Abstract
Dear Sir In a recent paper Fan et al. (1) reported results of calcitonin gene-related peptide (CGRP) sampled from cubital veins in paediatric migraine patients during and outside attacks. They suggested that increased CGRP measured during migraine attacks can be used as a biomarker for migraine in children (1). The results are given as pg/ml in plasma and CGRP levels were 198 pg/ml during migraine attacks and 43 pg/ml outside attacks for the nine children investigated both during and outside a migraine attack (1). These results correspond to 53 pmol/l and 12 pmol/l, respectively. When CGRP is increased in plasma during migraine it is presumed to originate in the cephalic circulation. Thus CGRP was found to be increased in the external jugular vein in two studies, 60 (2) to 90 pmol/l (3), whereas this was not the case in three studies with intrapatient comparison, 33, 81 and 86 pmol/l (4,5). For a review, see (6). In one study (n = 5) there was a maximum concentration of CGRP in internal jugular blood during migraine attacks of 77 pmol/l (7), but in another study (n = 4) with both internal carotid arterial and internal jugular venous blood determinations of CGRP (mean = 65 pmol/l) in migraine with aura there was no increase during the onset of migraine (8).
If the increased CGRP in the cubital blood that represents the general circulation were to originate from the cephalic circulation this must be caused by a considerable increase in blood levels of CGRP in this cephalic circulation. It can be calculated, by using the relation of external carotid blood flow (186 ml/min per artery) (9) to cardiac output (5000 ml/min) resulting in a dilution factor of 27 (5000/186), that the blood levels of CGRP in the external jugular vein should be 1102 pmol/l (41/186 × 5000) if the contribution was from one external jugular vein in half-sided migraine. Alternatively, by using the relation of total (external plus internal carotid) blood flow (900 ml/min) (9) to cardiac output (5000 ml/min), it can be calculated that the blood levels of CGRP in internal and external jugular blood on average should be 227 pmol/l (41/900 × 5000) if the whole cephalic circulation was contributing with CGRP.
In the first study on CGRP in the external jugular vein during migraine the concentrations were increased to approximately 90 pmol/l (3). There was, as would be expected from the dilution factor of 27 for one side of the external jugular circulation vs. general circulation, no increase of CGRP in cubital venous blood (3). The increase in CGRP of 41 pmol/l (1) is thus unlikely to be the result of an increase of CGRP in extracerebral cephalic blood. Could the increase of CGRP in cubital venous blood then be due to a huge increase of the peptide in the total cephalic blood? The maximum CGRP level measured in a small study in the internal jugular vein was 77 pmol/l (7) and in another study it was 65 pmol/l (8), both values far lower than the 227 needed (see above).
These calculations should, however, be taken cum grano salis since they are based on blood flow values and cardiac output in adults. Furthermore, the comparisons are based on the assumption that the analyses of CGRP in different studies are equivalent. This is most likely not the case (see (1,3,4,10–12)). Thus the control levels of CGRP outside migraine attacks in the external jugular vein in adults varied from 17 pmol/l (4), 32 pmol/l (4), < 40 pmol/l (3) to 81 pmol/l (5) and in cubital vein the CGRP levels varied from 12 pmol/l in children (1), 37 pmol in adolescents (10) to 20 pmol/l (12) and 49 pmol/l (11) in adults.
The quadruple increase (12 to 52 pmol/l) of CGRP in cubital blood during a migraine attack in children as observed by Fan et al. (1) seemingly supports the finding that CGRP is increased in migraine attacks (2,3,7,10,12). The observed increase of CGRP (1) is, however, unlikely to originate only from the cephalic circulation, and alternative explanations, e.g. a systemic extracephalic source such as the gastrointestinal tract as suggested by Gallai et al. (10), need to be explored.