The significant differences in MBFV throughout the study and those in CVR on the SBP nadir, overshoot and return to baseline time points provide compelling evidence for disordered cerebral autoregulatory mechanisms in CSS. In the related neurally mediated disorder vasovagal syncope, analyses of several case series have shown a rise in CVR during head‐up tilt‐induced presyncope and syncope,12,24,27
but later work related this apparently paradoxical cerebral vasoconstriction to hyperventilation‐induced hypocapnia.28
Our findings echo those of Grubb et al
Levine et al12
and Bondar et al
showing significantly higher CVR in patients with CSS at SBP nadir, overshoot and return to baseline despite a highly significant average MBFV 23% lower in patients than in controls. In the presence of normocapnia (as in our study population) the converse is expected. In previous studies, cerebral blood flow velocity and carbon dioxide concentration fell during LBNP sufficiently to induce presyncope and syncope (with a potentially causal relationship between the two), but we observed neither of these changes in our study, presumably reflecting the relative modesty of the LBNP stimulus essential to our study design.
It has been argued that augmented sympathetic nervous activity during LBNP causes cerebral vasoconstriction, which overwhelms the usual mechanisms promoting vasodilatation in the face of a fall in MBFV.12,14,27
Indirect support for this contention came from a recent study of healthy young subjects examined by TCD during LBNP and ganglion blockade, in which Zhang et al29
elegantly showed that the cerebral circulation is likely to be under tonically active autonomic neural control. Although cerebral autoregulation was maintained in both patients with CSS and controls in response to LBNP, the wide differences between the groups in the variables described above suggests a baseline difference in autoregulation in those with CSS. Data are emerging showing a high prevalence of cognitive impairment and dementia in patients with CSS.30
This is attributed to small vessel disease reflected in a higher prevalence of white matter lesions in patients with CSS, with the density of white matter lesions on magnetic resonance imaging correlating with the degree of carotid sinus massage‐induced hypotension.31
We hypothesise that the abnormalities in cerebral autoregulation at baseline are due to such microvascular disease, manifesting as abnormal cerebral autoregulation. Our results raise the intriguing possibility that patients with CSS are prone to relative (and paradoxical) tonic intracerebral vasoconstriction, which predisposes them to further inappropriate vasoconstriction during CSS‐mediated vasodepression and asystole, when vasodilatation should otherwise supervene. We speculate that such paradoxical vasoconstriction preferentially affects areas intimately related to short term memory and consciousness level, with the clinical corollary being CSS presenting as falls.
Although TCD during carotid sinus massage would arguably provide a more realistic assessment, we deliberately avoided this approach because of the possibility of neurological complications during repeated carotid sinus massage21
and the confounding influence of unilateral cerebral artery occlusion on CVR in the contralateral side. Others have done so, however, and in two small, uncontrolled series Leftheriotis et al16,17
examined cerebral blood flow velocity in patients with CSS during carotid sinus massage after 10 min in the head‐up tilt position. Cerebral autoregulation failed only during a fall in systemic blood pressure below the lower limit for normal cerebral autoregulatory function—that is, 50 mm Hg32
—with cerebral perfusion falling by 50% and CVR rising (non‐significantly) during carotid sinus massage, then falling rapidly immediately afterwards.16,17
These results are consistent with those presented above and with the vasovagal data of Carey et al
As with all TCD assessments of cerebral autoregulation, the technique is dependant on several assumptions. Firstly, middle cerebral artery cross‐sectional diameter is assumed to be constant. Secondly, as the Doppler principle depends on velocity, derivative measurement of blood flow relies on a linear relationship between flow and velocity. These factors have proved controversial, with some early criticism of the technique on the basis of the assumptions made.7,8,32
Later research comparing direct measures of internal carotid artery flow (during carotid surgical procedures) with middle cerebral artery velocity measured by TCD found that TCD flow measurements accurately mirrored changes in internal carotid arterial flow.9
Others similarly showed that changes in middle cerebral artery velocity correlated with cerebral blood flow,8,33,34
although with the caution that absolute velocity should not be used as an indicator of cerebral blood flow.8
Nonetheless, as middle cerebral arterial diameter was not measured as part of the study, this cannot be absolutely excluded. Furthermore, although the derivation of CVR from indirect measures of systemic blood pressure can be criticised, Zhang et al29
recently found a close correlation between digital photoplethysmographically measured blood pressure and intra‐arterial pressure during LBNP‐related orthostatic stress.
Cerebral autoregulation is abnormal in patients with CSS and may explain some of the clinical features of the disorder. Additional studies, with power calculations based on this work and by using TCD during more profound hypotension (induced by tilt, LBNP or carotid sinus massage‐induced asystole), may help explore this issue further.