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1 Seizure 20 (2011) Contents lists available at ScienceDirect Seizure journal homepage: Review Migralepsy and related conditions: Advances in pathophysiology and classification 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, Italy b Muscular and Neurodegenerative Diseases Unit, G. Gaslini Institute, University of Genova, Italy c Neurology Clinic, Department of Neuroscience, Sant Anna Hospital, Como, Italy d Child Neurology, Pediatric Headache Centre, Sleep Disorders Centre, Chair of Pediatrics, Second, Faculty of Medicine, Sapienza University, Via di Grottarossa, , Rome, Italy ARTICLE INFO ABSTRACT 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 Basic and clinical neuroscience research findings suggest that cortical spreading depression (CSD) and epileptic foci may facilitate each other; furthermore, the threshold required for the onset of CSD has been suggested to be lower than that required for an epileptic focus. These data may explain the prevalence 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 ) (so-called migralepsy ) among the complications of migraine, and defines hemicrania epileptica ( ) 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 suggest that 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 those rare 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. ß 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. 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 * Corresponding author at: Child Neurology, Headache Paediatric Center, Paediatric Sleep Disorders, Chair of Paediatrics, II Faculty of Medicine, Sapienza University, c/o Sant Andrea Hospital, Via di Grottarossa, Rome, Italy. Tel.: addresses: pasquale.parisi@uniroma1.it, parpas@iol.it (P. Parisi). occurrence of both disorders in the same individual is more frequent than 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 than the prevalence of epilepsy in the general population (0.5 1%). 3 Moreover, the frequency of migraine in the epilepsy population is high, ranging from 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 underlying the onset of both diseases. 2 In migraine, however, hyperexcitability 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 /$ see front matter ß 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi: /j.seizure

2 272 A. Verrotti et al. / Seizure 20 (2011) 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 antiepileptic drugs (AEDs), including valproate, topiramate and gabapentin, 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 In recent years, the inaccuracy of the current definition and classification of migralepsy and conditions related to migralepsy has become increasingly apparent 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 characteristic of epilepsy. 7 Since then, approximately 50 cases have been described in the literature, the majority of which have been the criticized by other authors It is 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 the recent report of the ILAE Commission on the Classification and Terminology of seizures and epilepsies 15 ; however, according to the current International Classification of Headache Disorders II (ICHD-II), 16 migralepsy is included among the complications of migraine (paragraph coded ) and is defined as a migraine triggeredseizure that must fulfill two diagnostic criteria: (a) migraine fulfilling 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 classification. The term ictal epileptic headache has recently been proposed by Parisi et al and defined as the sole ictal epileptic phenomenon without any other associated ictal epileptic 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 a variety 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 without aura (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 the ICHD-II definition be 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, the diagnosis in many of the cases 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, spike wave complexes and sharp waves, mainly localized in the temporal and/or occipital lobes. As regards the ictal EEG 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 syndrome, as well as in patients with a deep epileptic focus arising, for example, from the orbito-mesial frontal zone 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-neurophysiological variables (fiber size, myelination and extent of polysynaptic interconnections). 18,21 23 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. 17,24 27 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 And what would the clinical and EEG features of the ictal-eeg recording in the ictal epileptic headache cases be? Unfortunately, there is no specific EEG picture in these cases either, with

3 A. Verrotti et al. / Seizure 20 (2011) numerous different EEG associated patterns having been recorded during migraine-like complaints. 10,11,17 22,24 27 These patterns include: (i) high-voltage, rhythmic, Hz activity with intermingled spikes over the right temporo-occipital regions ; (ii) high voltage theta activity intermingled with sharp waves over the occipital region 17 and (iii) bilateral continuous spike-andslow-wave discharges. 25 Furthermore, a photoparoxysmal response 24 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 remission of the headache and 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 diazepam 17,25,26 or phenytoin. 27 According to the definition provided in the ICHD-II, migralepsy is 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 MwA 18 ; 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, theta delta activity 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 may be that they are the 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 region 26,27 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 secondary trigemino-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 zonisamide and levetiracetam may help prevent the onset of migraine. 31,32 4. Pathophysiological and genetic aspects Although the pathophysiology of migraine-induced seizures is still undefined, it has been hypothesized that 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 (2 6 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 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. 36 Opinions are still divided as to whether CSD plays a physiological or a neuroprotective role 36 ; it is, however, believed to cause the activation of TVS, consisting of the cascade release of numerous inflammatory molecules (sterile inflammation) and neurotransmitters, 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 emerge 38 ; 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 appear to be hierarchically divided according to how likely they 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 be stressed 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, increased awareness 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 event has 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 seizures. 10,18,21 The threshold required for the onset of 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

4 274 A. Verrotti et al. / Seizure 20 (2011) 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 hyperexcitability 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 metabolism 47 and ion channel function are impaired in both. 48 Mutations in genes coding for ion channels, 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 rare autosomal 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 Ca v 2.1 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 gene ATP1A2 is located on the long arm of chromosome It codes for the a 2 subunit 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 Mutations have 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 POLG 58, C10 and F2 59, 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. Voltagegated ion channels are part of an extensive signaling pathway that affect neuronal excitability through various mechanisms 60 ; 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 described in 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 defined more 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 migraine-triggered seizure ) is, despite being theoretically possible, 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. 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