) [16].

However, during un-blinded long-term follow-up, all subjects were crossed over to active

treatment with fish oil, and 5/19 (26%) had > 50% reduction in seizures [16].

A third RCT trial was reported by DeGiorgio et al. in 2015 [17]. The study design

was a phase II 3-period crossover study. This trial compared 2160 mg EPA+DHA (six

1200 mg fish oil capsules/day) to 1200 mg EPA +DHA (three 1200 mg fish oil

capsules/day) as well as placebo [17]. The primary reduction was percent-change in

seizure frequency compared with placebo. Twenty-four highly drug-resistant subjects (>

three seizures/month, median 18.34 seizures/month) were randomized. No changes in

AED’s were allowed. Low dose fish-oil (1080 mg EPA+DHA total) was associated with a

11
33.6% reduction in seizures (12.18 SE 2.72 seizures/day) compared with placebo [17].

High dose fish-oil (2160 mg EPA+DHA) was no different from placebo (-3.6%, 17.67 SE

4.56 versus placebo) [17]. In addition, low dose fish-oil was associated with twenty-five

percent of subjects experiencing a > 50% reduction in seizures during the treatment

period [17]. With these results, this phase II study met its primary endpoint, i.e., a

significant reduction in seizures compared with placebo [17].

Of interest, low dose fish-oil was also associated with a reduction in blood

pressure, (-1.95 mmHg) [17]. Reasons for the positive study may include the crossover

design, which provides greater statistical power with a smaller cohort. Since all

comparisons are within group, variability is reduced compared with parallel designs. This

is the first study to evaluate low-dose fish-oil (1080 mg EPA+DHA/day, 2-capsules of

fish oil per day), and to demonstrate the superiority of low dose versus high dose.

Limitations include the small size of the cohort, indicating a large phase III trial will be

needed to confirm the results [17].

9. Summary

The weight of evidence from animal studies in rodents indicates that -3 fatty

acids have an anticonvulsant effect. This effect may be maximal when administered

over the long-term and in conjunction with standard antiepileptic drugs. Human phase II

studies of -3 fatty acids have shown mixed results. Most recently, lower dose -3 fatty

acids (i.e. 1080 mg EPA+DHA/day), equivalent to three fish oil capsules/day were

effective in a phase II randomized controlled trial [17]. -3 fatty acids may have other

health benefits in people with epilepsy, including reductions in blood pressure and

improvements in cardiovascular risk which one can extrapolate from large trials in heart

12
disease [7, 17]. Based on the phase II data, a large multicenter Phase III randomized

controlled trial of -3 fatty acids for epilepsy is warranted.

10. Expert Commentary

-3 fatty acids have significant health benefits. These include lowering serum

triglyceride levels, reducing mortality and sudden death after myocardial infarction,

and improving developmental outcomes in newborn infants following maternal DHA

supplementation during pregnancy. In epilepsy, basic science and animal data

provide substantial evidence to support a role of -3 fatty acids in reducing seizures.

In contrast, the data supporting human clinical use is limited to three small to

medium size randomized controlled trials with mixed results. Most recently, a phase

II RCT found that low to moderate dose -3 fatty acids (1080 mg/day EPA+DHA)

reduce seizures by 33% in patients with drug resistant epilepsy. However, a large,

multicenter randomized controlled trial is needed to confirm or refute the evidence.

The safety, health effects, low cost, and ease of use make -3 fatty acids an

intriguing alternative therapy for drug resistant epilepsy. At this time, clinical trial data

is not sufficient to support a claim of efficacy in seizure disorders.

11. Five-year view

A multi-center randomized controlled trial, likely in the range of 100-200 subjects, will

require involvement of 10-20 centers, and will take 2-4 years to be completed.

Though safety data indicates the risk of supplementation with -3 fatty acids is low,

phase III pivotal data will be needed to demonstrate efficacy. If this trial is positive, it

13
will provide important evidence to justify supplementation with -3 fatty acids in

people with epilepsy.

12. Key Issues

• -3 fatty acids are essential fatty acids (DHA and EPA) which lower triglyceride

levels, reduce the risk of death after myocardial infarction, and improve

developmental outcomes in infants.

• -3 fatty acids (with B-vitamins) may reduce the rate of cerebral atrophy in elderly

subjects.

• -3 fatty acids are incorporated into lipid membranes, where they modulate

sodium and calcium flux, and reduce neuronal and hippocampal excitability.

• Multiple experiments in animal models of epilepsy show evidence of an

anticonvulsant effect.

• Human clinical trial data is conflicting, with two small to medium sized trials

demonstrating no efficacy. More recently, a small randomized crossover trial

found that 1080 mg of DHA+ EPA as fish oil reduced seizures compared to

placebo by 33.6%.

• A large, multicenter randomized controlled trial of low to moderate dose -3 fatty

acids (fish oil) is now indicated.

Funding

This paper was supported by a research grant from the NIH National Center for

Complementary and Integrative Health, Grant # NIH/NCCIH R21AT003420-02; and

14
unrestricted research support to UCLA by Beverly and James Peters, and Linda and

Robert Brill.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization

or entity with a financial interest in or financial conflict with the subject matter or

materials discussed in the manuscript. This includes employment, consultancies,

honoraria, stock ownership or options, expert testimony, grants or patents received or

pending, or royalties.

15
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