Esophageal Motility Dysfunction in Children With Rett Syndrome

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					Esophageal Motility Dysfunction in
Children With Rett Syndrome,
Gastroesophageal Reflux, and

                                            (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
 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
 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
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