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Esophageal Motility Dysfunction in Children With Rett Syndrome, Gastroesophageal Reflux, and Dysphagia (LES) pressure and percent relaxation, KEY WORDS: Rett syndrome, mean peak esophageal body contrac- manometry, gastroesophageal reflux tions, and percent of swallows with disease (GERD), dysphagia abnormal peristalsis were quantified. ABSTRACT Results: Patients with GERD (n = 13) or Background: Rett syndrome is a neu- dysphagia (n = 11) had 37% and 34% of rodevelopmental disorder associated swallows followed by abnormal with gastroesophageal reflux disease esophageal peristalsis, respectively, com- (GERD) and dysphagia. pared to 8% in patients without symp- toms (P < 0.01). Patients with Objective: Correlate esophageal motility fundoplication (n = 4) had 45% of swal- disturbances with symptoms of GERD lows followed by abnormal esophageal and dysphagia and with MECP2 gene peristalsis versus 17% in those without mutations in children with Rett syn- fundoplication (P < 0.05). drome. Fundoplication patients showed higher LES resting pressures (35 mmHg vs 23.5 Study Design: Thirty-two consecutive mmHg, P < 0.01) compared with Rett patients with a mean (range) age of patients without previous anti-reflux 6.2 (2.3-14) years with prior history of surgery. There was no association feeding problems underwent esophageal between esophageal motor disturbances manometry. Lower esophageal sphincter and MECP2 mutations. 84 Vol. 7, No. 3, 2007 • The Journal of Applied Research Table 1. Percentage abnormal esophageal peristalsis during esophageal manometry after swallows in patients with Rett syndrome. Asymptomatic patients served as controls. Subjects with symptoms of GERD or dysphagia were compared to controls. Patients with GERD only (no dysphagia), dysphagia only (no GERD), and patients with both GERD and dysphagia were also compared to controls. Symptoms Abnormal Peristalsis (%) P Value Controls (n = 15) 8 GERD (n = 13) 37 0.004 Dysphagia (n = 11) 34 0.007 GERD only (n = 5) 31 0.02 Dysphagia only (n = 3) 18 0.16 Both GERD and dysphagia (n = 8) 41 0.003 Conclusions: Decreased esophageal terminus (proximal) had a greater num- peristalsis is a common finding in Rett ber of gastrointestinal problems and patients with symptoms of GERD and often required early gastrostomy for dysphagia with or without fundoplica- severe malnutrition.7 tion. Prospective studies are needed to The primary GI neuromuscular or determine if esophageal manometry motility mechanism underlying GERD should be used to screen Rett patients and dysphagia in Rett patients has not for esophageal motility dysfunction yet been defined. It is unclear if the before anti-reflux procedures. pathophysiology of GERD in patients with Rett syndrome can simply be INTRODUCTION explained through transient relaxations Rett syndrome is a neurodevelopmental of the lower esophageal sphincter disorder affecting postnatal brain (TLESRs).8-11 Gastroesophageal reflux growth that characteristically occurs in disease and dysphagia may also be influ- females with a prevalence of 1:10,000 to enced by disordered esophageal body 1:22,000.1 In approximately 70%-80% of peristalsis resulting in impaired clear- patients, clinical features of Rett syn- ance of acid from the esophagus or dis- drome are associated with mutations in ruption of bolus transit, respectively. the methyl CpG binding protein 2 Although dysmotility of the esophagus (MECP2) gene located in the chromo- may occur as a secondary phenomenon some Xq28 region.2-4 Failure of brain related to esophageal injury from chron- growth results in developmental regres- ic exposure to refluxed gastric contents, sion and is accompanied by seizures, res- an underlying inherent motility disorder piratory irregularities, and severe mental of the esophageal body may contribute retardation. Patients also have signifi- to symptoms of GERD and dysphagia in cant autonomic involvement resulting in children with neurologic impairment.12-14 gastrointestinal (GI) abnormalities and Antireflux surgery has been a main- peripheral vasomotor instability.5,6 The stay of treatment for severe GERD in common GI manifestations seen in Rett children since the 1960s.15,16 A review of syndrome include gastroesophageal the Pediatric Health Information Survey reflux disease (GERD), dysphagia, feed- database has shown an upward trend in ing impairment that often results in fail- the rate of fundoplication.17 Among ure to thrive, and constipation. We have these patients, 14% underwent fundopli- previously shown that patients with cation without a prior gastroenterology mutations closer to the MECP2 amino- consultation.17,18 Common side effects The Journal of Applied Research • Vol. 8, No. 2, 2008 85 Table 2. Classification of patients by mutation type and GI symptoms. Number of patients with proximal, distal, and no mutation of the MECP2 gene and the clinical GI symptoms for each mutation are listed. Specific mutation types are noted for each category. Number of Patients Reflux Failure to Thrive Dysphagia Constipation Proximal T158M 8 4 7 3 6 R133C 4 0 1 1 0 R168X 1 1 1 1 1 Deletion exon 3 & 4 1 0 1 0 1 1164 del/A140V 1 1 0 0 1 Distal R270X 4 1 2 3 3 R306H 2 1 2 0 1 R306C 2 2 1 1 1 R294X 2 1 1 0 1 R255X 1 0 0 0 1 P322L 1 0 0 0 0 Del 1152-1192 1 1 0 0 0 996_997 ins A 1 1 1 1 0 807 del 1 1 1 1 1 1163 del 26 1 1 1 0 1 1161 del 6 1 0 0 0 0 No mutation 2 0 2 0 0 related to the surgery include: dyspha- in terms of mutations at the MECP2 gia, gagging and retching, nausea, and gene and esophageal symptoms and abdominal distension. Postoperative manometric findings. complications or procedure failure can be as high as 25% in neurologically PATIENTS AND METHODS impaired children and may reflect an Patients inherent esophageal or gastric motility Thirty-two consecutive patients with disorder.19-26 Rett syndrome who were seen between Studies defining the manometric September 2004 and March 2006 were characteristics of the esophagus in neu- included in this study. These patients had rologically impaired children before and a history of feeding problems and were after fundoplication are limited.27 Since referred for neurologic assessment children with Rett syndrome demon- either to the Johns Hopkins University strate a high incidence of GERD and Children’s Center or the Kennedy- dysphagia in the setting of severe neuro- Kreiger Institute. Feeding problems logical impairment, it was the objective were defined as inability to consume of this study to better define esophageal adequate calories orally, prolonged feed- neuromuscular function in these chil- ing time, or food refusal/selectivity. dren. We also assessed esophageal motil- Gastroesophageal reflux disease was ity in Rett patients with previous defined based on prior clinical assess- fundoplication. Finally, we examined the ment and diagnostic evaluation of association between patients’ genotype patient’s referring physician. Children 86 Vol. 8, No. 2, 2008 • The Journal of Applied Research Figure 1. The lower panel shows failure of LES relaxation in a child with Rett syndrome and symp- toms of GERD and dysphagia. The mean LES resting pressure for this patient was approximately 26 mmHg (arrow). The top and middle panels show esophageal peristalsis immediately after a wet swallow. Time is represented in minutes. were considered to have GERD for Esophageal Manometry symptoms of effortless regurgitation or Esophageal manometry was performed vomiting and improvement of symptoms without sedation after a 4-hour fasting after acid suppression, a history of an period. A flexible 4-channel Koningberg abnormal pH probe, or endoscopic evi- solid-state catheter (Medical dence of esophagitis. A diagnosis of dys- Measurement Systems USA, Inc. phagia was based on evaluation by a [MMS], Dover, New Hampshire, USA) pediatric gastroenterologist in consulta- was utilized. Pressure results from the tion with a speech pathologist. Children esophageal body and LES were ana- were considered to have dysphagia if lyzed using MMS computer software. they exhibited symptoms of gagging or Patients were studied for approximately choking with oral intake, complaints of 20-30 minutes. Pressure readings were pain with eating, or an abnormal video obtained at the LES and the esophageal fluoroscopic swallow study performed body at distances 3-5 cm and 5-10 cm with a speech pathologist. A diagnosis of proximal to the LES based on the size failure to thrive was made by a pediatric of the patient. Pressure results after gastroenterologist in consultation with a approximately 5-10 wet swallows (mini- pediatric dietitian using Waterlow’s cri- mum 3 mL of water or juice) were teria.28 A history of prior gastrostomy or recorded in mmHg. Nissen fundoplication and gastrostomy The following manometry results was also noted for all patients. All sub- were quantified: LES resting pressure, jects underwent MECP2 mutation mean percent LES relaxation after all analysis and esophageal manometry swallows, mean LES residual pressure testing. The study was approved by The after all swallows, mean peak amplitude Johns Hopkins University Institutional for esophageal contractions after all Review Board. swallows, and percent of swallows fol- The Journal of Applied Research • Vol. 8, No. 2, 2008 87 Figure 2. The top and middle panels show esophageal peristalsis immediately after a wet swal- low with abnormally high amplitude esophageal body contractions in a child with Rett syn- drome, prior fundoplication and symptoms of dysphagia. The arrow in the middle panel depicts an esophageal contraction in excess of 250 mmHg (arrow). Lower esophageal sohincter relax- ation is shown in the lower panel. Time is represented in minutes. lowed by abnormal esophageal peristal- tested negative for MECP2 mutations, sis. Lower esophageal sphincter resting were detected to have large deletions in pressures from 6-25 mmHg were consid- the gene by Multiplex Ligation-De- ered normal; LES relaxation less than pendent Probe Amplification (MLPA) 90% and LES residual pressures greater technology.31 Mutations defined as prox- than or equal to 8 mmHg were consid- imal mutations occurred closer to the ered abnormal. Esophageal peristalsis amino-terminus, prior to amino acid 255, was considered abnormal if less than compared with mutations toward the 80% of waves propagated in an ante- carboxyl-terminus (distal). grade direction, or if the peak amplitude of contraction was greater than 100 Statistical Analysis mmHg or less than 30 mmHg. All analyses were performed using the statistical software package STATA ver- Genomic DNA Isolation, PCR, sion 8.0. We used Student t-tests for con- Genotyping, and Mutation Analysis of tinuous outcomes and chi-squared MECP2 analyses for categorical and dichoto- Genomic DNA was isolated from mous outcome data. A P value <0.05 peripheral blood samples or lym- was considered statistically significant. phoblast cell lines using methods described by Miller et al.29 Mutation RESULTS analysis was performed using a combi- Demographics nation of denaturing high pressure liq- All patients in this study (n = 32) were uid chromatography (DHPLC)30 and female. The mean (range) age of the 32 direct sequencing.4 Patients, who initially patients was 6.2 (2.3-14) years. The mean 88 Vol. 8, No. 2, 2008 • The Journal of Applied Research Figure 3. The upper 3 panels show simultaneous esophageal body contractions (arrows) in a patient with Rett syndrome immediately after a wet swallow. The lower panel shows an elevated LES resting pressure of approximately 62 mmHg (dashed arrow) with LES relaxation (arrowhead). Time is represented in minutes. (range) age of patients at time of diag- completely normal LES and esophageal nosis of Rett syndrome was 2.8 (0.8-8.8) peristalsis. Abnormal LES relaxation years. A clinical history of GERD was was demonstrated in 12 (37.5%) of the documented in 13 (40.6%), dysphagia in patients. The degree of incomplete relax- 11 (34.4%), failure to thrive in 21 ation ranged from 38% to 88%. Figure 1 (65.6%), and constipation in 17 (53.1%) shows an example of incomplete relax- patients. There were 15 patients without ation of the LES in a patient. symptoms of GERD and dysphagia, and Abnormally high residual pressures 8 with both GERD and dysphagia. A were found in 6 (18.8%) of the patients, gastrostomy tube had been placed in 3 and these pressures ranged from 8 to 16 (8.8%) and a combined Nissen fundopli- mmHg. In 9 patients (28.1%), LES rest- cation and gastrostomy tube placement ing pressures were abnormally high, had been performed in 4 patients ranging from 26-49 mmHg. No patients (11.8%). exhibited LES pressures below normal. Studies were limited to 30 minutes, and Esophageal Manometry during this period of time TLESRs were High quality esophageal motility trac- not observed. ings were achieved in 30 of the 32 After wet swallows, 16 (53.3%) of patients with Rett syndrome. The per- the patients demonstrated abnormally centage of peristaltic contractions was high pressures in the esophageal body at not calculated in 2 patients due to arti- either 3-5 or 5-10 cm proximal to the fact. The patients averaged 6.7 swallows LES. The pressures ranged from 101-201 per study (range 2-17 swallows). mmHg (Figure 2). One patient demon- Only 8 (25%) patients demonstrated strated mean pressure amplitude in the The Journal of Applied Research • Vol. 8, No. 2, 2008 89 esophageal body of 326 mmHg. This tion (P < 0.01). There was a trend observation was reproduced on a subse- towards abnormal LES relaxation in quent manometric study performed for patients with fundoplication (70.5% persistent symptoms of dysphagia. Nine relaxation versus 87.6%, P < 0.09). (28%) of the patients showed abnormal Among the 4 patients with a fundoplica- propagation of esophageal waves tion, 3 had symptoms of dysphagia and 3 (Figure 3). Two patients underwent were being treated with ranitidine for repeat manometry testing 6 months later persistent symptoms of GERD at the for persistent dysphagia, and abnormali- time of esophageal manometric assess- ties in esophageal pressures and LES ment. function were persistent and similar compared to the original study. Genetics Seventeen patients (50%) had a distal Esophageal Manometry Results in mutation, 15 (44.1%) had a proximal Patients With and Without GERD and MECP2 mutation, and 2 (5.9%) had no Dysphagia Symptoms mutation. A total of 8 patients (23.5%) Patients without symptoms of GERD had the T158M mutation, the most com- and dysphagia (n = 15) had 8% of wet mon genotype in the population studied. swallows followed by abnormal peristal- There was no statistical association sis. Patients with GERD or dysphagia found between symptoms of GERD, had 37% and 34% of wet swallows fol- failure to thrive, dysphagia, or constipa- lowed by abnormal peristalsis, respec- tion and mutation class (distal or proxi- tively (P < 0.01). In patients with mal). In addition, there was no GERD alone (n = 5), 31% of wet swal- correlation between any individual lows were followed by abnormal peri- mutation types and clinical variable stalsis (P < 0.03). In those with (Table 2). dysphagia alone (n = 3), 18% of wet swallows were followed by abnormal DISCUSSION peristalsis (P < 0.2). In patients with Children with various neurologic impair- both GERD and dysphagia (n = 8), 41% ments have an increased risk of GERD of patients demonstrated abnormal peri- compared with children who are neuro- stalsis (P < 0.004) (Table 1). Mean LES logically normal.32 The explanation for resting pressure was almost identical for increased GERD in neurologically patients with GERD (25.5 mmHg) and impaired children is not well defined. dysphagia (25.7 mmHg), respectively Children with Rett syndrome are often (normal 6-25 mmHg). There was no profoundly neurologically disabled and association between failure to thrive or have autonomic dysfunction, which has constipation and abnormal manometry. been associated with several gastroin- testinal manifestations such as GERD, Esophageal Motility After Nissen dysphagia, failure to thrive, and consti- Fundoplication pation. The results of this study suggest Patients with a prior fundoplication had that abnormalities in esophageal peri- 45% of wet swallows followed by abnor- stalsis may represent another compo- mal peristalsis compared to 17% in nent in the spectrum of motility changes those without a fundoplication (P < exacerbated by acid and non-acid reflux. 0.05). Patients with a fundoplication also Poor esophageal peristalsis may play a demonstrated increased LES resting role in impaired esophageal clearance pressure (35 mmHg) compared to 23.5 resulting in a higher incidence of dys- mmHg in patients without fundoplica- phagia and persistent GERD among 90 Vol. 8, No. 2, 2008 • The Journal of Applied Research patients with Rett syndrome. We found explaining the persistence of symptoms abnormalities in peristalsis after 37% of despite maximal medical management. wet swallows in patients with GERD Another unusual esophageal motility and 34% of wet swallows in patients observation in Rett patients was high with dysphagia compared to 8% in amplitude esophageal contractions after asymptomatic subjects. The abnormal swallowing. Some patients exhibited esophageal contractions were simultane- mean pressures over 150 mmHg and as ous, retrograde, or non-transmitted, and high as 326 mmHg. There was no statisti- were often high-amplitude. cal association between these high pres- In a study in 1999, Rett patients with sures and symptoms of GERD and GERD and dysphagia were evaluated dysphagia, Nissen fundoplication, or by an oral feeding assessment by a abnormal esophageal peristalsis. The sig- speech pathologist, a videofluoroscopic nificance of these high pressure contrac- swallow study, and an upper gastroin- tions is unclear, but may be attributed to testinal series.6 Esophageal dysmotility the underlying autonomic nervous sys- was found in 46% of patients. The tem dysfunction in Rett syndrome. High esophageal motility abnormalities amplitude esophageal contractions are observed by x-rays were absence of pri- not characteristic of routine GERD and mary or secondary peristaltic waves, support the notion that other mecha- esophageal atony, and esophageal nisms need to be considered in Rett syn- spasm. Using more sensitive esophageal drome and other neurologically affected manometric recordings we found about children. 75% of our patients demonstrated Among the 4 patients who had a pre- esophageal motility abnormalities in vious fundoplication, all had abnormal either abnormal LES or esophageal esophageal peristalsis, and 3 of the 4 had peristalsis. symptoms of dysphagia. Preoperative These abnormalities of the manometric data were not available on esophageal body raise the possibility of these patients to determine an inherent an additional neuromuscular mechanism esophageal dysmotility prior to surgery. for GERD and dysphagia in Rett The symptoms described in our postfun- patients. Sondheimer et al32 attributed doplication Rett patients are consistent symptoms of GERD to hypotensive with symptoms commonly observed in LES in neurologically impaired children. children with neurologic impairment, In their study, patients with clinical respiratory disease, and previous GERD had a mean basal LES pressure anatomic anomalies such as esophageal almost 17 mmHg less than those without atresia.33-38 The incidence of late postfun- GERD (12.5 mmHg versus 29.0 mmHg, doplication complications is approxi- respectively), and 27% of patients mately 26% for neurologically impaired demonstrated failure of esophageal peri- children compared to 12% for neurolog- stalsis. In our study, 28% of Rett patients ically normal children.34 Postoperative had abnormal esophageal peristalsis. mortality is high in neurologically However, the LES pressure was normal impaired children and ranges from 6% or increased in our Rett patients with to 12%.34,35,39,40 Since these postfundopli- GERD and dysphagia. Thus, in Rett syn- cation complications do not appear as drome, abnormal peristalsis in the frequently in neurologically normal chil- esophageal body may contribute to dren41-43 or adults,44-49 manometry has GERD and dysphagia. Poor esophageal not been considered mandatory in these peristalsis may further impair clearance patients. Our results in post-fundoplica- of acid or non-acid refluxate, thereby tion raise the concern that some patients The Journal of Applied Research • Vol. 8, No. 2, 2008 91 with Rett syndrome may demonstrate relation. primary abnormalities in esophageal Rett syndrome is an uncommon dis- peristalsis and may benefit from pre- order and our study overall was limited fundoplication manometry testing to by the small number of patients studied. determine if alternative methods to treat Our control group (non-GERD, non- reflux should be considered in these dysphagia) consisted of subjects with children. Future prospective esophageal Rett syndrome and feeding problems. motility studies before and after fundo- Future studies of patients with feeding plication are needed to address this pos- disorders without a diagnosis of Rett sibility. may allow more specific conclusions Diffuse neuromuscular dysfunction about the relationship between auto- of the GI tract may explain the discrep- nomic instability and esophageal neuro- ancy in postfundoplication outcomes in muscular disorders in this syndrome. In neurologically abnormal compared to addition, when pH, impedance, or neurologically intact children. Abnormal esophageal biopsy results were not esophageal motility related to the LES available, the diagnosis of GERD was and antroduodenal motility has been based on symptom history with evidence observed in animal models12 and in chil- of improvement during treatment with dren with brain injury.12-14,50 Delayed gas- acid reducing agents. Future studies tric emptying in neurologically impaired including pH, impedance, or endoscopic children has also been well- and histologic findings will allow more described.36,51,52 Indeed, when delayed objective evidence of GERD. gastric emptying is identified preopera- In conclusion, patients with Rett syn- tively, an improved clinical outcome is drome have a high incidence of GERD often observed post-Nissen fundoplica- and dysphagia, which are associated with tion when combined with pyloroplasty.36 abnormal esophageal peristalsis and not An association between abnormal hypotensive LES pressures or incom- esophageal motility and a patient’s plete relaxation of the LES. Abnormal- MECP2 genotype was not found in this ities in esophageal peristalsis may be study. Naidu et al7 demonstrated that secondary to acid and non-acid reflux; patients with more proximal mutations however, this study raises the possibility in MECP2 had a greater number of GI of primary esophageal body dysmotility symptoms (GERD, dysphagia, failure to in some patients with Rett syndrome, thrive, and constipation) than those with which may be attributed to their under- distal MECP2 mutations. Our failure to lying autonomic nervous system instabil- find an association between GI symp- ity. Esophageal motility testing may be toms or esophageal motility and considered in children with Rett syn- MECP2 mutations may be explained by drome and symptoms of GERD or dys- the limited number of Rett patients and phagia and before fundoplication. the wide variety of mutation types for the respective proximal and distal ACKNOWLEDGEMENTS MECP2 mutation groups. It also raises The study is funded by grants from PO1- the possibility that alternative genetic HD24448, FD-R-002408, MO1RR00052, mechanisms may be responsible for the and the Thomas Wilson Award (AD). clinical GI symptoms seen in Rett syn- The authors would also like to thank Dr. drome. Future studies with greater num- R. Thompson for his statistical analysis. bers of specific mutation types and Rett patients are needed to determine the REFERENCES existence of a genotype-phenotype cor- 1. Kozienetz CA, Skender, ML, MacNaughton 92 Vol. 8, No. 2, 2008 • The Journal of Applied Research N, et al: Epidemiology of Rett syndrome: a 15. Nissen R: Gastropexy and “fundoplication” in population-based registry. Pediatrics surgical treatment of hiatal hernia. Am J Dig 1993;91:445-450. Dis 1961;6:954-961. 2. Amir RE, Van den Veyver IB, Wan M, et al: 16. 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"Esophageal Motility Dysfunction in Children With Rett Syndrome"