ORIGINAL ARTICLE
Management of Functional Esophagogastric
Junction Outflow Obstruction
A Systematic Review
Stephanie Garbarino, MD,* Megan von Isenburg, MSLS,†
Deborah A. Fisher, MD, MHS,‡§ and David A. Leiman, MD, MSHP‡§
Goals: Awareness of functional esophagogastric junction outflow
obstruction (fEGJOO) has increased, but because there is no con-
sensus on its management, we performed a systematic review of the
literature to explore treatment strategies and outcomes.
Background: EGJOO is a heterogenous disorder defined by high-
resolution manometry parameters of elevated integrated relaxation
pressure with preserved esophageal peristalsis. The etiology may be
mechanical obstruction or idiopathic, the latter being fEGJOO.
Study: The PubMed/MEDLINE, Embase, and the Cochrane
library electronic databases were searched through June 2018 for all
studies of adult patients describing a treatment strategy for fEGJOO
or incomplete lower esophageal sphincter relaxation. The search
strategy yielded 1792 studies and 8 (0.4%) met inclusion criteria.
Results: All but one included studies were retrospective (n = 184
patients). There were 5 interventions described, with botulinum
toxin (Botox) injection (n = 69) and expectant management (n = 82)
the most frequently reported, with success rates of 58% and 54%,
respectively. There was substantial heterogeneity among patients
and treatments were not directly compared, though reported
symptom resolution was similar among all strategies with a mean
follow-up time of 15 months.
Conclusions: There are a variety of management strategies available
for fEGJOO and some patients may not require any intervention.
However, among 4 potential approaches aimed at disrupting lower
esophageal sphincter hypertonicity, the largest existing evidence
base supports either a therapeutic challenge of Botox injection or
watchful waiting. Ultimately, these data indicate the need for fur-
ther study with controlled trials to identify a definitive approach.
Key Words: esophagogastric junction outflow obstruction, esoph-
ageal motility disorders, lower esophageal sphincter, systematic
review
(J Clin Gastroenterol 2020;54:35–42)
Received for publication October 3, 2018; accepted October 8, 2018.
From the *Department of Medicine, Duke University Medical Center;
†Duke University Medical Center Library, Duke University Medi-
cal Center; ‡Division of Gastroenterology, Duke University Medi-
cal Center; and §Duke Clinical Research Institute, Durham, NC.
The authors declare that they have nothing to disclose.
Address correspondence to: David A. Leiman, MD, MSHP, Medicine,
Division of Gastroenterology, Duke University School of Medicine,
2400 Pratt Street, Suite 8007, Durham, NC 277105
(e-mail: david.leiman@duke.edu).
Supplemental Digital Content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML
and PDF versions of this article on the journal’s website, www.jcge.
com.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MCG.0000000000001156
J Clin Gastroenterol  Volume 54, Number 1, January 2020
Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.
E sophagogastric junction outflow obstruction (EGJOO)
is a heterogenous disorder defined by high-resolution
manometry (HRM) parameters of elevated integrated
relaxation pressure (IRP) with preserved esophageal peri-
stalsis. It can result from both mechanical obstruction and
neuromuscular dysfunction.1,2 It is formally described in the
Chicago classification (CC)3–5 but may have been under-
appreciated in the era of standard resolution manometry.6
Since the first description in 2012, it is an increasingly
recognized manometric finding with several potential
underlying clinical etiologies such as esophageal strictures
and eosinophilic esophagitis.7 For patients with underlying
anatomic obstruction, treatment should be targeted to cor-
rect this defect.1 In the absence of a mechanical cause, idi-
opathic or functional EGJOO (fEGJOO) has been described
as an incipient or variant achalasia.8 The natural history of
this entity is uncertain and represents a spectrum of disease,
which can include concurrent hypercontractility as well as
medication effects. As a result, management in this scenario
is less clear and no consensus on appropriate therapy exists.
In this study, we aimed to identify treatment strategies for
patients with functional EGJOO through a systematic
review of the literature.
MATERIALS AND METHODS
Literature Search
Articles were identified by searches of PubMed/MED-
LINE, Embase, and the Cochrane Library databases through
June 2018. The search strategy was developed and defined by
the investigators in conjunction with a librarian with expertise
in systematic reviews. Searches were based on controlled
vocabulary including medical subject heading (MeSH) terms
when possible (eg, “esophagogastric junction” and “esoph-
ageal motility disorder”). In addition, a combination of
keywords and database-specific subject headings for esoph-
ogogastric junction outflow obstruction, lower esophageal
sphincter (LES) relaxation, and the pharmaceutical (calcium
channel blockers, nitrates, diltiazem, nifedipine, verapamil,
sildenafil citrate, or botulinum toxins) and procedural (dila-
tation, dilation, or myotomy) therapies of interest were
included (Appendix 1, Supplemental Digital Content 1, http://
links.lww.com/JCG/A465). Because EGJOO is a relatively
new diagnosis, we intended to include studies that may have
met diagnostic criteria before the introduction of this term so
our search also included terms such as incomplete LES
relaxation and hypertensive LES.
The bibliographies of studies included in the final
analysis as well as relevant reviews also were screened for
additional relevant articles. The website ClinicalTrials.gov
www.jcge.com | 35
Garbarino et al
was searched for ongoing studies not indexed in the above
databases. Authors of relevant studies were contacted to
inquire about completed studies not yet published. Two
independent reviewers (D.A.L. and S.G.) evaluated articles,
with each citation screened first for relevance by title, then
for appropriateness by abstract, then all final articles were
screened in full text form. Disagreements were resolved by
consensus.
Data Extraction and Risk of Bias Assessment
All studies evaluating management in adult patients
(older than 18 years of age) with fEGJOO were included in
the review. No restrictions were placed by date or language.
Editorials, case reports, letters, qualitative studies, clinical
guidelines, systematic reviews, and narrative reviews were
excluded, as were studies describing mechanical EGJOO,
those without any management strategy defined and in
which no identifiable outcome was measured.
All studies evaluated symptomatic response with
improvement defined as either complete resolution or sig-
nificant improvement in symptoms. Symptoms included
dysphagia, regurgitation, heartburn, chest pain, epigastric
pain, cough, globus, abdominal fullness, bloating, early
satiety, and weight loss. Using a standardized form, the 2
reviewers (D.A.L. and S.G.) independently extracted data
for inclusion in the analysis and assessed study risk of bias
and quality using the Newcastle Ottawa Scale (NOS).9 Any
disagreements were resolved by consensus.
Statistical Analysis
Data on study design, location, date, diagnostic criteria,
intervention, outcome, and follow-up were extracted. Sum-
mary data are reported but a pooled estimate was not calcu-
lated. Across all studies there were a total of 5 management
strategies described with no head-to-head comparisons made
between these approaches. There was heterogeneity among
outcome measurements and follow-up intervals. As a result,
meta-analysis was not appropriate and a narrative synthesis
was therefore performed. Given the overall small number of
studies, there was insufficient power to assess for reporting
bias using a Begg test and it was therefore not performed. The
study was indexed within the PROSPERO register of sys-
tematic reviews (2017:CRD42017056184).
RESULTS
Article Selection and Identification
The initial database search identified 1792 citations
after removal of duplicates. Five additional citations were
identified through supplemental review (Fig. 1). After eval-
uating titles and abstracts, 1749 studies were excluded. Of
the remaining 43 studies, 8 met inclusion criteria and no
additional studies were identified through manual review.
All included studies were cohort studies. There were 6 ret-
rospective studies10–15 and 1 prospective study16; 1 study
included both prospective and retrospective components
(Table 1).17
Interventions
A total of 184 patients with fEGJOO were evaluated in
8 studies, and 4 different treatment options in addition to
expectant management were studied (Table 2). None of the
strategies were directly compared within studies and there
were no randomized control trials.
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J Clin Gastroenterol  Volume 54, Number 1, January 2020
Some patients had no direct intervention11,15–17 (n = 82,
45%), either due to their own or their provider’s preference,
and were analyzed in an “expectant management” group.
Given the relatively small number of patients who under-
went medical therapy (n = 15, 8%), these interventions were
all grouped together under the category “pharmacologic
intervention.” This category encompasses multiple medi-
cation classes such as proton pump inhibitors11 medications
which act at the LES via muscle relaxation such as calcium
channel blockers, nitrates,11,16 and less commonly used
medications such as hyoscyamine and amitriptyline.11 One
study cited “pharmacologic therapies” without defining
which medications were used.17 Targeted injection of bot-
ulinum toxin (Botox, Allergan, Dubline, Ireland) to the LES
was the most frequently assessed intervention, and was
evaluated in 7 of 8 studies (n = 69, 37%).10–15,17
Endoscopic therapy also was performed (n = 14, 7%),
with both standard and pneumatic dilation (PD).10,11,14,15,17
Surgical intervention with Heller myotomy was uncom-
monly reported (n = 4, 2%)11,14 and there were no cases of
per oral endoscopic myotomy (POEM) in the included
studies.
Outcomes
The majority (82%) of the patients in these studies
either were given no specific intervention or received a
Botox injection. Outcomes were similar with each approach,
with success of 54% and 58%, respectively. Other inter-
ventions that were not considered definitive treatment
included medications, which together resulted in symptom
improvement 60% of the time. Among the 4 patients who
underwent Heller myotomy, there was a 100% success rate.
Endoscopic PD or standard dilation was successful in 57%
of cases.
Assessment of Study Quality
None of the studies evaluated were randomized or
controlled, therefore a quality assessment was made using
the NOS, which has been validated for both case-control and
cohort studies.9,18 This scale assesses several axes of rele-
vance, including selection criteria, comparability between
studies and outcomes measures (Table 3). Using the NOS,
study quality was defined based on whether patients had
appropriately diagnosed fEGJOO, reported on outcomes
assessed at least 6 months from treatment decision and had
fewer than 10% loss to follow-up rate. Studies were also
evaluated on whether a comparator group was included.
For the purposes of generating the NOS, potential
confounding factors were identified and included the use of
medications affecting LES pressures as well as pooling of
data for both mechanical and functional EGJOO. We
accounted for potential confounding among included sub-
types of EGJOO by explicitly analyzing only patients with
fEGJOO. Studies that achieve at least 6 stars are considered
high quality and all of the studies included in the analysis
had at least 7 stars. No studies in the search were discarded
because of assessed quality and no quantitative analysis was
performed.
Overall, studies were determined to have a homoge-
nous population with respect to their manometric diagnosis,
given the consistency in documenting functional EGJOO
based on CC criteria in all but 2 studies. In the studies that
predated HRM, the authors analyzed a cohort with
“incomplete LES relaxation” that met manometric criteria
for EGJOO.
J Clin Gastroenterol  Volume 54, Number 1, January 2020
FIGURE 1. PRISMA flow diagram of article search and identification.
There was heterogeneity identified in both follow-up
interval and outcome measurements. The average follow-up
time varied by study and ranged from 611,12,15,17 to
37 months.16 Most studies focused on patient-reported
outcomes, but these varied and included data from patient
calls using nonstandardized surveys to assess patient
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Management of Functional EGJOO
satisfaction. Studies also measured outcomes according to
perceived need for further intervention.14 Only 3 studies
used standardized scoring systems to quantify patient’s
symptom improvement10,12,13 and that scoring system
included the Eckardt scoring system, a 5-point Likert scale,
and a numeric (1 to 10) patient satisfaction score.
www.jcge.com | 37
Garbarino et al J Clin Gastroenterol  Volume 54, Number 1, January 2020

TABLE 1. Characteristics of Studies Included in the Systematic Review

Chicago Follow-up
References Design Classification Intervention (n) Outcome Measured (mo) Results
Aliperti and Single center NA Pharmacologic Patient-reported global 37 Pharmacologic
Clouse, USA16 Prospective cohort therapy (5) symptom therapy (3/5)
Expectant improvement on Expectant
management (19) follow-up phone call management
(14/19)
Scherer et al, Single center v1.0 Heller myotomy (3) Satisfactory symptom 16 Heller myotomy
USA14 Retrospective Botox (3) response such that no (3/3)
case-control Pneumatic dilation (3) further intervention Botox (0/3)
Standard dilation (1) recommended for Pneumatic
12 mo dilation (0/3)
Standard dilation
(0/1)
Porter and Multicenter NA Botox (36) Patient assessed 36 Botox (21/36)
Gyawali, Retrospective cohort symptom
USA13 improvement score
assessed by survey
Marjoux et al, Multicenter v2.0 Botox (5) Achieved Eckardt 6 Botox (3/5)
France12 Retrospective cohort score <3
Van Hoeij et al, Single center v2.0 Botox (5) Patient-reported global 6-10 Botox (5/5)
The Retrospective cohort Pneumatic dilation (3) symptom Pneumatic
Netherlands15 Expectant improvement based dilation (1/3)
management (26) on chart review Expectant
management
(5/26)
Clayton et. al, Single center v3.0 Botox (11) Patient assessed Botox: 12 Botox (7/11)
USA10 Retrospective cohort Pneumatic satisfaction score Pneumatic Pneumatic
dilation (4) dilation: dilation (4/4)
8.75
Perez-Fernandez Single center v3.0 Pharmacologic Patient-reported 6 Pharmacologic
et al, Spain17 Retrospective and therapy (6) complete resolution therapy (3/6)
prospective cohort Botox (3) of symptoms Botox (3/3)
Pneumatic dilation (2) Pneumatic
Expectant dilation (2/2)
management (12) Expectant
management
(12/13)
Lynch et al, Single center v2.0/3.0 Botox (6) Patient-reported global 6 Botox (1/6)
USA11 Retrospective case- Expectant symptom Expectant
series management (25) improvement based management
Pharmacologic on chart review (13/25)
therapy (4) Pharmacologic
Standard dilation (1) therapy (3/4)
Heller myotomy (1) Standard dilation
(1/1)
Heller myotomy
(1/1)
Botox indicates botulinum toxin; NA, not applicable.

The most significant source of heterogeneity was the
difference in interventions studied. In total 5 different
interventions were studied among 8 studies, and only Botox
and dilation were studied in over half of the trials. Most of
the interventions were reported in fewer than 4 trials and
aside from Botox and expectant management, the total
number of patients who received the intervention was <20.
DISCUSSION
Management of patients with mechanical esophageal
outflow obstruction is ideally directed toward the underlying
cause, but evidence is lacking for an optimal treatment
strategy in those with fEGJOO. This systematic review
provides a comprehensive analysis of the reported treatment
options for adults with fEGJOO. Our study demonstrates
that a therapeutic trial of Botox injection at the LES and
expectant management are supported by the largest avail-
able body of evidence, though the significant heterogeneity
among patients’ symptoms and their reported management
within the literature limits a definitive treatment recom-
mendation as many will have symptomatic resolution with
no specific treatment.
Full understanding of the underlying etiology of fEG-
JOO is lacking and the causes are diverse.19 Some have
suggested this is incipient or variant achalasia, reporting on
cases that transform over time.20 Indeed, many patients in
our review had an excellent response to therapy targeted to
disruption of LES tone, supporting this hypothesis. Several
such strategies were studied but the most evidence is for

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J Clin Gastroenterol  Volume 54, Number 1, January 2020 Management of Functional EGJOO

improved with this intervention, that is similar to what

TABLE 2. Therapeutic Outcome for Functional Esophagogastric might be expected when used for achalasia.23–25 While
Junction Outflow Obstruction by Intervention Type
Botox would not be expected to confer long-lasting effects26
Intervention (n = Studies Evaluating Favorable Response it represents a practical therapeutic trial that can be both
Intervention) (n = Patients, %) effective and convincing before committing to more defini-
Expectant management (n = 4) 44/82 (54) tive treatment.
Botulinum toxin injection (n = 7) 40/69 (58) However, there is notably less evidence available to
Pharmacologic therapies (n = 3) 9/15 (60) guide a decision about a long-term approach. Indeed, within
Nitrates, calcium channel blockers, the available studies there are no direct descriptions of
proton pump inhibitors, manometric evolution to achalasia and the longest follow-
amitriptyline, hyoscyamine up period was 37 months. Despite the growing interest in
Dilation (n = 5) 8/14 (57) using POEM for nonachalasia motility disorders including
Pneumatic 7/12 (58%)
Standard 1/2 (50%)
fEGJOO, no studies met inclusion criteria for our review
Heller myotomy (n = 2) 4/4 (100) and limited conclusions can be made about its utility. While
the published data do report favorable response rates to
POEM, these are often reported in aggregate with other
foregut motility disorders or with mechanical and functional
injection of Botox at the LES, which had demonstrable EGJOO grouped together.7,27–29 In the studies included in
benefit. This approach mimics those previously described for our analysis, surgical myotomy had excellent success but
indeterminate cases and nonachalasia esophageal motility this was on the basis of scant data. We identified a success
disorders.21,22 Although only 58% of reported patients rate of 58% for PD, which is lower than would be expected

TABLE 3. Assessment of Study Risk of Bias and Quality Using the Newcastle Ottawa Scale
Aliperti Porter Van Perez-
Quality Assessment and Scherer and Marjoux Hoeij Clayton Fernandez Lynch
Criteria Acceptable* Clouse16 et al14 Gyawali13 et al12 et al15 et al10 et al17 et al11
Selection
Representativeness of Representative of the † † † † — † † †
exposed cohort? average patient with
fEGJOO in the
community
Selection of exposed Was there any control group † † † † — † † —
EGJOO cohort? drawn from same
community as exposed
cohort
Ascertainment of From secure record or † — † † † † † †
exposure? structured interview or
implemented by
investigators
Demonstration that Patients were symptomatic at † † † † † † † †
outcome of interest the start and were not
was not present at asymptomatic/resolved
start of study? when the study began
Comparability
Study controls for Controls for mechanical ‡ ‡ ‡ † ‡ ‡ ‡ ‡
mechanical causes EGJOO and other non-
of EGJOO or any fEGJOO manometric
other additional findings‡
factor?
Outcome
Assessment of Independent blind — † † — † — — †
outcome? assessment or record
linkage
Was follow-up long Follow-up ≥ 6 mo † † † † † † † †
enough for
outcome to occur?
Adequacy of follow- Complete follow-up or fewer — — † † † † † —
up of cohorts? than 10% lost to follow-up
or description provided of
those lost
Overall quality score* 7 7 9 7 7 8 8 7
(max = 9)
*All categories are graded as either 0 (—) or 1 (†) except “Comparability,” which can have a maximum score of 2 (‡).
EGJOO indicates esophagogastric junction outflow obstruction; fEGJOO, functional EGJOO.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.jcge.com | 39
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Garbarino et al
in an achalasia-like disorder30,31 but the treatment protocol
and balloon sizes are not clearly defined. Likewise, the 50%
response rate for standard dilation in fEGJOO is of uncer-
tain significance with insufficient data to draw meaningful
conclusions in this population, as there were a small number
of cases and no clear dilation diameter reported. The use of
PD in patients with EGJOO is apparently increasing,31
though these data may include patients with a mechanical
etiology. Full publication of these results should offer fur-
ther insights and, in cases of fEGJOO that represent an
achalasia-variant, it is likely that success rates will ulti-
mately prove to be high with all modalities already shown to
be successful for achalasia therapy. Further, there were not
many patients in the reviewed studies who received medi-
cation therapy and the medications that were used varied
widely among studies. There are preliminary data that did
not meet inclusion criteria for this review that suggest aco-
tiamide, a medication not available in the United States,
may decrease the IRP in EGJOO patients32 but not neces-
sarily fEGJOO in particular.
Interestingly, our review revealed that a substantial
number of patients will improve over time without endoscopic,
pharmacological or other interventions, which is supported by
other studies that did not meet our inclusion criteria.33 This
finding does not necessarily imply that watchful waiting is
always appropriate, as the diversity of symptoms reported in
the identified studies may help explain this finding. Symptoms
like epigastric pain or globus may be more likely to sponta-
neously resolve than dysphagia, but such definitive conclusions
cannot be made on the basis of the available data. Also, it is
not clear how similar the groups that did and did not receive
intervention actually are, with previous studies showing the
location of changes in peristaltic wave amplitude can differ-
entiate among subtypes of EGJOO.34 In some instances,
fEGJOO might be a normal variant, since the IRP cutoff is by
definition at the 95th percentile for normal subjects.21,35
Finally, the response identified could in fact represent a
symptom-free period analogous to the “compensated” acha-
lasia state.36 Ultimately, it is unlikely that so many patients
would have improved with this approach if the underlying
condition were similar to those treated with an intervention.
However, conclusive inferences cannot be made without
directly comparing treated and untreated patients with similar
symptoms, especially dysphagia, and these data are not
available.
The retrospective nature of the included studies and
limitations of data reporting preclude an assessment of
whether all of these patients truly had meaningful obstruc-
tion documented either on barium swallow or impedance
manometry. This may be another reason why so many
patients improved without any treatment. In that group,
fEGJOO may represent a transient or secondary phenom-
enon. It is possible that some of the patients with apparent
spontaneous resolution of symptoms had outflow obstruc-
tion due to medication effects like opioids,37,38 which may
have been discontinued during the follow-up interval. In
contrast, those patients who underwent intervention had
apparent improvement with significant follow-up, indicating
treatment is associated with a meaningful response.
Overall, patients across the cohorts included in this
systematic review had response rates of at least 50% to all
therapies. Although one study included a population of
patients with incomplete LES relaxation from the pre-HRM
era,16 their description comports with fEGJOO and
removing these data do not substantially affect the overall
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J Clin Gastroenterol  Volume 54, Number 1, January 2020
conclusions with respect to treatment success. And, while
publication bias could confound these findings, ultimately
our search and inclusion strategy attempted to minimize this
effect by including non-English language studies as well as a
broad review of both the existing and gray literature. The
findings may also be limited by the fact that none of the
treatment approaches were directly compared with each
other. There may be residual confounding given the lack of
standardized approach in the evaluation and follow-up of
the patients included. Given this heterogeneity, a formal
meta-estimate is not appropriate.
More specific conclusions regarding which patients to
observe versus intervene on cannot be made from the
available data. While one study17 indicated that patients
with predominantly symptoms of gastroesophageal reflux
were more likely to spontaneously improve, neither the
clinical decision making nor the symptoms that motivated
specific treatment routes were systematically discussed. A
more detailed phenotype or subgroup analysis was not
possible based on the available data. With respect to treat-
ment endpoints, there was heterogeneity observed both in
how symptomatic response was assessed and the duration of
follow-up. The Eckardt score is a reliable,39 though not
validated, measure of improvement after therapy for acha-
lasia, but this was used in only one of the studies and may
limit the generalizability of the results, at least with respect
to achalasia or achalasia variants.
Importantly, our study helps generate a greater under-
standing of fEGJOO, which itself may represent distinct
entities. Nonetheless, we identified 2 primary approaches to
managing this condition, including therapy targeted at dis-
rupting LES tone and expectant management. Without
better predictors of symptomatic disease that needs treat-
ment or a priori knowledge of which patients will self-
resolve, and based on the available data from our review,
there are 2 reasonable approaches to managing symptomatic
patients with functional EGJOO (Fig. 2). Considering cur-
rent recommendations and acknowledging that several
studies have not reinforced these conclusions,7 once a
mechanical etiology has been excluded it is still suggested to
rule out alternative causes with either a CT chest or endo-
scopic ultrasound. As the potential for early or variant
achalasia remains,40 when feasible, a diagnostic study with
impedance planimetry or timed barium swallow to further
evaluate for achalasia is suggested.41,42 If achalasia is sus-
pected based on these results, and in the absence of another
identifiable condition, a therapeutic trial of Botox injection
to the LES is supported by current evidence and may precede
more definitive surgical or endoscopic treatment. It is unclear
whether those with normal EGJ distensibility and upright
emptying would also benefit from a Botox trial, though in
patients with dysphagia this may be preferred given the
potential challenges in a watchful waiting approach when
significant symptoms are present. A joint decision should
guide these next steps. On the basis of the observed
improvement of patients in whom watchful waiting was
chosen, repeating a manometry in 6 to 12 months seems
prudent to exclude a change in underlying diagnosis.
No management guidelines exist for EGJOO, which
likely explains much of the heterogeneity observed in the
current analysis. Further work to clarify a treatment approach
should include evaluating a standardized assessment of
symptoms, identifying better predictors of those patients likely
to progress versus regress and, ultimately, a high-quality
randomized controlled trial to compare treatment approaches
J Clin Gastroenterol  Volume 54, Number 1, January 2020
FIGURE 2. Proposed management algorithm for functional EGJOO. CT indicates computed tomography; EGJOO, esophagogastric
junction outflow obstruction; EUS, endoscopic ultrasound; LES, lower esophageal sphincter; TBS, timed barium swallow.
within well-defined phenotypes. In conclusion, the currently
available data provide contextual evidence to help guide the
treatment of symptomatic patients with this diagnosis, though
conclusive and definitive recommendations cannot be made
on the basis of the currently available data.
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