SD has been observed in patients suffering from SAH using subdural electrocorticographic strip electrodes. It has been shown that SD has a high incidence in this type of cerebrovascular disease, reported to be between 66 and 100 %; there is also a relationship between delayed cerebral ischemia (DCI) and SD occurrence in approximately 44–88 % of the cases [40]. Repeated SDs with prolonged depression periods have been found as an early indicator of DCI after SAH [15]. This finding called into question the role of angiographic cerebral vasospasm as the main cause of DCI, suggesting that SD has a potential pathophysiological mechanism in its development [52]. It is expected that pathological conditions that occur after SAH, such as hypoxia, low glucose, high extracellular concentrations of K⁺, and nitric oxide depletion by free hemoglobin products, are capable of triggering SD [11, 12]. Then, SD is initiated under conditions when (1) metabolic demands are not met per se and (2) the hemodynamic response is turned from hyperemia to spreading ischemia. This could lead into a self-perpetuating cycle with consecutive cortical necrosis and DCI formation [9]. Therefore, treatments targeting SD should decrease DCI and improve clinical outcome. In this regard, there is indirect evidence that the l-type Ca⁺ inhibitors, nimodipine [14, 49] and nicardipine [50], or the NMDA receptor blocker ketamine [25] could improve outcome by SD suppression in patients.

In other cerebrovascular diseases, spontaneous SDs have also been observed with high incidence. In stroke, for example, SDs are present in 86–100 % of patients and their presence is associated with infarct growth. It is hypothesized that prevention and treatment of SD may also help to avoid secondary ischemia and fatal brain edema [8]. SDs have been found in 50–60 % of TBI patients and their presence is related to unfavorable outcome [22, 23].

SD is now widely recognized to be the neurophysiological substrate of MA and a potential trigger of the headache [29]. Genetic factors that favor hyperexcitability of the visual cortex may enhance susceptibility to SD, such is the case for familial hemiplegic migraine (FHM), a genetic form of migraine that involves mutations in genes that encode for voltage-gated P/Q-type Ca²⁺ channel subunits (FHM1), Na⁺/K⁺-ATPase subunits (FHM2) [19], or Na⁺ channel subunits (FHM3) [38]. Transgenic mice carrying FHM mutations show increased susceptibility to SD, with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple SDs after a single stimulus [33]. Another example is the K⁺ channel, TRESK, which is regulated by Ca²⁺ concentrations, where it has been shown that a dominant-negative mutation is linked to MA and SD [17]. Over the past years, several antimigraine drugs have been tested on SD. Tonabersat, a benzoylaminobenzopyran anticonvulsant, suppresses SDs in animal models after intraperitoneal administration; however, the clinical trials show conflicting results [2, 16]. Many other antimigraine drugs have been tested or are under investigation, e.g., valproate, propranolol, methysergide, amitriptyline, topiramate, gabapentin, lamotrigine, flunarizine, and olcegepant, although the results are contradictory. These drugs have an inhibitory effect on ion channels, receptors, and neurotransmitters such as Na⁺, l-type Ca²⁺, P/Q- and N-type Ca²⁺ channels, gap junctions, GABA_A, and calcitonin gene-related peptide receptors, thus, supporting the role of multiple targets [6]. Research into SD inhibitory antimigraine drugs could, therefore, have a collateral impact on cerebrovascular diseases and brain trauma.

When SD develops, a surge of [K⁺]_e occurs, which leads to depolarization of adjacent neurons and glial cells. At the same time, [Na⁺]_e decreases as it enters the cells accompanied by water. This process is followed by neuronal swelling and shrinkage of the extracellular space. At the same time, influx of Ca²⁺ also occurs, leading to release of glutamate and other neurotransmitters. Glutamate induces NMDA receptor activation, which may contribute to SD initiation, propagation, and, if released in excess, can generate excitotoxicity. Moreover, gap junctions are thought to play an important role in SD expansion by promoting intercellular Ca²⁺ and K⁺ waves. After SD, [K⁺]_e is restored by Na⁺/K⁺-ATPase and astrocytes [44]. This suggests Na⁺, K⁺, Ca²⁺ channels, Na⁺/K⁺-ATPase, gap junctions, and NMDA receptors as the main targets for SD modulation.