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REVIEW ARTICLE
Ictal epileptic headache: an old story with courses and appeals
Pasquale Parisi •Pasquale Striano •
Andrea Negro •Paolo Martelletti •Vincenzo Belcastro
Received: 6 July 2012 / Accepted: 13 September 2012
The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract The term ‘‘ictal epileptic headache’’ has been
recently proposed to classify the clinical picture in which
headache is the isolated ictal symptom of a seizure. There
is emerging evidence from both basic and clinical neuro-
sciences that cortical spreading depression and an epileptic
focus may facilitate each other, although with a different
degree of efficiency. This review address the long history
which lead to the ’migralepsy’ concept to the new
emerging pathophysiological aspects, and clinical and
electroencephalography evidences of ictal epileptic head-
ache. Here, we review and discuss the common
physiopathology mechanisms and the historical aspects
underlying the link between headache and epilepsy. Either
experimental or clinical measures are required to better
understand this latter relationship: the development of
animal models, molecular studies defining more precise
genotype/phenotype correlations as well as multicenter
clinical studies with revision of clinical criteria for head-
ache-/epilepsy-related disorders represent the start of future
research. Therefore, the definition of ictal epileptic head-
ache should be used to classify the rare events in which
headache is the only manifestation of a seizure. Finally,
using our recently published criteria, we will be able to
clarify if ictal epileptic headache represents an underesti-
mated phenomenon or not.
Keywords Cortical spreading depression Headache
Migraine Epilepsy Ictal epileptic headache
Historical background
That ‘‘migraine in the borderland of epilepsy’’ has been
recognized since Sir Gowers’ famous book published in
1907 [1]. In an epoch before electroencephalography
(EEG), Gowers most likely stated: ‘‘…the most frequent
relation of migraine to epilepsy is as source of error;….in
extremely rare instances one affection may develop while
the other goes on’’. More than 100 years later, in the era of
digital EEG recordings, we are firmly reporting that
sometimes ‘‘migraine itself can even be epilepsy’’: the
overlap being partial or complete, not always synchronous
(being mainly a peri-ictal phenomenon), but, in certain
cases (probably largely underestimated), ‘‘the headache
represents the only ictal phenomenon’’, and recently, we
named this condition ‘‘ictal epileptic headache’’ (IEH) [2].
P. Parisi (&)
NESMOS Department, Faculty of Medicine and Psychology,
Child Neurology, Headache Paediatric Center, Paediatric
Sleep Disorders, Chair of Paediatrics, Sapienza University,
c/o Sant’Andrea Hospital, Via di Grottarossa, 1035-1039 Rome,
Italy
e-mail: pasquale.parisi@uniroma1.it; parpas@iol.it
P. Striano
Pediatric Neurology and Muscular Diseases Unit-DINOGMI-
Department of Neurosciences, Rehabilitation, Ophtalmology,
Genetics, Maternal and Child Health, University of Genoa,
G. Gaslini Institute, Genoa, Italy
A. Negro P. Martelletti
Department of Clinical and Molecular Medicine,
Faculty of Medicine and Psychology, Regional Referral
Headache Centre, Sant’Andrea Hospital, Sapienza University,
Rome, Italy
A. Negro
Stroke and Neurovascular Regulation Lab,
Department of Radiology, Harvard Medical School,
Massachusetts General Hospital, Boston, MA, USA
V. Belcastro
Department of Neuroscience, Neurology Clinic,
Sant’Anna Hospital, Como, Italy
123
J Headache Pain
DOI 10.1007/s10194-012-0485-y
In particular, IEH is recognized as a headache (‘‘as sole
ictal epileptic manifestation’’) lasting from minutes to days
with evidence of ictal epileptiform EEG discharges, which
resolves after intravenous antiepileptic medications [2]
(Table 1).
In this review, the terms headache and migraine are used
interchangeably, as in pediatric age it is often impossible
clinically to distinguish migraine from other forms of
pediatric headache (e.g., tension-type headache). It is also
important to stress that IEH has to be included among
‘‘secondary headache’’, being-by definition-an ‘‘ictal epi-
leptic manifestation’’. Yet, being a ‘‘secondary headache’’,
it can also have similar but not typical migraine features;
moreover, family history of epilepsy and headache, as risks
factors, are often associated.
Since the 1950s, there have been described cases from
German [3], English [4] and Italian [5,6] literature, sug-
gesting that ‘‘headache’’ can just be ‘‘an epileptic head-
ache’’ and ‘‘…. it can be even the only clinical
manifestation of idiopathic epilepsy’’ [5]. Thus, the con-
cept of ictal headache is indeed old [3–6]. However, in the
1960s the term ‘‘migralepsy’’ was coined [7] which has
been permeating the epilepsy and headache culture till
now. Migralepsy comes literally from combining the words
migraine and epilepsy. This term was introduced to
describe a condition wherein a migraine with aura attack is
followed by symptoms characteristic of epilepsy. To make
a diagnosis of migralepsy, a temporal relationship between
the migraine aura and a seizure event (within an hour) is
necessary.
With regard to migralepsy cases from literature, recent
articles [8–11] have provided a clear demonstration of the
inadequacy of the current ICHD criteria definition of
migralepsy. After the first ‘‘migralepsy’’ concept by Len-
nox and Lennox [7], during the 1980s [12,13] and more
recently till now [14,16–23], an increasing number of
‘‘ictal headaches’’ have been reported. Consequently, we
have suggested [2,10,11,17,23–33] that the ‘‘migralepsy
sequence’’ may not exist at all and that the initial part of the
‘‘migralepsy sequence’’ may be simply an ‘‘ictal epileptic
headache’’ [2] followed by other ictal autonomic and/or
sensory and/or motor and/or psychic features.
Emerging physiopathological aspects
It has been stressed that hyperexcitation occurs in epilepsy,
while in migraine a brief hyperexcitation period (depolar-
ization) is followed by a long hypoexcitation period
(spreading depression), followed again by hyperexcitation,
as rebound phenomenon [34–36]. Moreover, a disexcit-
ability (hyper- and hypoexcitation in the same migrainous
patient at different points in time) condition has even been
demonstrated [37,38].
Migraine pathophysiology is still controversial [34–40].
In fact, although cortical spreading depression (CSD) has
been shown to activate the trigeminovascular system,
whether seizures or CSD causes true migraine typical
attack remains a matter of debate. Nevertheless, CSD
seems to be the connecting point between migraine and
epilepsy [35,39,40]. It is characterized by a slowly
propagating wave (2–6 mm/min) of sustained strong neu-
ronal 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 depolarization phase 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 [39].
The trigeminovascular theory [41] is nowadays the most
widely accepted theory in the physiopathology of migraine.
CSD would be able, as more recently demonstrated [42], to
constitute a nociceptive stimulus capable of activating
peripheral and central trigeminovascular neurons in the
spinal trigeminal nucleus (C1–C2) that underlie the head-
ache pain [42]. In other words, a wave of spreading
depression in the visual cortex can induce nociceptive
signals in the overlying meninges, resulting in sequential
activation of peripheral (first-order) and central (second-
order) neurons of the trigeminovascular pathway, which is
a likely mechanism of migraine headache.
In particular, the possible correlation between CSD and
migraine with aura (MA) [41–44] was first investigated,
whereas even in patients suffering from migraine without
Table 1 Proposed criteria for ictal epileptic headache (IEH)
Diagnostic criteria A–D should all be fulfilled in order to make the
diagnosis ‘‘IEH’’
A. Headache
a
(as sole ictal epileptic manifestation) lasting
minutes, hours or days
B. Headache, ipsilateral or contralateral to lateralized ictal
epileptiform EEG discharges (if EEG discharges are lateralized)
C. Evidence of epileptiform (localized
b
, lateralized or
generalized) discharges on scalp EEG synchronous to headache
complaints; different types of EEG anomalies can be observed
(generalized spike-and-wave or polyspike-and-wave, focal or
generalized rhythmic activity or focal subcontinuous spikes or
theta activity intermingle or not with sharp waves) with or
without photoparoxysmal response (PPRs)
D. Headache resolves immediately (within a few minutes) after
i.v. antiepileptic medication
a
A specific headache pattern is not required (migraine with or
without aura, or tension-type headache are all admitted)
b
Any localization (frontal, temporal, parietal, occipital) is admitted
J Headache Pain
123
aura (MoA), the presence of CSD in silent cortical areas
[45,46] as an underlying possible mechanism has been
hypothesized. It should be kept in mind that CSD is not a
phenomenon that is strictly linked to the cortical structures.
Cortical and subcortical areas appear to be hierarchically
divided according to how likely they are to develop CSD,
though the occipital lobe appears to be the most likely area
[23,24,28,45,47]. Therefore, in the central nervous
system, this hierarchical organization based on ‘‘neuronal
networks’’ (cortical and subcortical) may be more or less
prone to CSD (migraine) and epileptic focal discharges
(seizures) [23,24,28,46–48].
How CSD and epileptic discharges can, in more detail,
facilitate each other, although with different degree and
efficiency? In other words, why could the onset of epileptic
seizure facilitate the onset of CSD to a greater degree than
the onset of CSD facilitating the onset of epileptic seizure?
In this respect, we would like to have a look, deeply, in
more detail, at recent experimental and clinical literature
data on this topic.
The most interesting data about genetic defects leading
to both epilepsy and migraine are regarding familial
hemiplegic migraine (FHM) [49,50]. The FHM1 gene
CACNA1A codes for the pore-forming subunit of Ca
v
2.1
P-/Q-type calcium channels [51–53] and its mutations
might very well influence CSD, since P-/Q-type calcium
channels mediate glutamate release in cortical neurons
[52]. The FHM2 gene ATP1A2 [54] codes for the a
2
subunit of sodium/potassium ATPase, responsible for
pumping potassium ions into the cell and sodium ions out
of the cell [55]. Mutations have recently been found in
FHM families (FHM3), in the SCN1A gene located on
2q24, already known to be associated with epilepsy [56].
SCN1A mutations can also cause genetic epilepsy with
febrile seizures plus (GEFS?), severe myoclonus epilepsy
of infancy (SMEI) and some other rare epilepsy syndromes
[57]. There are insufficient genotype–phenotype correla-
tions in FHM, according to the different possible muta-
tions. For example, FHM1 mutations were also found in
family members with migraine only. This suggests that
gene mutations for FHM may also be responsible for the
common forms of migraine, probably due to different
genetic and non-genetic modulating factors [58].
With regard to the ‘‘cortex disexcitability’’ in migraine
subjects [37,38], new advances now support this point of
view [59]. In fact, considering the specific polysynaptic
inhibitory sub-circuit involving fast-spiking (FS) inter-
neurons and pyramidal cells (PC) that have been investi-
gated in the FHM1 mice [59], the gain of function of
glutamate release at the recurrent synapses between pyra-
midal cells would certainly increase network excitation; in
contrast, the gain of function of glutamate release at the
PC–FS synapses would lead to enhanced recruitment of
interneurons and enhanced inhibition. This analysis, even
though restricted to a specific sub-circuit, makes the
important point that the differential effect of FHM1
mutations on excitatory and inhibitory neurotransmission
may produce overexcitation in certain brain conditions, but
may leave the excitation–inhibition balance within physi-
ological limits in others, thus explaining the episodic nat-
ure of the disease with alternate hyperexcitation and
hypoexcitation in the same subject at different time (sup-
porting thus the disexcitability concept in migraine
subjects).
A plausible hypothesis explaining the clearly different
degree and efficiency for activating each other is that the
initiation mechanisms of CSD and seizure are similar, but
the evolution is different depending on whether the neu-
ronal hyperactivity and consequent increase in (K?)
exceed a critical level that causes self-regeneration of the
depolarization; in this hypothesis, CSD represents ‘‘a
poorly controlled seizure’’ in which (K?) regulation is
completely disrupted [59,60]. Indeed, in this regard, local
neuronal hyperactivity progressively recruiting a synchro-
nous discharge via recurrent excitatory collaterals and
(K?) accumulation has been proposed to initiate epileptic
discharge in slice models [61]. CSD, experimentally
induced in rats, increases cortico-cortical evoked responses
and strongly induces ‘‘brain-derived neurotrophic factor’’
with synaptic potentiation in vivo [62] and the induction of
a ‘‘long-term potentiation-like’’ (LTP-like) phenomenon by
CSD receives support from experimental evidence. Also,
there are also in vivo data reinforcing the idea of a CSD-
induced LTP-like phenomenon [63]. Another recent and
intriguing finding about CSD propagation is the model
based on interstitial (K?) diffusion, initiating in adjacent
dendrites the positive feedback cycle that ignites CSD, in
contrast to the hypothesis that CSD propagates through gap
junctions. In particular, the opening of the gap junctions
would not be required for CSD propagation, but is rather
necessary for extracellular homeostasis after CSD [64].
Using an in vitro model of CSD [59], a causative link
between enhanced glutamate release and CSD facilitation
has been shown. The synapse-specific effect of FHM1
mutations points to disruption of excitation–inhibition
balance and neuronal hyperactivity as the bases for epi-
sodic vulnerability to CSD ignition in migraine. This
finding provides direct evidence that the gain of function of
glutamate release at synapses onto pyramidal cells may
explain the facilitation of experimental CSD in FHM1
mutant mice, and thus provides novel insights into the
controversial mechanisms of CSD initiation and propaga-
tion. These data are consistent with and support a model of
CSD initiation, in which activation of pre-synaptic voltage-
gated Ca?channels with consequent release of glutamate
from recurrent cortical pyramidal cell synapses and
J Headache Pain
123
activation of NMDA receptors are key components of the
positive feedback cycle that ignites CSD. Moreover, the
role in particular of different voltage-gated Ca
2?
channels
in CSD has recently been investigated [65]. After blockade
of either the P-/Q-type Ca
2?
channels or the NMDA
receptors, CSD cannot be induced in wild-type mouse
cortical slices. In contrast, blockade of N- or R-type Ca
2?
channels has only a small inhibitory effect on CSD
threshold and velocity of propagation. These findings
support a model in which Ca
2?
influx through pre-synaptic
P-/Q-type Ca
2?
channels with consequent release of glu-
tamate from recurrent cortical pyramidal cell synapses and
activation of NMDA receptors are required for initiation
and propagation of the CSD involved in migraine [59,65].
Temporal and spatial associations of CSD and seizures
using electrocorticographic (ECoG) recordings in patients
with acutely injured cerebral cortex have been examined
[35]. The authors reported clinically overt seizures only in
one patient and each patient with CSD and seizures displayed
one of the following four different patterns of interaction
between CSD and seizures: (a) in four patients, CSD was
immediately preceded by prolonged seizure activity; (b) in
three patients, the two phenomena were separated in time and
multiple CSDs were replaced by ictal activity; (c) in one
patient, seizures appeared to trigger repeated CSDs at the
adjacent electrode; (d) in two patients, ongoing repeated
seizures were interrupted each time CSD occurred. The
reported four patterns were consistent within recordings from
the same patient, but differed between patients.
Of particular interest are patients 3 and 4 reported by
Fabricius et al. [35] whose seizure activity spread from
electrode to electrode at the same slow speed as CSD, but
preceded it by several minutes. This is noteworthy, since
the seizure activity under other conditions spreads much
faster than a CSD. To better understand the relevance of
this latter finding, it should be stressed that…. ‘‘A race car
as ‘‘Ferrari’’ can run at a speed of a ‘Fiat 500’ but not vice
versa’’. This point of view could explain why the onset of
epileptic seizure facilitates the onset of CSD to a greater
degree than the onset of CSD facilitating the onset of
epileptic seizure. The first (Ferrari) usually prefers to use
the highways (myelinic) and the latter (Fiat 500) mainly
uses the roads (amyelinic), although it is important to stress
that a ‘‘Ferrari’’ can easily follow the roads (amyelinic)
usually covered by a ‘‘500 Fiat’’, while the reverse is not
true. Accordingly with the above reflections, it is of note
that the patterns recorded by Fabricius et al. [35]were
consistent within recordings from the same patient, but
differed between patients: highways (myelinic) and little
roads (amyelinic) in the same patient usually do not change
so much, at least during a not too long period of time.
Yet, another important finding from Fabricius et al. [35]
which confirmed our point of view [2,16,23–29] is that, in
their sample, CSD was more often encountered than sei-
zures, since there were twice as many patients with CSD/
peri-infarct depolarization alone than with CSD/peri-
infarct depolarization plus seizures. Also, 10 of 11 patients
with seizure activity also had CSD, and clinical overt sei-
zures were only observed in 1 of the 11 patients, while
seizures were not suspected on clinical grounds in the other
10 patients.
Interestingly, in the described so-called IEH [12–23]
case reports, patients are, both, idiopathic (photosensitive
or not) and symptomatic; often, they also present a clinical
history (personal and/or familial) of epilepsy and migraine.
In the cases of positive photo-paroxysmal response, the
intermittent photic stimulation evokes headache and they
can also have visually induced seizures (Table 1)[2]. With
regard to the EEG abnormalities recorded in ‘‘ictal epi-
leptic headache’’ cases [2,12–23], the same wide spectrum
of different EEG patterns (spike-wave activity, ‘‘theta’’ or
even ‘‘delta’’ shape, without any spike activity) associated
with both CSD and/or seizures were also confirmed ‘‘in
vivo’’ by electrocorticography [35].
Drawbacks: the current ictal epileptic headache
definition will inevitably underestimate
the phenomenon
We have been suggesting that headache be classified as an
isolated ictal epileptic manifestation since 2007 [2,10,11,
16–18,23–33]. The proposed criteria are reported in Table 1.
Nonetheless, we would also like to stress that the IEH
criteria inevitably underestimates this ictal ‘‘autonomic’’
phenomenon. Thus, besides highlighting the strengths of
‘‘our forthcoming criteria’’, we would also like to point out
‘‘their inevitable drawbacks’’.
To date, headache and epilepsy classifications have
ignored each other [66]. In the ILAE classification, head-
ache is considered exclusively as a possible semiological
ictal phenomenon among the ‘‘non-motor’’ (point 2.0)
features. In particular, headache is described as a ‘‘cepha-
lic’’ sensation (sub-classified at sub-point 2.2.1.7) and is
not considered as the sole ictal expression of an epileptic
seizure. Moreover, headache is not classified as a ‘‘pain’’
(among the ‘‘somatosensory’’ features at 2.2.1.1) or ‘‘auto-
nomic’’ sensation (2.2.1.8), whereas signs of involvement of
the autonomic nervous system, including cardiovascular,
gastrointestinal, ‘‘vasomotor’’ and thermoregulatory func-
tions, are classified as ‘‘autonomic’’ features. Now, although
still considered a controversial issue, we must consider
that headache pain could in fact originate in the terminal
nervous fibers (‘‘vasomotor’’) in cerebral blood vessels;
consequently, headache should be classified as an ‘‘auto-
nomic’’ sensation in the ILAE Glossary and Terminology.
J Headache Pain
123
Headache could thus be interpreted as the sole expression
of an epileptic seizure and classified as an autonomic sei-
zure. To explain why headache may be the sole ictal epi-
leptic symptom, we previously suggested [2,10,11,16–18,
23–33] that an autonomic seizure (i.e., in IEH cases)
remains purely autonomic if ictal neuronal activation of
non-autonomic cortical areas fails to reach the symp-
tomatogenic threshold, as previously described for
other ictal autonomic manifestations in Panayiotopoulos
syndrome [67].
In addition, we believe that the social stigma attached to
epilepsy may explain a general reluctance (25) (not only in
the general public, but even among physicians) to recog-
nize the growing number of documented cases of IEH
[2,10,11,16–18,23–33].
Another notable point is that while unequivocal epi-
leptiform abnormalities usually point to a diagnosis of
epilepsy, the lack of clear epileptic spike-and-wave activity
is frequent in other ictal autonomic manifestations, as well
as in patients with a deep epileptic focus arising, for
example, from the orbitomesial frontal zone [68]. In such
cases, ictal epileptic EEG activity may be recorded from
the scalp or exclusively by means of deep stereo-EEG
recording.
An additional point deserving attention is the lack of a
clear, repetitive EEG headache-associated pattern, since
the ictal EEG recording in such patients does not yield a
specific EEG picture. Indeed, different patterns have been
recorded during migraine-like complaints in both symp-
tomatic and idiopathic cases [10,11,28]. Moreover, when
EEG anomalies are recorded, no specific cortical correla-
tions emerge (e.g., focal frontal, parietal, temporal, occip-
ital and primary or secondary generalized) [10,11,28].
Lastly, the criteria we propose do not offer the possi-
bility of confirming all suspected cases of IEH by means of
intravenous anticonvulsant administration, just as it is not
always possible for other types of epileptic seizures; in
fact, although in case of ‘‘autonomic seizures’’ such as in
IEH, the clinical response seems to be present in almost all
published cases, we cannot be sure that i.v. anticonvulsant
administration is able to stop a seizure in any cases in these
types of patients.
For all the aforementioned reasons, we firmly believe
that the diagnosis of IEH (even according to our proposed
new criteria) will remain an underestimated phenomenon
owing, in particular, to:
a. the psychosocial stigma attached to this disease;
b. the fact that IEH cannot always be detected from the
scalp;
c. IEH could rarely be responsive to antiepileptic i.v.
administration, as can happen for other type of
seizures.
Conclusion
The clinical pictures of IEH seem to be extremely rare [2]
and it has been documented in about 12 cases [12–14,
16–23]. Since its epileptic nature can be documented only
with ictal EEG recording and simultaneous intravenous
antiepileptic administrations, it is difficult to obtain firm
conclusions about the frequency of IEH on epidemiological
studies. In this regard, we have recently published an
‘‘editorial’’ completely dedicated to these epidemiological
aspects, their possible biases and the underestimation
potentially related particularly to pediatric age [69]. Based
on the current knowledge and clinical experiences reported,
migralepsy (coded in ICHD-II as 1.5.5 ‘‘migraine-triggered
seizure’’) is highly unlikely to exist as such. We therefore
propose to take from the Appendix of International Head-
ache Disorders Classifications this term until clear evi-
dence is provided of its existence.
‘‘Ictal epileptic headache’’ criteria [2,28,69] (Table 1)
should be used to classify the rare events in which head-
ache can represent the sole ictal epileptic manifestation.
‘‘These findings further highlight the important role of
EEG recording in patients with headache, which has been
traditionally opposed by the ancestral fierce adversity (25)
against the possible link between headache and epilepsy’’.
Rather, we certainly should think deeply about the inap-
propriate and exaggerated overuse of the brain CT in the
pediatric emergency room in children admitted simply for
idiopathic or more frequently ‘‘upper respiratory infec-
tions’’-associated headache.
In conclusion, using our proposed new criteria (Table 1)
[2] in a large pediatric population, we will be able to clarify
if ‘‘ictal epileptic headache’’ is really a phenomenon that
shows a marginal role or, vice versa, represents an under-
estimated event [68–70].
Conflict of interest None.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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