Migraine headache is very common in childhood [1]. It may be associated with migraine equivalents which are common clinical conditions, often occurring without a headache component, as repeated episodes with complete remission between episodes [3]. They include abdominal migraine, cyclical vomiting, benign paroxysmal vertigo, and benign paroxysmal torticollis [15]. There is also growing evidence showing increased comorbidity between migraine and several psychiatric conditions [4, 5] and abnormal electroencephalography (EEG) findings [6].
Inflammation has an important role in the process of migraine, and recently, studies showed that bilirubin has cytoprotective and antioxidant properties and that existence of neurogenic inflammation and high oxidative stress during migraine is associated with lower serum bilirubin concentration [9].
The purpose of our study was to assess the clinical association between serum bilirubin and migraine syndrome in children and adolescents.
This study was carried out on 40 children and adolescents suffering from migraine, diagnosed according to the ICHD, 3rd edition, beta version. They were compared to 40 controls of children and adolescents not suffering from migraine.
In our study, the main finding was that serum level of bilirubin was significantly lower in children and adolescent patients with migraine compared with healthy controls. Before 2015, there was no published study that had investigated the association between serum bilirubin and migraine. Our results agree with the results done by Peng and colleagues [16] and Cao and colleagues [17] who reported in their studies that Tbil, Dbil, and Ibil concentrations were significantly lower in patients with migraine than healthy controls. Possible explanation of lower serum bilirubin in migraine may be as follows: Inflammation plays a central role in the pathogenesis and etiology of migraine with emerging evidence that several cytokines such as interleukin-6 (IL-6), tumor necrosis factor (TNF), and interleukin-10 (IL-10) are implicated in the pathogenesis of migraine causing sensitization of nerve endings during headache attacks [18, 19]. Interestingly, a negative correlation between direct bilirubin and C-reactive protein (CRP), as a marker that is increased in inflammation, was well established in adult and old migraine patients. These findings, combined with our results, point in an indirect way to the possibility that serum bilirubin may provide a protection against inflammation irrespective to the studied age group [20]. But, whether lower bilirubin level in migraine results from an overconsumption of bilirubin by neurogenic inflammation or a primary deficit and not a physiological phenomenon associated with consumption by inflammation has not yet been established. Thus, future studies and investigations are still required about the exact mechanism.
Till now, there are no studies that disagree with our results as regards lower serum bilirubin in migraine.
On correlating serum bilirubin levels within the migraine group with different headache features and migraine associations, there was no statistically significant association between serum bilirubin concentration (Tbil, Dbil, and Ibil) and any headache feature or the presence or absence of migraine equivalents or abnormal EEG findings during headache attacks. On the other hand, during headache-free periods, migrainous patients with abnormal EEG findings had statistically significant lower levels of serum bilirubin concentration (Tbil, Dbil, and Ibil) than those with normal EEG findings. This may be explained by the fact that in the absence of headache (headache-free periods), migrainous patients with abnormal EEG findings have more lower bilirubin level than those with normal EEG; thus, more lower level of bilirubin reflects much more consumption by inflammation or being much more susceptible to neurogenic inflammation or the presence of subclinical electrical activity and that can be detected by EEG even in the absence of headache attack. But, this lower level does not affect the clinical expression of migraine or its associations. No previous studies had investigated this issue, so this observation requires much more investigations and larger studies to be ascertained.
For psychiatric comorbidity, there was statistically significant difference between migrainous patients with psychiatric comorbidity and those with no psychiatric comorbidity as regards serum indirect bilirubin concentration only, while there was no statistically significant difference between them as regards serum total or direct bilirubin concentration. In fact, no previous studies had investigated the association between serum bilirubin level and primary psychiatric disorders in general or psychiatric disorders comorbid with migraine. So, larger studies with larger sample size are needed to investigate this relationship before trying to find an explanation.
In our study, we had several limitations. A relatively small sample size was a major limitation. We did not compare levels of serum bilirubin between migraine patients on anti-inflammatory treatment and those with no anti-inflammatory treatment. Larger cross-sectional and prospective studies are needed to detect the possible mechanism of lower bilirubin levels in patients with migraine and to establish whether this may be used as a useful biomarker for neurogenic inflammation in patients with migraine guiding diagnosis and therapy. Studies are also required to correlate biomarkers of inflammation in migraine and the clinical expression of migraine features, its associations, psychiatric comorbidity, and EEG findings.