migralepsy2

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Review

Migralepsy and related conditions: Advances in pathophysiology andclassification

Alberto Verrotti a, Pasquale Striano b, Vincenzo Belcastro c, Sara Matricardi a, Maria Pia Villa d,Pasquale Parisi d,*a Child Neurology and Department of Pediatrics, University of Chieti, Italyb Muscular and Neurodegenerative Diseases Unit, G. Gaslini Institute, University of Genova, Italyc Neurology Clinic, Department of Neuroscience, SantAnna Hospital, Como, Italyd Child Neurology, Pediatric Headache Centre, Sleep Disorders Centre, Chair of Pediatrics, Second, Faculty of Medicine, Sapienza University, Via di Grottarossa,

1035-1039, 00189 Rome, Italy

1. Introduction

The clinically based hypothesis that migraine and epilepsy are

related dates back to the 19th century.1 Both disorders are

characterized by transient paroxysmal episodes of altered brain

function with a clinical, pathophysiological and therapeutic

overlap.2

The prevalence of migraine is low in childhood, peaks in adult

age and decreases in old age, whereas the incidence of epilepsy is

highest in childhood and old age.3 Nevertheless, there is a strong

epidemiological association between these two conditions, and the

occurrence of both disorders in the same individual is more

frequentthan is to be expected on the basis of a chance occurrence.

Indeed, the prevalence of epilepsy in the population of migraine

sufferers ranges, depending on the study, from 1% to 17%, with a

median of 5.9%,4 which is significantly higher thanthe prevalence

of epilepsy in the general population (0.51%).3 Moreover, the

frequency of migraine in the epilepsy population is high, rangingfrom 8.4% to 20%.1

Over the last decade, the possible common pathophysiological

mechanisms underlying these two conditions have received a

considerable amount of attention. Many of the studies that have

been conducted support the hypothesis of excessive neocortical

cellular excitability as the main pathological mechanism underly-

ing the onset of both diseases.2 In migraine, however, hyperexcit-

ability is believed to transition to cortical spreading depression

rather than to the hypersynchronous activity that characterizes

epilepsy. Notably, some forms of epilepsy and migraine are known

to be channelopathies.2 Mutations in the same genes can cause

Seizure 20 (2011) 271275

A R T I C L E I N F O

Article history:

Received 5 January 2011

Received in revised form 8 February 2011

Accepted 21 February 2011

Keywords:

Migralepsy

Hemicrania epileptica

Ictal epileptic headache

Epilepsy

Cortical spreading depression

Migraine

A B S T R A C T

Basic and clinical neuroscience research findings suggest that cortical spreading depression (CSD) and

epileptic foci mayfacilitateeach other; furthermore, thethreshold required forthe onset of CSDhas been

suggested to be lowerthan that requiredfor an epileptic focus. Thesedata may explain theprevalence of

epilepsy in migraine populations (ranging from 1% to 17%) and the frequency of migraine in epileptic

populations (ranging from 8.4% to 20%). There is currently a considerable amount of confusion regarding

this topic in both headache and epilepsy classifications (ICHD-II and ILAE). The ICHD-II includes

migraine-triggered seizure (coded as 1.5.5) (so-called migralepsy) among the complications of

migraine, and defines hemicrania epileptica (7.6.1) as an ictal headache (ipsilateral to the ictal

EEG discharge) that occurs synchronously with a seizure (partial epileptic seizure) recognized by ILAE

classification. However, neither migralepsy nor hemicrania epileptica are terms used in the current

ILAE classification.On the basis of data reported in the literature and our recent findings, we suggestthat

the terms migraine-triggered seizure and migralepsy be deleted until unequivocal evidence of the

existence of these conditions emerges. Ictal epileptic headache (IEH) should be used to classify thoserare events in which headache represents the sole ictal epileptic manifestation. On the other hand, the

term hemicrania epileptica should be maintained in the ICHD-II and introduced into the ILAE, and be

used to classify all cases in which an ictal epileptic headache coexists and is associated

synchronously or sequentially with other ictal sensory-motor events.

2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

* Corresponding author at: Child Neurology, Headache Paediatric Center,

Paediatric Sleep Disorders, Chair of Paediatrics, II Faculty of Medicine, Sapienza

University, c/o SantAndrea Hospital, Via di Grottarossa, 1035-1039 Rome, Italy.

Tel.: +39 6 33775971.

E-mail addresses: [email protected],[email protected] (P. Parisi).

Contents lists available atScienceDirect

Seizure

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y s e i z

1059-1311/$ see front matter 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.seizure.2011.02.012
http://dx.doi.org/10.1016/j.seizure.2011.02.012mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/10591311http://dx.doi.org/10.1016/j.seizure.2011.02.012http://dx.doi.org/10.1016/j.seizure.2011.02.012http://www.sciencedirect.com/science/journal/10591311mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.seizure.2011.02.012


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either migraine or epilepsy or, in some cases, both. Furthermore,

given the likely commonalities in the underlying cellular and

molecular mechanisms, it is hardly surprising that some antiepi-

leptic drugs (AEDs), including valproate, topiramate and gaba-

pentin, are also effective as antimigraine agents.5 Ionotropic

glutamate receptors are involved in both migraine and epilepsy,

with NMDA receptors, which are critical to cortical spreading

depression, playing a particularly important role in migraine.5

Migralepsy is a rare condition in which a migraine attack is

followed, within an hour, by an epileptic seizure.4,6,7 However, the

diagnosis of this condition is extremely challenging, as is the task

of differentiating it from epileptic seizures.811 In recent years, the

inaccuracy of the current definition and classification of migra-

lepsy and conditions related to migralepsy has become increas-

ingly apparent.1014

2. Definitions

The term migralepsy was first used in 1960 by Lennox &

Lennox (who quoted Dr Douglas Davison) to describe a condition

wherein ophthalmic migraine with perhaps nausea and vomiting

was followed by symptoms characteristicof epilepsy.7 Since then,

approximately 50 cases have been described in the literature, the

majority of which have been the criticized by other authors.1014 Itis surprising that so few case reports have been published despite

the fact that migraine and epilepsy are among the most common

brain diseases.12 Indeed, most of the cases of migralepsy that

have been reported are either complex cases that do not provide

unequivocal evidence of an association between migraine and

epilepsy or occipital seizures imitating migraine with aura.8,9

Migralepsy does not exist in previous classifications of the

International League Against Epilepsy (ILAE) or in therecent report

of the ILAE Commission on the Classification and Terminology of

seizures and epilepsies15; however, according to the current

International Classification of Headache Disorders II (ICHD-II),16

migralepsy is included among the complications of migraine

(paragraph coded 1.5.5.) and is defined as a migraine triggered-

seizure that must fulfill two diagnostic criteria: (a) migrainefulfilling the criteria for 1.2 Migraine with aura (MwA); (b) a

seizure fulfilling the diagnostic criteria for one type of epileptic

attack that occurs within 1 h of a migraine aura.16

Migralepsy is different from hemicrania epileptica, which is

defined in the ICHD-2 classification (International Headache

Society, 2004) (coded as 7.6.1) as an ictal headache (ipsilateral

to the ictal EEG discharge) that occurs synchronously with a

seizure (partial epileptic seizure) included in the ILAE classifica-

tion. The term ictal epileptic headache has recently been

proposed by Parisi et al. 1721 and defined as the sole ictal

epileptic phenomenon without any other associated ictal epilep-

tic signs/symptoms recognized by the ILAE.

Sances et al. 12 recently provided a demonstration of the

inadequacy of the current definition of migralepsy: MwA includes avariety of MwA subtypes (typical aura with migraine headache,

typical aura with non-migraine headache, typical aura without

headache, familial hemiplegic migraine, sporadic hemiplegic

migraine, and basilar-type migraine), though none of these has

been associated with migralepsy. In addition, migralepsy may even

be triggered by migraine withoutaura (MwoA) attacks or may occur

later than the 1-h post-aural time-frame stipulated by the ICHD-II

criteria.13 Sances et al. thus suggested that the definition of

migralepsy should only include those types of migraine that are

reported to be associated with the migralepsy clinical picture;

moreover, they recommended that theICHD-II definitionbe revised,

relocating migralepsy from the complications of migraine

paragraph to the ICHD-II Appendix (where novel entities that have

not been sufficiently validated by research studies are classified).

3. Clinical, EEG and neuroimaging aspects in migralepsy and

related conditions

There are at least fifty potential cases of migralepsy in the

literature.4,6,7,12,13 However, the diagnosis in the majority of these

cases (38%) was uncertain owing to the lack of unequivocal

information. Moreover, thediagnosis in many of thecases does not

fulfill the current ICHD-II criteria (30%) or is at least questionable

(28%).12 In the questionable cases,the description of the attack and

the EEG and brain imaging findings are all highly suggestive of

epileptic seizures (particularly occipital seizures). Therefore, only

4% of the cases display features supporting a diagnosis of a

migraine-triggered seizure and fulfill the ICHD-II criteria.12,16 In

the majority of the remaining cases, an EEG during the migraine

attack is either not available (68%) or is normal in the few cases in

which it is (4%); the main EEG abnormalities (28%) are periodic

lateralized epileptiform discharges (PLEDs) or localized theta

delta activity.

The interictal EEG in the published migralepsy cases is normal

in some cases (32%) but displays generalized (28%) or localized

(34%) abnormalities in the majority of them. These abnormalities

are characterized by spikes, spikewave complexes and sharp

waves, mainly localized in the temporal and/or occipital lobes.

As regards theictalEEG abnormalities in these types of patients,it should be borne in mind that while unequivocal epileptiform

abnormalities usually point to a diagnosis of epilepsy, the lack of a

clear epileptic spike-wave activity is frequent in other ictal

autonomic manifestations, such as Panayiotopoulos syn-

drome,1821 as well as in patients with a deep epileptic focus

arising, for example, from the orbito-mesial frontal zone.1821 In

such cases, ictal epileptic EEG activity might be recorded either

from the scalp or by stereo-EEG recording as a theta, or even

delta, shape without any spike activity. Interestingly, in one

patient with headache as the sole ictal epileptic manifestation, it

was not possible to record any EEG abnormalities from the scalp.22

It has been suggested that the neurobiological explanation for

these EEG features is closely related to anatomo-neurophysiologi-

cal variables (fiber size, myelination and extent of polysynapticinterconnections).18,2123

In the cases of migralepsy in the literature, the seizures

triggered by migraine attacks are prevalently generalized tonic

clonic seizures (GTC: 50%), though in some cases they are simple

partial seizures (SP: 8%) or complex partial seizures (CP: 16%) with

loss of consciousness.6,7,12,13 The elementary visual hallucinations

that precede pain onset in idiopathic or symptomatic occipital

seizures may represent the only symptom in such patients, thus

mimicking a typical aura migraine; these epileptic seizures with

post-ictal headache may thus be mistaken as migraine with aura,

basilar migraine, acephalalgic migraine or migralepsy. Moreover,

they are quite distinct from visual aura of migraine in their

individual elements of colour, shape, size, location, movement,

speed of development, duration and progress.8,9

Therefore,physicians need to be fully aware of the various diagnostic criteria

if they are to choose the most appropriate treatment.

Interestingly, the patients in many so-called ictal epileptic

headache case reports are photosensitive; they usually also

present a clinical history (personal and/or familial) of epilepsy and

migraine and a photoparoxysmal EEG response.17,2427 In two

cases, intermittent photic stimulation (IPS) evoked headache,

though it may also be possible to visually induce seizures in such

patients.17,24 The fact that headache itself is unlikely to be the sole

epileptic symptom, whether it is related to photosensitivity or not,

led to the proposal of the term ictal epileptic headache.1721

And what would the clinical and EEG features of the ictal-EEG

recording in the ictal epileptic headache cases be? Unfortunate-

ly, there is no specific EEG picture in these cases either, with

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numerous different EEG associated patterns having been recorded

during migraine-like complaints.10,11,1722,2427 These patterns

include: (i) high-voltage, rhythmic, 1112 Hz activity with

intermingled spikes over the right temporo-occipital regions26

27; (ii) high voltage theta activity intermingled with sharp waves

over the occipital region17 and (iii) bilateral continuous spike-and-

slow-wave discharges.25 Furthermore, a photoparoxysmal re-

sponse24 combined with complaints of a light pulsating headache

have been reported during intermittent photic stimulation.17 In

this respect, we would also like to stress the possible existence of

an isolated epileptic headache, with no associated ictal epileptic

manifestations or EEG abnormalities that can be recognized by

scalp EEG recording, whose ictal origin can be demonstrated by

depth electrode studies (see patient number 2 by Laplante et al.).22

In this regard, it should be borne in mind that in other types of

epilepsy, such as frontal lobe epilepsy, epileptic activity cannot be

detected from the scalp-EEG recording in as many as 40% of the

patients.23

It is noteworthy that complete remissionof the headacheand of

the epileptic abnormalities in most of these ictal epileptic

headache patients was achieved not by means of specific

antimigraine drugs, but following intravenous administration of

diazepam17,25,26 or phenytoin.27

According to the definition provided in the ICHD-II, migralepsyis considered to be associated with MwA attacks alone. Some

authors, however, believe that a MwoA attack acts as a trigger for

an epileptic seizure.12,13 Although such events are very rare, it is

possible that the development of a MwoA attack may favor the

recurrence of a seizure according to the pathophysiological

mechanism previously described for the MwA18; furthermore,

epileptic seizures have been reported to develop later than 1 h

after the MA attack.13

Transient brain MRI abnormalities, persisting for days, have

been reported in about 6% of patients with migralepsy.28 Blood

brain barrier damage and consequent edema have been suggested

to explain reversible radiological alterations in such cases.

In cases of migraine-triggered seizures (migralepsy), most EEG

recordings show a diffuse, irregular, high voltage, thetadeltaactivity during the episodes. The EEG abnormalities were, like the

MRI alterations, transient and disappeared at the long-term

follow-up.28 Although it is not easy to interpret these findings,

one explanation maybe that they arethe functional correlate of the

reversible MRI alterations observed in patients with migralepsy.

As regards the MRI features in the published cases of ictal

epileptic headache, brain MRI revealed secondary brain lesions in

the right temporo-parieto-occipital region along with limited

diffusion in the right occipital region26,27 or enlarged sulci in the

right parietal region.24 However, ictal epileptic headache has

also been reported in patients with idiopathic epilepsy.17,25

As regards the therapy, the effectiveness of AEDs in the

prophylaxis phase may be explained by the anticipation of the

cortical spreading depression (CSD) event that induces secondarytrigemino-vascular system (TVS) activation and lowers the seizure

threshold in the pathophysiology of migralepsy. Sodium valproate,

topiramate and gabapentin have all proved to be effective in

double-blind placebo controlled trials, the first two drugs having

also been approved by the U.S. Food and Drug Administration as

migraine preventive agents.5,29,30 Open trials suggest that zoni-

samide and levetiracetam may help prevent the onset of

migraine.31,32

4. Pathophysiological and genetic aspects

Although the pathophysiology of migraine-induced seizures is

stillundefined, it has beenhypothesizedthat the cortical excitation

threshold in migraineurs is lower than in normal subjects, thereby

favoring the occurrence of seizure; the lower cortical excitation

threshold might be due to several conditions, alone or in

combination, such as mitochondrial defects, disturbance in

magnesium metabolism or ion channels abnormalities.33

Cortical spreading depression (CSD) seems to be the connecting

point between migraine and epilepsy.10,34,35 CSD is characterized

by a slowly propagating wave (26 mm/min) of sustained strong

neuronal depolarization that generates transient intense spike

activity as it progresses into the brain tissue (resulting in a

transient loss of membrane ionic gradients and in a massive surge

of extracellular potassium, neurotransmitters and intracellular

calcium), followed by neural suppression which may last for

minutes. The depolarizationphase is associated with an increase in

regional cerebral blood flow, whereas the phase of reduced neural

activity is associated with a reduction in blood flow.36 Opinions are

still divided as to whether CSD plays a physiological or a

neuroprotective role36; it is, however, believed to cause the

activation of TVS, consisting of the cascade release of numerous

inflammatory molecules (sterile inflammation) and neurotrans-

mitters, which results in pain during the migraine attack.37 The

trigemino-vascular theory has become the most widely accepted

theory in the physiopathology of migraine,37 and the CSD is

considered to be the primary cause of TVS activation at the cortical

level.The correlation between CSD and MwA was the first to

emerge38; more recently, imaging studies in patients suffering

from MwoA have also highlighted the presence and role of CSD in

silent areas as an underlying mechanism.39 It should be borne in

mind that CSD is not a phenomenon that is strictly confined to

the cortical structures. Indeed, cortical and subcortical areas

appearto be hierarchically divided according to how likelythey are

to develop CSD,40 though the occipital lobe appears to be the area

that is most likely to be affected.41 Therefore, this hierarchical

organization in the central nervous system based on neuronal

networks (cortical and subcortical) may be prone to a greater or

lesser degree to CSD (migraine) and epileptic focal discharges

(seizures).10

On the basis of these neurophysiological data, it must bestressed that critical alterations in headache physiopathology may

occur anywhere (cortical and/or subcortical) along the convergent

pathways (retinal afferents, dural nociceptors, brainstem nuclei,

cortical neurons or even astrocytes and blood vessels), which

confirms that headache is not just a brainstem disease, but a

cortico-subcortical disease that may start at any level (cortical and

subcortical)10,42; consequently, increasedawareness of this feature

of headache should serve to motivate attempts aimed at

modulating (i.e. prophylaxis) rather than merely treating this

complex disorder on an ad hoc basis.42

Going back to the relationship (at the cortical level) between

CSD and an epileptic focus, onset and propagation are triggered

when these neurophysiological events reach a certain threshold,

which is lower for CSD than for the seizure. Once the cortical eventhas started, how it spreads depends on the size of the onset zone,

its velocity, semiology and type of propagation. Moreover, the

onset of CSD and that of the epileptic seizure may facilitate each

other.10,18,35,41 These two phenomena may be triggered by more

than one pathway converging upon the same destination:

depolarization and hypersynchronization.10,18,35,41

The triggering causes, which may be environmental or

individual (genetically determined or not), result in a flow of ions

that mediates CSD, through neuronal and glial cytoplasmic bridges

(intracellular gap-junctions) rather than through interstitial

spaces, as usually occurs in the spreading of epileptic sei-

zures.10,18,21The threshold required forthe onsetof CSD(migraine)

is likely to be lower than that required for the epileptic seizure. In

this regard, a migraleptic event is very rare because the threshold

A. Verrotti et al. / Seizure 20 (2011) 271275 273


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required for seizure onset and propagation is higher than that one

requested for CSD onset. Furthermore, recurrent seizures might

also predispose patients to CSD, thereby increasing the occurrence

of a peri-ictal migraine-type headache; moreover, accordingly, in

the clinical contest a post-ictal headache in epileptic patients is

much more common than all the other types (pre-ictal and ictal) of

peri-ictal headache.10,18,21

It is well known that CSD leads to significant changes in the

composition of extracellular fluid, including increases in glutamate

and potassium ions; these changes, in turn, result in hyperexcit-

ability and may lower the seizure threshold.43,44 A paroxysmal

change in cortical neuronal activity may occur during a migraine

attacks or epilepsy seizure; hyperexcitation occurs in epilepsy,

whereas in migraine hypoexcitation and hyperexcitation occur

sequentially as rebound phenomena (spreading depression).35

Much remains to be understood of the pathophysiology of these

diseases, though it is clear that glutamate metabolism,45 serotonin

metabolism,46 dopamine metabolism47 and ion channel function

are impaired in both.48 Mutations in genes coding for ionchannels,

such as those for sodium, potassium and chloride, cause abnormal

synchronization or increase the excitability of cortical neurons.49

No specific data are available on genetic aspects of migralepsy.

The best studies on genetic abnormalities that lead to epilepsy and

migraine regard Familial Hemiplegic Migraine (FHM),50 a rareautosomal dominant subtype of migraine with aura characterized

by unilateral motor weakness that occurs during the migraine

aura.16 The FHM1 gene CACNA1A codes for the pore-forming

subunit of Cav2.1 P/Q-type calcium channels and is located on the

short arm of chromosome 19; at present, 17 different mutations in

this gene are known.51 CACNA1A mutations might very well

influence cortical spreading depression, since P/Q-type calcium

channels mediate glutamate release in cortical neurons.49 The

FHM2 geneATP1A2is located on the long arm of chromosome 1.52

It codes for the a2subunit of sodium/potassium ATPase, which is

responsible for pumping potassium ions into the cell and sodium

ions out of the cell.53 Impaired sodium/potassium balance is

known to cause cortical spreading depression. As in FHM1, various

mutations in the ATP1A2 gene have been reported.51 Mutationshave recently been found in FHM families (FHM3), in the SCN1A

gene located on 2q24, which is associated with epilepsy.54 SCN1A

mutations can cause genetic epilepsy with febrile convulsions

(GEFS+), Dravet syndrome and other rare epilepsy syndromes.55

More than 150 different mutations in SCN1A have been described

in families with epilepsy.56

Several other genetic findings pointing to 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 transporter 1,57 POLG58,C10andF259, which

encode mitochondrial DNA polymerase and helicase twinkle. A

genetic defect in ion channels therefore seems to be a shared

pathophysiological mechanism of migraine and epilepsy. Voltage-

gated ion channels are part of an extensive signaling pathway thataffect neuronal excitability through various mechanisms60; in

addition, these channels can directly activate enzymes linked to

the signaling pathway and serve as cell adhesion molecules or

components of the cytoskeleton, while their activity is known to

alter the expression of other specific genes. Although it is likely

that voltage-gated ion channels are critically positioned in the

pathways associated with migraine and epilepsy, the contribution

of numerous other genes/proteins in the pathways of migralepsy

warrants further investigation.

5. Conclusions

The classification of migralepsy and related conditions

(hemicrania epileptica and ictal epileptic headache) represents a

hot topic that warrants revision to more accurately represent the

relationship between migraine/headache and epilepsy. Indeed,

migralepsy is a rare, ill-defined nosologic entity. In the majority of

cases describedin the literature, the clinical features are suggestive

of occipital lobe seizures, though the data available are not

sufficient to draw firm conclusions. Related conditions, such as

hemicrania epileptica (coded in ICHD II at point 7.6.1) and ictal

epileptic headache (recently proposed though not recognized or

classified yet) also need to be definedmore clearly. To date, neither

the International Headache Society nor the International League

against Epilepsy mention that headache/migraine may, on

occasion, be the sole ictal epileptic manifestation; this also applies

to the ICHD-II criteria as regards the classification of hemicrania

epileptica. Nonetheless, a growing body of evidence indicates that

headache per se may represent an epileptic seizure, and that it

may, in rare cases, even be the sole ictal manifestations of epilepsy.

This may result from an interplay between the epileptic focus and

CSD, which may in turn activate a common final pathway of pain

triggered by the TVS. These findings also highlight the diagnostic

importance of EEG recording during the attacks for classification

purposes. Our personal opinion, which is based on the knowledge

currently available and the clinical experiences reported here, is

that the existence of migralepsy (coded in ICHD-II as 1.5.5

migraine-triggered seizure) is, despite being theoreticallypossible, highly unlikely. We therefore propose relocating the

term migralepsy (migraine-triggered seizure) in the appendix

of both classifications (ICHD-II and ILAE) until clear evidence

emerges of its existence. Moreover, we also believe that ictal

epileptic headache should be used to classify those rare events in

which headache represents the sole ictal epileptic manifestation.

By contrast, the term hemicrania epileptica should be main-

tained in the ICHD-II and introduced into the ILAE, and be used to

classify all cases in which an ictal epileptic headache coexists

and is associated either synchronously or sequentially with other

ictal sensory-motor events.

Disclosure

None of the authors have any disclosures to declare.

Study funding

None.

Contributions

Study concept and design: PP, Drafting/revising of manuscript:

all the authors and Analysis of interpretation: all the authors

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