The occurrence of DINDs was first described five decades ago by Robertson (1949). This year of discovery fell into the era of cerebral angiography, which had been introduced by Moniz in 1927. When Ecker and Riemenschneider (1951) first demonstrated delayed arterial spasm after subarachnoid hemorrhage with cerebral angiography, it was believed that, in principal, the pathogenesis of delayed ischaemic neurological deficits was explained, i.e., arterial spasm of the Circle of Willis arteries causing cerebral infarction. Today, the key words “vasospasm subarachnoid hemorrhage” yield more than 2000 references in the medline. However, several findings have challenged the simplistic link between DINDs and vasospasm: (a) The clinical match between cerebral angiography findings and DINDs is low as briefly reviewed in the present paper. (b) Neil-Dwyer et al. (1994), in their prospective autoptic study, not even detected a significant difference regarding the occurrence of DIND-induced lesions between patients with and without angiographically demonstrated vasospasm. (c) Also, the pathoanatomical pattern, the widespread distribution of DIND-induced lesions in the cortex, suggests that the key pathophysiological problem is not related to the proximal segments of the cerebral arteries. (d) Animal studies of subarachnoid haemorrhage essentially failed to demonstrate DINDs or delayed lesions despite angiographically demonstrated arterial spasm.
As an alternative, we have proposed that direct action of RBC products on the microcirculation and neuronal/astroglial network may be responsible for the cortical lesions associated with DINDs. However, there are also limitations of our approach. The main limitation is related to the high concentrations of haemoglobin and [K+ ]ACSF used for the induction of cortical spreading ischaemia. The haemoglobin concentration applied in our [Seite 22↓] experiments was five times higher than that measured in human cerebral haematomas. The necessity of relatively high haemoglobin concentrations is possibly due to: (a) The higher ischaemic threshold and better collateralisation in small mammals compared with man. An influence of the species is supported by the fact that DINDs are not observed in animal SAH models (Megyesi et al. 2000). (b) The incubation time with haemoglobin is shorter in our experiments compared with that after SAH. (c) The site of haemoglobin application spares the base of the brain, so that spasm of basal arteries would not contribute to the energy compromise. However, in future studies, it will be interesting to investigate whether lower haemoglobin concentrations are sufficient for the induction of cortical spreading ischaemia if NO producing sources are disturbed in a similar way as it is probably the case after SAH (Pluta et al. 1996).
The level of [K+ ]ACSF was also relatively high in our studies. Extracellular K+ -levels of this magnitude were in fact measured in human cerebral haematomas (Ohta et al. 1983). However, the effect of the rise in baseline [K+ ]ACSF is probably mediated by a gradual rise in extracellular K+ in the cortex ([K+ ]o ), a concomitant down-regulation of the (Na+ )-(K+ )-ATPase activity and disturbance of the neuronal/astroglial repolarisation (Dreier et al. 2001). All these changes can probably also be achieved by other factors than elevated [K+ ]ACSF , which have been implicated in the pathogenesis of DINDs such as energy compromise (due to the arterial spasm) (Jamme et al. 1997; Nedergaard et al. 1993; Müller and Somjen 2000), a decline in intracerebral glucose concentration (Dreier et al. 2000; Unterberg et al. 2001), or a rise in endogenous ouabain-like factors (Dreier et al. 1997; Lusic et al. 1999).
Our results call for future studies analysing whether spreading depression-like depolarisations occur in patients after SAH using monitoring tools like DC-EEG, near-infrared spectroscopy, microdialysis or functional MRI. In addition, it will be necessary to [Seite 23↓] investigate whether the coupling between neuronal metabolism and CBF is fundamentally altered after experimental SAH in animals.
The coupling between neuronal activity and cerebral blood flow is a fundamental process, which underpins all cerebral functions. The topic of my Habilitation is the discovery of a new variant of ischaemia in which neuronal activation triggers a cerebral ischaemic event through the inversion of the coupling between neuronal activation and cerebral blood flow. This inversion occurs when red blood cell products are present in the subarachnoid space. The most distinct feature of this variant of ischaemia is its propagation in the cerebral cortex together with the wave of neuronal activation. Therefore, we named the phenomenon ‘cortical spreading ischaemia’.
The presented animal model may have implications for the delayed ischaemic neurological deficits after subarachnoid haemorrhage. The link with this clinical syndrome has been based: (a) on the induction of cortical spreading ischaemia by red blood cell products in the subarachnoid space, (b) the correspondence between the characteristic patterns of the cortical ischaemic lesions, (c) and the therapeutic effects of nimodipine and moderate hypervolaemic haemodilution in clinical syndrome and animal model. With the aid of this model, it was possible to experimentally confirm the hypothesis that red blood cell products can induce cerebral ischaemia. We hope that the model will contribute to develop new strategies for the treatment of patients with subarachnoid haemorrhage.
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