Functional abdominal pain disorders in children : Bridging the gap Galle Medical Association Oration 2018

25 In early twentieth century, Sir George Frederic Still , known as the father of British Paediatrics, wrote; “I know of no symptom which can be more obscure in its causation than colicky abdominal pain in childhood”. Today, a century later, colicky abdominal pain in children still remains an symptom which is often difficult to understand and management is a challenge. Half a century later, Dr. J Apley, another British Paediatrician, studied abdominal pain among children extensively named this symptom complex as “recurrent abdominal pain syndrome of childhood”

In early twentieth century, Sir George Frederic Still , known as the father of British Paediatrics, wrote; "I know of no symptom which can be more obscure in its causation than colicky abdominal pain in childhood". Today, a century later, colicky abdominal pain in children still remains an symptom which is often difficult to understand and management is a challenge. Half a century later, Dr. J Apley, another British Paediatrician, studied abdominal pain among children extensively named this symptom complex as "recurrent abdominal pain syndrome of childhood" He defined it as "at least three episodes of abdominal pain, severe enough to affect their activities over a period longer than three months" His findings formed the main guidelines for the paediatricians and researchers dealing with this problem for the next half of the century.
Dr. John Appley found that 10.5% of British schoolchildren were suffering from RAP in 1958. Since then it has been studied all over the world, including Asian countries, and has been reported to occur in 8-12% of school-aged children. According to previous epidemiological studies RAP is the second commonest painful health problem in schoolaged children, only second to a headache.
Several studies have shown 75 % to 90% of the RAP patients are suffering from none-organic type of RAP. When a child presents with organic pain, the clinician may be able to objectively test for, and diagnose, a physical cause for that pain. This is not the case with non-organic pain, as there is no definitive test. The investigation, at best, will only exclude organic disease it will not prove a functional origin. Therefore, the diagnosis of non-organic pain abdominal pain is both intellectually and medically challenging.
The vast majority of children and adolescents with recurrent abdominal pain have functional gastro -intestinal disorders. Functional gastrointestinal disorders are defined as "chronic or recurrent gastrointestinal symptoms, which are not explained by structural or biochemical abnormalities". It is a spectrum of clinical presentation diagnosed by symptoms based on Rome criteria.
The road to the development of the Rome criteria for FGIDs began from a landmark meeting in Rome. In th 1988, During the 12 International Congress of Gastroenterology in Rome a working team was set up to create guidelines for the management for IBS. This decision has revolutionized the approach to FGIDs by deviating the previous "diagnoses of exclusion" approach and introducing the "diagnoses of inclusion" approach. The first edition of Rome-Rome I was published in 1994 which outline the symptom-based diagnostic criteria for 21 FGIDs. Rome I diagnostic criteria was revised and in 1999 Rome II was published. Rome II included the diagnostic criteria for paediatric FGIDs for the first time. Rome III was published in September 2006 which is a nearly thousand-page document written by a collaborative effort of 82 international experts. The Rome III classification includes 28 adult and 17 paediatric diagnostic entities. The new Rome IV which was released on May 2016, is evidence-based, multicultural oriented and with clinical applications.
There are four functional gastrointestinal disorders, which are presented as the abdominal pain as the predominant symptom. Therefore Irritable bowel syndrome, abdominal migraine, Functional dyspepsia, Functional abdominal pain are known as functional abdominal pain disorders. In Rome IV, the label of abdominal pain-related functional gastrointestinal disorders (AP-FGIDs) was replaced by the term functional abdominal pain disorders (FAPDs).
Despite the high prevalence, underlying pathophysiology of this condition is poorly understood and effective treatment options are lacking. During this presentation, I would like to discuss Epidemiology, risk factors pathophysiology, the impact of the disease. Finally the management of the functional abdominal pain in children.

Epidemiology of FAPDs
The first Part my presentation is dedicated to the epidemiology of functional abdominal pain disorders. A recent meta-analysis of 58 epidemiologic studies on abdominal pain conducted from 1957 to 2014, including nearly two hundred thousand children, reported a global pooled prevalence of 13.5 %. According to different continents, the pooled prevalence was more stable, though was slightly lower in European studies and generally higher in studies from South-America and Asia. Most studies conducted in Europe, Asia and the USA did not show significant association between the socioeconomic status and the disease. However very few studies have reported the prevalence of FAPDs in 5 to 12 age group. Therefore an epidemiological study was conducted to determined the Sri Lankan prevalence in 5 to 12 age group. The findings of the epidemiological study were published th as abstracts in 5 Asian neurogastroenterology and th motility meeting in Osaka, Japan and The 14 Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting in Bangkok, Thailand.
The study was carried out using a self-administered parental questionnaire in western province of Sri Lanka. We have used standard and internationally accepted tools in data collection. All questionnaires were translated, validated and pretested in the native language (Sinhala). Ø Healthcare consultation details report The questionnaires were filled with the help of the research assistants, which increased the accuracy and validity of the research. A total of 1000 children recruited from four randomly selected schools. 653(65.3%) correctly filled questionnaires were included in the analysis . The prevalence FAPDs was 12.6% in 5 -12 age group. There were 82 children who fulfilled criteria for the FAPDs.
FAPDs was significantly prevalent in females. The commonest FAPDs subtype was Functional abdominal pain followed by IBS. The Prevalence of an Abdominal migraine was less than 1% in our cohort.
The pain profile showed that majority of the children had Ø Moderate to severe pain, lasting less than one hour for less than 3 months duration.
Ø Duration of abdominal pain was more than one year in 25% of children.
Ø Duration of abdominal pain was significantly higher in females children However, the severity of pain, duration of one pain episode and frequency of abdominal pain were not significantly different between males and females. Pain in another site, abdominal fullness and headache were the most common associated symptoms. However, there was no statistically significant difference between males and females with related to associated symptoms. Epigastric and periumbilical were the commonest sites for abdominal pain. However, most of the previous studies have reported the periumbilical area as the commonest site of abdominal. Higher prevalence of functional dyspepsia in this cohort who have epigastric pain may have contributed to the observed deviation in our study.

Risk factors and pathophysiological mechanisms in functional abdominal pain disorders
Second part is dedicated on risk factors and pathophysiological mechanisms in functional abdominal pain disorders. Rome IV has several recognized groups of risk factors that are associated with FAPDs. It is suggested that most of them complexly blend with other identified pathophysiological mechanisms to potentiate their effects at both central to generate symptoms.
I have assessed gender, exposure to the child abuse, early life events, and genetic factors as risk factors. th At 5 Asian neurogastroenterology and motility meeting, Osaka, Japan abstract was presented with related to the risk factor I have studied. Previous, school-based epidemiological study have shown that except from five to six-year age group, females had a higher prevalence of FAPDs in our study. This dominance in females was reported in all different continents across the world. In addition to that, the predominance of females has been also described in other functional complaints, like functional constipation and headache. Effect of sex hormones and higher visceral sensitivity have been proposed as contributing factor for female predominance in Functional pain. However, our sample includes children of a very young age who do not have a full female hormone profile. Therefore, the exact cause for the observed female predominance is not apparent in our study.
The findings related to the exposure to abuse as a risk factor were published in the Journal of Tropical Pediatrics which is indexed in science citation index .
This publication has received the national research council merit award for scientific publication.
School-based study was conducted in 13 -18 aged school children by using self-administered child questionnaire. The written consent was obtained from parents. Assent was also obtained from children in addition to parental consent A total of 1855 questionnaires were distributed and 1850 (99.7%) properly filled questionnaires were included in the study.
The prevalence of FAPDs was significantly higher in children exposed to all three main types of abuse physical, emotional and sexual abuse (Table 1). Observation was noted across the all age groups we have assessed ( Figure 1).

Review
In addition to that those with functional abdominal pain, exposed to abuse had a significantly higher severity score for bowel symptoms.
Very few researchers have studied the relationship between child abuse and functional pain disorders during the childhood, especially among teenagers. None of those previous studies has assessed the impact of abuse on symptom profile. This novel finding indicates the importance of child abuse in developing FAPDs. The Rome committee have used the result of this study and included child maltreatment as a risk factor in Rome IV guidelines.
Second risk factor I have assessed was early life events. Using a parental questionnaire, details of ELE were obtained from 182 children with FAPDs in the 5 -12 age group. 571 children were included in the control group. Prenatal complications were significantly higher in the FAPD group. Gestational diabetes and pregnancy-induced hypertension were the most common antenatal complications. Post-natal complications were also significantly higher in the FAPDs group. In addition to that receiving PBU care were significantly higher in the FAPDs group. The current study has added pre-natal and post-natal complications to the list of early life events associated with FAPDs. These findings signify the fact that adverse life events occurring during the fetal period and the neonatal period which is a vulnerable period for developing neurons may be an important contributory factor for the development of FAPDs. However, the duration of the gestational period was not different between FAPDs and control group. Another ELE significantly associated with FAPDs was low in the birth order. That means elder children in the family are more prone to develop the disease. Having a family member with a history of chronic abdominal or any other chronic pain was also significantly higher in FAPDs group. Adult studies have revealed a large number of genes associated with FAPDs especially with IBS and IBS patients are more likely to have a family history of similar illness. Our study has strengthen the idea of familial predisposition in FAPDs. I have studied the Gastric motility and autonomic functions as the pathophysiological mechanisms.

Pathophysiology of FAPDs
Motility studies have repeatedly shown Abnormalities in the gastrointestinal motor function as a potential pathophysiological mechanism in FAPDs. Dilated gastric antrum at fasting period, delayed gastric emptying, impaired initial distribution of a meal, impaired gastric accommodation to a meal and antral hypomotility have been reported as the abnormal motility patterns.
Autonomic nervous system is an integral part of the brain-gut axis that is involved in regulation of gastrointestinal motility. It is the one of the first mechanism investigated as a pathophysiology mechanism in functional pain. The Role of autonomic system in symptom generation is a controversial point. Available literature has shown that autonomic activity may present as normal, hypofunction or hyperactive status in functional abdominal pain in children. However, the relationship between autonomic function and gastric motility has not been studied in children. This phase of the study has been presented as four abstracts in st 1 federation of neurogastromotility meeting at th Guangzhou, China, 5 Asian neurogastroenterology and motility meeting, Osaka, Japan. A journal article is under review process in the World Journal of Gastroenterology as an invited article.
We have recruited 100 children with FAPDs for the laboratory study. Diagnosis were confirmed with thorough clinical and investigations procedures. Their motility and autonomic parameters were compared with 50 age, sex-matched healthy children. We were adhered to strict laboratory protocols to minimize investigators bias, environmental and diurnal variational impact on those physiological parameters. After a test meal, same time of the day, gastric motility parameters were measured by u previously validate real-time USS method in using a high-resolution real-time scanner. All gastric motility parameters were assessed by the same investigator who was blind to the diagnosis and results of the autonomic function tests results. Seven motility parameters were measured including gastric emptying rate and motility index as main motility parameters.
Four bedside, non-invasive, autonomic test were conducted to assess autonomic functions which were described by Ewings. Those test were previously used and validated for children. All the tests were conducted in thermo-neutral conditions (26C) and at the same time of day (9.30 a.m. -10.30 a.m.) in all the children. All the readings were recorded by a single observer to eliminate interpersonal bias.
Gastric motility results have shown that Gastric emptying rate, frequency of antral contractions, amplitude of antral contractions and motility index were significantly impaired in affected children (table 2).
In all four types of FAPDs main motility parameters gastric emptying rate and motility index were lower than the controls. There was a correlation between some motility parameters with pain parametres. In contrast to the motility, autonomic parameter were not significantly different between two groups (Table 3).
We have found that in the control group, several autonomic parameters were correlated with the motility.
This has indicated the intact physiological relationship between gut and brain in healthy children. In contrast to that, any of the autonomic parameters did not correlate with any of the motility parameters in FAPDs indicating affected children gut has failed to respond to the autonomic commands from the brain.
We named this phenomenon as functional extrinsic denervation in FAPDs.   Primary insults diminishing the extrinsic (autonomic) control over the stomach lead to automatic stomach in susceptible children who may having altered physiological mechanism as a result of early life events. Stress, psychosocial factors or infection may be acting as a primary insult. The behaviour of the uncontrolled automatic stomach and inhibited Ach release via dopamine 2 receptors may lead to development dysmotility. Abdominal pain is triggered by the Motility abnormalities. In the process, compensatory mechanism may try to gain control. We have no evidence on this statement in the current study.
However, the high parasympathetic flow may be the autonomic compensation demonstrated in previous studies BY Jorgensen et al., 1993 . Parasympathetic system failing and maladapting as indicated by low p a r a s y m p a t h e t i c f l o w. P a r a s y m p a t h e t i c maladaptation prolongs the duration of pain episode and may worsen the motility abnormalities. In a nutshell, Automatic stomach model would describe FAPDs are an "emerging rebel group when the local government (Gut) trying to get freedom from the empire (Brain)". Burden on the health care system is an important factor in health economy. We have evaluated the health care consultations in FAPDs which is an indirect measure of the burden on health economy. Healthcare consultations were significantly higher in FAPDs group. In 5-12 age group, 40% FAPDs children had nearly 3 healthcare consultations during the past one year for abdominal pain. Multiple logistic regression analysis showed that nausea and presence of a family member with chronic pain was significantly associated with healthcare consultations. A negative correlation was observed between the total HRQOL score and healthcare consultations for abdominal pain. However, the majority of the children did not seek consultations for abdominal pain. It may an indicator of the prevalence of ''silent suffers'' in the community.

Management of FAPDs
In this Final part of my presentation I will focus on the management of FAPDs. As the first step for diagnostic workup, it is essential to devote adequate time for the history and physical examination as pathophysiological mechanisms underlying FAPDs remain unclear and currently no diagnostic biomarkers exist. History taking should include details of abdominal pain, infectious episodes or stressful events associated with the onset of symptoms, psychosocial history, dietary triggers, history of previous treatments, and family incidence of gastrointestinal diseases. Physical examination should include thorough general examination to identify evidence of an organic disease. Careful attention needs to be paid to growth parameters as well. Detailed abdominal examination, perianal, and rectal examination are also crucial in confirming the diagnosis of FAPDs. Only when alarm symptoms or so-called red flags are present which may indicate an organic disease diagnostic testing are recommended.
It has been demonstrated that numerous laboratory investigations are performed during common diagnostic workup of children with FAPDs, without detecting clinically meaningful abnormalities, but with additional inconvenience and cost. There is the possibility of finding some false positive investigations, and frequently treated for a disease that actually does not exist. The failure in acknowledging this was already playfully called Ulisses' syndrome, in allusion to the Greek mythological hero Ulysses fought in the Trojan war but afterwards took 10 years, with many dangerous and pointless adventures, before he got back to where he had started. Similarly, the unnecessary and uncritical use of laboratory examinations, leading to long investigation journeys, and making the child and his/her family go through an unnecessary, expensive, and sometimes dangerous expedition, whose end is the starting point. However When clinicians or families require further reassurance, few judicial investigations can be performed. When no atypical clinical features are present, abdominal ultrasonography does not have significant diagnostic value.
The goal of management of functional abdominal pain disorders in children and adolescents is return to normal function rather than complete elimination of pain. When symptoms persist and disrupt a child's wellbeing, pharmacological or nonpharmacological treatment should be considered. Consecutive patients belonging to 5 -12 year age group who were eligible were recruited from paediatric outpatient clinics at teaching hospital, Ragama. All recruited patients were assessed by a Consultant Paediatrician. All patients were screened for organic diseases using history, examination (including growth parameters), stool microscopy, urine microscopy and culture, full blood count, Creactive protein, liver and renal function tests.
Special investigations performed based on findings of the initial evaluation and investigation in some patients included upper and lower endoscopy. A baseline electrocardiogram was also performed to rule out cardiac conduction abnormalities. Patients were not screened for coeliac disease and lactose intolerance since they are extremely rare in Sri Lanka. Children and parents were instructed not to change the diet or lifestyle of the child once the subjects were included into the trial.
All 100 children with AP-FGIDs recruited were randomized, using computer-generated random numbers, into two groups (50 in a group) irrespective of the symptom severity and gastric motility status. And we compared the primary and secondary outcomes in domperidone group according to the baseline motility parameters (table 5).
When primary outcomes were compared between children with normal motility and those with abnormal motility, percentage with cure and improvement of overall condition were not significantly different after administration of domperidone at 8 weeks and 6 months. When secondary outcomes were compared, reduction in pain severity was not different between the two groups. Domperidone resulted in significant improvement of gastric emptying rate and antral motility index in children with normal gastric motility. Therefore domperidone can be prescribed irrespective of the motility status. Safety and adverse effects during the trial also important.
One patient developed a skin rash during the trail. This presentation was not considered as an adverse effect of treatment. The child completed the trial without further problems. No treatment-associated adverse events were noted during the trial period.

Conclusions
In conclusion, The FAPDs is a common disorder with female predisposition in 5-12 age group.
Impact of AP-FGIDs are severe enough , Ø to reduce health-related quality of life in affected children.
Ø to increase health care seeking behaviour and cause a significant impact on the families of affected children.
Early life events are an important risk factor.
Main gastric motility parameters assessed were significantly lower in children with FAPDs. Assessment of autonomic functions in FAPDs show neither a significant difference compared to the control group nor a correlation with gastric motility abnormalities. Extensive investigations are of limited value in diagnosing. Because proposed pathophysiological mechanisms are usually not revealed by usual investigations. Domperidone, a prokinetic drug, has shown promising, long-lasting therapeutic value in management of functional abdominal pain in children. Therapeutic value of domperidone is not related to baseline gastric motility status. Therefore it can be prescribe without performing motility studies.