Curr Pain Headache Rep (2010) 14:276283
DOI 10.1007/s11916-010-0121-y
Migraine and Epilepsy: A Focus on Overlapping Clinical,
Pathophysiological, Molecular, and Therapeutic Aspects
Marino Muxfeldt Bianchin & Renata Gomes Londero &
Jos Eduardo Lima & Marcelo Eduardo Bigal
Published online: 22 May 2010
# Springer Science+Business Media, LLC 2010
Abstract The association of epilepsy and migraine has
been long recognized. Migraine and epilepsy are both
chronic disorders with episodic attacks. Furthermore,
headache may be a premonitory or postdromic symptom
of seizures, and migraine headaches may cause seizures per
se (migralepsy). Migraine and epilepsy are comorbid,
sharing pathophysiological mechanisms and common clin-
ical features. Several recent studies identified common
genetic and molecular substrates for migraine and epilepsy,
including phenotypic-genotypic correlations with mutations
in the CACNA1A, ATP1A2, and SCN1A genes, as well as in
syndromes due to mutations in the SLC1A3, POLG, and
C10orF2 genes. Herein, we review the relationship be-
M. M. Bianchin (*)
Division of Neurology, Hospital de Clnicas de Porto Alegre,
Universidade Federal do Rio Grande do Sul,
Ramiro Barcelos 2.350 Porto Alegre,
Rio Grande do Sul 90035-903, Brazil
e-mail: mmbianchin@hotmail.com
R. G. Londero
Medical Science Postgraduate Program,
Universidade Federal do Rio Grande do Sul,
Porto Alegre, Brazil
J. E. Lima
Department of Medicine, School of Medicine,
Universidade Federal de So Carlos,
So Carlos, Brazil
M. E. Bigal
Global Director of Scientific Affairs: Neurology and Psychiatry,
Merck Research Laboratories,
Upper Gwynedd, PA, USA
M. E. Bigal
Department of Neurology, Albert Einstein College of Medicine,
New York, NY, USA
tween migraine and epilepsy, focusing on clinical aspects
and some recent pathophysiological and molecular studies.
Keywords Comorbidity . Headache . Migraine . Epilepsy .
Paroxysmal disorders
Introduction
Epilepsy and migraine are among the most prevalent
neurological conditions. Migraine affects around 12% of
adults worldwide, with regional variations [1, 2]. The
world average lifetime prevalence of epilepsy has been
estimated as 10.3 out of 1000 people (ranging from 1.557
of 1000) [3]. Epilepsy is more prevalent in developing
countries versus developed countries [3, 4].
Migraine is one of the most frequent neurological
comorbidities in epilepsy, and this relationship has been
long recognized. In 1898, an editorial in the Journal of
the American Medical Association noted the need to find
...a plausible explanation of the long recognized affinities
of migraine and epilepsy [5]. More than 100 years later,
these affinities retain their scientific and clinical relevance.
Indeed, several epidemiological studies suggest that the
association of migraine and epilepsy occurs significantly
more often than would be expected based on statistical
chance, and that the diseases are therefore comorbid.
Revising this topic is beyond the scope of this review and
the readers are referred to the review by Hart et al. [6].
However, it is worth mentioning the study of Andermann
and Andermann [7], which reviewed 13 studies and
concluded by noting the important and bidirectional
comorbidity, similar to Ottman and Lipton [8] who found
that migraine was 2.4 times more common in patients with
epilepsy versus those without epilepsy. Due to its
Curr Pain Headache Rep (2010) 14:276283 277

Table 1 Symptoms common to both migraine and epilepsy First, they are both chronic diseases with episodic attacks
Symptom Migraine Epilepsy [6]. In between attacks, there is an enduring predispo-
sition to the attack that, although subclinical, can be
Systemic measured electrophysiologically by electroencephalogram
Vomiting + (EEG) in epilepsy and by demonstrating lack of habitua-
Nausea + tion in migraine [10]. During attacks, both are clinically
Diarrhea manifested by repeated episodes of paroxysmal events (eg,
Headache + seizures or headache attacks), very often preceded by
Visual disturbances prodromes and/or auras. Moreover, in patients with
Colored circles + migraine, the presence of aura, severe pain, presence of
Black and white lines + photophobia or phonophobia, and worsening by physical
Blindness activity are reported to be more frequent in patients with
Blurred vision + + epilepsy versus those without epilepsy [11]. These find-
Visual triggering factors + + ings further support the concept that epilepsy and migraine
Other neurologic share common mechanisms. Table 1 displays some clinical
Olfactory + similarities between migraine headaches and epilepsy
Vertigo + Although there are several clinical links between both
Confusion + conditions, some of them only recently have been incorpo-
Loss of consciousness ** + rated into classification systems. The second edition of the
Impaired consciousness + International Classification of Headache Disorders (ICHD-
Loss of memory + II) distinguishes three disorders: migraine-triggered seizures
Postevent lethargy + +
(migralepsy), hemicrania epileptica, and postictal head-
Depersonalization +
aches [12]. Other well-known syndromes, such as preictal
Paresthesias + +
or ictal headaches, are not accounted by the ICHD-II. These
syndromes are often neglected because the seizure over-
Hemiparesis ** +
shadows the headache for both patient and physician. They
Hemisensory loss ** +
are discussed below. Figure 1 presents prevalence of
Aphasia ** +
headache and migraine in epilepsy and its relationship with
+ denotes presence; denotes absence. ictal and interictal period.
**Present in hemiplegic migraine.

bidirectional link (ie, epilepsy increases the risk of

migraine and migraine increases the risk of epilepsy), the
authors postulated that both conditions shared biological
predisposition [9]. More recently, several other authors
have confirmed this association, adding new insights on
the relationship between migraine and epilepsy.

Clinical Aspects

The term comorbidity does not necessarily imply

direction or causation. It refers to co-occurrence of
diseases at a rate not explained by chance only.
Mechanisms of comorbidity include unidirectional or
bidirectional predisposition, as well as shared pathophys-
iological, genetic, and/or environmental risk factors. For
epilepsy and migraine, robust evidence suggests that both
conditions share important mechanisms as discussed
below. Epilepsy or migraine can precede or succeed
each other, or even occur simultaneously [6], and
several clinical aspects are common to both disorders.
Fig. 1 Time distribution of headache and migraine in epilepsy.
Migraine and epilepsy are comorbid. They are bidirectional and one
can precede or succeed the other or even occur simultaneously.
Numbers represent approximate percentage range of headache in
epilepsy. Prevalence representations are just illustrative. Prevalence
can be very variable depending on population, diagnostic, classifica-
tions, and type of epilepsy studied. According with seizures, headache
can be classified as interictal, preictal, ictal, or postictal
278
Peri-ictal Headaches
Peri-ictal headaches are common, occurring in 40% to 60%
of patients with epilepsy [1315]. They are subdivided as
preictal, ictal, and postictal. However, these forms of
headaches are not excluding. The same patients might
present more than one subtype of peri-ictal headache and
also experience interictal headaches. More than a nuisance,
they may have diagnostic importance. For example, in
temporal lobe epilepsy, headache location is strongly
correlated with the side of epileptogenic zone, being a
lateralization sign [13].
Preictal Headaches
Systematic studies of preictal headaches are rare, but this
form of headache seems to occur in 5% to 15% of patients
with epilepsy [15, 16]. Yankovsky et al. [14] studied
preictal headaches in 100 pharmacologically refractory
patients with partial epilepsy and found a prevalence of
11%. Based on direct surgical observations and neuro-
imaging findings, the authors suggested that the increased
blood flow that precedes epileptic seizures may trigger
trigeminovascular activation and consequent headaches.
Surgical control of epilepsy was very effective in rendering
patients free of preictal headache symptoms, a strong
evidence that some forms of headache share common
mechanisms with epilepsy [14].
A distinct form of preictal headache regards the
migraine-triggered seizures (migralepsy), in which seizures
happen during classical migrainous aura. Its prevalence is
unknown, but it has been particularly associated with
basilar-type migraine and menstrual migraines [17]. Mi-
grainous aura is the clinical manifestation of cortical
spreading depression (CSD), a potent excitatory electrical
neuronal wave followed by neuronal inhibition and glial
activation [18]. It may be postulated that the neuronal
activation generated by CSD further decreases the threshold
in the epileptic focus, increasing the risk of seizures [19].
Ictal Headaches
Ictal headaches are reported by less than 5% of patients
with epilepsy [20], and in some patients it might reflect a
true epileptic phenomenon [21]. The relatively low preva-
lence of ictal headaches might be a consequence of
cognitive or consciousness impairments provoked by
seizures. Alternatively, as some seizures propagate to the
thalamus, an analgesic status may be rendered, although the
evidence to support this hypothesis is lacking. Isler et al.
[22] found that hemicranial attacks of pain sometimes
coincide with seizure activity and typically last for seconds
to minutes (hemicrania epileptica); in rare cases, ictal
Curr Pain Headache Rep (2010) 14:276283
headache may last for hours. In patients with photosensitive
occipital epilepsy, it might be difficult to differentiate a
migraine attack from epilepsy based only on clinical
grounds [23]. In this syndrome, headache complaints might
be the clinical correlate of epileptic ictal EEG activity [21].
Postictal Headaches
Postictal headaches occur in 10% to 50% of patients with
epilepsy [15, 24]. It often resembles migraines, being
responsive to ergotamine derivatives or to triptans [25].
Postictal headaches are more common following general-
ized tonic-clonic seizures and epilepsy of the occipital lobe
[1524]. As for preictal headaches, headaches may occur as
following brainstem activation, with consequent trigeminal
activation and vasodilation [24, 25].
Epileptic Syndromes Strongly Associated
With Migraine
Benign occipital epilepsy of childhood (BOEC) is a clinical
syndrome characterized by visual symptoms followed by a
partial seizure and postictal migraine. The EEG reveals
occipital spikes. It is one of the epileptic syndromes more
strongly associated with migraine [26, 27]. Early-onset
BOEC is also known as Panayiotopoulos syndrome while
late-onset BOEC is also known as Gastaut type [27, 28,
29]. In Panayiotopoulos syndrome, children have rare
prolonged and nocturnal seizures. The spells are character-
ized by autonomic features such as vomiting, pallor, and
sweating followed by tonic and clonic motor symptoms
[27, 28]. Headaches or migraine-like symptoms are not
common. Differently, Gastaut-type BOEC is characterized
by brief seizures of visual symptoms, usually occurring
during the day, followed by hemiclonic seizures [27, 29].
Migraine-like symptoms (eg, pulsatile headache associated
with nausea, vomiting, and photophobia) occur in about
half of patients with BOEC [29].
Benign rolandic epilepsy is the most common epilepsy
syndrome in childhood. It is characterized by unilateral
somatosensory or motor seizures and centrotemporal spikes
[30]. Benign rolandic epilepsy has been associated with
migraine. Recently, Clarke et al. [31] reported a robust
association of migraine and rolandic epilepsy in children,
suggesting a common genetic background as substrate for
this association.
Migraine also has been reported to occur with other
cryptogenic or symptomatic partial epilepsies [32]. More-
over, the association of epilepsy and familial hemiplegic
migraines (FHM) or other specific neurological syndromes
is well known [33], [34]. Although described long ago,
molecular aspects of these disorders have been the focus of
Curr Pain Headache Rep (2010) 14:276283
intense research and important updates. For this reason,
relevant aspects and new molecular aspects are discussed
below in a specific topic. Finally, migraine and epilepsy are
also prominent features of other neurological disorders,
including mitochondrial encephalopathies, arteriovenous
malformations, and posttraumatic syndromes [6].
Despite Similarities, Migraine and Epilepsy Are Distinct
Disorders with Important Differences
If it is true that epilepsy and migraine share several
common features, it is also true that both conditions have
marked differences as well. Herein, we cite important major
examples of epidemiological and clinical differences of
migraine and epilepsy that drive both disorders apart. First,
the prevalence and epidemiological characteristics of
migraine and epilepsy are distinct. The prevalence of
migraine is lower during earlier childhood, decreasing
again in older ages. Migraine is far more frequent in
women than in men [35]. Epilepsy has an opposite bimodal
prevalence distribution, affecting mostly children and the
elderly, without marked sex prevalence differences [4, 6].
Epilepsy attacks are usually brief but characterized by a
constellation of clinical and behavioral aspects character-
ized by motor, sensory, visual, and emotional symptoms.
Marked positive findings suggest cortical hyperexcitability
and are often associated with consciousness [36]. Migraine
attacks are longer and characterized mainly by pain and
associated symptoms. Negative symptoms typically happen
during the aura phase and loss of consciousness is rare
[6]. Aura symptoms are also distinct in both conditions.
Duration is shorter in epilepsy; in migraine, visual aura
usually is characterized by negative symptoms, slow
spreading, and monochromatic aspects [6]. In its turn,
epileptic aura is more complex. When visual phenomena
occur, they are often bright and colored [37]. Other types
of auras (eg, feelings of dj-vu) are rare in migraine but
common in epilepsy [38]. Finally, epilepsy is a stigmatizing
disease, being a life-threatening condition, while migraine
has not been associated with reduced lifespan [4, 39].
Common Mechanisms of Migraine and Epilepsy
The mechanisms underlying the association of migraine
and epilepsy are yet to be elucidated, and because there are
several subtypes of migraine disorders and of epilepsy,
mechanisms are likely to be diverse. Nonetheless, patho-
physiological common aspects do exist.
Migraine was first understood as a vascular disorder, a
concept disseminated by Wolff in the 1940s based on previous
work. This concept has changed, and migraine is best
279
understood as a primary disorder of the brain [40, 41]. There
is abundant evidence that migraine is a familial disorder with
a clear genetic basis [34, 42]. Established theories of
migraine propose that migraine probably results from
dysfunction of the brainstem involved in the modulation of
craniovascular afferents [43]. Brainstem activation may also
lead to activation of ascending and descending pathways,
with initiation of perimeningeal vasodilation and neurogenic
inflammation. The pain is understood as a combination of
altered perception (due to peripheral or central sensitization)
of stimuli that are usually not painful, and the activation of a
feed-forward neurovascular dilator mechanism in the first
(ophthalmic) division of the trigeminal nerve [44]. Alterna-
tive theories consider that the initial problem in migraine
resides in the brain, not brainstem, and consists of cortical
hyperexcitability. CSD is the presumed substrate of migraine
aura; spreading depression also occurs in migraine without
aura [18]. While the brainstem theory acknowledges that
CSD exists and explains aura, the theory also considers that
CSD is not necessary to trigger the migraine pain. The
hyperexcitable theory considers that CSD happens most of
the time and triggers a cascade of events that are responsible
for the pain.
Regardless of the discrepancies, CSD may be the
connecting point between migraine and epilepsy. CSD is a
self-propagating wave of neuronal and glial depolarization.
Cascading depolarization marching across the cortical
mantle initiates a series of cellular and molecular events,
resulting in transient loss of membrane ionic gradients and
massive surges of extracellular potassium, neurotransmit-
ters, and intracellular calcium [45]. This is followed by a
long-lasting suppression of neural activity. The depolariza-
tion phase is associated with an increase in cerebral blood
flow, whereas the phase of reduced neural activity is
associated with a reduction in flow. This is thought to
cause activation of trigeminal nerves and subsequent
release of neuroinflammation mediators [46]. During
CSD, oxygen free radicals, nitric oxide, and proteases such
as the matrix metalloproteinases are increased, which may
further increase vascular permeability. As a clinical corol-
lary, effective migraine prophylactics seem to share the
ability to block CSD in rats despite being from different
pharmacological classes [47].
The occipital cortex is particularly vulnerable to CSD
[48] and raises the idea that both migraine and epilepsy are
characterized by lower neuronal threshold in the cortex.
The clinical findings that postictal headaches, often having
migraine-like characteristics, occur more in occipital epi-
lepsy support this view. The hypothesis of higher cortical
excitability shared by both conditions also could provide a
plausible explanation for why some antiepileptic drugs (eg,
valproic acid, topiramate, and gabapentin) work for
migraine prophylaxis as well [6].
280
Table 2 Selected anticonvulsants in the preventive treatment of migraine
Agent Daily dose
Gabapentin 6001200 mg
Topiramate* 100 mg
Valproate/divalproex* 5001500 mg/d
Levetiracetam tablets 15004500 mg
Zonisamide capsules 100400 mg
* Approved by the FDA for the preventive treatment of migraine.
FDA U.S. Food and Drug Administration.
Common Genetic and Molecular Aspects
Migraine and epilepsy may be linked by genetic and
molecular substrates in some syndromes. Several genes
associated to specific forms of migraine have been reported
to be associated with epilepsy as well. Below, we briefly
review recent clinically relevant studies showing a common
molecular background linking epilepsy and migraine.
The best studies of genetic abnormalities leading to
epilepsy and migraine are those studying FHM [34, 42].
FHMs are rare forms of autosomal dominant familial
disorders characterized by the occurrence of unilateral
weakness or even hemiplegia as the aura. Diagnosis is based
on three main clinical criteria [12]. First, the patients present
headaches that fulfill criteria for migraine. Second, patients
present some degree of hemiparesis that may be prolonged.
Third, at least one first-degree relative has identical attacks.
So far, mutations in several genes have been associated with
FHM [34, 42]. Of them, three are better characterized.
Mutations in CACNA1A were associated with FHM type 1
(FHM1). Mutations in ATP1A2 were associated with FHM
type 2 (FHM2), and mutations in SCN1A cause FHM type 3
(FHM3). Although the association with epilepsy is stronger
in FHM2 (where epilepsy presents in 20% of families),
epilepsy also occurs in FHM1 and FHM3 [34, 42].
As described by Ophoff et al. [49], FHM1 is caused by
mutations of the CACNA1A gene on chromosomal locus
19p13. Nystagmus and other signs of cerebellar dysfunction
are often present, and epilepsy might be observed. The
CACNA1A gene codifies pore-forming 1A-subunit of
voltage-dependent P/Q-type calcium channels. These
voltage-sensitive calcium channels mediate the entry of
calcium ions into excitable cells and are also involved in a
variety of calcium-dependent processes. In the brain, these
channels are mainly found in the cerebellum, cerebral cortex,
Curr Pain Headache Rep (2010) 14:276283
Comment
Dose can be reached to 3000 mg
Start 1525 mg at bedtime
Increase 1525 mg/wk
Attempt to reach 50100 mg
Increase further if necessary
Associated with weight loss, not weight gain
Start 250500 mg/day.
Monitor levels if compliance is an issue
Max dose is 60 mg/kg/d
thalamus, and hypothalamus. Abnormalities in the CACNA1A
gene in FHM are associated with neuronal hyperexcitability
[50, 51]. Interestingly, episodic ataxia type 2 and spinocer-
ebellar ataxia type 6 are also associated with CACNA1A
mutations.
De Fusco et al. [52] reported FHM2 as being associated
with mutations of the ATP1A2 gene on chromosome 1q23, a
gene that encodes the pore forming 2-subunit of the
electrogenic Na+, K+- ATPase. Clinically, FHM2 patients
present hemiplegic migraine, frequently associated with
epilepsy. Na+/K+-ATPase is an integral membrane protein
responsible for establishing and maintaining the electrochem-
ical gradients of sodium and potassium ions across the plasma
membrane. These gradients are essential for osmoregulation,
sodium-coupled transport of a variety of organic and inorganic
molecules, and electrical excitability of neurons [42, 52].
Abnormalities in the ATP1A2 gene are associated with
generation of nonfunctional proteins, leading to impaired
membrane expression or altered extracellular K+ affinity and
reduced enzyme turnover [42, 52]. Deprez et al. [33]
examined ATP1A2 mutations in 20 families with a history
of migraine and epilepsy. The ATP1A2 mutation was found in
one family with occipitotemporal epilepsy and migraine and
in one family with the FHM phenotype. However, recurrent
ATP1A2 mutations (ie, mutations that occurred on different
genetic backgrounds) also suggest that ATP1A2 mutations
might occur more broadly than thought [53]. Nonetheless,
because of the limited data, it is not clear whether families
with migraine and epilepsy should be screened to ATP1A2
mutations.
Dichgans et al. [54] reported that FHM3 was associated
with mutations on SCN1A, a gene that codifies voltage-gated
sodium (Na) channel 1-subunit. Mutations in this gene also
have been associated with different forms of epilepsy [54, 55],
including severe myoclonic epilepsies in infancy (SMEI or
Curr Pain Headache Rep (2010) 14:276283
Dravet Syndrome), borderline severe myoclonic epilepsies in
infancy (SMEB) [56], generalized epilepsy with febrile
seizures plus (GEFS+), intractable childhood epilepsy with
generalized tonic-clonic seizures, severe infantile multifocal
epilepsy, and other epileptic phenotypes [5557]. SCN1A
gene mutations cause variable loss or gain of function of
Nav1.1, affecting sodium currents in human cortex. More
recently, some evidences also suggest that loss of function in
SCA1A might lead diverse protein trafficking abnormalities
that could also account for some phenotypic variances
encountered in clinical practice [58].
Several other genetic evidences suggesting a link
between migraine and epilepsy have been reported. They
include mutations on SLC1A3, a member of the solute
carrier family that encodes excitatory amino acid transport-
er 1 [59], and POLG [60] and C10orF2 [61], genes that
encode mitochondrial DNA polymerase and helicase
Twinkle, respectively. Detailed review of all these muta-
tions, their molecular consequences, and genotype-
phenotype correlations are beyond the scope of this review.
However, it is interesting to note that mutations that lead to
channelopathies, impair neuronal or glial ionic homeostasis
(eg, sodium, potassium, and calcium), or that affect
GABAergic or glutamatergic systems or mitochondrial
functions might lead to a spectrum of nervous system
diseases with frequent migraine/epilepsy comorbidity.
Therapeutic Aspects
Because migraine and epilepsy are associated, clinicians
should be aware that individuals with one disorder are more
likely, not less likely, to have the other. The comorbidity of
migraine and epilepsy appears more prominently in research
studies than in clinical practice. This probably reflects reduced
rates of migraine diagnoses in persons with epilepsy.
When developing a treatment plan for a patient with both
epilepsy and migraine, the comorbidity should be consid-
ered. Tricyclic antidepressants and neuroleptic drugs are
often used to treat migraine; however, these medications
may lower seizure thresholds and caution is advisable in
patients with comorbid epilepsy [62]. When selecting drugs
for migraine prophylaxis, it is sometimes advantageous to
treat comorbid conditions with a single agent; for example,
when migraine and hypertension occur concomitantly, a -
blocker or calcium channel blocker is often appropriate. In
the same way, antimigraine anticonvulsants should be
considered as a simultaneous treatment for both disorders.
Antiepileptic drugs are increasingly recommended for
migraine prevention because of placebo-controlled double-
blind trials that prove them effective. Valproate or divalproex,
topiramate, and gabapentin have demonstrated efficacy in
double-blind controlled trials [63], and topiramate and
281
divalproex are approved by the U.S. Food and Drug
Administration as migraine preventive agents. Open trials
also suggest that zonisamide and levetiracetam may also be
useful in migraine prevention [64]. Table 2 presents selected
anticonvulsants in the preventative treatment of migraine.
Conclusions
Migraine and epilepsy share several characteristics, including
specific clinical features, overlapping pathophysiological
mechanisms, and therapeutics. For specific syndromes,
molecular dysfunctions are shared as well. Nonetheless, both
conditions are distinct and also have important differences. By
being comorbid, the presence of one disorder increases the
likelihood of the other. Thus, the diagnosis and treatment of
each disorder must take into account the potential presence of
the other. Both epilepsy and migraine are among the most
prevalent disorders seen not only by neurologists, but also by
general physicians. Accordingly, providers must be aware of
the migraine/epilepsy comorbidity, its clinical spectrum, and
its treatment aspects.
Acknowledgments Dr. Marino M. Bianchin is supported by Con-
selho Nacional de Desenvolvimento Cientfico e Tecnolgico grant
#305501/2007-0.
Disclosure Dr. Marcelo E. Bigal is a full-time employee of Merck &
Co., and holds stocks and stock options in the company. No other
potential conflicts of interest relevant to this article were reported.
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