J Neurogastroenterol Motil 2023; 29(4): 478-485  https://doi.org/10.5056/jnm22173
Multiple Sclerosis Is Associated With Achalasia and Diffuse Esophageal Spasm
Yeseong Kim,1 Fahmi Shibli,2 Yuhan Fu,1 Gengqing Song,2 and Ronnie Fass2*
1Department of Internal Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA; and 2Division of Gastroenterology and Hepatology, The Esophageal and Swallowing Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA
Correspondence to: *Ronnie Fass, MD, MACG
Division of Gastroenterology and Hepatology, The Esophageal and Swallowing Center, MetroHealth Medical Center, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
Tel: +1-216-778-3145, Fax: +1-216-778-2074, E-mail: rfass@metrohealth.org
Received: October 10, 2022; Revised: April 12, 2023; Accepted: April 12, 2023; Published online: August 2, 2023
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background/Aims
Multiple sclerosis (MS) is an inflammatory disease characterized by the demyelination of primarily the central nervous system. Diffuse esophageal spasm (DES) and achalasia are both disorders of esophageal peristalsis which cause clinical symptoms of dysphagia. Mechanisms involving dysfunction of the pre- and post-ganglionic nerve fibers of the myenteric plexus have been proposed. We sought to determine whether MS confers an increased risk of developing achalasia or DES.
Methods
Cohort analysis was done using the Explorys database. Univariate logistic regression was performed to determine the odds MS confers to each motility disorder studied. Comparison of proportions of dysautonomia comorbidities was performed among the cohorts. Patients with a prior diagnosis of diabetes mellitus, chronic Chagas’ disease, opioid use, or CREST syndrome were excluded from the study.
Results
Odds of MS patients developing achalasia or DES were (OR, 2.09; 95% CI, 1.73-2.52; P < 0.001) and (OR, 3.15; 95% CI, 2.89-3.42; P < 0.001), respectively. In the MS/achalasia cohort, 27.27%, 18.18%, 9.09%, and 45.45% patients had urinary incontinence, gastroparesis, impotence, and insomnia, respectively. In the MS/DES cohort, 35.19%, 11.11%, 3.70%, and 55.56% had these symptoms. In MS patients without motility disorders, 12.64%, 0.79%, 2.21%, and 21.85% had these symptoms.
Conclusions
Patients with MS have higher odds of developing achalasia or DES compared to patients without MS. MS patients with achalasia or DES have higher rates of dysautonomia comorbidities. This suggests that these patients have a more severe disease phenotype in regards to the extent of neuronal degradation and demyelination causing the autonomic dysfunction.
Keywords: Achalasia; Database analysis; Diffuse esophageal spasm; Esophageal dysphagia; Multiple sclerosis
Introduction

Multiple sclerosis (MS) is a degenerative condition of the central nervous system primarily modulated by inflammation, demyelination, and axonal degradation.1,2 The etiologies of these processes, however, remain largely debated.3,4 The most widely accepted theory is that MS is an autoimmune process characterized by autoreactive lymphocytes, causing microglia activation and chronic neurodegeneration,5,6 leading to both debilitating symptoms and psychological abnormalities. The gastrointestinal manifestations of multiple sclerosis are well documented, primarily consisting of dysphagia, constipation, gut microbiota dysbiosis, and dysmotility.7 Dysphagia is prevalent in MS, affecting up to 43% of the patients, and is mediated by dysfunction of the oral and pharyngeal phases of deglutition.8,9

The cortical regions of the brain governing volitional swallowing include the insula, inferior frontal gyrus (BA44), primary motor cortex, and primary sensory cortex.10 Seamless communication and feedback among these pathways which constitute the swallowing network is essential in producing a coordinated swallow, a highly vulnerable process in patients with MS. While the oropharynx and upper esophagus mainly consists of striated skeletal muscle, the proportion of smooth muscle increases distally; an autonomic neural network consisting of inhibitory (nitric oxide) and excitatory (cholinergic) neurons follow this gradient as well, with increasing proportion of inhibitory neurons progressing distally.11 Dysfunction of these inhibitory neurons caused by neuro-inflammatory conditions, such as MS, could potentially lead to the development of esophageal motor disorders.

Achalasia is a major disorder of esophagogastric outflow, usually resulting from the degeneration of neurons in the esophageal wall.12 Diagnosis is made via high-resolution esophageal manometry (HREM).13 Achalasia is defined by findings of an elevated integrated relaxation pressure, demonstrating impaired esophagogastric junction relaxation, and failed esophageal peristalsis. Diffuse esophageal spasm (DES), is a major disorder of esophageal hypercontractility.13 Clinically and diagnostically distinct from achalasia, DES is categorized as a major disorder of peristalsis, with a normal integrated relaxation pressure, unlike achalasia.

Multiple mechanisms behind the pathogenesis of MS exist, with some theories suggesting a post-viral T cell inflammatory cause.14,15 A more accepted theory proposes an autoimmune mechanism, where auto-reactive CD3/4 T cells are recruited inappropriately to myelin.16 Degeneration of the myenteric plexus is a well-known histopathological finding in achalasia; the degree of T cell infiltration, which is thought to be the cause of esophageal inflammation and fibrosis, is inversely correlated with the number of preserved ganglia.17 Given the impaired LES relaxation seen in achalasia, the inflammatory process is thought to be selective for inhibitory neurons crucial for normalizing resting smooth muscle tone. Several studies investigating the role of nitric oxide (NO) have shown that artificial inhibition of NO synthase mimic physiological findings seen in achalasia.18,19 DES also shows similar findings of impaired inhibitory neurons leading to inappropriate esophageal contractions, with several studies showing absence of deglutitive inhibition and restoration of function with NO production.20,21

Both achalasia and DES share a common proposed mechanism of impaired inhibitory innervation of the esophagus. Given that a similar mechanism of neuronal degeneration is seen in MS, as evidenced by the higher prevalence of dysautonomia in these patients,22 aimed to determine whether there is an association between multiple sclerosis and achalasia or DES.

Materials and Methods

Database Description

Explorys (IBM Explorys, Cleveland, OH, USA) is a cloud-based database which returns de-identified, aggregated electronic medical record data from 360 healthcare institutions and over 73 million individual patients across the United States. This software places a healthcare gateway server behind the firewall of each participating healthcare institution, and precludes the investigators from seeing institution or patient-level data. The data is regularly updated every 24 hours, and retrieved from a variety of health information systems including laboratory values, billing inquiries, electronic health records, which is then uploaded onto a data grid. This grid is accessible via web application and allows the user to search and analyze the standardized, aggregated, de-identified, and normalized population level data.23 Population-level data can be retrieved by users by accessing the web application, navigating the mapped ontology, and by defining search and input criteria for target cohorts.

Explorys exports that data according to common clinical standards; diagnoses are categorized International Classification of Diseases, Tenth Revision, Clinical Modification, which are then mapped into Systemized Nomenclature of Medicine–Clinical Terms (SNOMED-CT). Findings and procedures are also mapped onto the SNOMED-CT ontology. Prescription drugs are mapped onto RxNorm, and laboratory tests are mapped onto Logical Observation Identifiers Names and Codes. This standardization of medical linguistics facilitates rapid searching and indexing. For Health Insurance Portability and Accountability Act compliant statistical de-identification purposes, population counts are reported to the nearest 10, or as less than 10 if between 0 and 10. The Explorys database has been utilized for clinical research purposes in a variety of fields, including cardiology, oncology, as well as gastroenterology.24-26 This study did not involve patients or identifiable patient information, and therefore was exempt from institutional review board approval.

Study Design and Population

Population-based data retrieval using Explorys was performed to identify cohorts within a 15-year time frame from 2004 to 2019 with a diagnosis of MS; this initial diagnosis was established as the index event. A secondary inquiry criteria of a subsequent diagnosis of either achalasia or DES, at least 180 days after the index event, was performed to identify 2 separate cohorts for each esophageal dysmotility. This lag time was utilized to ensure that a diagnosis of motility disorder followed the diagnosis of MS, thus establishing a temporal causal or contributory association. Cohorts were queried for population returns until the time point of diagnosis of either motility disorder. Adult patients above the age of 18 in the inpatient and outpatient settings were included in the study. Patients with prior diagnoses of diabetes mellitus, chronic Chagas’ disease, systemic sclerosis, mixed connective tissue disorder, CREST syndrome, or chronic opioid use were excluded from the study as these confounders may potentially cause abnormal findings on various swallowing tests—including HREM, barium swallow, and patient symptom questionnaires. Prevalence data of 4 co-morbid dysautonomia disorders, consisting of urinary incontinence, gastroparesis, impotence, and insomnia, commonly encountered in patients with MS were collected from each cohort. Terms used for population querying were “multiple sclerosis,” “diffuse spasm of esophagus,” “achalasia of esophagus,” “systemic sclerosis,” “chronic Chagas’ disease,” “calcinosis, Raynaud’s phenomenon, esophageal dysmotility, and telangiectasia syndrome,” “chronic use of opioids,” and “diabetes mellitus.”

Sensitivity analysis of the database was performed by querying incidences of asthma in MS patients compared to non-MS patients. It was reasoned that if this negative control cohort, with a condition known to be unrelated to multiple sclerosis, returned a non-significant odds ratio, this would prove that our search strategy and input criteria of terms displayed high internal validity, and that any bias rendered by underlying confounders in the cohorts would be negligible. Furthermore, we attempted to validate the database by querying annual incidence data of achalasia, DES, and MS from 2004-2019 to see if correspondence with known values could be replicated.

Results

Characteristics of Multiple Sclerosis Patients With Achalasia or Diffuse Esophageal Spasm

Baseline patient characteristics and demographic data were collected for all patients with either achalasia or DES, with or without MS (Table 1). In all cohorts, the majority of patients were under 65 years of age, except DES patients without multiple sclerosis, which had a majority of patients above 65. All cohorts showed a predominance of female patients. In all cohorts, gastroesophageal reflux disease (GERD) showed the highest prevalence among gastrointestinal-specific comorbidities; hypertension had the highest prevalence of non-gastrointestinal specific comorbidities.

Table 1 . Baseline Demographics and Clinical Characteristics

Patient characteristicsMS/achalasia (n = 110)MS/DES (n = 540)No MS/achalasia (n = 20 330)No MS/DES (n = 66 680)
Age (yr)
≤ 65 yr60 (54.54)300 (55.56)10 530 (51.80)29 710 (44.56)
> 65 yr50 (45.46)240 (44.44)9800 (48.20)36 970 (55.44)
Sex
Female90 (81.82)460 (85.19)11 390 (56.03)44 790 (67.17)
Male20 (18.18)80 (14.81)8940 (43.97)21 390 (32.08)
Race/ethnicity
African American10 (9.09)50 (9.26)2160 (10.62)5480 (8.22)
Caucasian80 (72.73)460 (85.19)15 180 (74.67)51 320 (76.96)
Other20 (18.18)30 (5.56)2990 (14.70)9880 (14.82)
Insurance
Medicare50 (45.45)270 (50.00)7570 (37.24)26 970 (40.45)
Medicaid10 (9.09)60 (11.11)1460 (7.18)5040 (7.56)
Private50 (45.45)210 (38.89)10 700 (52.63)32 270 (48.40)
Other0 (0.00)0 (0.00)600 (2.95)2400 (3.60)
Co-morbidities
GERD80 (72.73)410 (75.93)12 650 (62.22)48 380 (72.56)
with esophagitis30 (27.27)340 (62.96)3090 (15.20)11 690 (17.53)
without esophagitis50 (45.45)70 (12.96)9560 (47.02)36 690 (55.02)
Hypertension60 (54.54)350 (64.81)10 290 (50.61)39 060 (58.58)
Hyperlipidemia50 (45.45)340 (62.96)9100 (44.76)37 520 (56.27)
Ischemic Heart Disease20 (18.18)100 (18.52)2330 (11.46)10 520 (15.78)
Chronic Kidney Disease20 (18.18)70 (12.96)1880 (9.25)7690 (11.53)
Obesity40 (36.36)190 (35.19)3880 (19.09)16 060 (24.09)
Current Alcohol Use40 (36.36)200 (37.04)6210 (30.55)21 140 (31.70)
Current Smoker30 (27.27)120 (22.22)2350 (11.56)8870 (13.30)
Cirrhosis10 (9.09)10 (1.85)270 (1.33)820 (1.23)

MS, multiple sclerosis; DES, diffuse esophageal spasm; GERD, gastroesophageal reflux disease.

Data are presented as n (%).



Incidence of Achalasia and Diffuse Esophageal Spasm

Of 167 990 adult patients with a diagnosis of MS, 110 (0.07%) and 540 (0.32%) developed achalasia and DES, respectively, within the 15-year period. A total of 66 680 and 20 330 were diagnosed with DES or achalasia in the absence of MS, respectively. A total of 57 665 970 patients without either MS or the 2 esophageal dysmotility disorders were identified. Univariate logistic regression modeling revealed the odds that MS patients will develop achalasia or DES were (OR, 2.09; 95% CI, 1.73-2.52; P-value < 0.001) and (OR, 3.15; 95% CI, 2.89-3.42; P-value < 0.001), respectively (Fig. 1).

Figure 1. Forrest plot displaying odds ratios of multiple sclerosis (MS) patients having either achalasia or diffuse esophageal spasm (DES) compared to the general population. Sensitivity analysis showing non-significant association between MS and asthma.

Prevalence of Co-morbid Dysautonomia

In the MS/achalasia cohort, 30 (27.27%), 20 (18.18%), 10 (9.09%), and 50 (45.45%) patients had urinary incontinence, gastroparesis, impotence, and insomnia, respectively. In the MS/DES cohort, 190 (35.19%), 60 (11.11%), 20 (3.70%), and 300 (55.56%) had these aforementioned symptoms, respectively. In MS patients without esophageal motility disorders, 18 720 (12.64%), 1170 (0.79%), 3270 (2.21%), and 32 370 (21.85%) had these symptoms. Chi-squared test between patients with MS and achalasia, and patients with MS but no esophageal motility disorders showed χ2 values of 24.6, 456.3, 27.0, and 44.2 for urinary incontinence, gastroparesis, impotence, and insomnia, respectively. Between patients with MS and DES, and patients with MS but no motility disorders, χ2 values of 215.5, 498.1, 6.32, and 310.5 were obtained for these symptoms, respectively. All P-values were < 0.001, except impotence, between MS/DES and no motility disorder cohorts (0.012) (Fig. 2).

Figure 2. Bar chart depicting prevalence of dysautonomic comorbidities among the various multiple sclerosis (MS) cohorts. DES, diffuse esophageal spasm. *P < 0.05, ***P < 0.0001.

Database Validation and Sensitivity Analysis

To validate our search strategy and analysis, the odds of MS patients having asthma, which has no reasonable association with the disease was analyzed. On sensitivity analysis, no association between MS and asthma were identified (OR, 1.04; 95% CI, 0.84-1.24; P-value 0.61), indicating that the search criteria we utilized were valid and that potential unmeasured confounding factors were noncontributory (Fig. 1). In addition, data regarding annual incidence rates of achalasia, DES, and MS that were queried from Explorys showed reasonable concordance with known values (Table 2), further validating the real-world accuracy of the data contained within the system.27,28

Table 2 . Annual Incidences of Studied Motility Disorders and Explorys Total Population

YearAnnual incidenceTotal population in Explorys annually
MSAchalasiaDES
2004-200574805206806 592 340
2005-2006948061010206 947 170
2006-200711 88085014808 091 250
2007-200815 0901090202012 079 240
2008-200918 5801360276012 678 670
2009-201023 7501850372013 776 740
2010-201129 1702460587015 663 030
2011-201236 5403310806017 783 190
2012-201346 370410011 50020 297 920
2013-201454 510520014 60021 790 890
2014-201564 440640018 04055 106 960
2015-201671 150709020 58059 723 510
2016-201774 420774022 60063 849 240
2017-201877 080805022 76065 487 230
2018-201977 600821022 47068 495 130

MS, multiple sclerosis; DES, diffuse esophageal spasm.


Discussion

In this population-based study using a nationwide de-identified database, we demonstrated that patients with MS are at a higher odds of developing achalasia and DES as compared to patients without MS. Subgroup analysis further revealed that patients with MS and either dysmotility disorder have higher prevalence of co-morbid conditions of dysautonomia than MS patients without an overlap with esophageal dysmotility.

To our knowledge, this is the first study to investigate the relationships between multiple sclerosis and achalasia or DES. Dysphagia in MS is well described in the literature, with the majority of studies characterizing abnormalities with the oropharyngeal phase of deglutition in these patients. In one study, Calcagno et al29 evaluated 143 patients with MS, of which 34.9% were found to have symptoms of dysphagia; all symptoms were due to dysfunction of the oral and pharyngeal phases of swallowing, evidenced by impairment in tongue coordination during bolus propulsion, lip movement, and glottic closure. This estimated prevalence where one-third of MS patients experiencing dysphagia has been well documented in the literature, with multiple studies reproducing this prevalence. The pathophysiology of MS symptoms in this patient population originate from dysfunctions in the corticobulbar tracts, cranial nerves, cerebellum and brainstem, as well as from cognitive deficits.30 Of these factors, severe brainstem involvement was the highest independent factor to predict dysphagia in MS patients, as the cranial nerves involved in food bolus propulsion and swallow initiation are located within the brainstem.29

The prevalence and association between MS and well characterized intrinsic esophageal motility disorders, such as achalasia or DES, are less known. Dysphagia is the predominant symptom of achalasia, with patients typically reporting progressive dysphagia to solids followed by liquids, often causing weight loss and nocturnal aspiration.31 Symptoms of dysphagia in patients with achalasia are caused by incomplete relaxation of the lower esophageal sphincter (LES), most often caused by the degeneration of NO-producing inhibitory neurons within the walls of the esophagus.32 Although the exact etiology of this degeneration of neurons in primary idiopathic achalasia is largely unknown, several hypotheses exist, with some studies suggesting an association with viral infections, or an autoimmune inflammatory neuro-degeneration etiology. These are based on the observation that patients with achalasia often have serum antibodies against enteric neurons, and that the disease is associated with genetic variants in the human leukocyte antigen DQ region.33-35 Lymphocytic infiltration of these inhibitory neurons leads to aperistalsis and elevation of the LES basal pressure, hallmark findings of achalasia. In one study, Clark et al36 showed that the majority of lymphocytes infiltrating the myenteric plexus are CD3+ T cells, most of which were also CD4+. Goldblum et al37 demonstrated in 42 patients who underwent esophageal resection for end-stage disease, the majority of inflammatory cells were lymphocytes, and to a lesser degree eosinophils and mast cells. Degeneration of the ganglion cells of the dorsal motor nucleus of the vagus nerve, as well as the vagal nerve fibers innervating the esophagus have been shown on histological examinations of some achalasia patients, suggesting dysautonomia as a contributing factor to the disease process.38 We believe that the mechanism behind the relationship between achalasia and MS is driven by similar environmental triggers such as viral infections, and T cell autoimmunity directed at pre and post-ganglionic neurons. Thus, susceptibility to one increases the risk for the other via a shared underlying mechanism (Fig. 3).

Figure 3. Shared mechanisms in the pathogenesis of achalasia and multiple sclerosis. LES, lower esophageal sphincter; EBV, Epstein-Barr virus; HSV, herpes simplex virus; VZV, varicella-zoster virus; HLA-DRB/DQ, human leukocyte antigen DRB and DQ alleles; MHC, major histocompatibility complex; CNS, central nervous system.

Although the etiology of DES is incompletely understood with multiple theories proposed, most experts agree that impaired inhibitory innervation by malfunction of endogenous NO synthesis is the predominant mechanism.18,21 Experimental inhibition of NO via NO-scavengers have shown to induce rapid simultaneous esophageal contractions and produce shortened distal latency, a specific finding in DES. There is a paucity of studies in the literature investigating the mechanistic process which leads to this inhibitory neuron dysfunction in DES; one study from Japan suggested that autoimmune autonomic ganglionopathy is potentially a causative process, with anti-ganglionic acetylcholine receptor antibodies found in elevated levels in a patient with DES.39

The limitations of our study are most inherent to the Explorys system and database analysis. Whereas Explorys offers broad population-level patient information that confers high generalizability, individual patient level data such as esophageal manometric readings and MS severity scores were not available. Furthermore, the diagnosis of achalasia was grouped into a single diagnosis, as the database did not allow differentiation of achalasia into the 3 known subtypes. Additionally, we were not able to analyze other types of esophageal dysmotility, such as ineffective esophageal motility, esophagogastric junction outflow obstruction, hypercontractile esophagus etc, as these diagnoses were not available within the database.

Finally, as individual patient level data were not available, there is always a concern that the data returned by the database is inconsistent. We believe, however, that we attempted to mitigate this issue by performing sensitivity analysis of the database, as well as comparing incidence data to known values reported in the literature. Nonetheless, an example of this may be the high prevalence of GERD in achalasia patients, as these diseases reflect the opposite ends of the spectrum regards to LES pressures. Several studies, however, have shown that these 2 entities can co-exist, and that achalasia patients often do experience high rates of heartburn.40,41 Spechler et al40 have shown that achalasia patients who have higher prevalence of heartburn have lower LES pressures compared to achalasia patients without heartburn, as well as objective findings of GERD such as esophagitis and Barrett’s esophagus, although these latter findings showed lower prevalence. This indicates that there is a wide range of LES pressures among achalasia patients, and that lower values can predispose these patients to acid reflux.40 In addition, esophageal food retention in achalasia patients may lead to inflammation and heartburn sensation. Another possible discrepancy is the higher female prevalence in achalasia patients with MS, compared to achalasia patients without MS. This, however, is an expected finding, as MS affects females more than males in a 2.5-3:1 ratio.42,43 It is likely that the sex difference between these 2 cohorts is driven by the presence of MS, not achalasia.

In summary, patients with MS have an increased odds of having achalasia or DES. Patients with both MS and achalasia or MS and DES displayed higher prevalence of dysautonomic conditions than MS patients without abnormal manometric findings. This may suggest that the presence of an esophageal motor disorder in a MS patient is indicative of a more severe phenotype of the disease.

Financial support:

None.

Conflicts of interest

None.

Author contributions

Yeseong Kim performed study conceptualization and design, data collection, statistical analysis, and manuscript preparation; Fahmi Shibli performed manuscript editing; Yuhan Fu performed data collection and manuscript preparation; Gengqing Song performed manuscript editing; and Ronnie Fass performed study conceptualization, manuscript editing, and project supervision.

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