The cortical spreading depression/migraine aura hypothesis – Finally some definitive evidence

Despite the decades-long acceptance of the hypothesis that cortical spreading depression (CSD) is the physiological substrate of the typical migraine aura, it has always been just this—a hypothesis. There has been indirect human evidence supporting this hypothesis but until now, no direct demonstration of the canonical electrophysiological changes of CSD associated with the migraine aura. The study by McLeod et al.1 provides such evidence, describing the electrophysiological signature of CSD associated with migraine aura in a patient being continuously monitored with intracranial electrodes as part of the evaluation for a seizure disorder. This is a highly significant case report that advances our understanding of migraine pathophysiology. The patient described in the paper by McLeod et al.1 had a history of migraine with aura in addition to a seizure disorder, each with distinct clinical presentations. She experienced a typical attack of migraine with aura that was captured with implanted electrodes, which showed a slowly propagated wave of low-voltage suppression starting in the left mesial occipital cortex. This wave of suppression, which was correlated with her visual aura symptoms, was similar to that which occurs in animal models and in humans with traumatic brain injury.2 This is the first description of CSD associated with a migraine aura. Why has it taken so long? There are multiple possible reasons. First, CSD is very difficult to measure with surface electroencephalography (EEG), such that as in this study, intracranial electrodes may be required. Previous studies of migraine aura with surface EEG recordings have not consistently demonstrated significant changes.3 Although in this case the propagated wave extended to most of one hemisphere (as it does in lissencephalic animal brains4), one of the challenges in measuring CSD with surface EEG may be that the changes associated with it may be more typically limited to a very small area, and the very slow rate of spread may not allow for sustained changes in any one region that enable identification of a spatially propagated phenomenon. Mapping of the visual aura onto the visual cortex indicates a limited area of spread that may follow a sulcal or gyral pattern,5 unlike the concentric “pebble in a pond” spread that is observed in lissencephalic animals that have a smooth cortex, and that is often represented in schematic diagrams of the migraine aura. In addition, although migraine auras have in the past been captured with surface EEG recordings, this requires either serendipity or continuous recording with detailed attention to ongoing clinical symptoms as was done in this study. This kind of recording is typically done in the investigation of seizure disorders, such that migraine symptoms may be overlooked. It is important to recognize that although this study shows CSD in association with migraine aura, this does not mean that CSD is the initiating phenomenon for a migraine attack nor the cause of headache. Although it is tempting to conclude based on the observation in this case that the aura precedes headache (as it usually does), this temporal relationship is not true in all cases.6 Further, most individuals who have migraine with aura also have migraine without aura, and migraine aura without headache is common. These observations show that aura is neither necessary nor sufficient to cause migraine headache and suggest that the same holds for CSD. CSD may therefore be one manifestation of the migraine “brain state” that is not a requisite part of a migraine attack. Consistent with this concept, functional imaging has shown changes in brain activity, particularly in the hypothalamus, preceding migraine attacks both with and without aura in the same patient.7 In this case report, the electrophysiological changes consistent with CSD spread widely, eventually involving most of one hemisphere. Given how significant and widespread these changes were, it is surprising that the event was associated with only visual aura symptoms, and not sensory, language, or motor symptoms or other neurological symptoms. An increased understanding of how CSD could spread widely in presumably eloquent areas of the brain without causing more significant symptoms could lead to better understanding of migraine pathophysiology in general. This is a case report of a single patient with a seizure disorder who had intracranial instrumentation, which raises questions as to whether the described results can be generalized to those without seizure disorders who are not being invasively monitored. Intracranial electrodes could act as a focus of initiation of CSD and thereby change its characteristics, and the concomitant seizure disorder could also alter CSD. On the other hand, the fact that typical aura symptoms occurred in conjunction with the classical CSD changes suggests that the CSD event could also be typical. This case is an example of how an “n of 1” study can show what is possible, even if it is not yet clear that the results are generalizable. This study also highlights the importance of not simply accepting hypotheses about migraine pathophysiology that are based largely upon animal models but rather continuing to strive for definitive human evidence to address these hypotheses to advance the field of headache medicine. None. Andrew C. Charles has served as a compensated consultant for Abbvie, Amgen, Eli Lilly, Aurene, Lundbeck, Pfizer, and Vectura. He receives royalties from Oxford University Press. He is the immediate past President of the American Headache Society. Peter J. Goadsby reports, over the last 36 months, personal fees from Aeon Biopharma, Abbvie, Aurene, CoolTech LLC, Dr. Reddy's, Eli-Lilly and Company, Epalex, Kallyope, Linpharma, Lundbeck, Pfizer, PureTech LLC, Satsuma, Shiratronics, Teva Pharmaceuticals, and Vial, and personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, Vector Metric, and fees for educational materials from CME Outfitters and Web MD, and publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer, and a patent magnetic stimulation for headache (number: WO2016090333 A1) assigned to eNeura without fee.