Tsunamis hiding in plain sight: spreading depression in clinical neurology

Spreading depression is a neurophysiological phenomenon that is observed in the central nervous system of many species, from insects to humans. In essence, spreading depression is a slowly propagating wave of mass depolarization (that is, spreading depolarization), aptly termed a ‘brain tsunami’, which successively engulfs contiguous brain regions, causing transient neuronal hyperexcitability at its leading edge, followed by complete but reversible neuronal silence lasting minutes. This wave cannot be detected in routine scalp EEG recordings, which contributes to its under-recognized status as a disease biomarker. Here, we present an evidence-based view of spreading depression as a probable cause of characteristic neurological signs and symptoms in numerous neurological conditions. Although migraine aura is a widely recognized manifestation of spreading depression, the clinical signs and symptoms of spreading depressions arising from structural brain pathology have remained an orphan concept with no established name or place in clinical terminology. Therefore, clinicians have long used the term ‘migraine aura’ to describe the transient neurological manifestations of spreading depression that occur entirely outside of the context of a migraine attack. As migraine is a primary headache disorder not caused by known structural pathology, this terminology is not only erroneous but could also lead to serious misdiagnoses. Consequently, we advocate for the clinical adoption of the more specific mechanistic term spreading depression to describe these clinical episodes. We believe it is imperative to recognize spreading depression as a generic mechanism underlying certain inherited or acquired neurological deficits and to differentiate between structural and non-structural aetiologies, as is done in seizure disorders.