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Migralepsy explained … perhaps‽

Posted in Special Feature on 1st Sep 2021

Andrew LarnerAndrew Larner, Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ   UK.
Provenance and peer review: Submitted and reviewed internally
Date first submitted: 19/04/21
Acceptance date: 3/05/21

Published online: 8/9/21

Published under a Creative Commons license

What is migralepsy? Etymologically the explanation is simple: a blend or portmanteau word combining “migraine” and “epilepsy”.  But what about the clinical definition?  Does this simply imply an association between the two conditions?  Since both are common, some association would be expected by chance concurrence alone.  Or does it suggest comorbidity, some shared pathophysiology (both are paroxysmal disorders)?  If so, is this to mean a unidirectional link, such that migraine triggers epilepsy? Or could the link be bidirectional, and hence equally reasonably labelled as “epigraine”?

The term migralepsy apparently originates with the American epileptologist William G. Lennox (1884-1960) who, in his 1960 textbook of epilepsy, used it to describe the condition in which “ophthalmic migraine with perhaps nausea and vomiting was followed by symptoms characteristic of epilepsy”.1  Examining other authoritative sources, I find no entry in the online Oxford English Dictionary, and the term does not appear in either the ICD10 classification or in the 2017 International League Against Epilepsy (ILAE) classification of seizure types.

The International Classification of Headache Disorders 3rd edition (ICHD3; is more helpful, including a category (1.4.4) of “migraine aura-triggered seizure”, which, it is acknowledged, is “sometimes referred to as migralepsy”.  This is defined as a “seizure triggered by an attack of migraine with aura” and has the following diagnostic criteria:

  1. A seizure fulfilling diagnostic criteria for one type of epileptic attack, and criterion B below
  2. Occurring in a patient with 1.2 Migraine with aura, and during or within 1 hour after an attack of migraine with aura
  3. Not better accounted for by another ICHD-3 diagnosis.

The implication here is clearly of a unidirectional process (i.e. epilepsy does not trigger migraine).

The condition is acknowledged to be rare (I cannot recall seeing a case in 20+ years as a consultant neurologist).  Indeed, fewer than 30 references are recovered on Pubmed when using “migralepsy” as a title word.  Diagnostic issues include the risk of misinterpreting occipital lobe seizures as migraine visual auras.

Accordingly, some have argued strongly for the deletion of the term, favouring ictal epileptic headache.2  But this judgment may possibly be premature.  Migraine stroke is rare, but nonetheless not discounted as a plausible diagnostic category.  As noted by Miller Fisher in this context:

Unusual cases [of migraine], while disconcerting to the clinician, have a special importance, for any theory of the mechanism of migraine must explain not only the commonplace but also these aberrant forms; indeed in our current state of knowledge they provide special information and may suggest additional avenues for speculation.3

In 1991, the philosopher Daniel Dennett published a book entitled “Consciousness explained”, but not all readers entirely concurred that this was, as the title might imply, the last word on the subject.  In the same provisional, rather than definitive, spirit, I tentatively suggest the following explanation for migralepsy.

When considering the possible pathogenesis of migralepsy, it is of note that, according to ICHD3, “Evidence of an association [of seizure triggered by an attack of migraine] with 1.1 Migraine without aura is lacking”.  Hence, aura would seem to be a sine qua non for migralepsy by this definition, suggesting the possibility of a neurophysiological continuum between migrainous aura and epileptic seizure.

The possibility that migraine aura may be a consequence of the phenomenon of Leão’s spreading depression4 was first suggested by Milner (1958) and then by Lauritzen (1985) and Pearce (1985).5-7  It is now widely assumed that this is indeed the mechanism, albeit “cortical spreading depression” is now often characterised as part of a continuum with spreading depolarization (SD), a wave of electrophysiological hyperactivity followed by a wave of inhibition which propagates across the cerebral cortex at between 1-10 mm/min.  The changes in neuronal electrical activity are mediated by changes in extracellular ion concentrations, particularly increased K+, toxic release of glutamate, dispersion of electrochemical gradients from failure of Na+/K+-ATPase pumps, mitochondrial dysfunction, and cytotoxic oedema, leading to prolonged neuronal membrane depolarization and refractoriness to neuronal impulse and synaptic transmission.  SD has also been implicated in the neurological sequela of other disease processes, including ischaemia, hypoxia, hypoglycaemia, and epilepsy.8  

The relationship between SD and epileptic activity is complex and poorly understood,8 but certainly in some circumstances SD may facilitate the onset of seizure activity, for example by lowering seizure threshold and/or enhancing spontaneous epileptiform activity,9 or accelerating interictal to ictal transitions.10  SD might therefore account at a mechanistic level for the neurophysiological continuum between migrainous aura and epileptic seizure, triggering two clinically distinct events sequentially as the wave progresses across the cerebral cortex.  This possibility has previously been suggested, the rarity of “migraleptic event” being accounted for by the higher threshold for seizure onset and propagation than for migraine aura-associated SD.11  The differential thresholds would also explain the much higher frequency of ictal and peri-ictal headaches.

Another example of such a sequential process, with shared pathophysiology but distinct clinical manifestations, may be pertinent to this argument.  Episodes of transient global amnesia (TGA) are reported on occasion immediately to precede a typical migraine headache, prompting the suggestion that TGA may sometimes be a form of migraine aura.  Because of its relationship to migraine, both clinical and epidemiological, TGA has also been suggested to be a consequence of spreading depression12,13 or, more recently, SD.14  The rarity of this occurrence may reflect the lower susceptibility of the hippocampus to develop SD compared to other brain regions, the occipital cortex being the most vulnerable area.15

Shared mechanisms might also contribute a possible explanation for the rare occurrence of migraine stroke or, as per ICHD3 terminology, migrainous infarction (category 1.4.3. One or more migraine aura symptoms occurring in association with an ischaemic brain lesion in the appropriate territory demonstrated by neuroimaging, with onset during the course of a typical migraine with aura attack).  Again, as for migralepsy, this definition indicates that aura is a sine qua non, suggesting the possibility of a neurophysiological continuum between migrainous aura and infarction.  The haemodynamic response to SD is variable, including both monophasic hypo- or hyperperfusion and biphasic vasoconstriction and vasodilation.8  A profound SD-related hypoperfusion in the appropriate vascular territory might therefore account for ischaemic infarction associated with migraine aura.  This possibility has also been previously suggested.16  Migraine aura has on occasion been reported as the only symptom of neuroradiologically-confirmed ischaemic stroke.17

These considerations, even if wrong, highlight the importance of looking at mechanisms, and the possibility that “aberrant forms” of migraine may shed light on theories of mechanism, as Miller Fisher presciently suggested.3  In this context, it has been suggested that SD may be a “universal principle” of lesion development.18  If so, this mechanism might underpin different paroxysmal clinical phenotypes (aura, seizure, amnesia, stroke).  An argument for such a biology-first approach, agnosic to phenotype, with secondary definition of patient subgroups according to biomarkers, has previously been advocated for neurodegenerative diseases such as Parkinson’s and Alzheimer’s, even though this segregation may not result in homogeneous clinical clusters.19  Maybe this will be the way neurology is pursued in the future.


  1. Lennox WG, Lennox MA, Epilepsy and related disorders (2 volumes). London: J&A Churchill, 1960.
  2. Belcastro V, Striano P, Kasteleijn-Nolst Trenité DG, Villa MP, Parisi PJ. Migralepsy, hemicrania epileptica, post-ictal headache and “ictal epileptic headache”: a proposal for terminology and classification revision. J Headache Pain 2011;12:289-294.     
  3. Fisher CM. An unusual case of migraine accompaniments with permanent sequela – a case report. Headache 1986;26:266-270.
  4. Leão AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944;7:359-390.
  5. Milner PM. Note on a possible correspondence between the scotomas of migraine and spreading depression of Leão. Electroencephalogr Clin Neurophysiol 1958;10:705.
  6. Lauritzen M. On the possible relation of spreading cortical depression to classical migraine. Cephalalgia 1985;5(Suppl2):47-51.
  7. Pearce JM. Is migraine explained by Leão’s spreading depression? Lancet 1985;2:763-766.
  8. Cozzolino O, Marchese M, Trovato F et al. Understanding spreading depression from headache to sudden unexpected death. Front Neurol 2018;9:19.
  9. Gorji A, Speckmann EJ. Spreading depression enhances the spontaneous epileptiform activity in human neocortical tissues. Eur J Neurosci 2004;19:3371-3374.
  10. Rathmann T, Ghadiri MK, Stummer W, Gorji A. Spreading depolarization facilitates the transition to neuronal burst firing from interictal to ictal state. Neuroscience 2020;441:176-183.
  11. Parisi P. Why is migraine rarely, and not usually, the sole ictal epileptic manifestation? Seizure 2009;18:309-312.
  12. Olesen J, Jorgensen MB. Leão’s spreading depression in the hippocampus explains transient global amnesia. A hypothesis. Acta Neurol Scand 1986;73:219-220.
  13. Ding X, Peng D. Transient global amnesia: an electrophysiological disorder based on cortical spreading depression-transient global amnesia model. Front Hum Neurosci 2020;14:602496.
  14. Larner AJ. Transient global amnesia: model, mechanism, hypothesis. Submitted.
  15. Bogdanov VB, Middleton NA, Theriot JJ et al. Susceptibility of primary sensory cortex to spreading depolarizations. J Neurosci 2016;36:4733-4743.
  16. Eikermann-Haerter K. Spreading depolarization may link migraine and stroke. Headache 2014;54:1146-1157.
  17. Waters MJ, Cheong E, Jannes J, Kleinig T. Ischaemic stroke may symptomatically manifest as migraine aura. J Clin Neurosci 2018;55:62-64.
  18. Hartings JA, Shuttleworth CW, Kirov SA et al. The continuum of spreading depolarizations in acute cortical lesion development: examining Leão’s legacy. J Cereb Blood Flow Metab 2017;35:1571-1594 [at p.1572].
  19. Espay A, Stecher B. Brain Fables. The hidden history of neurodegenerative diseases and a blueprint to conquer them. Cambridge: Cambridge University Press, 2020.