1 s2.0 S0753332221003425 Main

Biomedicine & Pharmacotherapy 139 (2021) 111557
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Genetics, pathophysiology, diagnosis, treatment, management, and

prevention of migraine
Johra Khan a, Lubna Ibrahim Al Asoom b, *, 1, Ahmad Al Sunni b, Nazish Rafique b, Rabia Latif b,
Seham Al Saif b, Noor B. Almandil c, Dana Almohazey d, Sayed AbdulAzeez e,
J. Francis Borgio e, f, **, 2
a
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia
b
Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31541, Saudi Arabia
c
Department of Clinical Pharmacy Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441,
Saudi Arabia
d
Department of Stem Cell Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
e
Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
f
Department of Epidemic Diseases Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441,
Saudi Arabia
A R T I C L E I N F O A B S T R A C T
Keywords: Migraine is a neurological ailment that is characterized by severe throbbing unilateral headache and associated
Migraine with nausea, photophobia, phonophobia and vomiting. A full and clear mechanism of the pathogenesis of
Pathophysiology migraine, though studied extensively, has not been established yet. The current available information indicates
Endocrine
an intracranial network activation that culminates in the sensitization of the trigemino-vascular system, release
Metabolic syndrome
Diagnosis
of inflammatory markers, and initiation of meningeal-like inflammatory reaction that is sensed as headache.
Genetics Genetic factors might play a significant role in deciding an individual’s susceptibility to migraine. Twin studies
have revealed that a single gene polymorphism can lead to migraine in individuals with a monogenic migraine
disorder. In this review, we describe recent advancements in the genetics, pathophysiology, diagnosis, treatment,
management, and prevention of migraine. We also discuss the potential roles of genetic and abnormal factors,
including some of the metabolic triggering factors that result in migraine attacks. This review will help to
accumulate current knowledge about migraine and understanding of its pathophysiology, and provides up-to-
date prevention strategies.
1. Introduction disturbances are common in this condition [1].

Migraine is defined as severe throbbing plus unilateral headache
Migraine is the most common multidisciplinary and multifactorial related to nausea, photophobia, phonophobia and vomiting [5]. The
neurologic disorder that is characterized by recurrent attacks of head term migraine is of Greek origin and comes from the word hemicranias,
ache (Figs. 1 and 2) [1–5]. Migraine occurs either in episodic or in which means “half of the head”. This is a striking feature of the disease,
chronic form, with or without aura. It is a neurological disorder that was as most individuals feel pain in one half of the head. However, bilateral
regarded as a “hypoglycaemic headache” in the early years of the pain is also common and occurs at the front and back of the head. The
twentieth century [1]. A plethora of transient motor and somatosensory nature of the pain is throbbing, which worsens with exertion or
* Corresponding author.
** Corresponding author at: Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University,
Dammam, Saudi Arabia.
E-mail addresses: [email protected] (J. Khan), [email protected] (L.I.A. Asoom), [email protected] (A.A. Sunni), [email protected] (N. Rafique),
[email protected] (R. Latif), [email protected] (S.A. Saif), [email protected] (N.B. Almandil), [email protected] (D. Almohazey), asayed@iau.
edu.sa (S. AbdulAzeez), [email protected], [email protected] (J.F. Borgio).
1
ORCID ID: 0000-0002-0371-2367
2
ORCID ID: 0000-0001-7199-1540.
https://doi.org/10.1016/j.biopha.2021.111557
Received 24 January 2021; Received in revised form 23 March 2021; Accepted 27 March 2021
Available online 17 May 2021
0753-3322/© 2021 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
J. Khan et al. Biomedicine & Pharmacotherapy 139 (2021) 111557
movement. Migraine attacks are usually moderate or severe. to more than US$17 billion. Nearly half of the affected cases have 50%
Research addressing the underlying mechanism of migraine has re reduced productivity or ability to work during attacks [15]. These in
ported that activation of the trigeminovascular system is the main fac dividuals are usually absent from school or work once every 3 months,
tor. Both genetic and environmental factors play a significant role in the on average [15].
development of migraine [2]. It has been postulated that the patho Migraine is classified into two forms: migraine with aura (MA) and
genesis of migraine is associated with energy deficit syndrome [3]. migraine without aura (MO). Migraine can also be classified into chronic
Research findings about migraine clearly indicate the importance of and episodic migraine. Hemiplegic migraine is another type of MA and is
migraine research and the extensive involvement of researchers from a severe and rare condition that affects one side of the body and causes
various fields (Fig. 2). About 75% of the studies have been from the USA temporary numbness [23].
(publications n = 10,081, percentage of contribution 33.326%) Italy
(n = 3346; 11.061%), England (n = 2329; 7.699%), Germany 2. Genetics
(n = 1884; 6.228%), Spain (n = 1099; 3.633%), the Netherlands
(n = 1084; 3.583%), Denmark (n = 1067; 3.527%), Turkey (n = 921; Studies have reported that genetic factors play important roles in
3.045%), France (n = 914; 3.021%), and Canada (n = 846; 2.797%). defining an individual’s susceptibility to migraine (Fig. 3). Twin studies
In this review, we describe recent advances in the field of genes and have demonstrated that a single gene polymorphism can lead to the
genetics, associated root causes, diagnosis, treatment, management disorder in individuals with monogenic migraine disorder [24]. Com
strategies, and preventive measures for migraine. We also discuss the mon migraine heritability is reported in 30–60% of cases [25]. MA and
metabolic triggering factors that result in migraine attacks and the po MO are caused by small changes in many genetic loci and thus are
tential impact of genetic and abnormal factors. This comprehensive re considered polygenic variants. Efforts have been made to understand the
view will briefly describe recent advances in knowledge of this disorder genes involved in the developmental process of the monogenic and
and understanding its pathophysiology. polygenic variants. Linkage mapping of genetic biomarkers, associated
The worldwide prevalence of migraine affecting both males and fe with sequencing of the genes of interest, has highlighted many of the
males is estimated to be 15–18% [6]. Migraine is a disabling condition genes associated with migraine [26–29].
that is ranked eighth in the world and fourth in women in terms of Several genome-wide association studies have been performed in
burden [14]. According to a recent report, approximately 44.5 million patients with migraine. These studies have been helpful in identifying
adults in the USA, comprising 18% of women and 6% of men, have single nucleotide polymorphisms. Identifying different alleles in this
experienced migraine. The prevalence is higher in Caucasians and it way helps to identify genomic regions associated with different diseases
peaks within the 18–44 years age group. While migraine is no more than in an individual [26]. A recent genome-wide association study in a large
an inconvenience for many people, it is ranked among the top 40 con patient cohort reported 28 genetic loci associated with headache. Of
ditions in the world for causing disability based on figures from the these 28 loci, 14 were previously reported to be associated with
World Health Organization. Headache comprises 4.4% of all medical migraine. That study also reported a significant association between the
consultations in general practice [7,8]. h It also accounts for 5% of brain and genetic mutations [27]. The discrepancy between the already
hospital admissions, and it accounts for approximately 20% of consul reported loci and the newly found loci could be related to the involve
tations in neurological outpatient departments [9]. In Western Europe, ment of other broader headache pathways, such as tension-type head
multiple epidemiological studies have demonstrated that 4.5% of in ache. The co-occurrence of migraine with tension-type headache has
dividuals suffer from headaches [10]. been shown in another face-to-face interview study [28].
The economic burden imposed by migraine on society is substantial
[11]. In the USA, the estimated direct costs related to migraine accounts
Fig. 1. Factors that trigger migraine [1–63].
2
2.1. Genes associated with familial hemiplegic migraine (FHM) transforming-growth-factor-β signaling pathways have been identified
to be modifiers of CACNA1A [33]. Studies in transgenic mice have also
The prevalence of hemiplegic migraine in the European population is reported that female sex hormones act as modifying factors. This may
approximately 0.01%, which includes the sporadic and familial forms. explain why migraine disorders predominantly affect females [34]. Two
FHM usually has a heterogeneous autosomal dominant inheritance other neurological disorders, such as spinocerebellar ataxia type 6, and
pattern, which has been reported to be monogenic (Table 1). Linkage episodic ataxia type 2, have been associated with heterozygous muta
studies have identified three main causative genes responsible for this tions in CACNA1A. The clinical features of these two conditions have
condition: ATP1A2, CACNA1A and SCN1A [29]. overlapping features [35].
The first FHM gene identified was CACNA1A. This gene is present on The second gene identified as a causative agent for FHM is ATP1A2.
chromosome 19p13 and was identified by positional cloning and mu This particular gene encodes the Na+/K+-ATPase ion transport pump
tation studies. Four missense mutations were detected in the conserved (α2 isoform) catalytic domain. This domain is responsible for main
regions of this gene [30]. This gene usually encodes the pore-forming α1 taining the electrochemical gradients in the smooth muscle cells present
subunit of the neuronal voltage-gated Cav2.1 channel. Moreover, one in the heart, skeletal muscle, and central nervous system (CNS) [36].
study reported that different migraine phenotypes are associated with These mutations display an autosomal dominant inheritance pattern in
deletion of the CACNA1A gene. More than 25 pathogenic variants have patients with a range of clinical presentations. The clinical symptoms
been identified in FHM patients and are inherited as an autosomal include epilepsy, seizures, recurrent coma, fever, and mental retardation
dominant trait [31]. [37–39].
It has also been reported that all missense mutations are close to the The third mutation associated with FHM is SCN1A. This gene is
functional domains associated with calcium channels, and that the present on chromosome 2q24.3 and is responsible for FHM. This is a rare
severity of the condition is based on the variant type. Different animal variant compared with the other two. SCN1A encodes the voltage-gated
model studies have been conducted to search for genetic modifiers. A C- sodium channel Nav1.1 protein, which is responsible for maintaining
beta knockdown model of a Drosophila phospholipase showed that re permeability of the excitable membranes present in the CNS [40]. Mu
ceptors associated with intracellular calcium stores are partially allevi tations in the SCN1A region are commonly reported in epilepsy syn
ated with an FHM mutation [32]. Genes in the notch and dromes. Collectively, 11 mutations have been reported in patients with
Fig. 2. Numbers of published articles on migraine. (A) Numbers of published articles with either migraine in the title or as a topic as per the Web of Science as of 1
January 2021, Arabian Standard Time 11.38. (B) Various fields of research and the numbers of published articles with either migraine in the title or as a topic as per
the Web of Science as of 1 January 2021, AST 11.38. Green dotted line indicates the exponential trend in the number of publications with migraine in the title. (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
3
Fig. 3. Genes associated with the development of migraine and associated disorders [23–40].
and stroke like episodes) is a condition of abnormal mitochondrial

Table 1
function existing in vascular, muscular and neurological tissue precipi
Monogenic neurological disorders associated with migraine and their causal
tate a cascade that leads to migraine like pain. The monogenic variant
genes and mutations [25].
associated with this syndrome is 3243A>G mutation in the mitochon
Disorder Causal Mechanism of mutation drial transfer RNA Leucine [41]. CADASIL is a disease of the small
gene
vessels of the cerebrum. The abbreviation CADASIL stands for cerebral
Familial hemiplegic CACNA1A Missense mutation, gain of function autosomal-dominant arteriopathy with subcortical infarcts and leu
Migraine (FHM) ATP1A2 Missense mutation, partial to complete
koencephalopathy. The disease precipitate infarction in the brain lead
loss of functionality
SCN1A Rare and highly complex mutation; ing to cognitive impairment and inherited by an autosomal dominance
mechanism unclear mode of the mutant gene NOTCH3 [42]. Retinal vasculopathy with ce
Mendelian migraine KCNK18 A frameshift mutation in the TRESK rebral leukoencephalopathy (RVCL) is a neurovascular disease pre
with aura potassium channel sented with multiple systemic involvement including neurological
Episodic ataxia type 2 CACNA1A Loss-of-function mutation results in
decreased channel function and thereby a
manifestations as hemeparasis, aphasia, stroke, and to a lesser extent
decrease in intracellular Ca2+ epilepsy and migraine. It has also some more common derangement
Spinocerebellar ataxia CACNA1A Expansion of ‘CAG’ polyglutamine repeats involving the kidneys and liver. RVCL is characterized by monogenic
type 6 in the tail of the CACNA1A protein inheritance in TREX1 gene [43,44]. HIHRATL (hereditary infantile
hemiparessis, retinal arteriolar tortuosity and leukoencephalopathy) is
an another small vascular disease associated with stroke and migraine.
FHM disorder, which is inherited as an autosomal dominant trait [25].
HIHRATL is inherited via a mutation in the gene COL4A1 located on
chromosome 13 [45].
2.2. Monogenic inheritance conditions associated with migraine
MELAS (Mitochondrial myopathy, encephalopathy, lactic acidosis,
4
3. Pathophysiology intracellular network cascade that causes inhibitory or excitatory

neurotransmission. Receptors of serotonin are dispersed in the brain,
Headache has been known for almost 600 years. The modern concept including those used in pain-signaling circuits and cranial blood vessels.
of chronic migraine was known at the beginning of the 17th century. In Therapies for treating migraine have been tailored to modulate seroto
the early days, the pathophysiology of migraine was principally based nin receptors. The modulation is directed toward amplifying the sero
on neurological or vascular mechanisms; the metabolic aspects of this tonin signal, leading to pain relief via vasoconstriction of blood vessels
disorder were reported only relatively recently [46]. Migraine is divided and inhibition of peptides, for example substance P21 and calcitonin
into four phases including (Premonitory, Aura, Headache and Post gene-related peptide (CGRP) [21,22].
dromal) (Fig. 4). These phases can occur sequentially or may show The International Classification of Headache Disorders (ICHD) is a
significant overlap. standardized tool that helps in the identification of primary and sec
Meningeal vasodilation together with inflammation is caused by ondary headache. The diagnosis of headache disorders is based mainly
activation of vascular networks, resulting in headache [12,13,16]. The on the clinical manifestations of the different phases. The aura and
pathophysiology of migraine involves modulating pain originating in headache phases are the main focus, as these mainly require medical
disrupted neural networks in the head [17]. Studies have shown that attention [47–49].
brain stem and diencephalic nuclei control the trigeminovascular sys
tem, which comprises efferent neurons supplying vascular networks and 3.1. Premonitory phase
afferent neurons that feed information to the trigeminal nucleus caudalis
[17,18]. Head pain is perceived as meningeal inflammation and vaso This phase starts before the typical migraine headache. The symp
dilation due to activation of these networks [19,20]. toms precede the headache phase by about 72 h. Although these
Neurotransmitters, such as serotonin, also play critical roles in the symptoms have been listed in the literature for many years, they have
pathophysiology and the treatment of migraine. Serotonin initiates an been neglected in most cases. The symptoms include irritability, food
Fig. 4. The mechanisms of the different phases of migraine. An overlap of the different phases is possible.
5
cravings, mood swings, fatigue, stiff neck, and phonophobia [48]. These 3.6. Metabolic dysfunction and triggering factors
symptoms persist during the aura and even during the headache phase,
and indicate the association between the premonitory phase and the Most of the triggering factors associated with migraine are associated
hypothalamic origin. Imaging studies have reported increased blood with metabolic derangements. Fasting; changes in sleep pattern;
flow in the hypothalamic region of the brain, indicating the role of the changes in ovarian hormone secretion, particularly during menstrua
hypothalamus in the early stages of a migraine attack [49]. tion; physical exercise; alcohol; and weather changes can lead to
Hunger, bright light, or sleep deprivation can trigger migraine in migraine headache [56]. Another set of factors called “premonitory
migraineurs, or they can indicate premonitory symptoms. Notably, de factors” also act as triggering factors. Premonitory photophobia is
scriptions of triggering factors differ between clinical studies and mistaken as light for a triggering factor. A particular threshold is reached
questionnaire surveys, which might be due to misconceptions of patients when a few of these triggering factors combine, suggesting that some of
regarding the triggering factors and their association with migraine at these triggering factors act on common pathways [57].
tacks [50]. Any psychological or physiological stress can be regarded as a trig
gering factor. Hormonal changes are another potential metabolic de
3.2. Aura phase nominator. Even changes in oxidative stress caused by psychological or
physiological stress can be a triggering factor [58]. It has also been re
This phase is seen in one-third of migraine patients. Depolarization of ported that hypoxia can increase the prevalence of headache, as people
the cortex and creation of a transient wave are the main pathological living at high altitudes show a higher occurrence of migraine [59].
mechanisms associated with the aura phase, which is also known as Migraine triggers were reported in a study of 182 Indian patients [60],
cortical spreading depression (CSD) [51]. Researchers have shown that which found that 87.9% of patients had triggering factors. Most of these
this mechanism is the main contributory factor behind the aura phase. patients suffered emotional stress as the main triggering factor, followed
The retinotopic propagation in the visual cortex implies a potential role by fasting and exhaustion. Multiple triggering factors were present in
of CSD in migraine. This is the main characteristic feature of the aura 34.4% of the patients [60]. Oestrogen levels are associated with
phase, as supported by imaging studies [52,53]. In contrast, several migraine in females [61]. This hormone is associated with insulin
other studies have rejected an association between CSD and migraine sensitivity, insulin secretion, and nutrient homeostasis. These findings
[46]. imply that migraine triggers are associated with energy metabolism and
oxidative stress [61]. The foods most commonly reported to act as
3.3. Headache phase triggering factors are chocolate, citrus fruits, dairy products, fatty and
fried food, tea, coffee, caffeinated beverages, monosodium glutamate,
The headache phase is marked by unilateral, pulsating, pain of sucralose, gluten, alcoholic beverages and food coloring [56–61].
moderate to extreme severity [5]. This pain can be explained by the Metabolic abnormalities such as oxidative stress in peripheral tis
neurovascular theory where the activation of trigemino-vascular system sues, glucose metabolism and mitochondrial enzyme dysfunction are
is initiated by the earlier activity of higher intracranial centers such as also associated with migraine [62]. Studies have shown that mito
the hypothalamus and thalamus. Consequently, nociceptive fibers, chondrial enzyme activity is reduced in patients with migraine. The
innervating the vascular supply of the dura matter and originating from activities of succinate dehydrogenase, NADH dehydrogenase, cyclo
the trigeminal ganglion, are sensitized and release inflammatory medi oxygenase, and monoamine oxidase decrease in the platelets of migraine
ators such as calcitonin gene-related peptide (CGRP) substance P, and patients [62]. Mitochondrial DNA is more affected by nuclear DNA when
vaso-inhibitory peptide (VIP). These mediators initiate signals along the there is oxidative stress and this condition is also reported in migraine
trigemino-vascular pathway. The afferent nerve fibers from the tri pathophysiology. Mitochondrial abnormalities are also found in
geminal ganglion and the afferent from skin and muscles of the neck migrainous stroke patients [63].
synapse on second-order neurons in the trigeminal cervical complex Patients suffering from metabolic syndrome have a higher preva
(TCC), which explains the upper neck pain. Ascending fibers from the lence of migraine. Insulin levels are higher in patients with migraine,
TCC carry signals to multiple cortical areas after passing brainstem, and almost 11.1% of patients suffered from insulin resistance [64]. The
thalamic, hypothalamic, and basal ganglia nuclei leading to the association between metabolic syndrome and a migraine attack and its
expression of pain [1,54]. severity needs more evidence to establish a significant correlation.
It is quite evident from studies that most cases of migraine trigger
3.4. Thalamo-cortical circuits, thalamic circuits and migraine increased oxidative stress. Migraine patients with increased oxidative
stress can develop deep white-matter hyperintensities (WMHs). In one
Changes in brain functionality have been reported during the pre study, 32 migraine patients and 17 healthy controls were evaluated
monitory phase. Electrophysiological studies have reported increased [65]. In the migraine group, 18 patients had WMHs and 14 did not. The
blood flow, particularly in circuits connecting the thalamus-cortex. levels of superoxide dismutase (SOD), and glutathione peroxidase,
Differences in thalamic and thalamocortical activity have also been re catalase (CAT) were examined together with those of malondialdehyde
ported by functional and structural imaging studies. Changes in brain (MDA). The results revealed that CAT levels decreased significantly in
functionality in migraine patients have also been reported in electro serum samples of migraine patients with WMH compared to controls or
physiological studies. Imaging studies have shown changes in thalamic patients without WMH [65].
activity during an attack in these patients [55]. Among all studies examined oxidative biomarker levels, the SOD
level was most often associated with migraine; in patients with
3.5. Postdromal phase migraine, SOD levels were consistently lower compared to other
markers [66]. Differences in results could be due to differences in
This phase is the least studied in the literature. It is mostly ignored methodology and patient-selection criteria. However, in many studies,
and unreported by the patients. However, it is sometimes a distinct levels of nitric oxide and oxidative stress increase during a migraine
phase of the disease or a continuation of the same pathology. Patients attack [66]. Another possible marker for migraine is heavy metal con
might report symptoms like tiredness, muscle weakness, mood changes, centrations; free-iron concentrations are higher in patients with
difficulty in concentration and reduced appetite. A possible explanation migraine. Levels of free iron deposited in the brainstem of patients are
of the postdromal phase might be the persistent activation of the also higher depending on disease duration [67].
brainstem and diencephaly while and after processing the pain stimuli The human brain is dependent on glucose as the main energy source,
[56]. as little glycogen is stored in the brain, which could predispose the brain
6
to hypoglycemic. The association between hypoglycemic and migraine recovery or a sudden headache that starts and does not go away. The
has been known for almost a century. The similarities in the symptoms of former is called a transformed migraine, and the latter is known as a new
the conditions also indicate an association between them. Symptoms, daily persistent headache [72,73]. It is important to recognize these
such as cold hands and feet, low blood pressure, fatigue, shaking, pale patterns, as they highlight the underlying cause. Establishment of the
skin, and slurred speech are common in both hypoglycaemic and correct phenotype is vital for an accurate diagnosis as well as for suc
migrainous patients. All of these symptoms are caused by glucose cessful treatment.
insufficiency in the brain, which releases catecholamines as a result of
sympathetic activation [68]. 4.2. Recognition of the migraine phases
Cutaneous allodynia is reported in some patients with migraine, and
its incidence is more in chronic migraine. It is manifested as a reduced The most common cause of recurrent headache is migraine, which is
nociceptive threshold of the skin leading to a painful sensation from experienced by 10% of men and 20% of women. Although there is a
nonpainful stimuli. It is believed to be a part of the general central genetic basis for migraine, the attacks are usually triggered by external
excitation occur in the migraine patients. Although multiple studies or internal stimuli and sometimes appear for no apparent reason. An
showed the association of cutaneous allodynia with chronic migraine aura is experienced by around 20% of migraine patients. The aura
specifically, it is not yet listed in the criteria of chronic migraine in the consists of visuals, as negative phenomena (blind spots caused by loss of
International Classification of Headache Disorders, Third Edition, Beta vision) or positive phenomena (flashes of light, floaters, expanding or
Version (ICHD-III Beta) [69]. Matrix metalloproteinases (MMPs) are a moving zig-zag patterns). Tingling or numbness is also experienced as a
group of enzymes involved in the regulations of multiple cellular func sensory aura by many individuals which occurs on the arms, lips,
tions such as cellular growth, differentiation and inflammation. It is tongue, face, and hands. Premonitory symptoms are observed by
recently reported that some MMPs are associated with migraine irre 10–20% of individuals for nearly 48 h before an episode [48,74]. These
spective to the presence of aura. In addition, in these cases of migraine, symptoms include an abnormal burst of energy, yawning, neck stiffness,
MMPs reflected an association with metabolic disturbance too [70]. The fatigue, and frequent urination. The active areas of the brain during the
proposed role of MMPs in migraine is related to their influence on the premonitory phase have been identified [75]. A postdrome is also
peripheral nociceptors and increasing the sensitivity of these receptors experienced by most cases, including a bruised feeling in the head,
to inflammatory markers [71]. grumbling headache, nausea, fatigue and sensitivity to smell, noise, light
and movement [74].
4. Diagnosis of migraine
4.3. Detailed history
The guidelines for diagnosing migraine were formulated by the In
ternational Headache Society [5] and are summarized in Table 2. There The diagnostic process requires an accurate and detailed history of
is a difference in the diagnostic criteria for MA and MO. The features of the condition. Individuals should be given sufficient time to explain and
MA involve a minimum of five headaches in 4–72 h. Also, MA demon describe the episode and clarification should be made with targeted
strates either pulsation, unilateral location, intense pain, or exacerba questions. Furthermore, a physical examination should be performed to
tion of headache with routine activities. These features are accompanied identify ailments that are exacerbating the individual’s tendency for
by vomiting, nausea and phonophobia or photophobia [5]. migraine. Inspection, funduscopy, and palpation of the neck and head
Notably, the symptoms and headache should not be attributed to structures may be performed together with brief neurological and car
other diseases. The diagnostic features for migraine with the typical aura diovascular screening examinations [76].
include a minimum of five headaches, among which at least two epi The screening questions are aimed at recording the pattern of the
sodes must be accompanied by an aura. The headache should begin or pain; the beginning and end of headaches; the nature of the headache,
occur within 60 min of the aura. The aura must consist of reversible whether episodic or continuous; duration of the attack; and any possible
dysphasic speech or unilateral sensory or homonymous visual symp triggering factors. The character, location and severity of pain are
toms. There must be at least one symptom that gradually increases with ascertained. Symptoms associated with the headache should be recor
time, with each symptom ranging from 5 to 60 min [5]. The features ded. These may account for the aura or prodrome, e.g. yawning, tired
should not be accounted for by a secondary disorder. ness, urination, vertigo, neck stiffness, sensory or visual disturbances.
Symptoms, such as conjunctival injection, eye-watering, ptosis, nasal
4.1. Pattern recognition congestion, neck stiffness, eyelid edema, agitation, sweating, fever or
rash, which could form the basis for primary or secondary types of
Initial diagnosis requires an assessment of how the headache origi headache, should also be recorded [76]. A detailed history of the
nated. The patterns involve either pre-existing headache ailments, with treatment taken before and after initiation of the headache is also
an increase in the frequency of attacks, which reach a stage of non- important. A list of medications used previously, including the dosage,
must be recorded, and the reasons for discontinuing any medicine must
Table 2 be discussed. Complementary or alternative therapy is sought based on
The diagnostic criteria for migraine headache as formulated by the International this information [76]. Any medical history of depression, sleep issues or
Headache Society [5]. anxiety are recorded. The record should include a history of allergy,
Without aura With aura
current medications for other conditions, social history, family history,
smoking, occupation, and caffeine and alcohol consumption. History of
• Minimum of five headaches within • Minimum of five headaches, among
recurrent abdominal pain, and the tendency for hangover or motion
4–72 h. which at least two episodes must be
• Pulsation. accompanied by an aura. sickness should be considered [76].
• Unilateral location. • The headache should begin with, or be
• Intense pain. within 60 min of, the aura. 4.4. Investigations
• Exacerbation of headache with The aura must consist of
routine activities. • reversible dysphasic speech.
These features are accompanied by • unilateral sensory. No specific investigations are required to diagnose migraine.
vomiting or nausea and phonophobia • homonymous visual symptoms. Migraine is mainly diagnosed by history. However, imaging techniques
or photophobia. Minimum of one symptom that gradually and blood tests can be performed to exclude other possible causes of
increases with time and each symptom headache. Although a clinical examination can reveal multiple neuro
ranges from 5 to 60 min.
logical abnormalities and diagnoses, computed tomography (CT)
7
neuroimaging and magnetic resonance imaging (MRI) can be used for were driven by caffeine or painkiller overuse [95], or psychological
confirmation. abnormalities such as depression or anxiety, or physical situations such
as significant life events or sleep apnea. A definite diagnosis may not be
4.5. CT neuroimaging studies possible in some cases. Nonetheless, if signs of severe and chronic
headache are interfering with normal daily activities, then treatment
CT studies have been conducted on patients with migraine. These should be provided based on migraine being the most likely cause. It is
studies have highlighted abnormalities in a certain proportion of vital to make a diagnosis and to explain it to the patient. The discussion
migraine cases. One study conducted on 94 individuals highlighted the should include reassurance that nothing serious has happened. This is
presence of glioma in two, cerebral infarcts in six and periventricular the first step in treatment; the next step is to prescribe medication, and in
edema in six patients [78,79]. In another study, 25 of 53 cases showed rare instances an intervention may be required.
focal atrophy, generalized atrophy and other abnormalities [80]. A
choroid plexus papilloma was detected in one of 453 migraine cases. 5. Treatment strategies
Ventricular enlargement and low-density areas have been identified in
hospitalized cases [81]. Acute infarction, subarachnoid hemorrhage, The main goal of treatment for migraine is to reduce the severity and
metastatic neoplasm, primary neoplasm, hydrocephalus and subdural duration of the migraine attack [96]. Other objectives include restoring
hematoma have also been observed in some studies [82]. Focal atrophy functioning ability, reducing the use of rescue medications and pro
is of high prevalence in older individuals [83]. Frequently observed moting overall management with no or minimal side effects [97]. The
abnormalities include ischemia, atrophy, calcifications in basal ganglia current therapies for migraine include acetaminophen [98,99], triptans
and ventricular enlargement. The atrophy usually reflects aging [84]. (sumatriptan, eletriptan, rizatriptan, almotriptan, frovatriptan, nara
triptan and zolmitriptan) [100,101], Nonsteroidal Anti-Inflammatory
4.6. MRI neuroimaging studies Drugs (NSAIDs) (naproxen sodium, acetylsalicylic acid (ASA),
ibuprofen, and diclofenac potassium [102–105], dihydroergotamine
MRI studies have highlighted white-matter lesions that were corre [106], non-opioid analgesics (ASA, acetaminophen, and caffeine) [107],
lated with the clinical features and individual demographics of patients NSAID-triptan combinations [108], and anti-emetics (chlorpromazine,
with migraine [85]. Patients with heart disease, hypertension or dia metoclopramide and prochlorperazine) [109–111]. Drugs such as acet
betes have a higher prevalence of white-matter abnormalities [85]. aminophen, butorphanol and tramadol show some efficacy; however,
Patients with MA have significantly more frequent foci in white matter the disadvantages of NSAIDs surpass their benefits and hence they are
than do patients with MO [86]. The incidental findings include hetero less recommended for use [96,112]. Opioids should be avoided due to
topy and atrophy of the frontoparietal and cortical areas. Patients with their addiction risk [97]. Opioids can reduce the efficacy of triptans and
headache have more frequent intracranial abnormalities than in promote sensitization to medications [113,114]. Chronic migraine pa
dividuals who do not suffer from headache. Some younger individuals tients always require prophylactic treatment, while migraine patients
with migraine also exhibit white-matter lesions [87]. In addition, studies with low frequency of symptoms can be managed with effective acute
have shown cortical abnormalities [88], petrous apex cholesterol cysts therapy. OnabotulinumtoxinA has been approved for treating chronic
[89] and meningiomas [90] in some migraine patients. MRI studies have migraine in European Union, since it was in use countries like Italy
revealed pituitary abnormalities and WMHs. [115]. CGRP receptor antagonists was reported for decreasing migraine
frequency [116]. The most important risk due to the overuse of symp
4.7. Combined CT and MRI studies tomatic medication should be considered during migraine progression.
A key component of migraine therapy involves over-the-counter
Both CT and MRI scans have been used to assess the neurological medications, which are considered the first-line therapy by most peo
state of patients with migraine. Wang et al. observed abnormalities on ple suffering from migraine. Medications such as naproxen, ibuprofen,
MRI scans in 4 of 688 subjects; however, no significant abnormalities acetaminophen and aspirin form the first line of treatment for a migraine
were observed on CT scans [91]. The abnormalities included tumors of attack [96]. These medications have fewer side effects and a favorable
the nose and throat and hydrocephalus. The CT and MRI scans from administration route, in addition to low cost and high efficacy [96,117].
late-onset migraine i.e. after the age of 40 years, show cerebral infarc
tion and carotid atheroma in a few participants. However, 93% of the 5.1. Acetaminophen
subjects have normal neuroimaging [92]. A comparison of MRI and CT
scans was performed in 74 subjects and multiple foci were observed on The common name for acetaminophen is paracetamol. It is a non-
T2 MRI but not on CT scans. In another study, 26 subjects had gener opioid analgesic and antipyretic agent that relieves pain and treats
alized ventricular or focal enlargement on both CT and MRI neuro fever. It is used to treat both mild and moderate forms of migraine, as a
imaging [93]. An occipital lobe infarct was observed in one of the single agent [96]. The action mechanism is not fully understood, but
participants. Neuroimaging of new sequential patients was reviewed acetaminophen is speculated to act by inhibiting cyclooxygenase (COX),
over 5 years [94]. Among 167 subjects, abnormalities were observed in which inhibits prostaglandins. The inflammatory response is mediated
two with secondary headache. Frequent abnormalities are observed on significantly by prostaglandins. Acetaminophen inhibits the COX
MRI and CT scans in patients with migraine and in normal subjects. Loss pathway exclusively in the central nervous system [118]. The side ef
of vision and a neurosurgical history are significant pathologies fects are insomnia, headache, vomiting, nausea, itching, constipation,
observed on MRI and CT scans. and atelectasis. Severe liver disease and hypersensitivity to acetamino
phen are contraindications.
4.8. Diagnosis
5.2. Nonsteroidal anti-inflammatory drugs (NSAIDs)
Chronic headache lacks a clear phenotype. An a priori assumption is
useful in this case, depending on which cases presented to doctors are 5.2.1. Naproxen
primary headache diseases and not a secondary headache. It is less Naproxen is used to treat inflammation, pain and fever [18]. This
common for individuals to seek medical consultations for mild head drug is available as a sodium salt and a free acid. It is absorbed quickly
ache, such as those related to stress and tension. An individual’s head by the gastrointestinal tract. The use of naproxen is preferred as anal
ache episodic pattern is revealed during evaluation of a history that gesia. The drug shows its effects within 1 h of consumption and lasts for
progressed into a chronic form of migraine. Sometimes these headaches 8–12 h [119]. The half-life of the drug is 15 h, which is much longer
8
than that of ibuprofen. The side effects are headache, dizziness, heart 5.3.1.1. Sumatriptan. Sumatriptan is the first triptan introduced in
burn, bruising, gastrointestinal bleeding and gastric ulcer [119]. Nap 1991 [137]. It is the most extensively studied triptan and considered as
roxen therapy is used for the early treatment of migraine. The the "Gold standard" till today [138,139]. It is available in a variety of
contraindications for naproxen include hypersensitivity to NSAIDs or dosage forms (tablet, nasal spray, and subcutaneous injection). The
aspirin and ulceration. subcutaneous formulation has the fastest onset of action; therefore it is
preferred in patients with severe headache. Also, in patients who cannot
5.2.2. Ibuprofen tolerate oral tablets due to excessive nausea/vomiting, subcutaneous
Ibuprofen has analgesic, antipyretic and anti-inflammatory effects preparation is the drug of choice. Because of its selectivity for cranial
for migraine treatment [120]. This drug inhibits COX-1 and COX-2 vasculature, it may produce minimal cardiovascular adverse effects
[121], which play important roles in prostaglandin synthesis. The [140].
half-life is 2–4 h and the serum concentration peaks at 1–2 h after intake Due to its low oral bioavailability and short half-life [141], “sec
[121]. Side effects include gastric ulcer, gastric discomfort, rash, nausea, ond-generation” triptans (frovatriptan, zolmitriptan, eletriptan, almo
heartburn and vomiting [120]. triptan, naratriptan, rizatriptan) having a better pharmacokinetic profile
have been formulated [142,143].
5.2.3. Aspirin
Aspirin is used to treat chronic headache, both in combination and 5.3.1.2. Zolmitriptan. Zolmitriptan is available in the form of tablets,
alone [122]. Aspirin inhibits the COX enzymes [122], which hinders the nasal spray and orally disintegrating tablets. Zolmitriptan nasal spray
synthesis of thromboxane. Aspirin is also used as antiplatelet therapy, can be used safely in children aged 12 years or more [144,145].
which causes a risk for bleeding. Aspirin can be administered through
the oral or venous routes. 5.3.1.3. Almotriptan. Almotriptan is available as oral tablets having a
half life of 3 h. Almotriptan has been approved for use in adolescents
5.2.4. Acetaminophen, aspirin, and caffeine suffering from migraine headache of at least 4 h duration [146].
Acetaminophen, aspirin, and caffeine are together used as triple
therapy to treat chronic migraine. The combined effect is analgesic and 5.3.1.4. Frovatriptan, naratriptan. They are available as oral tablets.
has been observed in many studies [123]. Migraine and tension-type Frovatriptan having the longest half life (26 h) is suitable for Migraine
headache are indications for use of these drugs as a triple therapy patients in whom headache lasts longer. Frovatriptan has specificity for
[96]. The effectiveness of the combination of these drugs is more than the cerebral vascular system with limited vasoconstrictive activity.
the efficacy of an individual drug. Naratriptan also has a longer half-life and higher bioavailability than
sumatriptan. Frovatriptan and naratriptan are used for the prevention of
5.2.5. Melatonin menstrual migraine as well [147].
Melatonin is a hormone involved in the regulation of circadian
rhythms that is released from the pineal gland. Melatonin acts on hy 5.3.1.5. Eletriptan, rizatriptan. Eletriptan and Rizatriptan are available
pothalamic receptors to promote sleep [124]. It is used as a short-term as Oral tablets having variable half-life: 4 h and 2 h, respectively.
treatment for insomnia and the prevention of migraine. An immediate Rizatriptan is available as orally disintegrating tablets as well [148].
release dose of 3 mg is administered for migraine prophylaxis [125]. Contraindications for triptans includes poorly controlled hypertension,
Common side effects are abdominal cramps, drowsiness and dizziness. hemiplegic migraine, severe hepatic and renal impairment, basilar
Breastfeeding and pregnancy are contraindications for melatonin. migraine, and coronary artery disease. Long-term use of triptans (more
Patients with migraine should be re-evaluated by specialists if the than ten days per month) may cause "Triptan-overuse headache" [148].
first and second line treatments fail. Non-pharmacological options, such
as a greater occipital nerve block, should be considered in these cases.
These techniques reduce pain in 50% of patients [126]. Thus, neuro 5.4. Lifestyle modifications
surgical methods, such as deep brain stimulation or occipital nerve
stimulation, are used to treat rare challenging cases [127]. Specific triggers of severe headache can be difficult to identify.
Triggers start to become obvious if there is improvement in headache
with treatment. Regular routines for hydration, eating, stress and sleep
5.3. Acute migraine headache: treatment strategies are beneficial for reducing migraine. Although recognizing the impor
tance of these factors is easy, busy lives and the environment make these
5.3.1. Triptans adjustments much more difficult [128].
In acute attacks of moderate to severe Migraine (with or without Many patients suffering from migraine harbor other ailments that
aura), Triptans are the most efficient "First-line therapy", especially in aggravate headache, including anxiety, depression and pain syndromes
patients whose pain is not relieved by analgesics/NSAIDS [4,128–130]. such as neck and head pain, fibromyalgia and sleep apnea. It is necessary
Triptans are selective Serotonin-agonists. Triptan binding to the Sero to manage these ailments properly to maximize the outcome of migraine
tonin receptors (5-HT1B) in intracranial vessels (which are dilated treatment. The recognition and management of overuse of medication
during a migraine attack), produces vasoconstriction. Triptan binding to are very important, as preventive treatment can be rendered ineffective
the neurogenic and central Serotonin receptors (5-HT1D) inhibits Sub [128].
stance P and CGRP release and blocks pain signals to the brain by
inhibiting nociceptors [131,132]. In this way, Triptans can potentially 6. General management
reverse various steps of trigeminovascular activation in Migraine. As
compared to Ergot alkaloids which are non-selective Serotonin agonists, Lifestyle triggers and comorbidities must be addressed. It is impor
Triptans have more favorable risk profile [133]. tant to recognize and manage sleep issues, dietary triggers such as
There are seven Triptans commercially available. Although the cheese, alcohol, chocolate, caffeine overuse or dehydration. Exercise
pharmacology of the triptans is very similar, individual patient re and maintenance of a healthy body weight are recommended. Patients
sponses can vary remarkably to different triptans because of the role of may benefit from psychological, behavioral or physical therapies
genetic factors in Migraine [134]. The relative efficacy of one triptan depending on their triggers. The natural remedies commonly used to
over the other is unknown, largely because in majority of studies Trip treat migraine are riboflavin, feverfew, coenzyme Q-10 and magnesium.
tans were compared with placebo [22,135,136]. These preventive agents have varied efficacy and hence are not
9
considered primary treatments for migraine [150,151]. cases of migraine can help to reduce the disability associated with
Drugs can be used to treat or reduce the frequency of migraine epi migraine and increase the functioning of the individual.
sodes in acute cases. The therapeutic guidelines on the general princi
ples, recommended doses, guidance on headache and instructions for 7. Preventive measures
pregnant women and children have been updated. Migraine treatment
aims to relieve the headache in 1–2 h. Treatments can be effective but Preventive therapy is an important factor in migraine treatment. The
have no significant impact on prodromal symptoms or the aura or frequency of attacks can be reduced by using preventive pharmacolog
postdromal phases. Headache should be managed as soon as possible. ical agents. The response to the treatment regimen can also be increased
Combination therapies are required in some cases, such as aspirin, by using preventive therapy. Moreover, this approach improves the
paracetamol, other NSAIDs, triptans, and anti-emetics [152]. quality of life in migraine patients and reduces the cost of effective
treatment. Although studies have indicated the importance of preven
6.1. Nausea management tive treatment in patients with migraine, only a small fraction of these
patients receive or have ever received preventive migraine medication
Management of nausea is important as it can impair absorption. [159]. There has been little overall improvement in migraine preventive
Administration of antiemetics with analgesics helps the management therapy since 2012. Several agents, including beta-blockers, antide
and treatment process [153]. The route of administration can be pressants and anticonvulsant agents, such as sodium topiramate, botu
changed if an individual is unable to take a medicine orally; options linum toxin A and flunarizine, are common migraine preventive
include ondansetron wafers for vomiting, NSAID suppositories, non-oral treatments [1].
triptan formulations and prochlorperazine suppositories. Migraine pharmacological treatment can be acute or preventive and
both approaches are required in patients with persistent serious head
6.2. Management of menstrual migraine ache. Preventive treatment is used to minimize the duration, frequency,
and intensity of attacks. Added benefits include enhancing the response
These types of migraine attacks are difficult to treat due to their to acute procedures, improving the functional potential of a patient and
severity and recurrence. The use of an oral contraceptive may limit the reducing disability. Preventive treatment may also contribute to
number of episodes and help identify the timing of attacks linked to decreasing the cost of healthcare [160].
menstruation. The use of an oral contraceptive must be avoided in pa A preventive migraine regimen is effective if it improves the condi
tients with MA, because of the chance of stroke. Naproxen, in addition to tion by 50% within 3 months of the treatment start period. According to
acute therapies, may aid in perimenstrual symptoms [154]. the American Migraine Prevalence and Prevention Report, among
38.8% of migraine patients, 13.1% should be considered for preventive
6.3. Aerobic exercise therapy. About 26% of patients should be given preventive migraine
treatment. Sadly, the underuse of preventive migraine drugs is empha
The use of physical activity and exercise is prescribed in some cases. sized by the fact that only 13% of all migraine patients are utilizing
Exercise affects the severity, duration and total number of days of pain preventive therapy [128,161].
attacks. Many studies have evaluated the impact of aerobic exercise on Several preventive drugs are available for migraine, and guidelines
migraine, and the results have shown a 22–78% reduction in the number have been developed for their use. Comorbidities must be considered
of migraine-attack days [155–157]. After pooling data from different when selecting preventive medications for migraine patients. However,
studies, aerobic exercise had a significant effect i.e. 10–12 weeks with a the use of two separate drugs requires a proper understanding of
p-value of 0.0006 in 176 individuals. The mean reduction in headache migraine and the comorbid conditions. No biological markers or clinical
days/month was 0.6 ± 0.3, which was observed in the intervention features predict the response to a specific preventive drug for migraine.
group. The data were pooled based on diagnostic similarity, treatment An examination of the natural history of these patients can also help to
and outcome. One of the studies showed an effect of high-intensity prevent migraine [159].
training and moderate aerobic exercise in patients with migraine
compared to healthy controls. 8. Diet
The effects of exercise on the intensity of pain and the duration of
attacks have also been studied. A 20–54% reduction in pain intensity The most common preventive measure reported for migraine is diet.
was observed in previous studies and the duration of attacks was Migraine has recently been regarded as a metabolic and endocrine dis
reduced by 20–27% [155–157]. The outcomes of studies conducted on order. Different dietary compounds act as triggers for migraine. An
the duration and intensity of pain were not pooled because of hetero elimination diet has been introduced based on these findings [162]. The
geneity in the measurement outcomes. Exercise also resulted in a 71% amount of food consumed can also trigger headache. A relatively high
reduction in the use of analgesic medication [156]. Although this was a amount of MSG will produce a headache. On the other hand, with
significant observation, the study was not intended to identify these drawing some foods can also cause headache to start. Triggering factors
changes. No significant differences in medication usage have been re differ among groups. People with different immunological responses
ported. One study reported no difference between groups of individuals differ as regards the foods that act as migraine triggering factors [163].
who were on a drug treatment compared to those on a drug while Hence, it becomes difficult to identify particular foods that trigger
participating in an exercise regimen [157]. Another study highlighted migraine. Genetic factors can also act as predisposing factors. Some
that fewer medications were being used by individuals in an exercise people are susceptible to different food ingredients and others are sus
regimen compared to individuals maintaining normal activities [158]. ceptible to some types of beverages. Avoiding these triggers can help to
However, the results were not significant after a statistical analysis. prevent migraine [164].
Migraine is managed after an appropriate diagnosis. Acute attacks This is the main concept behind the elimination diet. Few studies
should be treated early with the use of effective medicines. Triptans are have reported the importance of a comprehensive diet in patients with
used in cases when simple analgesics fail to relieve symptoms. Strategies migraine. Probiotics help modify the gut bacteria. However, as migraine
for prevention include modifications in lifestyle, managing comorbid is a multiphase disorder, more studies are required to address the role of
ities, physical and behavioral therapies and medications. The medicines diet in migraine. A multimodal approach including dietary interventions
are prescribed based on adverse effects, potential interactions and in can prove helpful in migraine patients. The following section describes
dividual comorbidities. Recent therapies, such as anti-CGRP monoclonal the details of diets used for migraine patients [165].
antibodies, are targeted therapies. The management of severe and acute
10
8.1. Elimination diets who consumed a ketogenic diet, the frequency of headache during the
transition period was worse. However, the frequency of headache
An elimination diet requires identifying dietary ingredients that improved significantly in the low-calorie diet group after the 3- and
trigger headache first and then eliminating these ingredients from the 6-month follow-up visits [173].
regular diet. This is a personal approach in which the individual iden
tifies the ingredients that start or intensify the headache. Consequently, 8.5. Relationship between adipokines and migraine
these ingredients are eliminated from the diet. This concept should not
be confused with food allergy [163]. An association between adipocyte-released factors known as adipo
A trigger can also be identified in a structured manner. If a food kines, such as adiponectin and leptin, and migraine headache has been
causes headache within 1 day after exposure then it can be regarded as a reported [174]. This association provides information about the role of
trigger. In most patients, multiple triggering factors are present; there adipose tissue in migraine pathophysiology. Adiponectin concentrations
fore, it becomes difficult to identify single ingredients. Moreover, some may increase between migraine attacks and decrease during attacks.
foods contain more than one ingredient, making the task more compli However, further research is required to draw a definitive conclusion
cated [166]. However, an elimination diet also has negative effects, as it [174].
can result in malnutrition or undernutrition because of inadequate
intake of protein and micronutrients. This can lead to frequent infections 8.6. Low-glycaemic diet (LGD) and migraine
and other physiological problems [167,168].
Obtaining 50–55% of total calories from carbohydrates has
8.2. Comprehensive migraine diet commonly been recognized as a safe diet. A LGD is an important alter
native in some cases, such as hyperlipidaemia, diabetes, epilepsy, and
Together with an elimination diet, the idea of a migraine-specific diet weight management [175].
was developed recently. Different diet plans are beneficial in patients
with this disorder. Some are evidence-based and others are suggested 8.7. Low-fat diet and migraine
based on the mechanism of headache propagation. Foods that act on
neuronal excitability and are responsible for the pathophysiology of Several studies have addressed the effect of a low-fat diet on
migraine, platelet aggregation, mitochondrial functioning in the brain, migraine prophylaxis. A 1999 study investigated the effect of a fat-
neuroinflammation and hypothalamic function are recommended reduced diet in the management of migraine in 54 adults. Patients
[168]. were told that their fat consumption would decrease to <20 g/day (12
A low-fat, high-folate and ketogenic diet rich in omega-3 and omega- weeks) after 28 days of run-in. As a result, a substantial reduction in the
6 fatty acids has beneficial effects in patients with migraine. The incidence, severity and need for headache medications was identified
modified Atkins diet provides neuroprotection, improves serotoninergic [176].
dysfunction, suppresses neuroinflammation and improves mitochon
drial functioning. A ketogenic diet increases the concentration of ketone 8.8. Epigenetic diet
bodies produced, which is helpful in patients with headache [168]. A
low glycaemic diet also improves the state of inflammation. Maintaining This type of diet was first introduced for cancer patients. The diet is
a delicate balance between the omega-6 fatty acids and intake of modified in such a way that it potentially interferes with disease path
omega-3 reduces inflammation, maintains vascular tone and enhances ogenesis. Some dietary compounds with unique mechanisms of action
platelet function [168]. are included. Ingredients with specific cellular structures and molecules,
such as DNA, are the main targets of these diets [177]. The epigenetic
8.3. Low-sodium diet diet is based on the strategy that different dietary factors are capable of
interfering with the epigenetic profile of the patient. Hence, this type of
An analysis of cerebrospinal fluid has shown a higher level of sodium diet benefits disease prevention [178].
in patients with migraine, particularly while they are experiencing a Folate, is beneficial to patients with migraine, which is involved in
headache attack, compared with controls. However, the effect of a low- DNA methylation, and has captured further attention in the form of the
sodium diet depends on many factors, so the effects should be evaluated epigenetic diet. A diet that targets DNA methylation may provide a
in detail before considering a low-sodium diet [169]. A low-sodium diet future route for epigenetic dietary research studies linked to migraine,
can effectively reduce the occurrence of headache in elderly patients such as the diet rich in folate that has been reported [179]. However, at
with hypertension. In addition to controlling blood pressure, a molecular and cellular levels of the epigenetic profile, few data are
low-sodium diet decreases the incidence of headache [170]. In contrast, available to describe the underlying mechanisms. Therefore, this dietary
a high-sodium diet helped to reduce the frequency of migraine attack in component would block the underlying mechanisms of migraine.
a young female population with a low to normal body mass index Furthermore, the feasibility of an epigenetic migraine diet and its po
without hypertension. This contrasting finding indicates that a sodium tential benefits are still not clearly understood [180].
diet should be tailored based on the patient population. For instance, a
patient suffering from hypertension might benefit from a low-sodium 9. Conclusion
diet, whereas a patient with low blood pressure might benefit from a
high-sodium diet [171,172]. In this review, we have discussed the genetic and metabolic bases of
migraine. Migraine is a multifactorial chronic neurological condition
8.4. Difference between low calorie and ketogenic diets that varies in frequency, severity and its effect on the quality of life.
Genetic makeups play a significant role in defining an individual’s
A ketogenic diet is more beneficial to patients with migraine susceptibility to migraine. In these patients, the pathophysiology
compared with a low-calorie diet. A low-calorie diet is not beneficial for stresses the presence of different triggers that initiate a headache attack
migraineurs (n = 108) [173]. In another study, a ketogenic diet signif or increase the frequency of the attacks. Treatment options should
icantly improved headache features and decreased the frequency of at consider not only the symptoms, diagnosis, and co-existing or comorbid
tacks and the use of medications in these patients. Continued conditions of the patient, but also the desires, wishes and aspirations of
improvement was observed for 2 months after the ketogenic diet was the patient.
stopped. Although the frequency of headache was reduced in patients To conclude, while migraine is a prevalent condition, it is often
11
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pathophysiology, Curr. Opin. Neurol. 15 (2002) 287–295.
[11] D.C. Buse, A.N. Manack, K.M. Fanning, D. Serrano, M.L. Reed, C.C. Turkel, R.
The project is funded by the Deanship of Scientific Research (IFP- B. Lipton, Chronic migraine prevalence, disability, and sociodemographic factors:
2020-46), Majmaah University, Al-Majmaah, Saudi Arabia. results from the American migraine prevalence and prevention study, Headache
52 (2012) 1456–1470.
[12] J. Peck, I. Urits, J. Zeien, S. Hoebee, M. Mousa, H. Alattar, A.D. Kaye,
Author contributions O. Viswanath, A comprehensive review of over-the-counter treatment for chronic
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Conceptualization, writing—original draft preparation, project [13] T.A. Smitherman, R. Burch, H. Sheikh, E. Loder, The prevalence, impact, and
treatment of migraine and severe headaches in the United States: a review of
administration, supervision, J.H.; L.A.A.; S.A. and J.F.B.; funding statistics from national surveillance studies, Headache 53 (2013) 427–436.
acquisition, J.H.; validation, data curation, writing—review and editing, [14] T. Vos, A.D. Flaxman, M. Naghavi, R. Lozano, C. Michaud, M. Ezzati, K. Shibuya,
A.A.S.; N.R.; R.L.; S.A.S.; N.B.A., and D.A. J.A. Salomon, S. Abdalla, V. Aboyans, J. Abraham, I. Ackerman, R. Aggarwal, S.
Y. Ahn, M.K. Ali, M.A. AlMazroa, M. Alvarado, H.R. Anderson, L.M. Anderson, K.
G. Andrews, C. Atkinson, L.M. Baddour, A.N. Bahalim, S. Barker-Collo, L.
H. Barrero, D.H. Bartels, M.G. Basáñez, A. Baxter, M.L. Bell, E.J. Benjamin,
Declaration of conflicting interests D. Bennett, E. Bernabé, K. Bhalla, B. Bhandari, B. Bikbov, A.B. Abdulhak,
G. Birbeck, J.A. Black, H. Blencowe, J.D. Blore, F. Blyth, I. Bolliger,
A. Bonaventure, S. Boufous, R. Bourne, M. Boussinesq, T. Braithwaite, C. Brayne,
The authors declare that they have no competing interests. L. Bridgett, S. Brooker, P. Brooks, T.S. Brugha, C. Bryan-Hancock, C. Bucello,
R. Buchbinder, G. Buckle, C.M. Budke, M. Burch, P. Burney, R. Burstein,
B. Calabria, B. Campbell, C.E. Canter, H. Carabin, J. Carapetis, L. Carmona,
Acknowledgments
C. Cella, F. Charlson, H. Chen, A.T.A. Cheng, D. Chou, S.S. Chugh, L.E. Coffeng, S.
D. Colan, S. Colquhoun, K.E. Colson, J. Condon, M.D. Connor, L.T. Cooper,
The authors thank the Dean, Institute for Research and Medical M. Corriere, M. Cortinovis, K.C. de Vaccaro, W. Couser, B.C. Cowie, M.H. Criqui,
M. Cross, K.C. Dabhadkar, M. Dahiya, N. Dahodwala, J. Damsere-Derry,
Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dam
G. Danaei, A. Davis, D. De Leo, L. Degenhardt, R. Dellavalle, A. Delossantos,
mam, Saudi Arabia, for her continuous support and encouragement. The J. Denenberg, S. Derrett, D.C. Des Jarlais, S.D. Dharmaratne, M. Dherani, C. Diaz-
authors thank Mr. Ranilo, M. Tumbaga, and Mr. Horace T. Pacifico for Torne, H. Dolk, E.R. Dorsey, T. Driscoll, H. Duber, B. Ebel, K. Edmond, A. Elbaz, S.
their assistance. E. Ali, H. Erskine, P.J. Erwin, P. Espindola, S.E. Ewoigbokhan, F. Farzadfar,
V. Feigin, D.T. Felson, A. Ferrari, C.P. Ferri, E.M. Fèvre, M.M. Finucane,
S. Flaxman, L. Flood, K. Foreman, M.H. Forouzanfar, F.G.R. Fowkes, R. Franklin,
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Biomedicine & Pharmacotherapy 139 (2021) 111557

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Genetics, pathophysiology, diagnosis, treatment, management, and

1. Introduction disturbances are common in this condition [1].

Fig. 1. Factors that trigger migraine [1–63].

and stroke like episodes) is a condition of abnormal mitochondrial

MELAS (Mitochondrial myopathy, encephalopathy, lactic acidosis,

3. Pathophysiology intracellular network cascade that causes inhibitory or excitatory

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