Recommendations for the management of gastrointestinal comorbidities with or without trofinetide use in Rett syndrome

ABSTRACT

Introduction

Although gastrointestinal (GI) comorbidities are experienced by over 90% of individuals with Rett syndrome (RTT), a neurodevelopmental disorder associated with mutations in the MECP2 gene, many neurologists and pediatricians do not rank the management of these comorbidities among the most important treatment goals for RTT. Trofinetide, the first approved pharmacologic treatment for RTT, confers improvements in RTT symptoms but is associated with adverse GI events, primarily diarrhea and vomiting. Treatment strategies for GI comorbidities and drug-associated symptoms in RTT represent an unmet clinical need.

Areas covered

This perspective covers GI comorbidities experienced by those with RTT, either with or without trofinetide treatment. PubMed literature searches were undertaken on treatment recommendations for the following conditions: constipation, diarrhea, vomiting, aspiration, dysphagia, gastroesophageal reflux, nausea, gastroparesis, gastritis, and abdominal bloating.

Expert opinion

The authors recommend a proactive approach to management of symptomatic GI comorbidities and drug-associated symptoms in RTT to enhance drug tolerance and improve the quality of life of affected individuals. Management strategies for common GI comorbidities associated with RTT are reviewed based on authors’ clinical experience and augmented by recommendations from the literature.

KEYWORDS:

• Aspiration
• constipation
• diarrhea
• dysphagia
• gastroesophageal reflux
• Rett syndrome
• trofinetide
• vomiting

1. Introduction

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder associated with mutations in the MECP2 gene that occurs in about 5–10 per 100,000 females [1–3]. Common features of RTT are loss of purposeful hand use and verbal communication skills along with limited nonverbal skills, impaired motor skills, seizures, and behavioral and gastrointestinal (GI) issues [1,4,5]. Most individuals with RTT experience a period of developmental stagnation around the ages of 6–18 months, which is then followed by a rapid developmental regression around the ages of 1–4 years and then a plateau period that may last for decades [6–8].

GI comorbidities are common in individuals with RTT. A survey from the North American RTT family database found that GI problems were reported by 92% of 983 caregivers of children and young adults with RTT [4]. The most common GI comorbidities reported were those related to GI dysmotility, including gastroparesis (14%), intolerance to feeds (27%), constipation (80%), gastroesophageal reflux (39%), and oropharyngeal dysphagia (43%) [4]. The dysautonomia (autonomic dysfunction) present in individuals with RTT leads to many of these GI issues, including aerophagia resulting in abdominal bloating and disorders of GI dysmotility [9,10]. Despite the almost universal occurrence of GI comorbidities in individuals with RTT and their effect on quality of life [4,11], most neurologists and pediatricians do not rank GI comorbidities in their top 5 most important treatment goals for RTT [12].

Trofinetide, a synthetic analog of a tripeptide (glycine-proline-glutamate) enzymatically cleaved from the N-terminus of insulin-like growth factor-1 [13], was approved in March 2023 by the US Food and Drug Administration for the treatment of RTT in adults and children aged ≥2 years [14]. In the randomized, double-blind, placebo-controlled, phase 3 LAVENDER study of girls aged 5–20 years [15], clinically meaningful and statistically significant treatment benefits were observed for trofinetide versus placebo. Clinically meaningful effects were seen in the caregiver-reported Rett Syndrome Behaviour Questionnaire (p = 0.0175) and the clinician-reported Clinical Global Impression – Improvement (CGI-I; p = 0.0030) at week 12 for trofinetide versus placebo. The open-label, phase 2/3 DAFFODIL study established the safety and tolerability of trofinetide in girls aged 2–4 years [16] similar to that seen in LAVENDER. Exploratory efficacy results in the DAFFODIL study showed that the CGI-I score improved over time from week 2 to week 12. The most commonly reported treatment-emergent adverse events (TEAEs) with trofinetide in the clinical trials at week 12 were diarrhea (80.6% in LAVENDER, 73.3% in DAFFODIL) and vomiting (26.9% in LAVENDER, 46.7% in DAFFODIL) [15,16]. Diarrhea was the main TEAE leading to discontinuation of trofinetide in the LAVENDER trial (12/93; 12.9%). One (1/15; 6.7%) participant discontinued the DAFFODIL trial because of diarrhea [16].

In the authors’ experience, the most common responses to trofinetide treatment were improvements in alertness, gross motor function (eg, gait stability), and use of the Tobii eye tracking device. The majority of individuals receiving trofinetide experienced meaningful changes in several areas that resulted in caregivers continuing the medication when provided with adverse event management strategies, as evidenced by the clinical trial data.

GI comorbidities are common in individuals with RTT regardless of treatment with trofinetide. Here we present recommendations for the management of symptomatic GI comorbidities, spanning from those commonly found in individuals with RTT to those reported with trofinetide treatment.

2. Management recommendations for GI comorbidities in RTT, including during trofinetide treatment

The general considerations for GI management in RTT include symptom-directed evaluation and diagnosis, attention to nutrition, and proactive management of symptoms before initiating trofinetide therapy. In addition to providing the individual with RTT a better quality of life, this approach may enhance tolerance if the individual initiates treatment with trofinetide. Comprehensive strategies for managing GI conditions should be used, as several GI comorbidities in RTT can contribute to the intolerance of trofinetide. For each GI comorbidity seen in RTT, it is useful to establish the goal(s) of therapy with the caregivers. An example goal for an individual with constipation may be 1 bowel movement per day. GI comorbidities in RTT frequently require primary management and/or referral to a gastroenterologist, dietitian, and/or a speech, occupational, or feeding therapist. A summary of recommendations for GI management in individuals with RTT is provided in Table 1.

Table 1. Summary of recommended treatments for gastrointestinal comorbidities in RTT. First-line treatment options are noted in boldface.

Management strategy/treatment	GI comorbidity
	Consti pation	Diarrhea	Vomiting	Aspiration	Dysphagia	Gastroesophageal reflux	Nausea	Gastroparesis	Gastritis	Abdominal bloating
Feeding strategies
Dietary fiber, fiber supplements	x	x	x
Upright, seated position for feeding			x	x	x	x
Thickening agents, pureed foods				x	x	x
Monitor hydration	x	x	x		x
Smaller feeds/meals			x	x	x	x
Strategic placement of food in the mouth to aid chewing/swallowing				x	x
Small bites of food followed by liquids				x	x
Modification of diet to reduce foods that cause gas										x
Pharmacotherapy
Laxatives	x									x
Suppositories	x
Enemas	x
Discontinue/reduce laxatives		x
Loperamide		x
Antiepileptic drugs*			x
Proton pump inhibitors			x			x			x	x
H2 receptor blockers			x			x			x
Prokinetic agents^†			x			x		x		x
Ondansetron^†			x				x
Antacids						x			x
Antibiotics										x
Triple or quadruple therapy for H. pylori infection									x
Digestive aids^‡										x
Anti-gas medications										x
Specialists
Gastroenterologist	x	x	x	x	x	x	x	x	x	x
Feeding therapist				x	x
Occupational therapist				x	x
Speech therapist				x	x
Surgery
Fundoplication						x
Gastrostomy tube placement				x	x
Gastrojejunostomy tube placement			x	x	x	x		x
LINX Reflux Management System placement						x
Other
Gastrostomy tube venting										x
CPR training for caregivers				x
Herbal remedies							x			x
Raising head of bed						x
Specific to trofinetide treatment
Reduce, divide, or titrate trofinetide dose		x	x
Switch any concomitant medications with sugar alcohols to pill form if possible		x
Reduce liquid volume before and after trofinetide administration			x
Experiment with timing trofinetide dosing closer to or farther from mealtimes			x				x

*To maintain control of seizures.

^†Should be avoided in individuals with long QT syndrome.

^‡Lactaid, Beano.

CPR = cardiopulmonary resuscitation; GI = gastrointestinal; RTT = Rett syndrome.

2.1. Constipation

Constipation is the most common GI comorbidity associated with RTT, occurring in approximately 80% of individuals [4]. At study baseline, 77.0% (144/187) of participants in the LAVENDER study [15] and 66.7% (10/15) of participants in the DAFFODIL study had a history of constipation. In fact, constipation is one of the top 5 concerns of caregivers of participants in the US Natural History Study of RTT [17], which is notable given the large number and range of RTT-related symptoms. Given the predilection of trofinetide to cause diarrhea, it is not surprising that constipation symptoms frequently improve with trofinetide, with no reports of constipation as a TEAE in the trofinetide group in the LAVENDER trial and 1 report in the DAFFODIL trial over 12 weeks.

The authors recommend initiating a dialogue to educate caregivers on appropriate bowel habits and goals and a plan on how to accomplish them. Initial recommendations for the management of constipation are to increase dietary fiber intake (fruits such as avocado or berries, vegetables such as peas, and certain types of beans) and/or fiber supplements (psyllium, wheat dextrin, flaxseed), and to ensure adequate fluid intake [9,18–20]. Increased physical activity is often recommended for constipation [9,20,21], but this may be difficult given the prevalence of mobility issues in those with RTT. Laxatives usually are required, with osmotic laxatives, including polyethylene glycol (macrogol), magnesium products, and lactulose, generally recommended as initial treatment [9,18,19,22–24]. Stimulant laxatives include sennosides (senna glycoside) and bisacodyl, both of which reduce colonic transit time and increase the water content of the stool [19,22,24–26]. Prescription secretagogue laxatives [19,22,24], including lubiprostone (chloride channel activator) [27], plecanatide (guanylate cyclase-C agonist) [28], and linaclotide (guanylate cyclase-C agonist) [29], are FDA-approved for the treatment of chronic idiopathic constipation in adults. Linaclotide also is approved for functional constipation in children older than 6 years of age [29]. Prucalopride (a serotonin-4 receptor agonist) is a prescription prokinetic laxative approved for the treatment of chronic idiopathic constipation in adults [22,24,30]. Vibrant, a drug-free prescription capsule that sends micro-vibrations to the colon, can be used in adults [31]. Suppositories, including those with glycerin, bisacodyl, or docusate, may be used, as can enemas [9,19,22,23].

In general, when choosing an effective treatment for constipation, there must be consideration for the likely mechanism of constipation. Those with hard stools will require some degree of stool softening to help lubricate the stool for ease of evacuation, which can be accomplished with osmotic laxatives. In cases where there may be inadequate ‘push,’ the addition of a stimulant laxative or a prokinetic agent can be helpful. In patients who develop tachyphylaxis with daily use of a stimulant laxative, intermittent dosing (ie, 2 or 3 days per week) may be considered. In addition, rectal evacuation dysfunction (dyssynergic defecation) can be present, and a suppository or enema may help to stimulate bowel movements. In addition, there has been some success with the use of anal sphincter botulinum injection in children, and this approach could be considered for refractory cases of dyssynergia [22,32]. Finally, surgical cecostomy placement, partial colonic resection, or ileostomy placement has been performed for intractable obstipation [19,24,33–36].

The use of probiotics for the treatment of constipation is controversial. Current studies differ in probiotic species or strains, doses, and/or duration of treatment, as well as the definition of treatment success [37,38]. Although there is not enough evidence to support the universal use of probiotics for constipation in children [23,37–40], in the authors’ experience, some parents report favorable outcomes with their use.

Many individuals with RTT who initiate treatment with trofinetide experience diarrhea, even those with prior constipation. Thus, caregivers should be advised to reduce or discontinue constipation medications at the time of trofinetide initiation. (See expanded discussion in the diarrhea section below.)

2.2. Diarrhea

Diarrhea is rare in individuals with RTT in the absence of trofinetide treatment. In a cohort of individuals with RTT from US claims databases, 5.7% (340/5940) reported diarrhea [12], and 3.2% (6/187) of LAVENDER trial participants had a history of diarrhea at trial baseline. Paradoxical diarrhea may occur in the presence of fecal impaction due to overflow incontinence [20,24,41]. Such occurrences may be mistaken for diarrhea and can worsen with treatments that further loosen stools.

Diarrhea was the most common TEAE in the phase 3 trofinetide clinical trials, with 80.6% (75/93) reporting diarrhea in the trofinetide group in the LAVENDER trial [15] and 73.3% (11/15) in the DAFFODIL trial [16], both over 12-week treatment periods. Most cases were of mild or moderate severity (97.3% in LAVENDER and 100% in DAFFODIL) [15,16]. In the LAVENDER trial, 12.9% (12/93) in the trofinetide group discontinued treatment owing to diarrhea [15]. Diarrhea was less common in the phase 2 trials of trofinetide for RTT (11–56%), but lower doses of trofinetide were used [42,43]. Exposure-response modeling has shown a higher probability of diarrhea with trofinetide from treatment initiation to 12 hours after dose administration. While data on the time to diarrhea in terms of hours is not available from the clinical trials, 68.3% of those with diarrhea had their first episode a median of 5 days after their first dose of trofinetide. Diarrhea occurred on average about 1 week (range, 1–49 days) after starting trofinetide in the LAVENDER trial [44]. No demographic, disease, or other characteristics were found to affect the development of diarrhea TEAEs with trofinetide treatment [44].

The cause of diarrhea with trofinetide use is unknown but may be caused by the presence of maltitol in the current formulation of trofinetide [14]. Maltitol is a sugar alcohol that is broken down in the intestines into glucose and sorbitol, thereby increasing the osmotic load in the colon [45,46]. It also is of interest to speculate that trofinetide may have a neuroendocrine effect in the gut, similar to glucagon-like peptide-1 receptor agonist (GLP-1 RA) drugs, which may cause diarrhea or constipation [47].

The possibility of diarrhea should be explained to families as part of a risk-benefit discussion on starting trofinetide. Recommendations on the management of diarrhea with the use of trofinetide have been published for healthcare providers [44] and in a plain-language format for caregivers [48]. In brief, these recommendations are: obtain a 7-day diary of bowel activity before initiation of trofinetide; on initiation of trofinetide, reduce or stop constipation medications, switch any concomitant medications with sugar alcohols to pill form if possible, and add fiber supplements such as psyllium, pectin, wheat dextrin, or flaxseed; on the occurrence of diarrhea, initiate oral loperamide and ask the caregiver to track consistency and frequency of bowel movements.

For diarrhea that persists despite the discontinuation of constipation medications, as well as the addition of dietary fiber and/or fiber supplements and antidiarrhea medications such as loperamide, consider a 50% dose reduction of trofinetide that may be titrated back up to the full dose once diarrhea is resolved [14]. Another approach is to reduce the dose of trofinetide to the previous dose used before the occurrence of diarrhea. The authors also have found that dividing the dose of trofinetide from twice daily to 3 or even 4 times daily resulted in decreased diarrhea, presumably because the osmotic load within the intestine is reduced with divided doses. Finally, another author has found that feeding rice cereal along with trofinetide reduces diarrhea in some individuals. Rice cereal appears to allow greater maltitol/sorbitol absorption, perhaps by slowing transit in the small intestine, similar to a study that found a suppressive effect of soluble and insoluble dietary fiber on osmotic diarrhea in humans [49] and a study in which rice gruel and starch reduced sorbitol-induced diarrhea in rats [50]. Nevertheless, a regular diet should be continued for individuals who are not dehydrated. Dehydration should be monitored, and constipation medications can be resumed as needed if there has been no bowel movement for 24 hours [44].

An alternative approach to mitigate the development of trofinetide-related diarrhea could be to initiate trofinetide at a lower dose and gradually titrate up to a higher dose over the course of several weeks. Titrating the trofinetide dose could help clinicians find the dose that maximizes trofinetide benefit while reducing the incidence of diarrhea or rendering it more manageable. Trofinetide dose modifications were common in the phase 3 clinical trial program. This titration strategy has been reported in the phase 4 observational LOTUS study of trofinetide treatment for RTT in the real world (data on file). Clinicians are encouraged to follow their patients for a longer period of time (at least 6 months) to find a dose that balances tolerability and treatment benefits.

2.3. Vomiting

The prevalence of vomiting in individuals with RTT has been reported at 10% from the North American RTT family database [4]. In addition, 10.7% (636/5940) of a cohort of individuals with RTT from US claims databases had vomiting or regurgitation [51]. At baseline in the LAVENDER and DAFFODIL trials, 2.1% (4/187) and 13.3% (2/15) of individuals, respectively, had a history of vomiting. While the authors agree that the prevalence of vomiting in their patient populations is consistent with these trends in the literature, they note that vomiting may be underreported, as families frequently determine their own methods of management and may not mention vomiting at office visits. Furthermore, there is uncertainty among families and clinicians for what constitutes vomiting (eg, spit-up, retching, reflux), particularly when tube feeds are involved [52,53].

In the trofinetide clinical trials, vomiting was the second-most commonly reported TEAE over 12 weeks, with 26.9% (25/93) in the LAVENDER trial [15] and 46.7% (7/15) in the DAFFODIL trial [16]. Most cases were of mild or moderate severity (96.0% in LAVENDER and 100% in DAFFODIL). One participant in the trofinetide group of the LAVENDER trial and 1 participant in the DAFFODIL trial discontinued treatment due to vomiting [15,16]. As with diarrhea, lower rates of vomiting (0–22%) were observed in the phase 2 trials, which used lower doses of trofinetide [42,43]. Exposure-response modeling has shown a higher probability of vomiting with increasing maximum concentration (C_max) of trofinetide. Whereas the amount of time to vomit following administration of trofinetide is not known in minutes or hours, 40.0% of those in the clinical trials who vomited had their first occurrence of vomiting a median of 5 days from the first dose of trofinetide, and 26.7% vomited for the first time within 15 days from the first dose. The cause of vomiting with trofinetide use is unknown. However, it is of interest to speculate that trofinetide may have a neuroendocrine effect in the gut, similar to GLP-1 RA drugs, which also may be associated with nausea and vomiting due to delayed gastric emptying (gastroparesis) [47].

When considering initiation of trofinetide treatment, families should be informed about the risk of vomiting as part of the overall risk-benefit discussion on starting a new drug. Management of vomiting with trofinetide typically has been reactive rather than proactive because vomiting in RTT in the absence of trofinetide is not common. In the authors’ experience, vomiting events with trofinetide may be decreased in individuals with well-managed upper GI comorbidities. Individuals with RTT who are more likely to experience vomiting with trofinetide may include those with gastroesophageal reflux, gastroparesis, abdominal bloating, dysphagia, or other GI issues at baseline; a history of feeding or formula volume intolerance; or vomiting as a result of seizures. Seizures are common in individuals with RTT, with a reported prevalence of 81% [4], and may lead to vomiting, so it is important to maintain seizure control with antiseizure medications. Of note, vomiting has been an issue with both oral and gastrostomy tube (G-tube) administration of trofinetide, with rates of 27.3% (15/55) in those who received trofinetide orally and 26.3% (10/38) in those who received it via G-tube. Nevertheless, because the response to trofinetide is highly individualized, it is recommended that trofinetide-induced vomiting be considered in all symptomatic individuals with RTT.

For the management of vomiting in individuals with RTT, it must first be determined whether it is caused by gastroesophageal reflux or a different underlying problem before trofinetide administration. Reflux may be characterized as having less effort than vomiting and is not always acid-related. An upright position during feedings (and trofinetide administration, if being treated) should be used [54]. Smaller feeds to reduce gastric volume may be considered [54]. Acid suppression with proton pump inhibitors (PPIs) may be used in an effort to reduce discomfort, the amount regurgitated, or feeding intolerance. In cases where impaired motility is suspected, prokinetic agents can be considered [55], but it should be noted that some of these medications such as erythromycin may cause prolongation of the QT interval [52,56,57] and thus may not be advisable for some individuals [9,58,59]. In individuals with a G-tube and prolonged and uncontrolled vomiting, slower rates of feeds may be helpful, and the G-tube may need to be replaced with a gastrojejunostomy (G-J) tube to bypass feeds going to the stomach [18], though trofinetide should be administered through the G-port [14]. Note that when dysmotility is suspected, constipation management should be optimized since ongoing constipation may be associated with vomiting as well [53]. Pharmacologic interventions for vomiting include antiemetic agents. A trial of an antinausea medication such as ondansetron may be pursued if necessary [55,60].

In the event of vomiting with trofinetide treatment, management approaches include reducing the volume of liquids before and after trofinetide administration and reducing or dividing the dose of trofinetide. Note that an additional dose of trofinetide should not be taken if vomiting occurs after administration of trofinetide; rather, treatment should continue with the next scheduled dose [14].

It is unclear whether the timing of meals relative to trofinetide treatment influences the likelihood of vomiting. The clinical experience of the authors suggests that vomiting can occur soon after dosing and can be impacted by a recent meal. Some individuals tolerated the administration of trofinetide but vomited 10–15 minutes later. There has been some success in managing vomiting episodes by reducing meal volume and/or separating trofinetide administration further from mealtime. The original protocol of the LAVENDER trial stipulated that participants should not eat 1 hour before or after administration of trofinetide. However, several caregivers found that drug administration closer to breakfast and dinner seemed to reduce vomiting in their children on trofinetide, and the trial protocol was later modified to remove the eating restrictions on trofinetide administration [61]. Thus, the vomiting response to trofinetide relative to meals appears to vary by the individual. Anecdotally, some parents have found a reduction in vomiting by mixing trofinetide with food.

One author reported that there is a subset of individuals who become irritable and vomit 2–3 hours following a dose of trofinetide. This appears to be due to a different mechanism than those who vomit closer to trofinetide administration, possibly hypoglycemia or gastroparesis. In rare cases, intractable vomiting has occurred following each trofinetide dose and with rechallenges. For this problem, the authors advise discontinuation of trofinetide and ensuring that the individual is well hydrated. Unlike other medications, such as antiseizure medications, trofinetide can be stopped abruptly. The possible non-trofinetide triggers of vomiting, such as reflux, timing of dosing with other liquids, etc., should be well managed, and then the individual can be rechallenged with trofinetide at a lower dose.

2.4. Aspiration

The prevalence of aspiration in individuals with RTT is unknown. Reports in the literature all studied a small number of individuals (<25 per study). Of these, 15.0% [62], 61.5% [63], 72.7% [64], and 78.3% [65] of individuals with RTT aspirated with liquids, as measured via fiber optic endoscopy or videofluoroscopy. One confounding factor is that the identification of the clinical event of aspiration often involves choking and/or later development of pneumonia and/or asthma, while aspiration testing involves imaging. Aspiration rarely occurred in the trofinetide clinical trials, with no cases reported in the phase 2 trials or the DAFFODIL trial and 2 cases of pneumonia aspiration reported in the trofinetide group in LAVENDER. The 2 reported cases were considered to be unrelated to trofinetide use.

Rates of death due to aspiration in individuals with RTT have been reported. Aspiration/asphyxiation was the second-most common cause of death in individuals who had died over a follow-up period of up to 20 years in the Australian Rett Syndrome Database, with rates of 31.6% (18/57), behind lower respiratory tract infection (36.8%; 21/57) [66]. Of 36 girls or women with RTT, 13.9% had a ‘respiratory (with or without aspiration/pneumonia)’ cause of death over a follow-up period of up to 9 years in the US RTT Natural History Study [67].

The risk for aspiration with trofinetide often is discussed in the context of vomiting, and counseling for aspiration should be included in the discussion for families considering trofinetide treatment. Aspiration can occur directly from oropharyngeal contents (food, fluids, or oral secretions) or from reflux and vomiting of gastric contents. To assess for aspiration, clinical feeding evaluations by occupational and/or speech therapists and/or radiographic swallow function studies may be conducted for choking/gagging during feeds and/or frequent respiratory illnesses [59]. When there are concerns for oropharyngeal dysphagia and risk of aspiration, a videofluoroscopic swallow study or fiber optic endoscopic evaluation of swallowing is recommended [18,68,69]. Often through guidance by a speech therapist, thin liquids can be thickened with banana flakes, oatmeal, fiber, or a commercial thickener such as Thick-It [20,59]. Pureed foods and foods of similar consistency such as applesauce or pudding can be served [20]. An upright seated position should be used for feeding [69]. Food may be placed strategically in the mouth to aid in chewing and swallowing, with small bites of food offered followed by liquids. Other feeding techniques may be provided by occupational or speech therapists. For recurrent aspiration, oral feedings may be stopped [20], and a G-tube or G-J tube may be indicated for severe feeding dysfunction [18,20,59]. Cardiopulmonary resuscitation training for parents and caregivers should be encouraged to manage acute episodes.

3. Underlying GI conditions that may contribute to vomiting and/or aspiration

The etiology of vomiting in individuals with RTT is unclear, though there are general GI conditions to consider. Some potential causes include GI conditions (gastroesophageal reflux, gastritis, ulcers, Helicobacter pylori infection, gastroparesis, pancreatitis, biliary tract disease, gastroenteritis, intestinal obstruction) and non-GI conditions (infections, central nervous system disorders [including seizures], metabolic or endocrine disorders) [53,70]. In some cases, vomiting may be a manifestation of an intolerance to feeds, whether it is related to the specific formula, reflux, or gut dysmotility. In addition, some drug-related and formulation-related factors can lead to vomiting, such as unpleasant taste, volume, consistency, excipients used, and drug effect. Age also appears to be a factor, as vomiting appears to be more common in younger individuals [4,51]. Symptomatic vomiting in RTT generally can be ascribed to dysphagia, gastroesophageal reflux, gastroparesis, gastritis, or gas bloating, all of which increase the risk of aspiration.

3.1. Dysphagia

Difficulty swallowing was reported in 43% of individuals with RTT from the North American RTT family database [4]. At study baseline, 4.8% (9/187) of LAVENDER trial participants had a medical history of dysphagia. No TEAEs of dysphagia were reported during the LAVENDER trial, and one participant (6.7%; 1/15) reported dysphagia during the DAFFODIL trial.

Frequent coughing or choking with meals or increased drooling portends swallowing dysfunction in individuals with RTT [18,69]. Evaluation of dysphagia via a videofluoroscopic swallow study or a referral to an occupational, speech, and/or feeding therapist may be recommended [18,69]. Management approaches are similar to those for aspiration, including the use of an upright seated position for eating and administration of medication [18]. Liquids may be thickened and foods pureed. Food should be given in smaller volumes, and adequate hydration should be maintained [69]. Placement of a G-tube or G-J tube may be considered [69]. Of note, trofinetide is to be administered through the G-port in a G-J tube [14].

3.2. Gastroesophageal reflux

Gastroesophageal reflux was reported in 39% of individuals with RTT from the North American RTT family database [4]. In a cohort of individuals with RTT from US claims databases, 18.2% (1079/5940) had gastroesophageal reflux [51]. At baseline, 44.4% (83/187) of participants in the LAVENDER trial had a medical history of gastroesophageal reflux disease, but few participants in the trofinetide group in the LAVENDER trial (3.2% [3/93]) reported gastroesophageal reflux as a TEAE. In the DAFFODIL trial, 33.3% (5/15) had a history of gastroesophageal reflux disease at baseline, and 13.3% (2/15) reported a TEAE of gastroesophageal reflux.

Gastroesophageal reflux can often be identified by the colloquial ‘see it, hear it, or smell it.’ Because individuals with RTT may not be able to effectively communicate the feeling of reflux, caregivers and physicians can take care to observe or smell possible reflux. However, reflux may be silent, requiring a high index of suspicion. Gastroesophageal reflux may be diagnosed by an upper GI contrast study, upper GI endoscopy, or esophageal pH study [52,54,71].

Treatment of gastroesophageal reflux is as per standard of care, beginning with more conservative strategies of giving smaller, more frequent feedings, thickening liquids, and positioning in an upright posture during eating [9,20,52,54,59]. For nocturnal symptoms, elevating the head of the bed may help [9,54,71,72].

Pharmacotherapy of gastroesophageal reflux includes over-the-counter antacids such as aluminum hydroxide/magnesium hydroxide, calcium, or sodium bicarbonate [20,71]. PPIs generally are recommended as first-line treatment [9,18,20,54,71]. H₂-receptor acid blockers could also be considered, though they may be less effective [72,73]. Prokinetic agents may also be used, although some of these drugs may cause prolongation of the QT interval [52,56,57] and thus may not be advisable for some individuals [9,58,59]. Recently, a potassium-competitive acid blocker, vonoprazan, which is more potent and longer-acting than PPIs, was approved for the treatment of erosive esophagitis in adults [74].

If control of reflux is not achieved through pharmacotherapy, a gastroenterologist may order further testing and determine whether gastroparesis is a factor. Individuals with a G-tube may need a G-J tube for uncontrolled reflux [18,52], although trofinetide should be administered through the G-port [14]. Rarely, interventions aimed at enhancing the lower esophageal barrier could be explored. The LINX Reflux Management System, a newer device for adults, is a flexible ring of magnetic titanium beads that is laparoscopically placed on the lower esophageal sphincter to control reflux [75]. Fundoplication surgery, in which the fundus is wrapped around the lower esophageal sphincter, may be considered for reflux unresponsive to medical management [9,18,20,52,54,71].

3.3. Nausea

Because communication difficulties are common in individuals with RTT, they may not be able to relay feelings of nausea to their caregivers. Consequently, no prevalence data on nausea in individuals with RTT were found in the literature, likely due at least in part to the inability to effectively communicate this sensation. In clinical trials, 1 participant in the LAVENDER trial had a history of nausea and 1 participant in LAVENDER reported a TEAE of nausea.

If nausea is suspected in an individual with RTT, antinausea medications such as ondansetron could be considered [55]. However, ondansetron should be avoided in those with long QT syndrome [55,76]. Other approaches to nausea management include altering the feeding/medication schedule and herbal remedies such as ginger [55] or peppermint oil.

3.4. Gastroparesis

Gastroparesis was reported in 14% of individuals with RTT from the North American RTT family database [4]. There were no reports of gastroparesis in the LAVENDER or DAFFODIL trials. Symptoms associated with gastroparesis include postprandial regurgitation, vomiting, or formula intolerance [77]. A radionuclide gastric-emptying scan may be obtained to confirm the diagnosis [77,78].

To manage gastroparesis or decreased gastric emptying, a prokinetic agent such as bethanechol, prucalopride, metoclopramide, or erythromycin (or less commonly, cyproheptadine) may be tried [77,79]. Of note, some prokinetic agents such as erythromycin may prolong the QT interval [56,59] and/or exacerbate diarrhea. The prokinetic agent metoclopramide typically is avoided due to the potential for side effects such as extrapyramidal symptoms [57,80]. A G-J tube may be considered as a replacement for a G-tube [77], although trofinetide should still be administered through the G-port [14]. Referral to a gastroenterologist for gastroparesis is recommended.

3.5. Gastritis

No prevalence data on gastritis in individuals with RTT was found in the literature, and there were no reports of gastritis in the LAVENDER or DAFFODIL trials. Although gastritis may be nonspecific, 2 conditions, H. pylori gastritis and eosinophilic gastritis/esophagitis, warrant further attention. Gastritis usually is associated with abdominal pain or discomfort. Upper endoscopy with biopsy may be required for persistent symptoms.

Nonspecific gastritis may be managed by PPIs [81]; renal issues are not of significant concern with this class of medications, but the time of day and food intake should be considered. H₂-receptor acid blockers may be trialed, but these drugs are less effective than PPIs. Calcium-based antacids may be used for gastritis; they have potential for calcium loading but may help to ameliorate diarrhea. Sucralfate is used if active GI bleeding is present.

Testing for the presence of H. pylori should be considered, followed by triple or quadruple therapy if infection is identified [81,82]. Although it is not generally recommended to screen for H. pylori in the absence of ulcer-like symptoms, it is difficult to be certain of symptoms in nonverbal individuals who can be irritable for unknown reasons. Further, H. pylori infection occurs with much higher frequency in the Hispanic and Black populations [83,84], so screening is especially relevant for Hispanic or Black individuals with RTT. Eosinophilic gastritis/esophagitis may be treated with PPIs or steroids [85]. Referral to a gastroenterologist often is recommended for gastritis.

3.6. Abdominal bloating

Abdominal bloating was found in 42.4–50.0% of individuals with RTT [86–88]. There were no reports of abdominal bloating in the LAVENDER or DAFFODIL trials of trofinetide.

Dietary modification (lactose-free dairy) or dietary aids (eg, Lactaid, Beano) may help in the management of abdominal bloating [89,90]. Possible medications include PPIs, prokinetics, selected antibiotics (metronidazole), anti-gas medications (simethicone), and laxatives [9,89,90]. Herbal products such as peppermint oil, fennel, aloe vera, artichoke leaf extract, chamomile, turmeric, or glutamine may be helpful, but their efficacy remains controversial. For management of bloating in individuals with a G-tube or G-J tube, venting to release pressure is a common practice [9,91], but this procedure may only provide temporary relief of symptoms. During tube feedings, the use of a Farrell bag or 60-mL syringe allows gas to escape.

Individuals with RTT often swallow air (aerophagia) due to anxiety and dysautonomia [9,92], and bloating can result [87,93]. In cases where bloating is the result of air swallowing, one of the authors has found that aggressive venting of the G-tube and large doses of simethicone can be helpful. Simethicone is inert and not orally absorbed, so systemic side effects have not been observed [94]. Adverse events such as mild diarrhea and nausea have been observed at very large doses of simethicone (3–13 times the recommended maximum of 500 mg simethicone in 24 hours) [95].

A referral to a gastroenterologist may be needed for refractory gastric bloating, as other causes of abdominal bloating, such as celiac disease or Giardia infection, may need to be ruled out.

4. Conclusion

GI issues are common in individuals with RTT either with or without trofinetide treatment. The recommendations provided here may ameliorate GI symptoms and lead to improved quality of life in those with RTT as well as in their caregivers. Other published guidelines on managing GI comorbidities in RTT are older and do not incorporate more recent treatments [9], or do not address GI events that may occur with trofinetide treatment [96]. As many GI conditions influence and contribute to other GI conditions, several common strategies emerge, such as the use of certain feeding techniques and drugs. Overall, a proactive approach to the management of GI comorbidities in RTT is recommended. However, addressing GI issues can take time and should not discourage clinicians or caregivers from initiating a trial of trofinetide.

5. Expert opinion

As nearly all individuals with RTT experience GI comorbidities, and the most common adverse events of trofinetide, the first approved drug for RTT, are diarrhea and vomiting, there is a great need for management of these conditions. Despite the high prevalence of GI comorbidities in individuals with RTT, few (<9%) neurologists and pediatricians consider GI comorbidities as one of their top 5 most important treatment goals for RTT [12]. In contrast, the development of an RTT-specific questionnaire for GI health [97] and a recent caregiver perspective article [61] highlighted the importance of GI comorbidities to the caregivers of those with RTT. This situation speaks to a need for better awareness of the GI symptoms of RTT as well as for improved communication and referrals among the multidisciplinary care team for an individual with RTT. Implementation of the management strategies for the GI comorbidities detailed in this article should improve the quality of life for both individuals with RTT and their caregivers. As mentioned earlier, trofinetide was approved by the US Food and Drug Administration in March 2023 for the treatment of RTT. Subsequent real-world experience with trofinetide will inform future treatment paradigms. In particular, additional data on trofinetide use will assist in optimizing dosing relative to the development of GI comorbidities, which may include dose titration with the initiation of trofinetide treatment.

In a broader view, the dysautonomia present in individuals with RTT leads to dysphagia (that may lead to aspiration and respiratory morbidity) [86] and abnormal breathing patterns, including aerophagia that can result in abdominal bloating [87,92]. Dysautonomia can also be associated with intestinal dysmotility with symptoms such as feeding intolerance, vomiting, and refractory constipation. There are multiple other ways dysautonomia may affect an individual, such as temperature dysregulation, sleep disorders, and anxiety such that there is likely a great impact on quality of life. Dysautonomia is poorly understood and rarely discussed as a contributor to GI function, but emphasis on basic counseling and management may be helpful, including physical therapy, adequate fluids, and quality sleep. Additional research into the dysautonomia of RTT may improve GI comorbidities and the quality of life of those with RTT.

In addition, future research on the gut microbiota and metabolome may give a greater understanding of GI comorbidities and the response to trofinetide in individuals with RTT, particularly for the symptoms of constipation and diarrhea. The characterization of the gut microbiota and its metabolome across the lifespan has been an active field of research [98]. It has been established that the gut microbiome can affect host health [99]. However, the published research in individuals with RTT is varied, with 2 studies reporting alterations in the gut microbiota in those with RTT relative to healthy controls, with less diversity and with different relative abundances of specific bacterial taxa [100,101], and another study finding similar relative abundances of bacterial taxa [88]. The 2 studies that showed differences in bacterial taxa also found differences in metabolites (short-chain fatty acids) derived from fecal bacteria in those with RTT, though the implications of this observation are unknown [100,101]. Evidence of a mild inflammatory state in the intestines of individuals with RTT also was observed [101]. The third study found differences between RTT and unaffected individuals in gamma-aminobutyric acid and other amino acids, leading to speculation that the microbiome may affect neurotransmitter activity [88], and ultimately, GI dysmotility. A better understanding of the differences in the GI tract between individuals with RTT and healthy individuals also may explain why individuals with RTT appear to be more susceptible to trofinetide-induced diarrhea.

More comprehensive knowledge of the optimal gut microbiome in healthy humans will benefit those with RTT, as there would be the potential for more targeted supplementation with beneficial prebiotics, probiotics, and foods. The gut microbiota have been shown to degrade sorbitol in the GI tract, thus preventing sugar alcohol–induced diarrhea [102]. In addition, probiotic use can reduce the duration of diarrhea [103], though this is yet to be tested for trofinetide-associated diarrhea. A greater understanding of the gut-brain axis potentially may impact the neurologic and motor symptoms of RTT as well. Rodent models of RTT have shown shifts in the gut microbiome and metabolites preceding the emergence of neurologic and motor phenotypes [104,105]. Overall, the convergence of scientific and clinical research in the coming years should positively influence treatments and management strategies to improve the lives and health of those with RTT.

Article highlights

• Gastrointestinal (GI) comorbidities frequently occur in individuals with Rett syndrome (RTT)

• Management strategies for common GI comorbidities are presented here, based on the published literature and the authors’ clinical experience

• Two adverse events, diarrhea and vomiting, commonly occur with the use of trofinetide, the first approved pharmacologic treatment for RTT

• Management strategies for trofinetide-associated adverse events also are presented in an attempt to ameliorate symptom intensity and improve tolerance to drug use

• A proactive approach to the management of symptomatic GI comorbidities and trofinetide-associated adverse events is recommended to enhance clinical outcomes and improve the quality of life of individuals with RTT

Abbreviation

CGI-I	=	Clinical Global Impression – Improvement
GI	=	Gastrointestinal
G-J	=	Gastrojejunostomy
GLP-1 RA	=	Glucagon-like peptide-1 receptor agonist
G-tube	=	Gastrostomy tube
PPI	=	Proton pump inhibitor
RTT	=	Rett syndrome
TEAE	=	Treatment-emergent adverse event

Declaration of interest

KJ Motil has received funding for clinical research studies from the International Rett Syndrome Foundation and funding for consulting from Acadia Pharmaceuticals Inc. A Beisang is a consultant to Acadia Pharmaceuticals Inc. C Smith-Hicks serves on the Acadia Advisory Board and receives research support from the Kennedy Krieger Institute, which has an institutional agreement with Acadia. A Lembo has relationships with Acadia Pharmaceuticals Inc., Ardelyx Inc., Atmo, Bristol Myers Squibb, Evoke Pharma, Ironwood Pharmaceuticals, Johnson & Johnson, Salix Pharmaceuticals, Takeda Pharmaceuticals, and Vibrant LTD. SM Standridge is a consultant to Acadia Pharmaceuticals Inc. E Liu is a consultant with Takeda Pharmaceuticals and receives royalties from UpToDate for contributions to the section on celiac disease.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from Expert Review of Gastroenterology & Hepatology for their review work but have no other relevant financial relationships to disclose.

Acknowledgments

Jennifer L. Giel, PhD, on behalf of Evidence Scientific Solutions, Philadelphia, PA, USA, provided medical writing services that were funded by Acadia Pharmaceuticals Inc.

Additional information

Funding

This paper was funded by Acadia Pharmaceuticals Inc.