Seizure 18 (2009) 309–312

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Review Why is migraine rarely, and not usually, the sole ictal epileptic manifestation?

Pasquale Parisi *

Child Neurology and Pediatric Headache Centre, Department of Pediatrics, ‘‘La Sapienza’’ University, Viale Regina Elena 324, 00161 Rome, Italy

ARTICLE INFO ABSTRACT

Article history: Purpose and methods: Migraine, with or without aura, affects from 10% to 14% of the population, and is as Received 14 September 2008 such one of the most common headache disorders. A uniﬁed hypothesis for the physiopathology of Received in revised form 8 November 2008 migraine and its relationship with epileptic migraine and migralepsy has yet to be formulated. Accepted 16 January 2009 Trigemino-vascular system (TVS) activation is believed to play a crucial role in the ‘‘pain phase’’ in migraine; cortical spreading depression (CSD) is considered to be the primary cause of TVS activation. Keywords: On the basis of data in the literature, I would like to stress that TVS activation may originate at Migraine different cortical and subcortical levels. For example, as recently reported, an epileptic focus, originating Epilepsy and propagating along cortical non-eloquent/silent areas, through CSD, rarely causes TVS activation with Hemicrania epileptica Ictal epileptic headache migraine as the sole ictal epileptic manifestation. Cortical spreading depression Results and conclusion: The multiple considerations that arise from this hypothesis, including the under- CSD diagnosed ictal epileptic headache, are discussed; EEG (ictal and inter-ictal) recording with intermittent Trigemino-vascular theory photic stimulation (IPS), according to the standardized international protocol, is strongly recommended in selected migraine populations. ß 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Contents

1. Links between CSD and the migraine trigemino-vascular theory ...... 309 2. Link between CSD and cortical focal paroxysmal discharge (neurophysiopathologic and genetic link level) ...... 310 3. Link between migraine and epilepsy (clinical link level)...... 310 4. Final hypothesis, suggestions and future directions...... 310 4.1. Why is migraine rarely, and not usually, the sole ictal epileptic phenomenon?...... 311 References...... 311

1. Links between CSD and the migraine trigemino-vascular physiopathology of migraine have attracted the attention of the theory leading experts in this field.12–13 The discovery of CSD represents a perfect example of so-called Functional neuroimaging1 and neurophysiological studies2–7 ‘‘serendipity phenomena’’. In other words, it illustrates how an have revealed that primary headaches (both tension-type and unexpected, chance observation, if made by an alert experimenter, migraine type) may be characterised by different activation can open a new, major area of investigation.14–15 In animals, CSD can patterns of the central and peripheral pain modulatory structures, be triggered by focal stimulation (electrical, mechanical, with high most of which have been identified by numerous authors in recent extracellular K+ or glutamate, persistent intracellular sodium influx, decades as possible sites of specific impairment (functional or inhibition of the Na+–K+ ATPase pump), as well as by several other structural) involved in the physiopathology of headache.2–11 stimuli of the cerebral cortex, more readily in the occipital region Among these, studies on the role of cortical spreading depression than in other regions.14–16 CSD is characterized by a slowly (CSD) and trigemino-vascular system (TVS) activation in the propagating wave (2–6 mm/min) of sustained strong neuronal depolarization that generates transient (in the order of seconds), intense spike activity as it progresses into the tissue, followed by neural suppression which may last for minutes. CSD represents a * Tel.: +39 06 49979311; fax: +39 06 49979312. regenerative ‘‘all-or-none’’ event (a neurophysiologic characteristic E-mail address: [email protected]. shared with the ‘‘membrane depolarization’’ underlying a focal

1059-1311/$ – see front matter ß 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2009.01.010 310 P. Parisi / Seizure 18 (2009) 309–312 epileptic discharge event) that propagates slowly in a wave-like seizure-like discharges and CSD in a model neuron.33 Data thus fashion in brain tissue. The depolarization phase is associated with confirm that CSD (migraine) and cortical focal discharges an increase in regional cerebral blood flow (rCBF), whereas the phase (seizures) facilitate each other. of reduced neural activity is associated with a reduction in rCBF. Lastly, it is highly interesting that these data are supported, Opinions are divided as to whether CSD plays a physiological17 or a going back into the past, by Leao himself, who described, while neuro-protective role.18 studying ‘‘experimental epilepsy’’,34 CSD onset due to the Moskowitz and co-workers have, since 1993, been making a propagation of electrically provoked seizure discharges in the major contribution, by means of experimental data12,13,19 and cerebral cortex and, in the same article, the similarity in the ways functional neuroradiological investigations in humans,1 to the in which CSD and seizures propagate. search for possible correlations between CSD onset and TVS activation; TVS activation is considered to represent ‘‘the common 3. Link between migraine and epilepsy (clinical link level) final pathway’’, which consists of a cascade release of numerous inflammatory molecules (sterile inflammation) and neurotrans- The association between headache/migraine and seizures is a mitters that are a ‘‘sine qua non’’ condition resulting in pain during widespread, well-known event. Headache/migraine are associated the attacks. CSD is considered to be the primary cause for TVS with seizure occurrence in 34–58% of epileptic patients, 60% of activation. These studies by Moskowitz and co-workers have whom have a peri-ictal headache alone, i.e. headache/migraine in strongly contributed to the formulation of the ‘‘trigemino-vascular such subjects are always temporally related to seizures. According theory’’, which has become the most widely accepted theory in the to the international criteria,35 about 37% of headaches are tension- physiopathology of migraine. The correlation between CSD and type while about 55% are migraine (75% MoA and 15% MA)36–39; migraine with aura (MA) was demonstrated first12,13,19; more the rate of peri-ictal headache reported in the literature (34–58%) recently, imaging studies in patients suffering from migraine is very similar in both past36 and more recent37–39 studies. The without aura (MoA) have also pointed to the presence of CSD in temporal relationship between migraine/headache and seizures silent areas as an underlying mechanism.20–23 allows us to subdivide headaches as follows36–39: 5–27% are only It should be borne in mind that CSD is not a phenomenon that is pre-ictal, 2.2% are ictal,38 30–70% are only post-ictal, while 7–27% ‘‘strictly’’ peculiar to the cortical structures. Cortical and sub- are both pre-ictal and post-ictal. cortical areas appear to be hierarchically divided according to how Problems have arisen in international criteria regarding the likely they are to develop CSD,14,24 though the occipital lobe definition of the rare condition in which migraine (even more appears to be the area most likely to be affected. rarely, tension-type headache) may be the sole semeiologic manifestation of the epileptic seizure. 2. Link between CSD and cortical focal paroxysmal discharge Our group recently described40 a 14-year-old girl who had a (neurophysiopathologic and genetic link level) photosensitive occipital epileptic seizure followed by a status migrainosus that lasted 3 days. An EEG revealed occipital status Worthy of attention is an old finding in the literature regarding epilepticus during her migraine attack; intravenous administra- the properties and the critical role that the Na+–K+ ATPase pump tion of diazepam, under continuous EEG recording, suppressed plays in the regulation of both seizure onset, by acting on both the epileptiform discharges and headache complaints. Three membrane depolarization (due to inhibitory potential post- days later, we evoked visual aura and migraine in this patient synaptic modulation), and CSD, by modifying the local K+ during an EEG recording by means of intermittent photic concentration. This old experimental finding linked both seizure stimulation (IPS).40 It is particularly intriguing that IPS can trigger and CSD onset to the ability of the Na–K pump to regulate K+ both migraine attacks and epileptic seizures. On the basis of our extracellular concentrations.25 Intriguingly, thirteen years later, observations, we also recently suggested that the diagnostic this experimental finding was confirmed in humans by a novel criteria for ‘‘hemicrania epileptica’’ in Migraine and Epilepsy mutation in the Na+–K+ ATPase pump associated with two International Classifications35,41 be revised, and that the impor- phenotypically different pictures: familial hemiplegic migraine tance of EEG recordings with standardized IPS be stressed.42,43 We (FHM) and benign familial infantile convulsions (BFIC).26 More- also proposed the term ‘‘ictal epileptic headache’’ for ‘‘migraine/ over, a monogenic defect in familial occipital lobe epilepsy headache’’ as the sole semeiologic epileptic ictal phenomena.43 associated with MA was reported.27 Another noteworthy point is the existence of migraine attacks An important role in the phenomenon linking the onset of CSD that occur separately in-between epileptic seizures (interictal and cortical focal epileptic discharges might be played by migraine), which may (rarely) represent the sole ictal epileptic complementary mechanisms responsible for ionic diffusion in manifestation in subjects previously diagnosed as epileptic and both these events (i.e. epileptic depolarization and CSD onset). The (even more rarely) in patients in whom epilepsy was not velocity of ionic diffusion across neuronal cytoplasmic bridges (gap diagnosed. In this regard, the role of EEG recording should not junctions) is different from that through interstitial spaces, though be underestimated. both converge in the membrane excitability modulation. Synchro- nization in CSD has been hypothesized to be caused by the non- 4. Final hypothesis, suggestions and future directions synaptic interaction between neurones mediated by the excitatory neurotransmitter glutamate or through ‘‘gap junctional’’ interac- The ‘‘sine qua non’’ condition for headache is TVS activation, tions.28 Moreover, the previously reported gap junction properties which is believed to be the only neural pathway able to induce in the modulation of CSD onset29 and spreading14,29 as well as the migraine (with or without aura). anticonvulsant properties of gap junction blockers30 have been In the central nervous system, there appears to be a hierarchical documented. Yet other data highlight the role of gap junctions in organization based on ‘‘neuronal networks’’ (cortical and sub- synchronizing the human neocortical network, which in turn cortical) that may be more or less prone to CSD (migraine) and increases epileptiform activity.31 epileptic focal discharges (seizures). Onset and propagation are More recently,32 CSD has been reported to facilitate synaptic triggered when these neurophysiological events reach a certain excitability in human neocortical tissues, thus contributing to the threshold (‘‘all or-none events’’), which is lower for the onset of hyperexcitability of neocortical tissues in patients suffering from CSD than that of the seizure. Once the cortical event is started, the migraine. Moreover, calcium-sensitive current can promote both way in which it spreads depends on the size of the onset zone, its P. Parisi / Seizure 18 (2009) 309–312 311 velocity, semeiology and type of propagation of the cortical event, secondary generalization. In this respect, an ictal EEG (during the all of which may vary within the same patient at different times. migraine attack) should be recommended in every migraine The onset of CSD and of the epileptic seizure may facilitate each patient, even in subjects who are not known to be epileptic. During other.14,16,31,32 The underlying neurophysiological causes may be an interictal EEG (or video-EEG) recording, particular attention the same, with the two phenomena displaying the ‘‘all-or-none’’ should always be paid to the ictal onset of the clinical-EEG findings (as mentioned above) characteristic, which may be triggered by (and not the EEG abnormalities alone, which are relatively more than one pathway converging upon the same destination common) during IPS, performed according to the standardized (depolarization and hypersynchronization). The triggering causes, international protocol.47 As regards the criteria for the selection of which may be environmental or individual (whether genetically patients in whom a more thorough EEG investigation is warranted, determined or not), result in a flow of ions that mediate CSD above the abrupt onset of headache, a short attack duration (i.e. lasting all through neuronal (and probably glial) cytoplasmic bridges minutes) and the migraine-like characteristics of the attacks (as (intracellular gap-junctions) rather than through interstitial opposed to the tension-type ones) may be a good starting point. spaces, as usually happens in the spreading of epileptic Another intriguing issue is the difference between the clinical seizures.14,44 Furthermore, the threshold required for the onset picture of adult and that of childhood in both epilepsy and of CSD is likely to be lower than that required for the epileptic headache. Autonomic manifestations are more prevalent in the seizure. In other words, I believe that the onset of the epileptic childhood headache clinical picture, as well it is observed in most seizure facilitates the onset of CSD to a greater degree than the early benign focal idiopathic epileptic childhood syndromes, such onset of CSD facilitates the onset of the epileptic seizure. Thus, as as the well-known Panayiotopoulos syndrome (PS). In this regard, epidemiologic studies in the literature suggest,36–39,45,46 in the our group documented a child affected by PS48 whose interictal clinical context we are more likely to observe epileptic patients migraine attacks (in-between the nocturnal seizures) completely with ‘‘comorbid’’ (peri-ictal and interictal) migraine than migraine remitted (as did the seizures) after the administration of antic- subjects with ‘‘comorbid’’ epilepsy. onvulsant therapy. From the therapeutic point of view, the anticipation of the 4.1. Why is migraine rarely, and not usually, the sole ictal epileptic cortical event (CSD) that induces secondary TVS activation phenomenon? probably explains why AED treatment is more effective in the prophylaxis phase than in the pain phase (migraine attack). In Migraine without aura is thought to be the result of a CSD that order to ‘‘interfere’’ with this very complex polysynaptic and starts and propagates from silent cortical areas following TVS polymolecular cascade, several cortical and subcortical levels must activation (pain phase), without any additional signs/symptoms. be acted upon; the model proposed here (multiple different Similarly, an epileptic seizure, whose onset and propagation occur cortical and subcortical levels underlying the onset of migraine along silent/non-eloquent cortical areas, may activate the TVS, attacks) is supported in the literature by a number of molecules which results in a migraine attack without any additional epileptic with different pharmacological properties that have proved signs/symptoms.40,42–44 The latter condition is understandably (clinically and experimentally)8,19,49–55 to play a therapeutic role very rare, it being statistically highly unlikely that this type of in migraine. event might occur by chance. This observation is supported by the Future research is warranted to identify the various levels of the fact that peri-ictal headaches associated with other signs/ cortico-subcortical polysynaptic molecular cascade, which will symptoms during an epileptic seizure are very common (34– hopefully provide migraine (whether epileptic or not) therapy with 58%),36–39,45,46 which in turn confirms that the threshold for specific pharmacological properties tailored for individual migraine onset is lower than that of seizure onset. In this regard, a patients. ‘migraleptic’ event, i.e. a migraine attack followed by epileptic seizures, is also very rare because the threshold required for Conflict of interest seizure onset and propagation is higher. Therefore, migraine (with or without aura), along with all other I have no conflict of interest in publishing this article. headache types (the literature on other headache disorders is unfortunately more limited), is highly unlikely to be an epileptic References event, but rather the result of cortical or subcortical events that activate the TVS. These events might consist of CSD or ‘‘subcortical’’ 1. Hadjikhani N, Sanchez del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. spreading depression, or be caused by environmental, individual or Mechanisms of migraine aura revealed by functional MRI in human visual cortex. PNAS 2001;98(8):4687–92. genetic noxae, which cause an impairment that ‘‘interferes’’ with 2. Valeriani M, Rinalduzzi S, Vigevano F. Multilevel somatosensory system dis- the very complex polysynaptic and polymolecular cascade at the inhibition in children with migraine. Pain 2005;118(1–2):137–44. subcortical level in the TVS networks. 3. 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