Damage to the endothelium has been thought to play a key role in the pathogenesis of vasospasm following aneurysmal subarachnoid hemorrhage (aSAH), either through the loss of endothelial nitric oxide synthesis, a vasodilator and regulator of vascular tone, or through the overproduction of endothelin-1, a powerful vasoconstrictor. These two endothelial-derived substances and the possible imbalance in their production after aSAH have been the center of much experimental vasospasm research.^{Reference Findlay and Chen1}

Serlé et al. report here that elevated serum levels of five different biomarkers chosen to reflect endothelial “activation” (damage) unexpectedly did not correlate with delayed cerebral ischemia (DCI) (n = 75 patients). The study hypothesis had been that elevated levels due to overproduction or release from dysfunctional endothelial cells would be associated with DCI and poorer outcomes after aSAH, as has been found by others, and for the reasons alluded to above.

However, their results do not rule out an important role of the endothelium in the pathogenesis of vasospasm, and the reason lies in the definition of DCI used. The definition chosen is a clinical one based on neurological deterioration that “cannot be attributed to any other cause by means of clinical assessment, CT or MRI scanning of the brain and appropriate laboratory studies,” although imaging is not mandatory.^{Reference Vergouwen, Vermeulen and van Gijn2} This definition is problematic. Foremost are the many and varied causes of neurological fluctuations and decline in the days following aSAH other than ischemia. One example is progressing edema surrounding an area of parenchymal injury or hematoma, and another is exacerbation of an existing deficit by a slight disturbance in blood glucose or sodium. Assigning a cause of worsening can be nuanced, making it all too easy to attribute neurological deterioration from any cause as DCI. Since DCI was not proven by vascular or perfusion imaging, the biomarker profile might differ in those with proven DCI.

Those caring for aSAH patients need to be clear about the relationship between vasospasm and DCI.^{Reference Weir3} The authors’ statement that “the radiological definition (of DCI) often identifies DCI too late for effective intervention” is not correct. In a multidisciplinary approach, aSAH patients are imaged frequently, especially those difficult to examine clinically. When found, significant vasospasm proven on imaging is treated with hypertension and early balloon angioplasty to prevent cerebral infarction. Vasospasm causes DCI, and while we might suspect it based on physical signs and/or transcranial Doppler testing, it is diagnosed with vascular imaging.