Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury

Abstract

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

Figures

Figure 1

Effect of cortical spreading depression (CSD) on brain activity in normally perfused brain as exemplified in patients with migraine with aura. The figures represent lateral views of the human brain at different intervals after the beginning of the attack, spaced by ∼30 minutes. Outside of attacks, migraine brains have normal perfusion as indicated by the left cartoon. Colored bands indicate region of neuronal depolarization that causes and coincides with depression of cortical activity, a large-scale DC shift, failure of brain ion homeostasis, increased use of O2, glycogen and glucose, and rise in cerebral blood flow (CBF). Light blue area represents reduced CBF, reduced vascular reactivity and neurovascular coupling, and increased CMRO2 in the wake of CSD (Piilgaard and Lauritzen, 2009). The direction of propagation of CSD is indicated with arrows. At the start of migraine attack, a CSD emerges in the occipital pole in patients with a visual aura (1) while spreading anteriorly at the lateral, mesial, and ventral sides of the brain. At the CSD wave front, the transient ionic and metabolic disequilibria trigger the neurological symptoms in eloquent cortex. (2) Following CSD, cortical CBF decreases by 20% to 30%, neurovascular coupling is disturbed, and CMRO2 is increased for >2 hours. (3) Cerebral blood flow in regions not invaded by CSD remains normal. (4) The region of reduced CBF expands as CSD moves anteriorly. (5) Somatosensory symptoms from the extremities appear when the CSD invades the primary sensory cortex at the postcentral gyrus. (6) CSD in patients with migraine usually stops on reaching the central sulcus, but in many patients it does not even propagate this far. In patients with acute brain disorders, the susceptibility of the cerebral cortex to CSD is increased and propagation patterns are more diverse. (7) Full-scale attack. The CSD has stopped and is now detectable as a persistent reduction of cortical blood flow, neurovascular dysfunction and high-energy metabolism. After the attack, the cerebral cortex returns to normal. Modified with permission after original artwork presented in Lauritzen (1987).

Figure 2

Infarct growth associated with prolongation of the duration of electrocorticogram (ECoG) suppression with repetitive peri-infarct depolarization. The schematic diagram (upper panel) shows the temporal and spatial expansion of infarcted core tissue and the ischemic penumbra along the electrode strip into the healthy periphery of the infarct. This structural deterioration progresses over several days and corresponds to the progressive prolongation of the depolarization along the electrode strip during successive peri-infarct depolarizations. The two examples of ECoG recordings (lower panel: power of the ECoG, high-pass filtered at 0.5 Hz) taken in a patient suffering from malignant ischemic stroke 1 and 5 days after ictus indicate this worsening of ECoG recovery after depolarization. Note that on day 1 after stroke, brief episodes of ECoG suppression are present only on channels IV and III, whereas on day 5, ECoG suppression is prolonged and present on channels I to IV.

Figure 3

Schematic model of cycling of a peri-infarct depolarization around an ischemic core, and its effect on perfusion, and expansion of the core. Panel 1: A depolarization starts at the edge of the core (proposed to be a stochastic event most probably influenced by factors such as partial neuronal depolarization, limited availability of oxygen and glucose, and brain temperature). Panels 2 and 3: The cortical spreading depression (CSD) propagates most prominently around the edge of the core, where tissue is most susceptible to depolarization (Dahlem and Hadjikhani, 2009). Here, spread is clockwise only as anticlockwise spread is prevented by slow recovery from a previous event. The residual effect of the depolarization on perfusion is profound vasoconstriction nearest the core (blue component of arrow), sufficient to preclude repolarization and hence expanding the core. However, vasoconstriction further from the core (red section of arrow) is less severe or sustained, probably allowing repolarization from this event, but leaving tissue at this location vulnerable to a future depolarization. The net effect is shown in panel 4, with the core now expanded to include the original penumbral point of depolarization (Nakamura et al, 2010).

Figure 4

Normal and inverse response to cortical spreading depression (CSD) in patients with aneurysmal subarachnoid hemorrhage (aSAH). The upper half of the figure shows the normal hemodynamic response to spreading depolarization (CSD) in the human brain in a patient with aSAH. The subdural opto-electrode strip is shown in the upper right corner. The six traces represent simultaneous recordings of a single spreading depolarization that propagates from opto-electrode 6 (blue) to 4 (red). The calibration bar of trace 4 also applies to trace 3 and that of trace 6 also applies to trace 5. The four upper traces identify the spreading depolarization electrophysiologically. Traces 1 and 2: direct current (DC) electrocorticogram (ECoG) with negative shift of spreading depolarization. Traces 3 and 4: band-pass filtered ECoG (0.5 to 45 Hz) with spreading depression of activity. The spreading depolarization propagates at a rate of about 1.9 mm/min assuming an ideal linear spread along the recording strip. Traces 5 and 6: Normal spreading hyperemia in response to spreading depolarization recorded by laser-Doppler flowmetry as reported previously (Dreier et al, 2009). The lower half of the figure demonstrates the inverse hemodynamic response to spreading depolarization in another patient with aSAH. In this case, the spreading depolarization propagates from opto-electrode 5 (blue) to 3 (red) (propagation rate: 3.1 mm/min). The high-frequency activity is already suppressed by a preceding CSD at electrode 4 (trace 9), when depression of activity is induced by spreading depolarization at electrode 5 (trace 10). Traces 11 and 12: Typical inverse hemodynamic response to spreading depolarization as characterized by a severe decrease of regional cerebral blood flow (CBF) in response to the depolarization. Such severe decrease of regional CBF in response to CSD is termed spreading ischemia. The prolonged negative cortical DC shift (compare trace 8) is the defining electrophysiological feature for the inverse hemodynamic response. It indicates that the hypoperfusion is significant enough to produce a mismatch between neuronal energy demand and supply (Dreier et al, 1998, 2009).

Figure 5

Duration (in minutes) of recovery time of cortical electrical silence induced by depolarization in different diseases. The duration of the depression of cortical activity reflects the ability of the tissue to recover after cortical spreading depression (CSD) and thereby the perfusion and metabolic state at the point of measurement. The clinical deterioration of patients we have monitored is often accompanied by clusters of CSD, which show a gradual increase of recovery time. Therefore, assessment of recovery time may be an early warning sign that secondary damage is under development. So when is duration prolonged? In this figure, the mean duration of depression for all CSD episodes from 87 patients (intracerebral hemorrhage (ICH): 5, malignant hemispheric stroke (MHS): 13, subarachnoid hemorrhage (SAH): 43, traumatic brain injury (TBI): 26) is displayed in minutes. The figure suggests a bimodal distribution with a cluster below ∼8 minutes, probably reflecting a fast recovery and tolerable perfusion conditions, whereas the more widespread group above ∼8 minutes may reflect a reduced blood flow response indicating penumbral conditions. Interestingly, the small group of patients with ICH all showed a fast recovery, possibly because a widespread penumbra seems to be a rare feature in this condition.

Figure 6

Graded nature of cortical spreading depolarizations and their occurrence in disease states. Various electrocorticogram (ECoG) measures reflect the putative pathologic severity of cortical spreading depressions (CSDs) observed in the human brain, including (1) the duration of the DC shift, (2) the duration of depression of high-frequency spontaneous activity (HF-ECoG), (3) the extent of recovery of HF-ECoG after depression, and (4) the periodicity of recurrent CSD events. At one end of the spectrum, putatively benign CSDs appear sporadically with short-lasting DC shifts and depression periods and complete recovery of HF-ECoG. At the other end, depolarization durations (DC shift) are prolonged, with persistent HF-ECoG depression and no or incomplete recovery, and events recur repetitively in clusters. This latter type shares features in common with depolarizations observed in various experimental models where (1) perfusion deficits delay membrane repolarization and recovery of HF-ECoG and (2) CSD is proven to cause pannecrosis of affected cortex. The bottom panel shows the prevalence of each type of CSD in different diseases, based on current evidence, with the full spectrum observed in malignant hemispheric stroke (acute progressive infarction) but only short-lasting events believed to occur in migraine (no acute cortical damage). In some patients, the severity of CSD may increase progressively after injury through hours or days of recurring events.

Figure 7

Repetitive cycles of cortical spreading depression (CSD) during sustained elevated ICP in an elderly patient with delayed deterioration associated with a severe right temporo-parietal traumatic contusion. Top and middle traces show the low-frequency (LF-electrocorticogram (ECoG); low-pass filtered at 0.05 Hz) and high-frequency (HF-ECoG; high-pass filtered at 0.5 Hz) components of recordings from three bipolar channels of a linear subdural electrode strip. Arrows highlight individual CSDs, evidenced as propagating, large amplitude slow potential changes causing the suppression of HF-ECoG. Fourteen CSDs occurred in the 8-hour epoch shown; overall, a total of 105 CSDs were recorded in this patient during 70 hours of ECoG monitoring. Throughout this period, ICP remained elevated >20 mm Hg and often persisted at 30 to 40 mm Hg. The patient died 5 days after injury on withdrawal of ventilator support, in compliance with her living will.