Open Access Original

Article DOI: 10.7759/cureus.33777

Autonomic Nervous System Regulation Effects of

Epipharyngeal Abrasive Therapy for Myalgic
Review began 01/06/2023
Encephalomyelitis/Chronic Fatigue Syndrome
Review ended 01/14/2023
Published 01/14/2023 Associated With Chronic Epipharyngitis
© Copyright 2023 Ito Hirobumi 1
Hirobumi. This is an open access article
distributed under the terms of the Creative
Commons Attribution License CC-BY 4.0., 1. Otolaryngology, Ito ENT Clinic, Funabashi, JPN
which permits unrestricted use, distribution,
and reproduction in any medium, provided
Corresponding author: Ito Hirobumi, [email protected]
the original author and source are credited.

Abstract
Objective: To evaluate the autonomic nerve stimulation effect of epipharyngeal abrasive therapy (EAT) on
myalgic encephalomyelitis/chronic fatigue syndrome (CFS) associated with chronic epipharyngitis. Heart
rate variability analysis was performed. The study was conducted by analyzing heart rate variability.

Subjects and methods: A total of 29 patients with chronic epipharyngitis who underwent EAT from July 2017
to April 2018 were classified into two groups: 11 patients in the CFS group and 18 patients in the control
group without CFS. The patients were classified as phase 1 during bed rest, phase 2 during nasal endoscopy,
phase 3 during nasal abrasion, and phase 4 during oral abrasion. Electrocardiographic recordings were made,
and autonomic function was compared and evaluated by measuring heart rate, coefficient of variation on R-
R interval (CVRR), coefficient of component variance high frequency (ccvHF), and low frequency/ccvHF ratio
(L/H) for each of the four phases. The Shapiro-Wilk test was performed to confirm the normality of the two
groups, and the parametric test was selected. A repeated measures analysis of variance was performed to
assess changes over time between the four events in the two groups. Multiple comparisons were corrected by
the Bonferroni method. Comparisons between resting data and three events within each group were
performed by paired t-test.

Results: The CFS group had an increased baseline heart rate compared to the control group, and the CFS
group had a greater increase in parasympathetic activity and a decrease in heart rate with nasal abrasion.
Oral abrasion elicited a pharyngeal reflex and increased heart rate and both sympathetic and
parasympathetic activity.

Conclusion: The CFS group was in a state of dysautonomia due to autonomic overstimulation, with an
elevated baseline heart rate. The CFS group was considered to be in a state of impaired autonomic
homeostasis, with an increased likelihood that overstimulation would induce a pathological vagal reflex and
the Reilly phenomenon would develop. The direct effects of EAT on the autonomic nervous system were
considered to be vagus nerve stimulation and the regulation of autonomic function by opposing stimulation
input to sympathetic and parasympathetic nerves. As an indirect effect, bleeding from the epipharyngeal
mucosa due to abrasion was thought to restore the function of the cerebral venous and lymphatic excretory
systems and the autonomic nerve center.

Categories: Internal Medicine, Neurology, Otolaryngology

Keywords: heart rate, chronic fatigue syndrome, myalgic encephalomyelitis, myalgic encephalomyelitis/chronic
fatigue syndrome (cfs), epipharyngeal abrasive therapy (eat), autonomic nervous system regulation, reilly
phenomenon, vagus nerve reflex, heart rate variability analysis

Introduction
Various theories have been reported on the etiology of myalgic encephalomyelitis/chronic fatigue syndrome
(CFS), including viral infection, endocrine abnormalities, immune abnormalities, metabolic abnormalities,
and autonomic nervous system dysfunction. The various abnormalities seen in CFS are thought to form a
cascade in relation to each other [1], and the complaints in CFS are thought to be based on abnormalities in
brain function [2].

Hotta et al. reported three mechanisms of action of epipharyngeal abrasive therapy (EAT) [3-6]. The three
mechanisms are (1) direct mucocutaneous astringent, bactericidal, and anti-inflammatory effects of zinc
chloride; (2) improvement of local circulation by phlebotomy; and (3) vagus nerve stimulation (VNS). EAT
has been used as a treatment for chronic epipharyngitis [7]. EAT has also been reported to be effective as a
treatment for the sequelae of novel coronavirus disease (COVID) infection (long COVID (LC)) [8-10] and CFS
[11], but its mechanism of action is still largely unresolved.

How to cite this article

Hirobumi I (January 14, 2023) Autonomic Nervous System Regulation Effects of Epipharyngeal Abrasive Therapy for Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome Associated With Chronic Epipharyngitis. Cureus 15(1): e33777. DOI 10.7759/cureus.33777
 Tracey et al. reported that VNS has an inflammatory reflex that suppresses inflammation via the immune
system [12]. VNS, which applies the inflammatory reflex, has been used as a treatment for intractable
epilepsy, autoimmune diseases, intractable headaches, and depression [5]. EAT is expected to have the same
effects as VNS. However, stimulation of parasympathetic nerves may induce pathological vagal reflexes [13],
and chronic persistent stimulation of sympathetic nerves or inflammation-related factors may induce
pathological autonomic reflexes, resulting in decreased autonomic nervous system activity and autonomic
overstimulation syndrome (Reilly phenomenon) [14]. These pathological vagal reflexes and the Reilly
phenomenon may be responsible for the variety of symptoms caused by chronic epipharyngitis. Thus, it can
be inferred that EAT may have both a therapeutic effect and a potential for exacerbating chronic
epipharyngitis, two potentially conflicting effects.

The purpose of this study was to evaluate the efficacy of EAT in CFS associated with chronic epipharyngitis,
to clarify the pathogenesis of CFS, and to elucidate the mechanism of action of EAT on CFS. Heart rate (HR)
variability analysis is a noninvasive method to measure and evaluate autonomic function.

Ito reported that the mechanism of the effect of EAT on the autonomic nervous system was examined using
HR variability analysis [15]. In this study, we discuss the two conflicting mechanisms of action of EAT on the
autonomic nervous system, and report the results of this study, considering that one of the therapeutic
effects of EAT may be its autonomic modulatory effect.

Materials And Methods

A patient who visited our hospital with chief complaints of postnasal drip, hoarseness, abnormal feeling in
the throat, sore throat, etc. was diagnosed with chronic epipharyngitis according to Tanaka's diagnostic
criteria [4]. When patients complain of sore throat or dysphagia without any particular findings, a
differential diagnosis is made with consideration of diseases such as elongation of the styloid process (Eagle
syndrome) [16]. From July 2017 to April 2018, 288 patients with chronic epipharyngitis were examined, and
29 patients underwent EAT while monitoring the electrocardiogram: total mean age = 39.8 ± 17.1 years; five
males (mean age = 26.2 ± 17.5 years); 24 females (mean age = 42.6 ± 15.9 years); and male-to-female ratio =
1:4.8.

Eleven patients (33.7 ± 15.1; three males and eight females) with chief complaints of chronic fatigue and
autonomic neuropathy at the initial visit were classified as the CFS group. Eighteen patients (mean age 43.5 ±
17.6; two males and 17 females) who did not complain of other autonomic symptoms were classified as the
control group, and electrocardiographic recordings were compared between the two groups. Oral and
written informed consent was obtained from all patients, and the study was conducted in compliance with
the Declaration of Helsinki. When handling the data and other materials related to the study, we took great
care to protect the confidentiality of the subjects, and we did not include any information that could identify
the subjects when publishing the results of the study. This is a retrospective observational study based on
existing medical record information, and no new samples or information were obtained. The study was
approved by the Ethics Committee of the Chiba Prefecture Health Physicians Association (approval no.:
20210601008).

Diagnosis and treatment were performed using a band-limited optical endoscope system (Pentax EPK-i7000
Video Processor and VNL11-J10 Video Scope with a 3.5 mm diameter outer tip, PENTAX Medical, Tokyo,
Japan). After the patient was placed at rest, he was anesthetized with 1% Xylocaine as a nasal procedure to
prevent pain in the nasal cavity, and hyperemia and swelling of the nasal mucosa were removed with a 0.01%
solution of adrenaline. After confirming that the ECG was stabilized, an endoscope was inserted nasally and
a series of treatments with EAT was initiated. First, an endoscopic diagnosis was made, and then
epipharyngeal abrasion was performed nasally using a Rouze swab moistened with 1% zinc chloride solution
while observing the epipharynx. Next, epipharyngeal abrasion was performed orally using a Zhermack
pharyngeal crimp cotton swab soaked in 1% zinc chloride solution. After observation of bleeding, the
endoscope was removed and the EAT was terminated.

The ECG recordings were classified into the following four phases: (1) resting and waiting (phase 1); (2)
nasally inserting an endoscope for examination (phase 2); (3) nasal abrasion treatment of the epipharyngeal
mucosa (phase 3); and (4) oral abrasion treatment of the epipharyngeal mucosa (phase 4). HR variability
analysis was performed for each of the four phases. HR variability analysis was performed using HR
variability analysis software (Reflex Meijin, Crosswell Co., Ltd., Yokohama, Japan). HR is affected by
autonomic nervous activity involved in respiration and systemic circulation, and HR variability is observed
in the ECG R-R interval. High-frequency components (HFC) and low-frequency components (LFC) are
common indices of fluctuations in the cardiovascular system. The coefficient of variation on the R-R
interval (CVRR) is an aggregate of components (coefficient of component variance high frequency
(ccvHF), low frequency (LF), etc.) of frequency analysis results and is used as the sum of autonomic nervous
activity [17]. ccvHF is used as an index of parasympathetic function [18]. The LF component reflects
sympathetic and parasympathetic functions, and the LF/ccvHF ratio (L/H) divided by ccvHF is used as an
index of sympathetic function. Measurements were taken within the interval of each event, with a 30-
second ECG recording interval as one data length, and the R-R interval (detected by the peak interval of the
R wave) for each beat within that interval was sampled at a sampling frequency of 1000 Hz and the average

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 value was calculated. HFC and LFC were defined as 0.15-0.40 Hz and 0.04-0.15 Hz, respectively. Four items
(HR, CVRR, ccvHF, and L/H) were evaluated in the four phases and statistically examined.

An F-test confirmed that the two groups (CFS group and control group) had equal variances. A Shapiro-Wilk
test was performed for each endpoint to ensure normal distribution and a parametric test was selected. A
Smirnov-Grubbs test was performed on each endpoint measure and no outliers were identified. A repeated
measures analysis of variance (rm ANOVA) was performed to assess changes over time between the four
events. Multiple comparisons were corrected with the Bonferroni method. The statistical analysis was
performed by rm ANOVA for changes over time in phases 1-4, and comparisons were made among the four
events. Multiple comparisons were corrected by the Bonferroni method. The comparison between phase 2,
phase 3, and phase 4 of the CFS group and the control group was performed using a paired t-test, with phase
1 at rest before the start of EAT as the reference value. The mean value of phase 1 of each group was used as
the reference value, and the difference between the mean values of phase 2, phase 3, and phase 4 was used
to determine the rate of change for the comparison. The statistical software EZR version 2.6-2 was used for
statistical analysis. A difference with a risk rate of less than 5% was considered statistically significant.

Results
The 288 patients included 65 males, with a mean age of 43.8 ± 18.5 years, and 223 females, with a mean age
of 45 ± 15.1 years. The mean overall age was 44.7 ± 16.0 years, with a sex ratio of 1:3.5. Table 1 presents a
summary of the chief complaints of all patients. The CFS group consisted of 11 patients (3.8%), and the
control group consisted of 18 patients (Table 1).

Principal complaint Number of cases %

Posterior rhinorrhea 130 45.1

Hoarseness 42 14.6

Abnormal pharyngeal sensation 41 14.2

Sore throat 22 7.6

Dizziness 13 4.5

Cough 12 4.2

Chronic fatigue syndrome 11 3.8

Headache 10 3.5

Ear closure 4 1.9

Atopic dermatitis 4 1.9

IgA nephropathy 1 0.3

Pustulosis palmoplantaris 1 0.3

Rheumatoid arthritis 1 0.3

Sleep apnea syndrome 1 0.3

Total number of cases 288 100

TABLE 1: Summary of principal complaints

The following is a breakdown of the chief complaints of the 288 patients seen. Chronic fatigue syndrome was reported in 11 cases (3.8%).

The CFS group showed significant changes in HR (p = 0.000) and CVRR (p = 0.012) (Figures 1, 2). ccvHF was
close to significant with p = 0.077 (Figure 3). L/H showed no significant difference but showed a decreasing
trend with increasing ccvHF in phase 3 and an increasing trend with decreasing ccvHF in phase 4 (Figure 4).
In multiple comparisons, HR was significantly different between phases 2 and 4 (p = 0.044), and between
phases 3 and 4 (p = 0.009). CVRR was close to significant between phases 1 and 4 (p = 0.052). In the control
group, there was no significant change in HR (p = 0.000). The control group showed a significant change in
HR (p = 0.000). In multiple comparisons, HR was significantly different between phase 2 and phase 4 (p =
0.011), and CVRR was close to significantly different (p = 0.056).

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 FIGURE 1: Change in HR over time
The white bars represent the control group and the gray bars represent the CFS group. The vertical axis shows
HR in bpm. The abscissa shows the measured values of phases 1-4, indicating the time course. Measurements
are shown in the box and whisker diagram. The center line indicates the median value, and the X mark indicates
the mean value. The mean of each group is connected by a solid line. rm ANOVA showed that both the CFS group
and the control group were significantly different (p < 0.01). Multiple comparisons showed that the CFS group was
significantly different between phase 2 and phase 4 (p = 0.044) and between phase 3 and phase 4 (p < 0.01),
while the control group was significantly different between phase 2 and phase 4 (p = 0.011).

HR: heart rate; CFS: chronic fatigue syndrome; rm ANOVA: repeated measures analysis of variance.

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 FIGURE 2: Change in CVRR over time
The vertical axis indicates CVRR, expressed in %. The rm ANOVA showed a significant difference in the CFS
group (p = 0.012). Multiple comparisons showed that the CFS group showed a near-significant change between
phase 1 and phase 4 (p = 0.052). The control group showed no significant difference.

CVRR: coefficient of variation on the R-R interval; CFS: chronic fatigue syndrome; rm ANOVA: repeated
measures analysis of variance.

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 FIGURE 3: ccvHF change over time
The vertical axis indicates ccvHF, expressed in %. The rm ANOVA showed that the CFS group was close to
significant (p = 0.077), but not significantly different from the CFS group.

ccvHF: coefficient of component variance high frequency; CFS: chronic fatigue syndrome; rm ANOVA: repeated
measures analysis of variance.

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 FIGURE 4: Change in L/H over time
The vertical axis indicates L/H, and the units are ratios. L/H showed a decreasing trend in phase 3 and an
increasing trend in phase 4.

CFS: chronic fatigue syndrome; L/H: low frequency/ccvHF ratio.

Within the same group, a paired t-test comparison between the two groups at rest and between the three
phases is shown (Table 2). The CFS group showed significant changes in HR in phase 3, CVRR in phase 4,
and ccvHF in phase 3. A comparison of the mean HR in phase 1 between the control group and the CFS group
showed that the resting baseline HR of the CFS group was 5.3% higher than that of the control group. The
CFS group had a higher HR in phase 2 and phase 4, but the CFS group had a lower HR in phase 3. The
variability of HR and CVRR in phase 2 did not differ from that of the control group, while ccvHF and L/H
were more variable in the CFS group. The variability of ccvHF in phase 3 was higher in the CFS group (22.6%)
than in the control group (11.1%). The variability of L/H in phase 3 showed a decrease of 14.2% in the CFS
group versus a large decrease of 30.0% in the control group. The variability of CVRR in phase 4 showed an
increase of 17.4% in the control group versus a large increase of 35.6% in the CFS group.

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 P- P- P-
Item Unit Group Phase 1 Phase 2 Phase 3 Phase 4
value value value

83.82 ± 79.96 ± 78.44 ± 89.33 ±

HR bpm CSF group -4.6 0.063 -6.4 0.040 6.6 0.098
10.84 12.58 10.72 11.15

Control 79.59 ± 76.21 ± 78.69 ± 85.74 ±

-4.2 0.010 -1.1 0.497 7.7 0.045
group 13.16 11.46 12.79 15.96

CVRR % CSF group 5.62 ± 2.12 6.37 ± 2.51 13.3 0.335 5.76 ± 1.93 2.5 0.719 7.62 ± 2.37 35.6 0.009

Control
5.12 ± 1.76 5.89 ± 1.93 15.0 0.062 5.00 ± 2.06 -2.4 0.674 6.01 ± 2.80 17.4 0.106
group

ccvHF % CSF group 1.24 ± 0.51 1.39 ± 0.52 12.1 0.111 1.52 ± 0.64 22.6 0.030 1.33 ± 0.50 7.3 0.492

Control
1.16 ± 0.46 1.22 ± 0.47 4.3 0.504 1.30 ± 0.61 11.1 0.173 1.33 ± 0.71 12.0 0.152
group

- -
L/H Ratio CSF group 5.74 ± 3.01 4.65 ± 2.77 0.371 4.78 ± 2.06 0.295 6.09 ± 4.33 5.9 0.838
16.5 14.2

Control -
6.96 ± 5.59 6.51 ± 5.27 -6.5 0.771 4.87 ± 2.70 0.085 8.08 ± 8.95 16.1 0.483
group 30.0

TABLE 2: Measurements, percent change, and p-values for each phase of the CFS group (n = 11)
and the control group (n = 18)
Measurements are shown as mean ± standard deviation. Percentage change is shown as %. Within each group, two-arm comparisons between phase 1
and the other three phases (i.e., phase 1 vs. phase 2, phase 1 vs. phase 3, and phase 1 vs. phase 4) were performed by paired t-test. The CFS group
showed significant changes in HR in phase 3, CVRR in phase 4, and ccvHF in phase 3. The control group showed significant changes in HR in phase 2
and phase 4.

The resting baseline heart rate in phase 1 was higher in the CFS group, but the reduction in HR in phase 3 was greater in the CFS group. CVRR showed
a greater rate of increase in phase 4 in the CFS group. L/H tended to be more variable in the control group.

HR: heart rate; CFS: chronic fatigue syndrome; CVRR: coefficient of variation on the R-R interval; ccvHF: coefficient of component variance high
frequency; L/H: low frequency/ccvHF ratio.

Discussion
The purpose of this study was to analyze the pathogenesis of CFS with chronic epipharyngitis and to
elucidate the mechanism of action of EAT. Subjects were divided into two groups (CFS group and control
group), and EAT was performed. CVRR showed a significant change over time in the CFS group. This
indicates that the CFS group showed greater variability in response to EAT stimulation compared to the
control group.

First, the mean age of the 288 patients with chronic epipharyngitis in this study was 44.7 years, with a male-
to-female ratio of 1:3.5. Ohno reported that the mean age of chronic epipharyngitis cases was 42.9 years,
with a male-to-female ratio of 1:3 [19]. The results of this study suggest that chronic epipharyngitis is a
common disease among middle-aged women. The frequency of chief complaints among the examinees in
this study was as follows: posterior rhinorrhea in 45.1%, hoarseness in 14.6%, dysphonia in 14.2%, sore
throat in 7.6%, and CFS in 3.8%. Mogitate et al. reported the frequency of chief complaints among the
patients seen as posterior rhinorrhea in 41.2%, sore throat in 11.8%, abnormal sensation in 10.8%, IgA
nephropathy in 7.8%, and CFS in 7.8% [20]. The study population may reflect the average chronic
epipharyngitis case. Since chronic epipharyngitis cases are often associated with CFS, it is considered
important to evaluate autonomic function. HR variability analysis is a noninvasive method to evaluate
autonomic function. We conducted this study because we believe that HR variability analysis may be a useful
tool for elucidating the autonomic nerve-stimulating effects of EAT.

EAT has been reported to be similar to intranasal sphenopalatine ganglion stimulation (INSPGS). EAT
stimulation is thought to have parasympathetic stimulating effects [9]. In the present study, an increase in
parasympathetic activity during nasal abrasion with a concomitant decrease in HR was observed. Ito
reported on the autonomic reflex activity induced by EAT stimulation using HR variability analysis. Ito
reported HR variability analysis and autonomic reflex activity induced by EAT stimulation. During nasal
abrasion and nasal endoscopy, autonomic activity was increased and CVRR showed bimodal changes in
activity. During nasal abrasion, parasympathetic activity is stimulated and sympathetic activity is

2023 Hirobumi et al. Cureus 15(1): e33777. DOI 10.7759/cureus.33777 8 of 12

 suppressed. During oral rubbing, both sympathetic and parasympathetic nerves are stimulated
simultaneously, but sympathetic and parasympathetic nerves move oppositely, and there is a time lag in
their activity. Therefore, it was reported that EAT stimulation has both sympathetic and parasympathetic
stimulating effects, but the response depends on the timing and site of stimulation [15]. During nasal
abrasion, parasympathetic activity was increased and HR was decreased, but the decrease in HR was greater
in the CFS group than in the control group. It is known that stimuli such as mental stress, excessive pain,
excretion, and abdominal visceral disease induce vagal reflexes such as hypotension, HR reduction, and
syncope and that HR is reciprocally coupled with parasympathetic activity. EAT may induce vagal reflexes,
but the CFS group showed a greater decrease in HR than the control group. The CFS group was more likely
than the control group to have a vagal reflex induced by EAT.

Comparison within the same group showed that the CFS group had a higher baseline HR and a greater
decrease in HR during nasal abrasion than the control group, while the CFS group had a greater increase in
HR during oral abrasion. The CFS group also showed greater variability in ccvHF and CVRR. The CFS group
showed greater variability in autonomic and parasympathetic activities induced by EAT stimulation,
suggesting that the CFS group is more sensitive to stimulation. Kuratsune et al. reported that CFS patients
exhibit both sympathetically dominant and parasympathetically depressed states [21]. Persistent
inflammatory stimulation by chronic epipharyngitis stimulates the sympathetic reflex and exhausts the
parasympathetic function. Such a persistent state induces a state of autonomic ataxia. As a result, the
baseline HR is considered to be elevated in CFS with chronic epipharyngitis [22]. In the present study, an
elevated baseline HR was also observed in the CFS group. This increase in baseline HR may indicate a state
of decreased parasympathetic function. HR regulation by the sympathetic and parasympathetic nerves is
also a phenomenon called accentuated antagonism, in which HR regulation by the parasympathetic nerves is
enhanced in the presence of sympathetic activity [23]. The increased variability of HR in the CFS group may
be due to the fact that the sympathetic nervous system is stimulated by the persistent inflammatory
stimulus, and the sensitivity of the vagus nerve is also increased. In CFS caused by chronic epipharyngitis,
persistent inflammatory stimulation stimulates the sympathetic reflex and exhausts the parasympathetic
function, but the vagus nerve reflex is easily triggered.

It is known that overstimulation of the autonomic nervous system causes microcirculatory disturbances and
hemorrhagic lesions due to ischemia and reperfusion disorders in various organs throughout the body,
resulting in the Reilly phenomenon [14,24]. In the control group, the fluctuation of measured values is
relatively small, suggesting that autonomic homeostasis is at work. In the CFS group, the fluctuation of each
endpoint is large and autonomic homeostasis is considered to be impaired. The possibility that pathological
vagal reflexes are triggered by overstimulation and that the Reilly phenomenon may occur is considered to
be increased. The results of this study suggest that the CFS group is in a state of autonomic dysfunction due
to autonomic overstimulation and that the vagus nerve reflex is easily triggered. Porges proposed the
polyvagal theory, which states that the autonomic response to stress consists of a hierarchical regulatory
response of two types of vagal nerves (ventral and dorsal vagal systems) and the sympathetic nervous system
[25]. In the stress response, the ventral vagal system initially acts in an inhibitory manner and regulates the
HR and other functions. When the sympathetic nervous system is stimulated, the ventral vagal system is
released from its inhibitory role and a reflex response is triggered. One of the possible pathophysiologies of
CFS is the inability of the vagus nervous system to suppress and regulate sympathetic over-reactivity in
response to stress, i.e., vagal homeostasis may be impaired. CFS patients with persistent chronic stimulation
have impaired autonomic regulation and elevated baseline HR. During nasal abrasion stimulation, the
increase in parasympathetic activity and the associated decrease in HR are controlled by respiratory sinus
arrhythmia (RSA) in the ventral vagal system [26], whereas, in CFS, the ventral vagal system is over-
suppressed. In CFS, however, the ventral vagal system may be excessively suppressed, leading to the
development of autonomic neuropathy and other complaints.

The direct autonomic nerve stimulating effect of EAT may be, first, to stimulate the parasympathetic
function and restore the vagus nerve reflex. Second, by stimulating both sympathetic and parasympathetic
nerves simultaneously to induce the pharyngeal reflex, it may work to normalize the onset of the pharyngeal
reflex. However, the autonomic reflex activity by EAT may induce pathological vagal reflexes or Reilly's
phenomenon because the response differs depending on the stimulus intensity, stimulus duration, stimulus
site, and sensitivity of the individual.

Currently, the stellate ganglion block (SGB) is used as a treatment method to suppress or stimulate the
autonomic nervous system. SGB temporarily blocks the sympathetic nervous system to increase
parasympathetic activity. After SGB blocks nerve function, autonomic activity fluctuates due to a rebound
phenomenon [27]. SGB repetitive stimulation therapy shakes the autonomic nervous system, regulates the
autonomic nervous system balance of sympathetic and parasympathetic nerves, and activates self-repair
functions [28]. It is speculated that the mechanism of the therapeutic effect of EAT on the autonomic
nervous system is similar to that of SGB repetitive stimulation therapy and that the conflicting excitatory
and inhibitory input stimuli from simultaneous stimulation of the sympathetic and parasympathetic nervous
systems may induce the pharyngeal reflex to adjust and activate autonomic nervous system functions.

Tracey proposed an inflammatory protective system in the vagus nerve system and named it the
inflammatory reflex [12]. VNS, which applies this mechanism, has been used as a treatment for autoimmune

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 diseases and depression [29]. The results of this study revealed that EAT has vagus nerve stimulating effects,
suggesting that EAT may express anti-inflammatory effects through the inflammatory reflex. EAT is
considered to be a simple VNS treatment that is not invasive like SGB and does not require expensive
mechanical devices or surgery like VNS. Although it is not possible to compare the superiority of EAT to SGB
or VNS at this point, EAT may improve various clinical symptoms caused by chronic epipharyngitis through
its anti-inflammatory effect and activation of autonomic nervous system activity. EAT may be effective
against brain dysfunction in CFS, complaints due to autonomic dysfunction, and brain fog due to LC by
activating autonomic nervous system activity.

Kuroiwa et al. reported that the hypothalamus and periventricular organs are important as security gates of
the stress center [30], and Iliff et al. reported that cerebrospinal fluid dynamics are regulated by the
glymphatic system, and the nasopharyngeal circulation pathway is important as a drainage route for cerebral
waste products [31]. When the epipharyngeal mucosa becomes congested, circulatory disturbance of the
stress center is caused, resulting in various autonomic symptoms. Uebaba reported that Batson's venous
plexus is important in cerebral and spinal venous drainage. The vertebral venous plexus within the spinal
canal is called Batson's venous plexus, and it communicates with the venous plexus outside the spinal canal
to act as an excretory pathway. Since Batson's venous plexus has no valve structure, venous blood flow is
slow and prone to stagnation. Also, the direction of flow is easily reversed. Venular congestion is likely to
occur in chronic epipharyngitis, and venous congestion occurs in the vertebral venous plexus such as the
axis and atlas when circulation disorder occurs in the epipharyngeal mucosa. It has been reported that this
causes circulatory disturbance in the autonomic nerve center, resulting in autonomic dysfunction [32].

The pharyngeal veins and lymphatic vessels have an important function as cerebral veins and lymphatic
drainage channels, and when the circulatory disturbance is induced by chronic epipharyngitis, the cerebral
waste excretion system may be impaired, resulting in autonomic neuropathy. Directly, EAT has the function
of improving inflammation of the local mucosa and resolving the autonomic nervous system stimulation
state but it is also thought that physical abrasion and phlebotomy of the diseased epipharyngeal mucosa
may restore the function of the cerebral venous and lymphatic excretory system and improve autonomic
nervous system function in the brainstem, thalamus, and hypothalamus. Indirectly, EAT may also have an
effect on stimulating autonomic nervous system function.

The present study was a retrospective observational study and no controlled trial was conducted using
healthy subjects as controls. Further clarification of the differences between EAT-induced autonomic
reflexes and pathological vagal reflexes or the Reilly phenomenon is needed, such as the degree of difference
in stimulation intensity, stimulation duration, and stimulation site, as well as the difference in sensitivity
among individuals. In addition, this study did not examine the prognosis of CFS patients treated with EAT.
This is an issue for future studies.

Conclusions
The post-hoc analysis comparing the CFS group with the control group showed that the CFS group was in a
state of autonomic ataxia caused by autonomic nerve overstimulation and that the vagus nerve reflex was
easily induced. The EAT nasal abrasion increased parasympathetic activity and decreased HR in CFS
patients. Oral EAT rubbing induced the pharyngeal reflex and increased HR and autonomic nervous system
activity.

The direct effects of EAT on the autonomic nervous system may be the VNS effect by parasympathetic
stimulation and the autonomic regulation effect by opposing excitatory and inhibitory stimulus inputs to
sympathetic and parasympathetic nerves. Indirect effects on the autonomic nervous system may include
improvement of hypothalamic autonomic function through the recovery of cerebral venous and lymphatic
excretory system function. These autonomic nerve-stimulating effects may act synergistically to produce the
effect of EAT.

Additional Information
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of the
Chiba Prefecture Health Physicians Association issued approval 20210601008. The research plan and other
matters were approved based on the deliberations of the Ethics Committee of the Chiba Prefecture Health
Physicians Association held on June 1, 2021. Animal subjects: All authors have confirmed that this study
did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform
disclosure form, all authors declare the following: Payment/services info: All authors have declared that no
financial support was received from any organization for the submitted work. Financial relationships: All
authors have declared that they have no financial relationships at present or within the previous three years
with any organizations that might have an interest in the submitted work. Other relationships: All authors
have declared that there are no other relationships or activities that could appear to have influenced the
submitted work.

2023 Hirobumi et al. Cureus 15(1): e33777. DOI 10.7759/cureus.33777 10 of 12

 Acknowledgements
I would like to express my sincere gratitude to Dr. Manabu Mogitate, Director of Mogitate Otolaryngology,
for his guidance on the epipharyngeal abrasive therapy and the paper.

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