Cerebral vasospasm of large proximal arteries is regarded as the prime cause of delayed ischemic neurological deficit (DIND) after subarachnoid hemorrhage (SAH). It is, however, only 1 possible contributor to DIND.1, 2 Thus, a search is required for alternative or additional mechanisms to explain delayed deterioration after SAH.1, 3 DIND has recently been associated with cortical spreading depolarization (CSD),4 a striking electrophysiological phenomenon that was originally described as “cortical spreading depression” by Leão in 1944.5, 6 CSD is a self-propagating wave of neuronal and glial depolarization that has been extensively investigated in animals.6–8 A series of recent clinical studies using subdural electrocorticography (ECoG) filtered to include low frequencies provides direct and unequivocal electrophysiological evidence for the existence of CSDs in neurotrauma,9 malignant middle cerebral artery infarction,10 and SAH.4 These studies suggest that CSD may be a general phenomenon leading to secondary deterioration in various clinical entities.11
CSD waves are accompanied by propagating failure of brain ion homeostasis resulting in an interruption of cortical function.7 Under physiological conditions, the brain is able fully to recover from the metabolic challenge of reestablishing ion homeostasis during the repolarization phase of CSD without measurable tissue damage.12 This ability is mainly achieved by a compensatory vasodilatory response coupled to CSD. In contrast, recurrent CSDs emerging spontaneously in metabolically compromised tissue, such as in the ischemic penumbra (in this situation termed peri-infarct depolarizations, [PIDs])13 or after SAH,4 irreversibly damage brain tissue at risk and thereby may lead to lesion growth.10, 14, 15 Animal experiments have suggested that, under such conditions of impaired metabolic status, the vasodilatory response to CSD switches from a compensatory vasodilatory response to an inverse, vasoconstrictive neurovascular coupling, resulting in cortical spreading ischemia (CSI).16–19 In a rat model, it has been hypothesized that, in principle, CSD activates both vasoconstriction and vasodilatation in a biphasic fashion, the ratio between the 2 being shifted toward vasoconstriction by ischemic/hypoxic tissue conditions.20 Recently, combined recordings of regional cerebral blood flow (CBF) and ECoG using subdural optoelectrode strips have provided evidence that delayed ischemic stroke is associated with CSI in patients with SAH.15 To our knowledge, this is the first detailed report of continuously corecorded tissue oxygen pressure (ptiO2) and CSD in human cerebral cortex. We hypothesized that CSDs, in particular if they occur in temporal clusters, reduce cortical oxygen availability.
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- Supporting Information
Our study provides a unique insight into disturbed oxygen availability to the SAH-injured human cerebral cortex in association with CSD occurrence. Initially, the cortex is not too seriously affected, but it may later develop cortical microcirculatory vasospasm and increased O2 consumption as responses to spontaneous CSD clusters. It would now appear that delayed ischemic neurological deterioration may result not only from major proximal arterial vasospasm, but in addition from CSD clusters that in particular contribute to delayed ischemia by causing subtle but noticeable stepwise alterations toward hypoxic tissue conditions. In consequence, CSD clusters may play a crucial role in the development of delayed ischemia after SAH,4, 15, 26 possibly in synergy with other mechanisms known to affect SAH-injured tissue, such as inflammation, blood–brain barrier disruption with edema formation and resulting mass effects, and endothelial dysfunction and thromboembolism.1, 27, 28 Thus the demonstration that CSD clusters occur and can reduce brain ptiO2may go some way toward explaining the variable association of delayed ischemia with proximal arterial vasospasm,29 and the existence of such a dual mechanism of delayed ischemia.4, 15, 16
We detected CSD-associated ptiO2alterations in >53% of CSDs despite an electrode to ptiO2probe distance of ≤8mm and despite the fact that the effective cortical area sampled by an ECoG electrode records amounts to ∼250mm2, whereas the ptiO2 probe analyzes only an area of ∼7.1 to 15mm2, comprising both cortical and subcortical tissue.24 In individual patients, we found an incidence of CSD–ptiO2 associations of up to 90%, demonstrating that CSD-associated ptiO2 changes are common and therefore a relevant pathophysiological factor in cortical tissue of SAH patients. Moreover, it gives rise to the assumption that consequences of CSD and associated microcirculatory disturbance15 may not be restricted to cortical tissue. Occasional lack of ptiO2 response association in individual patients with some successive CSDs may be explained by varying routes of CSD wave propagation,9, 10, 19 if the waves were for example induced at different sites and came into the rather large effective detection range of the ECoG electrode but not into the smaller range of the ptiO2 probe.
The propagation velocity of CSDs was comparable with Leão's classical description5 and recent clinical studies.4, 9, 10 The rate of CSD initiation peaked at days 5 to 7 after SAH (see Fig 2C), suggesting a possible role of CSD in DIND development, which has been reported to occur within approximately the same time frame.1, 23 Other pathophysiological mechanisms develop earlier1, 30 or at more or less unpredictable time points after SAH.1 Because 89% of CSDs arose within clusters in DIND patients, and because clusters altered ptiO2 responses in particular, we consider that these clusters may also play a role in DIND evolution. In contrast, single CSDs may be less harmful.12 The high incidence of CSD clusters in our severe SAH patients is comparable with other conditions requiring neurocritical care and exhibiting secondary ischemic deterioration, such as malignant hemispheric stroke.10
How might CSD clusters contribute to secondary injury progression after SAH? Experimental and clinical evidence demonstrates that CSD does not invariably induce compensatory vasodilatation (normal neurovascular coupling, as is known for physiological perfusion conditions), but can instead induce vasoconstriction (inverse coupling) if tissue conditions are unfavorable.5, 15, 16, 31, 32 In an SAH model,16 it was shown initially that inverse neurovascular coupling led to widespread focal infarcts. Inverse coupling was likewise found during hypoxia or systemic hypotension, and in the boundary zones of focal ischemia after middle cerebral artery occlusion.18–20 It is well known that ptiO2is mostly linked to regional CBF.15, 24, 25, 33, 34 The variable ptiO2responses found in our SAH patients (see Fig 2A, C) resemble the patterns of CBF responses coupled to CSD/PID described in animals.16, 19, 20 Most of the ptiO2responses examined were biphasic in nature (see Fig 2C), resembling biphasic CBF response patterns in boundary zones of ischemic foci19, 32, 35; hence, we infer that our recordings were performed largely in metabolically disturbed but not yet severely injured tissue compartments. Monophasic hypoxic episodes indicate altered or missing secondary, compensatory hyperoxic phases, worsening in vascular reactivity, and thus deterioration of tissue conditions.
It seems, therefore, that the complex antagonism between vasoconstrictive and vasodilator mechanisms after SAH36 is progressively disturbed during ongoing CSD activity. Various intra- and extracellular mechanisms influencing coupled responses have been reported, some leading to intracellular calcium ([Ca2+]i) accumulation in smooth muscle cells.36, 37 Repetitive CSDs may support this [Ca2+]i accumulation and promote microvascular spasm and NO resistance.38 Other putative mechanisms may include activation of matrix metalloproteinase-9 followed by dysfunction of the neurovascular unit.39 As a mechanistic explanation for DIND, CSI has recently attracted interest.1, 4, 11, 40 It has been shown that in the presence of elevated extracellular potassium concentration ([K+]e), depletion of NO may alter the vasomotor response to CSD from vasodilatation to vasoconstriction, resulting in ischemic transformation.16, 32, 35 Elevated [K+]e generally characterizes any state of energy shortage. The vasoconstrictor capacity of [K+]e easily dominates SAH tissue, because NO is trapped by the potent NO scavenger hemoglobin, both hemoglobin and K+ being released from erythrocytes in the subarachnoid space after SAH. Vasoconstriction then worsens energy delivery to this tissue, and in turn, K+ release is enhanced, creating a vicious cycle that inhibits repolarization and augments ischemia. CSD clusters with repetitive neuronal and astrocytic de- and repolarizations will reinforce such a cycle, as does repetitive vasoconstrictive activation of smooth muscle cells, which also utilize adenosine triphosphate (ATP) and O2. Accordingly, an altered metabolic state has been described for perivascular sites during CSD.41 Smooth muscle relaxation, as a component of vasodilatation, also requires ATP (flexibilizer function of ATP). In the case of repetitive CSDs with ATP depletion due to ATP-depended vascular responses18, 19 and multiple neuronal and astrocytic repolarizations,7–9 the relaxation component of vasodilatation may therefore be negatively influenced. Furthermore, adenosine, a potential vasodilator and a metabolite of ATP degradation present in metabolically disturbed tissue, failed to improve vasodilatation after CSDs.32 Hence, CSD clusters may provoke repetitive vasoconstriction19 with gradually decreasing likelihood of vasodilatation, and progressively modified ptiO2 responses may finally result in cortical microvasospasm. Delayed laminar infarction in cortex, as found typically in SAH patients, supports this interpretation.38 Because in our study hypoxic portions of the CSD-associated ptiO2 response increased, and hyperoxic portions decreased or were completely absent after recurrent CSDs (see Fig 5), we assume that a rapid sequence of CSDs generates a vulnerable phase that potentiates hypoxic tissue conditions. Moreover, further studies are necessary to understand the complexity of delayed ischemia after SAH and the role of CSD clusters for this complication. The likely role of clusters in degrading tissue of marginal viability is illustrated by the detection with rapid sampling microdialysis of stepwise depletion of cortical tissue glucose during a cluster of CSDs.42
PtiO2 recordings inevitably reflect both delivery and consumption of tissue oxygen.24, 34 CBF alterations linked to CSD have recently been shown to correlate with ptiO2 changes.15 CSD—more specifically, repolarization of neuronal membrane potentials—markedly increases energy metabolism7–9, 13 and depletes brain glucose.40, 42 Complete loss of compensatory vasoreactive power would result in sustained reduction of CBF and/or ptiO2 to zero,19 reflecting spreading ischemia.15, 16, 19 We were not able to observe such a phenomenon by ptiO2 monitoring in our study, presumably because only by chance, recordings with strip electrodes positioned at only 1 site in the surrounding of SAH would pick up the phenomenon. Retrospective analysis of imaging results revealed that ptiO2 probes were never positioned in tissue compartments undergoing delayed ischemia, offering an explanation for the lack of sustained ptiO2 reduction. Responses with long monophasic ptiO2 reductions found particularly in DIND patients may be interpreted as a preliminary stage of such delayed, terminal transformation as seen in spreading ischemia.15, 16, 19, 35 It is obvious that recordings at only 1 location are suboptimal regarding a comprehensive analysis of the surroundings of injuries, and multiple site ptiO2 measurements would therefore be favorable but difficult to perform. A further limitation of the study is the lack of adequate and frequent imaging techniques like MRI (perfusion-weighted imaging, diffusion-weighted imaging) for the possible detection of spreading ischemia as shown in our examples. Logistic reasons and intensive care made this management impossible in some patients of our study. The COSBID plans a multicenter study that aims at following such sequential imaging protocol in all patients. In this study, we also aim to test intrinsic neurovascular function and the capacity for local cerebrovascular autoregulation and oxygen reactivity,1 because these factors may be of relevance for the biphasic ptiO2 cycle.
In conclusion, CSDs may impair microvascular function and O2 availability, likely with increased O2 consumption, in human cerebral cortex after SAH, especially if they occur in clusters. Our results indicate that this is related to secondary hypoxic transformation and the likelihood of DIND. The correspondence of experimental and clinical data suggests that we can now cautiously translate the well-known impact of depolarizations on pathophysiological outcome in experimental models into the clinical situation. Considering the importance for outcome of secondary deterioration in SAH, CSD may represent a promising target for therapeutic intervention to improve poor outcome and mortality after SAH.