What Is Known
- Constipation is one of the most common gastrointestinal complaints in children.
- Although most children do not require any diagnostic testing, a detailed assessment including the use of investigative tools is usually recommended in those children not meeting Rome criteria or unresponsive to conventional medical treatment.
What Is New
- During the last decade, there has been a remarkable increase in our knowledge of colonic and anorectal motility, and different techniques to measure transit, motility, and sensation have been developed.
- This review analyzes the possible diagnostic investigations for severely constipated children, focusing on their clinical indications and utility.
Constipation is one of the most common complaints in children with an estimated prevalence of 12% (1–3). Although several disorders may cause constipation, in >90% of children the underlying etiology is unrecognized and children labeled as having functional constipation (FC) (4). The diagnosis of FC is currently based on Rome IV criteria that define functional gastrointestinal disorders in children and have allowed symptom-based diagnosis, irrespective of invasive and expensive procedures (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/MPG/B239) (5). The majority of constipated children, indeed, do not require any diagnostic testing. Almost one-third, however, continue experiencing symptoms throughout adolescence despite medical treatment, giving importance to their early referral to specialized centers to evaluate the underlying pathophysiologic mechanisms or possible organic etiology and ultimately tailor effective treatment (6) (Supplemental Table 2, Supplemental Digital Content 2, http://links.lww.com/MPG/B240).
During the last decade, our knowledge of normal colonic and anorectal motility in children has improved remarkably and a number of techniques have been developed to evaluate intestinal sensory-motor function.
ABDOMINAL RADIOGRAPHY TO ASSESS FAECAL LOADING
A plain abdominal x-ray is often advocated as a first-line noninvasive technique for evaluating the presence of fecal impaction, particularly in children with an unclear medical history or unremarkable physical examination. Three scoring systems have been proposed to assess fecal loading severity based on fecal appearance on plain radiograph (Supplemental Table 3, Supplemental Digital Content 3, http://links.lww.com/MPG/B241), namely Barr et al, Blethyn et al, and Leech et al (7,8,13). Conflicting results, however, have since been reported in terms of specificity, sensitivity and interobserver agreement (9–12,14).
Van den Bosch et al (15) reported good intra- and interobserver agreement for all 3 scores, with the Leech score showing the highest reproducibility. Koh et al (16) similarly suggested the superiority of the Leech score finding, in addition, that all systems scores positively correlated with colonic transit time (CTT) and negatively with the Bristol stool form scale. Conversely, Moylan et al (17) reported poor interobserver reliability across all available scoring systems and Pensabene et al comparing CTT according to the Arhan method (18), Barr and Leech scores in children with FC or nonretentive fecal incontinence confirmed the limited value of plain abdominal x-rays (19).
Two systematic reviews found large heterogeneity in terms of study design and conflicting data, concluding that there was insufficient evidence to support the correlation between symptoms of constipation and fecal loading on abdominal radiographs (20,21). Based on this evidence, the recently published European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines concluded that abdominal radiography is not recommended for the diagnosis of FC (4).
COLONIC TRANSIT TIME STUDIES
CTT measurement provides useful information, especially in children with severe and persisting symptoms. The most widely used method to determine CTT in clinical practice is the radio-opaque marker (ROM) test (22). It is inexpensive, readily available and provides an accurate approximation of total and segmental CTT (23). Given excellent correlation with scintigraphic techniques, it may be considered the first-line investigation tool in children with refractory constipation (24,25). Current indications include the discrimination between constipation-related fecal incontinence and nonretentive fecal incontinence as well as between slow-transit constipation (STC) and rectal outlet obstruction. This understanding allows for the tailoring and evaluation of medical and surgical treatments and selection of those children who may benefit from more invasive motility investigations (26).
Several ROM test protocols have been suggested, ranging from a single or multiple capsule ingestion followed by single or multiple abdominal x-rays including at fixed times (4th day or 4th and 7th day) (18,27–31). Among these protocols, the most common are the Abrahamsson's (ingestion of 3 sets of distinctive pellets on 3 consecutive days followed by an x-ray on day 7) and Metcalf (x-ray on day 4) methods (23). As the single-radiograph technique allows significant reduction in radiation exposure and provides excellent correlation with other protocols requiring daily radiographs, it is now recognized as the most suitable for children (31). The ROM test can be performed in children as young as 2 years of age (18,32)
Overall CTT is calculated by counting the total number of markers on the plain x-ray, whereas segmental CTT is based on the number of retained markers in 3 colonic segments, namely right colon, left colon and rectosigmoid region (as described by Arhan et al) (18,27). The modified Metcalf formula is used to calculate segmental transit time (23,27). The number of markers per segment has to be multiplied by 1.2, a constant representing the ratio between the period during which the examination is performed (72 hours) and the number of markers ingested (#60), expressed in hours. Patients are considered as having slow CTT when there is a delay in transit with the pellets spread throughout the colon. When the delay occurs in the rectosigmoid, with >50% of the markers lying in this area, children are labeled as having rectal outlet obstruction. Normal transit time has been defined as a CTT <36 hours (33) (Fig. 1).
Recently, it has been reported that colonic filling state may considerably influence CTT measurement and the presence of fecal masses may bias CTT results, mimicking colonic inertia. Therefore, bowel disimpaction before ROM studies is helpful in avoiding this type of bias (34).
Colonic scintigraphy is a safe and noninvasive alternative investigation able to evaluate total and regional colonic transit (35–37). The main disadvantages are represented by the need for multiple image acquisition over consecutive days and limited availability due to high costs and need for specialized equipment (36). As images are captured on a γ-camera, the radiation burden, comparable to that of 2 x-rays, does not increase with the number of acquired images (38). Although its comparison with ROM test remains difficult due to the different test dynamics, the administration of radiolabeled meals appears more physiological than the administration of solid indigestible pellets, therefore allowing more reliable measurement of colonic transit (26,36).
111In-DTPA (2.8-day half-life) is the most common isotope used for labeling the liquid phase of colonic transit studies, although 99mTc (6 hours half-life) is also frequently used for labeling the solid test feed, also allowing the assessment of gastric emptying (37–39). The isotopes can be given orally in a nonabsorbable form with a test meal [99mTc or 67Ga (3.2-day half-life)], in water (111In or 67Ga) or in a capsule coated with a pH-sensitive material, which dissolves in the colon or terminal ileum (111In) (40,41). Theoretically, as 111In-DTPA can be administered in water, colonic scintigraphy can be performed at any age. Interpretation of scintigraphic colon transit studies requires both analysis of quantitative parameters and visual inspection of the images (42).
Data analysis and its presentation differ between studies and several reporting methods have been used. Results can be expressed as transit time in hours (T½), percentage of radioactivity retained (%RET), proximal colonic emptying, or center of mass (25). The geometric center (GC), which has been proposed as a measure of the progression of colon radiotracer activity across the duration of the study, is the weighted average of radioactivity over specific regions of interest (ROI) drawn around bowel segments. A variable number of ROIs, from 5 to 8, has been used across studies and the most commonly used are based on the Mayo Clinic (#5) and Temple University (#7) methods (38,43,44) (Supplemental Figure 1, Supplemental Digital Content 4, http://links.lww.com/MPG/B242). The GC is calculated by multiplying the fraction of counts in each ROI by the ROI number and summing the products: a low GC value indicates that the center of activity is in the proximal colon, whereas a high GC value indicates that the center of activity is in the rectosigmoid or has already been excreted (45). The GC can be determined for every time point that colon images are acquired. It has been suggested that the time points of greatest interest are 24, 48, and 72 hours (46) (Fig. 2). Since healthy individuals typically show complete colon evacuation by 72 hours, some authors suggest imaging only up to 48 hours. Scans at 72 hours may, however, be required to diagnose functional outlet obstruction or localize segmental abnormalities (37,38). Since CTT measured by ROM is comparable in children and young adults, it seems reasonable to use scintigraphic reference values derived from adults, although some normative data have been published in children (Supplemental Table 4, Supplemental Digital Content 5, http://links.lww.com/MPG/B243) (25).
Cook et al (45) performed colonic scintigraphy in 101 constipated children and showed it allows the accurate assessment of segmental colonic transit in children with FC and, by also assessing gastric and small bowel transit in the same study, it may help in identifying children with previously unrecognized pan-intestinal motility disorders. Sutcliffe et al (39), using both visual and quantitative analysis, identified 3 main patterns of transit: normal transit, anorectal hold-up, and slow colonic transit. The latter group was further subdivided into pan-colonic delay, discrete hold-up in the transverse colon, and abnormal small and large bowel transit. Whether these groups, however, are truly distinct requires further investigation (47). Mugie et al evaluated 26 children with severe constipation who underwent both colonic manometry (CM) and colonic scintigraphy showing fair agreement between the 2 modalities in the categorization of constipation, confirming that scintigraphy should be part of the management of refractory constipation (48).
In 2005, a task force committee stated “the scintigraphic method is the only one that reliably allows the determination of both total and regional transit times” (36). In a position paper published in 2011, the American and European Neurogastroenterology and Motility Societies recommended the use of colonic scintigraphy for assessing colonic transit in patients with constipation, despite its limited availability (49).
In summary, despite the disadvantages related to the lack of standardization, the wide range of normal values and its limited availability, colonic scintigraphy should be considered as the most sensitive noninvasive method for the evaluation of colonic motility disorders.
Anorectal manometry (ARM) is a commonly performed test in infants and children with defecation disorders providing an assessment of sensorimotor activity of the rectum and anal region (50). ARM allows direct measurement of anal resting pressures, anal relaxation upon balloon distension (recto-anal inhibitory reflex, RAIR) and squeeze pressures, which predominantly reflect internal and external anal sphincter function respectively. It also indirectly assesses defecation dynamics by measuring the recto-anal pressure gradient during straining and by the rectal balloon expulsion test. ARM is best conducted in a laboratory with the necessary technical and interpretative expertise. Anal resting pressure and RAIR should be always assessed and can be performed either awake or under sedation, during the test. Squeeze pressure and the recto-anal pressure changes during defecation attempt should also be evaluated when an evacuation disorder is suspected, but they require the child's active participation (Supplemental Table 5, Supplemental Digital Content 6, http://links.lww.com/MPG/B244). Indications for ARM include exclusion of Hirschsprung disease (HD), characterized by a nonrelaxing internal anal sphincter (Supplemental Figure 2, Supplemental Digital Content 7, http://links.lww.com/MPG/B245), assessment of fecal incontinence or conversely rectal outlet obstruction as well as the postsurgical assessment of anorectal motility in persistently symptomatic children previously operated for HD or imperforate anus. ARM may also help guide anal treatments, such as the botulinum toxin injection in children with a hypertensive or poorly relaxing anal sphincter (51). In children >1 year, ARM shows similar a diagnostic accuracy to suction rectal biopsy in the diagnosis of HD with a sensitivity of 91% and specificity of 94%. In infants (<1 year of age), however, it is less reliable with an error rate up to 26%, making a rectal biopsy mandatory (52,53). Although ARM can be done in children of any age, older children (usually >5 years) are typically able to cooperate with the sensory testing and dynamic components of the test (squeeze and bear-down maneuvers). Thus, for younger patients, ARM analysis is usually limited to anal sphincter resting pressure and RAIR assessment. Patients are usually encouraged to defecate before the study. If fecal impaction is suspected, an enema or suppository is used to prevent stool interference. Typically, as infants have soft stool no preparation is necessary, stressing again the limited utilization of this test in this age group.
Recent years have witnessed considerable advancements in ARM technology, with conventional water-perfused systems gradually being replaced by high-resolution (HRARM) and 3D high-definition manometry (HDARM).
Water-perfusion system consists of a flexible PVC catheter (diameter 3.5–7 mm) with 4 to 12 side holes circumferentially/spirally arranged and a central channel for balloon inflation, connected to perfusion apparatus with a pneumo-hydraulic pump. Newer solid-state manometric systems use high-resolution catheters with multiple closely spaced sensors (usually 36 sensors spaced at 0.5–1 cm intervals) allowing radial acquisition of pressure data. Data from HRARM can be displayed as topographical plot of intraluminal pressure rather than overlapping line traces (54). Given that catheters with outer diameters <5 mm are available, HRARM can, in theory, be done at any age.
In adults, the recent advent of HDARM has allowed for the first-time detailed assessment of pressure distribution in the anal canal (55). HDARM has 256 microtransducers distributed circumferentially 3 mm apart and provides topographical and three-dimensional (3D) pressure gradient representation of the anal canal. In adults, HDARM measurements correlate with anatomic structures defined by magnetic resonance imaging (MRI) or 3D-ultrasound (56). Therefore, HDARM allows better definition of the contribution of different components of the anal canal including the puborectalis muscle and the external and internal anal sphincters. Moreover, it evaluates the radial asymmetry of the anal canal, which could not be detected with 2D high-resolution manometry. This highly integrated method therefore allows for 3D dynamic representation of pressure changes within the anal canal both radially and longitudinally (56). These observations could have a major impact on the future evaluation of patients with incontinence and may provide a better data and disease classification to inform optimal therapeutic options. Currently, 3DHRAM uses a catheter with an outer diameter of almost 11 mm, which in theory could be used in infants. The linear relationship between catheter outer diameter and intraluminal anal pressure reading (Laplace's law), however, may result in the anal resting pressure being overestimated and anal canal dynamics upon balloon distension being misinterpreted. Although 3DHRAM has been used in children aged 2 years the technology is still in its infancy and likely to become more refined with time including the development of tools specifically designed for young children.
Despite its extensive use in clinical practice, validated, and reproducible ARM values for children are lacking. A number of different studies involving healthy subjects from varying pediatric age groups have provided baseline data on ARM (Table 1) (57–65). Recently, Banasiuk et al (65) determined normative values from HDARM analysis in a prospective study on 61 healthy children (mean age: 8.28 years, range: 2–17 years). The small sample size and heterogeneity in equipment and methodology used in the various studies, however, do not allow for reliable normative data for children. Moreover, it is always important to correlate the findings with symptom presentation.
Overall, ARM has been found to be a safe test with rare adverse effects. A small risk of colonic perforation exists; therefore, care should be taken in the placement and removal of probes. To minimize this risk, ARM should not be performed in children with significant bleeding and severe distal colonic/anorectal inflammatory disorders.
CM provides both a qualitative and quantitative assessment of colonic motor function by measuring intraluminal pressures and coordination of colonic muscle pressure activity (50,66). The 2008 consensus statement from the American Neurogastroenterology and Motility Society recommended the use CM in children and adults with intractable constipation with evidence of STC in the absence of an evacuatory disorder (67). Moreover, the latest joint ESPGHAN and NASPGHAN guidelines suggest that CM may be indicated in patients with intractable constipation before considering surgical intervention (4). An updated overview about technique, interpretation, and indications in children has recently been published by NASPGHAN (50). Nonetheless, the use of CM is far from routine and remains limited to few specialized centers around the world (68).
During the last decade, manometric techniques have sensibly improved from few pressure-recording channels to the development of high-resolution manometry, enabling more detailed definition of colonic segments and pressure data to be presented as color topographical maps (68). The catheter type, number of recording sites, and spacing between sensors differ among centers. Currently, there are 2 different types of CM catheters available on the market: water-perfused and solid-state catheters (Supplemental Table 6, Supplemental Digital Content 8, http://links.lww.com/MPG/B246). Under anesthesia, the catheter is placed into the colon either endoscopically or using fluoroscopic guidance. During endoscopic placement, the catheter tip may be fixed to the right colon wall using 1/2 hemostatic clips to minimize catheter dislodgment. A plain x-ray is ideally performed at the beginning and end of the recording to confirm the position of catheter. The recording is usually started 2 to 4 hours after the placement, when the patient is fully awake. Recent data, however, suggest that in children with abnormal results on the day of catheter placement the test should repeated the following day given what appear to be significant effects on colonic function and therefore overall interpretation of the study presumably secondary to the anesthetic and/or instrumentation (69). With regard to the actual procedure the CM recording is usually carried out 1 hour before and after a combined semisolid test meal (20 kcal/kg), and 1 hour after the delivery of 1 or 2 pharmacologic stimuli into the colon.
High-amplitude propagated contractions (HAPCs) are the most distinctive and best-studied components of colonic motor activity (70). HAPCs are defined as colonic contractions greater than 75 mmHg in amplitude (from 50 to 116 mmHg according to different studies) migrating ab-orally for at least 15 cm (60–74). HAPCs do not to propagate beyond the distal sigmoid colon and often associated with anal relaxation (colo-anal reflex) (74). They may occur spontaneously or in response to a meal, to pharmacological stimulation (bisacodyl, neostigmine, or other colonic irritants) or colonic distention (70,75,76). HAPCs have been considered the most important marker of colonic neuromuscular integrity and their absence after stimulation taken to imply significant dysfunction of colonic motility. Based on their propagation HAPCs are classified as fully propagated (reach the sigmoid colon; Fig. 3A and B), partially propagated (do not progress beyond the splenic flexure or descending colon; Fig. 3C and D) or absent (no contractions recorded along the whole colon; Fig. 3E and F) (74–78). HAPCs can be also classified as normal and abnormal based on the morphology of the pressure waves within sequences (71). Interestingly, in children with refractory constipation Koppen et al (79) found that the progression of HAPCs is inversely correlated to the diameter of colonic segments, and segmental colonic dilation was associated with premature ending of HAPCs.
Pharmacologic provocation during CM has become a routine tool for assessing colonic neuromuscular integrity (80–82). It is usually performed with bisacodyl, which is intraluminally infused either into the proximal colon through the central channel of the catheter (or via an ostomy opening if present), or into the rectum. Despite the attempts to define standard protocols, the ideal dose of bisacodyl is still undetermined and the test is usually performed with a dose of 0.2 mg/kg (max 10 mg). Recent data, however, suggested that in children with STC a double dose of bisacodyl (0.4 mg/kg, max 20 mg) increased the number of HAPCs, improved their propagation toward the distal colon and sharpened their morphology, suggesting that higher doses may be more useful in definitively assessing colonic residual motor function (83).
Upon neural and hormonal stimulation, normal colonic activity increases throughout the colon within few minutes after the meal and continues for up to 2½ hours depending on meal composition and caloric content (50). The absence of this gastrocolonic response to a meal could be indicative of abnormalities of the enteric nervous system (50). Another colonic motor pattern, characterized by a less vigorous propulsive activity (amplitude <45 mmHg) are low-amplitude propagating contractions (LAPCs), occurring 45 to 120 times per day, more often during the daytime after meals and upon waking (70,84). Their function as well as the significance of other colonic motor patterns, such as the absence of motor quiescence between bisacodyl-induced HAPSs, antegrade and retrograde cyclic propagating motor patterns, short single antegrade and retrograde events, and pre- and post-prandial long-single contractions is, however, still unknown (70,84–86).
In clinical practice, CM has been proven to have a significant impact on the diagnosis and management of constipation in children. Indeed, the identification and location of colonic motor dysfunction may provide useful information for therapeutic decision-making (50,80). CM is useful in discriminating between FC and intrinsic colonic dysmotility, in helping to plan surgical interventions in selected patients with constipation refractory to medical therapy, in determining whether a diverted colon may be re-anastomosed, in assessing improvement of colonic dysmotility after long-term use of antegrade colonic enemas, and in evaluating persistent symptoms following surgery, specifically for HD and anorectal malformations (73,77,81,87–89).
In conclusion, CM has become a routine diagnostic test in children with defecatory disorders with clear indications and standardized interpretation, and the advent of high-resolution technology is allowing physicians achieve a more in-depth understanding of the physiology/pathophysiology of colonic motor disorders.
MAGNETIC RESONANCE IMAGING
MRI may be used to rule out the presence of lumbosacral spine (LSS) abnormalities. Few studies have been performed to quantify the incidence of spinal malformations in children with defecation disorders. In a retrospective study, Rosen et al (90) found LSS malformations in 9% of children with intractable constipation not associated with major neurologic symptoms. Later, Bekkali et al (91) prospectively evaluated 130 children with intractable constipation and 28 with nonretentive fecal incontinence undergoing MRI and found LSS malformations in only 3% of children, none of which had clinical neurological features.
MRI should not be included in the routine workup of children with chronic constipation, whereas it should only be considered when there is strong suspicion of neurologic disorders, such as neurological findings in the lower extremity and midline defects in the skin over the lower back and gluteal cleft manifestations. In conclusion, no evidence supports the use of spinal MRI in patients with intractable constipation without other neurologic abnormalities (4).
WIRELESS MOTILITY CAPSULE
The wireless motility capsule (WMC) is a novel radiation-free device that provides a comprehensive assessment of gastrointestinal transit and motor function. It allows simultaneous measurements of intraluminal pH, pressure and temperature throughout the entire GI tract (92).
The WMC system (Smartpill, Medtronic, Minneapolis, MN, USA) consists of a single-use capsule (26.8 × 11.7 mm), a receiver, and data processing software. The patient ingests the capsule just before a standardized meal and is then discharged wearing the recording device for 3 to 5 days or until the capsule is excreted.
Characteristic patterns of temperature and pH are used to track the capsule throughout the GI tract (time of arrival into the stomach, small intestine, cecum, and eventual exit from the body). This information allows the determination of gastric emptying time (GET), small bowel transit time, CTT, and whole gut transit time (WGTT). In adults, normative values for these parameters have been determined to be 2 to 5 hours (GET), 2 to 6 hours (small bowel transit time), 10 to 59 hours (CTT), and 10 to 73 hours (WGTT) (93).
Clinical trials in adults have shown that CTT assessed with WMC is comparable with that assessed by ROM tests in both healthy and constipated subjects (94,95). In a study on 10 healthy adults who underwent simultaneous whole gut scintigraphy and WMC, good correlation was reported in both GET and WGTT (96). Although WMC has been used to measure contractility pressures in different segments of the gastrointestinal tract in constipated adults (97), its utility in measuring the contractile activity is limited by the presence of a single pressure sensor. Only 1 study has explored the feasibility of WMC in children referred for gastric scintigraphy and antroduodenal manometry for severe upper gastrointestinal symptoms. The WMC test was found being highly sensitive in detecting gastroparesis and more sensitive than antroduodenal manometry in detecting motor abnormalities (98). To date, no studies have been conducted on constipated children.
Although WMC could be considered an alternative tool in evaluating whole gut transit and colonic transit, its role in the routine clinical evaluation and management of children presenting with possible colonic dysmotility is still undetermined. The main drawback of WMC in children could be the practical difficulty of getting them to swallow the capsule as well as the possibility of capsule retention, especially in young children.
The rectal barostat is a valuable tool for assessing rectal muscle tone, pressure-volume relationships, and sensory thresholds (99). It is an electromechanical computer-driven air pump connected to a highly compliant balloon placed in the rectum and its principle relies in maintaining a constant pressure within an air-filled bag placed in the rectum. When the rectum contracts, the barostat aspirates air to maintain a constant intrabag pressure and when the rectum relaxes, air is injected into the barostat bag. The volume of air entering or leaving the bag is an indirect measurement of rectal tone changes. By using a pressure-controlled distending protocol, thresholds for sensation (first sensation, urge to defecate, and pain) can be determined. Different protocols have been used to determine visceral sensory threshold, with the ascending method being the most applied in children. It consists of delivering phasic intermittent stimuli of progressively increasing pressures (2–4 mmHg per step) until perceived by the subject. This method may be influenced by psychological bias (fear of pain) because the stimuli are predictable to the subject. To overcome this limit, further distension pressure sequences can be randomly delivered depending on the response of the previous distension (tracking technique). Although the tracking technique is less prone to psychological bias and allows multiple determinations rectal sensitivity threshold, it may transmit multiple painful stimuli that are less acceptable in children (100,101).
Although it was hypothesized that constipated children required higher threshold to trigger rectal sensation, more recent data using the barostat show that only a small proportion of patients have true rectal hyposensitivity (101,102). The barostat can also be used to assess rectal tone and compliance, which is defined as the ability to stretch (expand) in response to an imposed force and expressed as a pressure-volume relationship (mL/mmHg). It has been shown that although rectal compliance is higher in constipated adolescents compared to those who recovered from constipation, almost half of recovered subjects still had increased rectal compliance (103). Moreover, constipated children with significant increases in rectal compliance have more severe symptoms, and emptying the rectum by a regular use of enemas does not appear to improve rectal compliance (103).
Although the use of the barostat has increased our knowledge of the role of rectal sensitivity and compliance in the pathophysiology of defecatory disorders, its use is still limited to the research setting.
Considerable progress in assessing colonic and anorectal sensory-motor function has been achieved in the last decades. Although the majority of children with constipation do not require any diagnostic testing, the use some of the tests described above should be considered mainly for those children who are refractory to conventional treatment, as their judicious use may provide invaluable insight into underlying physiopathology and in turn help inform optimal management of these challenging conditions.
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