Migraine is one of the most frequent types of primary headache. In 2015, the Global Burden of Disease Study ranked it third as a cause of disability for men and women under 50 years of age.1 In 2017, the European prevalence of migraine was 20%, which was a 6% increase compared to 1997.2
In the pediatric population, the most recent epidemiological study3 estimated the prevalence of migraine to be 9.1%, and cross-sectional studies underline a constant increase of incidence of migraine with and without aura.4 Understanding the epidemiology and the prognosis of migraines in children and adolescents is important since the majority will continue to suffer into adulthood.3,5
Pediatric migraines differ from those experienced by adults, thus, their diagnosis can be challenging. Firstly, the diagnostic criteria are different:6 episodes are commonly bilateral (whereas they are typically unilateral for adults) and shorter (sometimes less than one hour, especially for young children).7 Secondly, we now acknowledge a broad spectrum of migraine-related episodes which are more frequently seen in children: abdominal migraine (AM), cyclic vomiting syndrome (CVS), and infantile colic.8 These episodes can have a great impact on the child’s and parent’s quality of life,9 particularly since migraineur children are frequently afflicted with other comorbidities. Obesity,10 atopy, or allergic disease,11 a dysfunctional family situation, a low level of physical activity and physical or emotional abuse have all been associated with migraine and to its onset or progression.12 The relationship between migraine and functional abdominal pain has been discussed at length among adults13-15 and identifies a connection between migraine and irritable bowel syndrome (IBS) and functional dyspepsia (FD), but further research is required among the pediatric population.16
These studies are evidence for the scholarly interest in understanding the pathophysiology behind migraines. The pathophysiology of migraine is a multifactorial phenomenon,17 dependent on genetic factors (more than thirty migraine-associated gene polymorphisms have been discovered),18 environmental factors (such as medication, diet, and stress) and metabolic factors (examples include neuroendocrine function, the menstrual cycle, and pregnancy). The activation of the hypothalamus results in an alteration in thalamo-cortical circuits and brain connectivity, which subsequently leads to calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) release. The release of PACAP triggers intra-cerebral vasodilatation, ultimately causing the symptoms of migraine. Today, the role of CGRP in the gut-brain axis bidirectional communication is well recognized: CGRP has an antimicrobial action on gut bacterial strains (for instance,
The diagnosis of migraine, its abdominal variants and functional abdominal pain can be challenging as they are often associated with each other. Early diagnosis is a good prognostic indicator of recovery for children and adolescents suffering from functional abdominal pain21 and migraines,5 thus the recognition of those conditions can have a great impact on children’s quality of life.
To date, reviews have studied either the association of abdominal variants or the functional abdominal pain disorders with migraine (Table 1).13,22-30 In this review, we aim to define the different abdominal variants of migraine (AM, CVS, and infantile colic) and the functional abdominal pain disorders associated with migraine (IBS and dyspepsia) (Table 2), to describe their relation to migraine (Table 3), their epidemiology and their evolution within the pediatric population, and finally to discuss current therapeutic management.
AM, CVS, and infantile colic are gastrointestinal episodic syndromes classified as variants of migraine by the international classification of headache disorders (ICHD)-3 (beta version).8 Among the episodic syndromes, we also acknowledge benign paroxysmal vertigo and benign paroxysmal torticollis, but these 2 conditions will not be discussed here as they do not involve the gastrointestinal tract.
AM has been described in children since 1984 by Symon and Russel31 and is now part of both the ICHD classification, and the Rome IV classification.32 The diagnosis of AM can be challenging as it is at the crossroads of multiple organ’s symptomatology. A positive clinical diagnosis of AM avoids unnecessary treatments and investigations.
A pragmatic clinical definition of AM in children is given by Angus-Leppan et al33 in 2018, adapted from definitions of Symon and Russel,31 ICHD-3 beta,8 and Rome IV32: (1) episodic central abdominal pain, usually lasting > 1 hour, (2) episodes interfere with normal activity, (3) episodes occur with one or more of pallor, anorexia, nausea, vomiting, photophobia, headache, or are associated with other episodic syndromes (particularly CVS well between episodes), and (4) normal physical and developmental examination.
Children with AM report similar triggers (stress and fatigue) and relieving factors (rest and sleep) to migraineurs.34 One key to the diagnosis is the absence of headache during episodes. Vomiting symptoms are also less severe than in CVS. The prevalence of AM is generally reported to be around 5% to 9% of the pediatric population34,35 but increases in children with a family history of migraine or depression.34-37 It is also higher among girls, with a reported sex ratio around 1.6/1 in Abu-Arafeh‘s first prevalence study in 1995.34
In the adult population, the diagnosis of AM remains very uncommon and few case reports have been published to date.38 Roberts and deShazo39 reported a cohort of 13 patients (11 from the medical literature and 2 from their clinic) and analyzed their symptoms by the IHCD-2 and the Rome III classifications of pediatric AM: 10 of their patients met some criteria for AM. Ninety percent of them had a family history of migraine.39 Their findings suggest considering AM in the differential diagnosis of recurrent abdominal pain in adults, especially if a family history of migraine is observed.
With respect to the pathophysiology hypothesis, in 2016, Devanarayana et al40 studied gastric motility of AM patients compared with control patients and showed that gastric and antral motility parameters were significantly lower in children with AM. They also noticed a significant correlation between symptom severity and gastric motility, a field of study within gut-brain axis diseases since it aids our understanding of the central innervation of the gut. Moreover, alteration of gut permeability has been proven in AM patients. In a study of 11 AM patients and 9 control children, Bentley et al37 showed that the mucosal permiability of small intestine was increased in AM patients. Furthermore, they longitudinally followed 3 AM patients and noticed a decrease in gut permeability correlated to the improvement of the AM symptoms. In some patients, the mucosal response to food allergens evidently seemed to trigger AM.37 The communication between the enteric and the central nervous system (CNS), best known as the gut-brain axis, helps us to understand how these intestinal changes are related to migraine.41
Children with AM have an excellent prognosis, with a majority demonstrating complete resolution of symptoms. It is unclear what causes AM to persist into adulthood since there are few case reports and small sample sizes.39 Although AM symptoms ultimately tend to evanesce, almost 70% of children will go on to develop classic migraine or recurrent abdominal pain syndrome.42,43
AM is now considered to be a pediatric precursor of migraine, consequently experts tend to extrapolate the usual migraine treatment to AM. However, to date, only 1 randomized control trial has been published within the field of pediatrics: pizotifen (a serotonin agonist) reduces the duration and the severity of AM when used as a preventive treatment44 Retrospective data on propranolol (a b blocker), cyproheptadine (an antihistamine), and flunarizine (a calcium channel blocker) as preventive therapies also seem to show a reduction in the frequency and severity of AM episodes.33 Lifestyle modifications are also recommended to prevent migraine crises.
CVS is part of the episodic syndromes associated with migraine as defined by the ICHD-3b classification.8 The symptoms of CVS are very typical and have been recently defined as8: (1) recurrent episodic attacks of intense nausea and vomiting, usually stereotypical to the individual and with predictable timing of episodes, (2) attacks may be associated with pallor and lethargy, and (3) there is a complete resolution of symptoms between attacks.
The diagnostic criteria include all of the following: (1) nausea and vomiting occurring at least 4 times per hour, (2) attacks lasting from 1 hour up to 10 days, and (3) attacks occurring 1 week apart.
The prodromal phase is characterized by intense nausea, pallor, tiredness, and abdominal pain. The vomiting phase is very intense within the first hour with a median frequency of 6 vomiting episodes per hour, declining during the next 4 hours to 8 hours. The recovery phase begins with the remission of nausea, continuing until recovery of appetite and strength. In 75% of children, the attacks begin between midnight and early morning.45
The prevalence of CVS is estimated between 0.3%46 and 6.1%47 making it less frequent in the pediatric population than migraine or AM. The pathophysiology of CVS remains unclear but different possibilities have been researched recently. Mitochondrial abnormalities have been explored as a maternal inheritance of CVS and 2 mitochondrial polymorphisms have been found to be highly associated with migrainous headaches and CVS.48 As with the migrainous pathophysiology, hypothalamic function is also influential in CVS as the control center of the CNS. In 2016, Ellingsen et al49 published the first functional MRI study to characterize altered brain connectivity in the insular cortex, the region of the brain involved in disease mechanisms responsible for both CVS and adult migraine. Autonomic dysfunction studies show a strong correlation between CVS, postural orthostatic tachycardia and an aberrant heart rate variability.50 Gastric motility has been explored in pediatric and adult patients suffering from CVS or migraine and mostly shows acceleration of gastric emptying, which implies altered autonomic function.
In comparison to AM, CVS has also been explored in the adult population and it is interesting to compare these cohorts. As children mature, their symptoms generally ameliorate or resolve; attacks become less intense and shorter in duration. In a Taiwanese pediatric study,51 9 out of 24 patients were symptom-free 4 years after diagnosis. On the other hand, newly diagnosed adult patients tend to have longer and more intense episodes than children52 but the vomiting pattern previously described remains consistent.53 Time to diagnosis is around 2 years for children whereas it is around 8 years for adults. The quality of life of CVS school-age children is often significantly affected; 85% had absences from school in the previous year due to their condition.45 An early diagnosis improves the quality of life of children suffering from CVS.54 Considering these data, the psychiatric profile of CVS patients has also been explored,55 with 1 study finding that 47% of children with CVS suffer from anxiety disorders. It is important to note that in this study parents reported significantly more psychiatric symptoms in their children than the children themselves. The hypothesis of anxiety transmission has also been explored for migraine and infantile colic.
The treatment of CVS in children is the same as for migraine: lifestyle modifications, plus medical management such as propranolol, flunarizine or mirtazapine, or anticonvulsants such as topiramate, phenobarbital, or levetiracetam. Antiemetic treatment such as aprepitant can also be used as a preventive treatment in CVS.56
Prognostically, it has been demonstrated that between 30% and 50% of CVS patients will develop migraines,57 with children diagnosed at an early age and those with more severe symptoms being the most likely to become migraineurs. Moreover, the clinical features (nausea, vomiting, and phono-photo-phobia), the periodicity, the triggers (stress and sleep deprivation) allow us to consider CVS as an equivalent and a precursor of migraine in children.
Infantile colic has recently been added to the ICHD classification, first appearing in the 2013 ICHD-3b.8 Infantile colic was first described and characterized by Wessel et al58 in 1954 to describe the “paroxysmal fussing” of infants under 4 months of age. It describes “paroxysmal fussing” or “infantile colic” as “possibly one of the earliest somatic responses to the presence of tension in the environment” leading to years of understanding infantile colic as a type of psychosomatic disorder. The ICHD classification’s diagnosis criteria are as follows: (1) A. Recurrent episodes of irritability, fussing, or crying from birth to 4 months of age, fulfilling criterion B; (2) B. Both of the following: episodes last for 3 hours per day and episodes occur on 3 days per week for 3 weeks; and (3) not attributed to another disorder.
A systematic review and meta-analysis of 2017 by Wolke et al59 studied the prevalence and crying duration of infantile colic and reported a high prevalence, 17-25%, of infantile colic under 6 weeks, decreasing shortly after 6 weeks to 11% and to 0.6% by 10-12 weeks.
The pathophysiology of infantile colic is also a good model of the gut-brain axis mechanism. The influence of microbiota on infantile colic has been investigated by means of stool studies60 and on the effect of intrapartum61 or neonatal antibiotic treatment.62 These studies show an increased risk of infantile colic for children who were administered antibiotics at birth or in the first week. It is widely recognized that antibiotic treatment modifies the gut and vaginal microbiota, and a review by Zeevenhooven et al63 studying children with colic identified a lower diversity in their intestinal microbiota, an abundance of microorganisms such as
Factors influencing the microbiota of children and their mothers have thus been widely explored by researchers, with particular attention paid to maternal medical and psychological status. Maternal health conditions such as obesity,66 migraine,66 tobacco consumption,67 anxiety,68 and depression represent risk factors for infantile colic. Paternal support to the expectant mothers,69 familial support and a couple’s level of happiness have also been linked to a lower risk of infantile colic. Moreover, paternal depression has been linked to infantile colic.70
The complexity of infantile colic is also influenced by an immature CNS. Indeed, the prevalence and the intensity of infantile colic decreases at around 8 weeks of age, which corresponds to the transition from reflex mechanisms to behavior controlled by the cerebral cortex.63 A perfect example of the effects of CNS immaturity is the preterm population where the risk of infantile colic is increased, and some studies have shown that increased prevalence corresponds with the degree of prematurity.71 Similarly, newborns with a lower birth weight tend to suffer more with colic.72 The immature enteric nervous system may contribute to infantile colic by way of gut dysmotility, which leads to altered mucus secretion and modification of microbial composition.
Although the pathophysiology of infantile colic is complex, there is a better understanding of the outlook for children with colic. In follow-up studies of children between 5 years old73 and 10 years old,74 an increase in sleep disorders, aggression or anger, and ADHD have been observed.75 Concerning somatic health problems, infantile colic has now been linked to recurrent abdominal pain74 and migraine29,30,76,77 in numerous studies. The first case report linking migraine to infantile colic was published by Katerji and Painter78 in 1994 and describes an infantile migraine presenting as colic. In 2013, a case-control study of 679 patients showed that children with migraine were more likely to have experienced infantile colic (OR, 6.61; CI 95%, 4.38-10.00;
Concerning the treatment of infantile colic, it has been at an impasse for many years. A recent systematic review from Hjern et al81 found moderate evidence to support the efficacy of
The Rome IV classification categorizes the functional gastrointestinal disorders (FGID) in children into 3 subtypes: (1) functional abdominal pain disorders, (2) functional nausea and vomiting disorders, and (3) functional defecation disorders.32
There are 3 subtypes of functional abdominal pain disorders: IBS, FD, and AM. Here we are interested in IBS and FD as they are the only 2 that studies have shown as being linked to migraine.13,14,16 They are not considered as abdominal variants of migraine, in comparison to AM, in the ICHD-3b as, so far as is known, they coexist with migraine, without being temporarily linked to it. The most frequent FGID identified in toddlers is functional constipation82 which is part of the functional defecation disorders, but again with no link to migraine proven to date.
The Rome IV classification32 defines IBS in children as: (1) abdominal pain in at least 4 days per month associated with 1 or more of the following: (a) related to defecation, (b) a change in frequency of stool, and (c) a change in form (appearance) of stool; (2) in children with constipation, the pain does not resolve with resolution of the constipation (in this case, the child has functional constipation); and (3) after appropriate evaluation, the symptoms cannot be fully explained by other medical conditions.
IBS can be divided into subtypes reflecting the predominant stool pattern: IBS with constipation, IBS with diarrhea, IBS with constipation and diarrhea, and unspecified IBS.
According to a meta-analysis of 16 studies on the prevalence of IBS in Asian children, the prevalence ranges from 2.8% to 25.7% with a pooled prevalence of 12.4%.83 The prevalence risk ratio for girls to boys is 1.39. The prevalence of IBS in children from the Mediterranean region of Europe is evaluated at 4.0%.84
IBS etiology is most likely multi-factorial involving biological, psychological, and social factors.85 Visceral hyperalgesia (or hypersensitivity) and visceral hypervigilance are key concepts in current research on pathophysiological mechanisms of IBS.86 Brain imaging studies show that the neural processing of visceral stimuli is altered in IBS.85 There is also growing evidence to suggest that peripheral immune mechanisms and disturbed neuro-immune communication could play a role in the pathophysiology of visceral hyperalgesia. The contribution of both stress and negative emotions on symptom frequency and severity has been studied for some time now amongst children.87 As a gut-brain axis disorder, the influence of microbiota has also been studied in IBS and Hollister et al88 observed a significant difference in bacterial species (
The relationship between food allergies and recurrent abdominal pain, IBS in particular, has also been widely explored.92 Some studies have shown an improvement in the severity and the frequency of pain in pediatric patients under fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exclusive-regime.93 In addition, the role of food on their symptoms is often expressed by IBS patients, whether they are adults or children.94
The role of personal beliefs and psychological factors is proven to impact the severity of symptoms. The transmission of somatic symptoms inside the family nucleus is part of the difficulty in acknowledging the symptoms of IBS patients, as shown by van Tilburg et al95 with mothers and fathers of IBS patients also tending to report more symptoms concerning themselves.96 The presence of adverse life events, inducing fear, increases the risk of IBS symptoms presenting in children.97 Thus, anxiety and depression are predictors of abdominal pain severity in IBS patients.87 In some families, the secondary benefit of having abdominal pain, such as providing an excuse to avoid household tasks, increases the risk of IBS in low-birth-weight children.98 These studies show the difficulties in understanding the underlying causes of such a multi-factorial syndrome.
The treatment of IBS in children is still mostly dominated by non-pharmaceutical interventions such as parental education, diet (FODMAP exclusion, gluten free or increase of fiber consumption) or behavioral therapy. Unfortunately, most of the trials regarding pharmaceutical therapies study children suffering from functional abdominal pain and not IBS or FD alone.98-100 A lack of clear evidence makes it very difficult to prioritize 1 treatment over another among: antiemetics (domperidone), antidepressants (tricyclic or selective serotonin reuptake inhibitors), acid suppressing agents, antispasmodics, and antihistamines. However, probiotics seem to be effective in treating IBS in children with an estimated number need to treat of 4 according to a meta-analysis of 19 randomized control trials (RCTs).101
Regarding the evolution of IBS in children, the majority (60%) will observe the disappearance of their symptoms over 2 years following the diagnosis, regardless of age, sex, and impact of symptoms.102,103 As exposed previously for abdominal variants of migraine, the initial diagnosis of IBS increases the chance of a symptom’s resolution, which makes the positive diagnosis a very important step in the support of IBS patients.21 Le Gal et al16 showed a 3.47 OR (95% CI, 1.81-6.62;
The diagnosis criteria for FD in children, as defined by the Rome IV classification,32 must include one or more of the following symptoms at least 4 days per month: (1) postprandial fullness, (2) early satiation, (3) epigastric pain or burning not associated with defecation, and (4) after appropriate evaluation the symptoms cannot be fully explained by other medical conditions.
Within FD, we describe 2 subtypes32: postprandial distress syndrome and epigastric pain syndrome. The postprandial distress syndrome includes bothersome postprandial fullness or early satiation that prevents finishing a regular meal, which can be associated with abdominal bloating, postprandial nausea, or excessive belching. The epigastric pain syndrome is defined as bothersome pain or burning localized to the epigastrium, without a retrosternal component and the ingestion of a meal being a trigger or an improvement factor. As for previous exposed syndromes, the diagnosis of FD requires clinical examination and history only. However, FD and gastroesophageal reflux can be difficult to distinguish, so the requirement of esophagogastroduodenoscopy in the diagnosis of FD has been debated.106 The Rome IV classification considers there is no compelling evidence to require an esophagogastroduodenoscopy in order to make a diagnosis of FD in the pediatric population.32
The prevalence of FD is described around 7.6%107 of children, using the Rome IV diagnostic criteria.
Concerning FD in the adult population, a recent review by Wauters et al108 consider it as the most common functional upper gastrointestinal disorder affecting 15% of the general population. Its symptoms do not differ in the Rome IV classification for either adults or children.
The pathophysiology of FD still remains unclear. It is a complex combination of physiologic, genetic, environmental, and psychological factors.109 We can distinguish 2 major mechanisms: gastric motility abnormalities and impaired gastric accommodation and visceral hypersensitivity.110 Gastric accommodation is defined by the ability of the stomach to distend appropriately during a meal with an increase in gastric volume in the absence of increased gastric pressure. Gastric motility can be explored by a number of different methods (sodium acetate breath tests,111 gastric emptying scintigraphy,112 or electrogastrography113 for example) and can be compared in FD and control patients in the pediatric and adult populations. Studies have shown delayed gastric emptying,111,112 antral hypomotility,113 and a negative correlation between gastric emptying rate and severity of abdominal pain114 among dyspeptic patients. This impaired accommodation may be linked to abnormalities of the vagal reflex and intrinsic inhibitory innervation.115 Studies on adults and children highlighted abnormal gastric sensorimotor function.116 The visceral hypersensitivity to gastric distention in FD can be considered as a model of a gut-brain axis disorder. The presence of inflammatory cells (eosinophilia and high mast cell density) can be found in the stomach and duodenum of children suffering from FD,117 especially if they are also suffering from headaches.118 An altered intestinal permeability, as observed in IBS or AM, was not observed in FD patients.119 The role of
An important intrinsic role for psychosocial factors and psychiatric disorders, especially anxiety and depression, has been described in the etiopathogenesis of FD, in addition to their putative influence on health care-seeking behavior. Around 50% of FD patients show high anxiety score responses.119
Finally, for a few years, studies have underlined a link between FD (postprandial distress syndrome or epigastric pain syndrome) and migraine in the pediatric population. Di Stefano et al123 were interested in the prevalence and pathophysiology of migraine in functional dyspeptic adult patients and demonstrated 54% of epigastric pain syndrome patients and 76% of postprandial distress syndrome patients also suffered from migraine. Among the postprandial distress syndrome patients, the severity of fullness and early satiation correlated to the severity of migraine.123 Cohort studies also showed an association between primary headache and FD: 25% of FD children declared having headache more than 3 times a month on an internet questionnaire survey,124 60% of adults migraineurs suffer from FD in a prevalence study,125 and Lankarani et al14 found a 1.68 OR (
The aim of this review is to summarize the recent knowledge on abdominal variants of migraine and functional abdominal pain disorders associated to migraine, as they appear to be part of a wider spectrum of diseases now being explored as brain-gut disorders (Table 2). Migraine and related syndromes have a great impact on the quality of life of children and their future as adults. The understanding of pathophysiological mechanisms underlying these conditions is crucial in order to improve diagnosis, treatment, and follow-up in these children.
In this review, we discussed whether the inflammatory mediators, gut microbiota profile, neuropeptides, serotonin pathway, stress hormones, and nutritional substances which are related with brain-gut axis could be a pathophysiology of abdominal variants of migraine and functional abdominal pain disorders associated to migraine. AM, CVS, infantile colic, and IBS appear to be mediated by neuroinflammatory and neuroimmune patterns that can also be found in migraine. For FD, alterations in motility and gastric accommodation are among the main hypotheses. Therefore, it is possible that alterations of the gut-brain axis could be involved in the underlying mechanism for all of the abdominal syndromes associated with migraine.
Léa LenglarT and Luigi Titomanlio: concept and design, drafting the paper, and revising the paper; Léa LenglarT, Delphine Wohrer, and Caroline Caula: collecting articles and revising the paper; and Thomas Moulding and Annabel Lyles: English revision of the paper.