![EHS/MCS physiopathological model based on low-grade neuroinflammation and oxidative/nitrosative stress-induced blood-brain barrier disruption, according to Reference [10].](https://www.researchgate.net/publication/339941905/figure/fig1/AS:879563764690961@1586715751328/EHS-MCS-physiopathological-model-based-on-low-grade-neuroinflammation-and_Q320.jpg)
![Age and sex ratio in EHS and/or MCS self-reported patients, according to Reference [10].](https://www.researchgate.net/publication/339941905/figure/tbl1/AS:879563764662278@1586715751385/Age-and-sex-ratio-in-EHS-and-or-MCS-self-reported-patients-according-to-Reference-10_Q320.jpg)
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International Journal of
Molecular Sciences
Review
Electrohypersensitivity as a Newly Identified and
Characterized Neurologic Pathological Disorder: How
to Diagnose, Treat, and Prevent It
Dominique Belpomme 1,2,3,* and Philippe Irigaray 1,2
1Association for Research Against Cancer (ARTAC), 57/59 rue de la Convention, 75015 Paris, France;
philippei.artac@gmail.com
2European Cancer and Environment Research Institute (ECERI), 1000 Brussels, Belgium
3Department of Cancer Clinical Research, Paris V University Hospital, 75005 Paris, France
*Correspondence: contact.belpomme@gmail.com
Received: 5 February 2020; Accepted: 5 March 2020; Published: 11 March 2020
Abstract:
Since 2009, we builtup a database which presently includes more than 2000electrohypersensitivity
(EHS) and/or multiple chemical sensitivity (MCS) self-reported cases. This database shows that
EHS is associated in 30% of the cases with MCS, and that MCS precedes the occurrence of EHS in
37% of these EHS/MCS-associated cases. EHS and MCS can be characterized clinically by a similar
symptomatic picture, and biologically by low-grade inflammation and an autoimmune response
involving autoantibodies against O-myelin. Moreover, 80% of the patients with EHS present with
one, two, or three detectable oxidative stress biomarkers in their peripheral blood, meaning that
overall these patients present with a true objective somatic disorder. Moreover, by using ultrasonic
cerebral tomosphygmography and transcranial Doppler ultrasonography, we showed that cases have
a defect in the middle cerebral artery hemodynamics, and we localized a tissue pulsometric index
deficiency in the capsulo-thalamic area of the temporal lobes, suggesting the involvement of the
limbic system and the thalamus. Altogether, these data strongly suggest that EHS is a neurologic
pathological disorder which can be diagnosed, treated, and prevented. Because EHS is becoming a
new insidious worldwide plague involving millions of people, we ask the World Health Organization
(WHO) to include EHS as a neurologic disorder in the international classification of diseases.
Keywords:
electrohypersensibility; multiple chemical sensitivity; neurologic disease; oxidative
stress; melatonin; O-myelin; inflammation; histamine; radiofrequency; extremely low frequency;
electromagnetic fields
1. Introduction
The term electromagnetic hypersensitivity or electrohypersensitivity (EHS) was first proposed in
1991 by William Rea to identify the clinical condition of patients reporting health effects while being
exposed to an electromagnetic field (EMF) [
1
]. This term was then used in 1997 in a report provided
by a European group of experts for the European Commission to clinically describe this unusual
pathology, which may imply EMF exposure [2].
In 2002, Santini et al. in France reported similar symptomatic intolerance in users of digital
cellular phones and among people living near wireless communication base stations [
3
,
4
]. In 2004,
because of the seemingly worldwide prevalence increase in EHS, the World Health Organization
(WHO) organized an international scientific workshop in Prague to define and characterize EHS.
Although not acknowledging EHS as being caused by EMF exposure, the Prague working group clearly
defined EHS as “a phenomenon where individuals experience adverse health effects while using or
Int. J. Mol. Sci. 2020,21, 1915; doi:10.3390/ijms21061915 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020,21, 1915 2 of 20
being in the vicinity of devices emanating electric, magnetic, or electromagnetic fields” [
5
]. WHO
then acknowledged EHS as an adverse health condition [
6
]. However, according to a previous 1996
International Program on Chemical Safety (IPCS)-sponsored conference in Berlin on multiple chemical
sensibility (MCS) [
7
], it was recommended to qualify such unknown new pathological conditions
under the term of “idiopathic environmental intolerance (IEI)”. Thus, following the Prague workshop,
instead of using the term EHS, it was proposed to use the term “idiopathic environmental intolerance
attributed to EMF (IEI-EMF)” to name this particular pathological condition, because of the lack of a
proven causal link between EHS and EMF exposure, and no proven physiopathological mechanism
linking EMF exposure with clinical symptoms.
That is indeed what WHO officially stated in its 2005 fact sheet 296 [
6
], indicating that “EHS
resembles MCS, another disorder associated with low-level environmental exposure to chemicals
. . .
” and that because of “non-specific symptoms” and “no clear diagnostic criteria”, this “disabling
condition” could not be diagnosed medically. In addition, in 2002 and 2013, WHO classified extremely
low frequencies (ELF) and radiofrequencies (RF) respectively as possibly carcinogenic (group IIB),
meaning that EMFs may cause cancer. This past scientific evolution is summarized in Table 1.
Table 1.
Electrohypersensitivity (EHS)/multiple chemical sensitivity (MCS) and cancer statements
including those of the World Health Organization (WHO) or on behalf of WHO. COST—European action
for co-operation in the field of science and technological research on biological effects of electromagnetic
fields; EMF—electromagnetic field; IARC—international agency for research on cancer.
1996 Berlin: WHO-sponsored workshop; MCS classified as idiopathic environmental intolerance (IEI)
1997 Stockholm: Possible health implication of electromagnetic field exposure; a report prepared by a
European group of experts for the European Commission
1998 Austria: COST 244 bis international workshop on EHS
1998 Atlanta (US): MCS 1999 consensus meeting
2002 IARC: Extremely low frequency (ELF) EMFs classified as possibly carcinogenic (Group IIB)
2004 Prague: WHO workshop; identification of idiopathic environmental intolerance attributed to EMF
2005 WHO: WHO fact sheet n◦292 aiming at defining EHS
2013 IARC: Radiofrequency (RF) EMFs classified as possibly carcinogenic (Group IIB)
2015 Brussels: Fourth Paris Appeal Colloquium; a focus on electromagnetic fields and EHS
However, since the 2005 WHO statement on EHS and a more recent 2014 WHO report on
mobile phone exposure and public health [
8
], much clinical and biological progress has been made
in identifying and characterizing EHS, as summarized during the international scientific consensus
meeting on EHS and MCS which we organized in May 2015 in Brussels at the Royal Belgium Academy
of Medicine [9].
Because we suspected that EHS prevalence was increasing worldwide, since 2009, we constituted
and maintained a database which was registered by the French Committee for the protection of
persons (CPP), under the registration number 2017-A02706-47, as well as in the European Clinical
*Trials* Database (*EudraCT*), under the registration number 2018-001056-36. This database presently
includes more than 2000 EHS and/or MCS cases. All the patients included in this series gave their
informed consent for clinical and biological research investigations. In addition, all these patients were
anonymously registered in the database.
By querying this database, we showed for the first time that EHS is frequently associated with
MCS [
10
], and that EHS and MCS are characterized by a common similar clinical picture which can be
identified objectively by the detection of similar biomarkers in the peripheral blood and urine [
10
,
11
],
and by similar pulsometric abnormalities in the brain [
10
,
12
]. Thus it finally appears that EHS and
MCS could in fact be two etiopathogenic aspects of a unique pathological disorder [
10
]. We would like
here to overview our original data and discuss the possibility that EHS is part of a true pathologic
neurologic disorder resulting from a comprehensive physiopathologic mechanism, in common with
MCS. We conclude that EHS—whatever its causal origin—is becoming a worldwide plague. Thus, as
Int. J. Mol. Sci. 2020,21, 1915 3 of 20
we showed that it can be diagnosed, treated medically, and eventually prevented, we ask WHO to
include EHS in the international classification of diseases (ICD).
2. Demography
In a prospective study involving systematic face-to-face questionnaire-based interviews and
clinical physical examinations of many patients constituting part of the database, we reported that
EHS is a well-defined clinico-biological entity [10].
Table 2presents the demographic data we obtained from the serial analysis of the first 726
consecutive cases included in the database. No children were included. Median and mean ages were
48 years for the EHS group, 48 and 47 years, respectively, for the MCS group, and 46 years for the EHS
and MCS-associated group. Sex ratio shows a clear predominance of women among patients, reaching
two-thirds in the EHS group and the MCS group, while it was three-quarters in the group of patients
presenting with both disorders. This strongly suggests that women are genetically more susceptible
than men to the environmental intolerance attributed to EMFs and/or chemicals.
Table 2. Age and sex ratio in EHS and/or MCS self-reported patients, according to Reference [10].
Demographic Data EHS MCS EHS/MCS
n(%) 521 (71.7%) 52 (7.1%) 154 (21.2%)
Age (mean ±SD) 48.2 ±12.9 48.5 ±10.3 46.7 ±11.2
Age (median (range)) 48 (16–83) 47 (31–70) 46 (22–76)
Sex ratio (women/men) 344/177 34/18 117/37
Female (%) 66 65 76
3. Clinical Description
Table 3presents the detailed symptomatic picture that we obtained during face-to-face interviews
and clinical examinations for the groups of (1) EHS self-reported patients, (2) MCS self-reported
patients, and (3) both disorder self-reported patients. Symptoms in patients with EHS were compared
with those from a series of apparently healthy control subjects that showed no clinical evidence of
EHS and/or MCS. As indicated in the table, EHS is characterized by the occurrence of neurologic
symptoms including headache, tinnitus, hyperacusis, dizziness, balance disorder, superficial and/or
deep sensibility abnormalities, fibromyalgia, vegetative nerve dysfunction, and reduced cognitive
capability, including immediate memory loss, attention–concentration deficiency, and eventually
tempo-spatial confusion. These symptoms were associated with chronic insomnia, fatigue, and
depressive tendency, in addition to emotional lability and sometimes irritability. A major observation
is that symptoms were repeatedly reported by the patients to occur each time they reported being
exposed to presumably EMF sources, even of weak intensity, and to regress or even disappear after
they left these presumed sources. With the exception of arthralgia and emotivity, which were observed
at a similar frequency range in the control group, all clinical symptoms occurring in EHS patients were
found to be significantly much more frequent than those in apparently normal controls.
Contrary to what was claimed from studies reporting clinical symptoms in EHS patients [
2
,
5
,
6
,
13
],
these symptoms were not all subjective. In many cases, they were confirmed by family members;
moreover, we were able to detect, at physical examination, a Romberg sign (objective posture test) in
5% of the cases and to observe the presence of cutaneous lesions in 16%. Overall, although many of
these symptoms are considered as non-specific in the scientific literature, the general clinical picture
resulting from their association and frequency strongly suggests that EHS can in fact be recognized
and identified as a typical neurologic disorder as it is also the case for MCS and MCS-associated EHS.
Int. J. Mol. Sci. 2020,21, 1915 4 of 20
Table 3.
Clinical symptoms in EHS self-reported patients in comparison with those in normal controls
and in comparison with those in MCS and EHS/MCS self-reported patients *, according to Reference [
11
].
Clinical Symptoms EHS (%)
Normal
Controls
(%)
p** MCS (%) p*** EHS/MCS
(%) p****
Headache 88 0 <0.0001 80 0.122 96 0.065
Dysesthesia 82 0 <0.0001 67 0.0149 96 0.002
Myalgia 48 6 <0.0001 48 1 76 <0.0001
Arthralgia 30 18 0.067 24 0.611 56 <0.001
Ear heat/otalgia 70 0 <0.0001 16 <0.0001 90 <0.001
Tinnitus 60 6 <0.0001 35 <0.001 88 <0.0001
Hyperacusis 40 6 <0.0001 20 <0.001 52 0.118
Dizziness 70 0 <0.0001 52 0.0137 68 0.878
Balance disorder 42 0 <0.0001 40 0.885 52 0.202
Concentration/attention
deficiency 76 0 <0.0001 67 0.210 88 0.041
Loss of immediate
memory 70 6 <0.0001 56 0.040 84 0.028
Confusion 8 0 0.007 0 0.0038 20 0.023
Fatigue 88 12 <0.0001 72 0.0047 94 0.216
Insomnia 74 6 <0.0001 47 <0.0001 92 0.001
Depression
tendency 60 0 <0.0001 29 <0.0001 76 0.022
Suicidal ideation 20 0 <0.0001 9 0.027 40 0.003
Transitory
cardiovascular
abnormalities
50 0 <0.0001 36 0.046 56 0.479
Ocular deficiency 48 0 <0.0001 43 0.478 56 0.322
Anxiety/panic 38 0 <0.0001 19 0.003 28 0.176
Emotivity 20 12 0.176 16 0.461 20 1
Irritability 24 6 <0.001 14 0.071 24 1
Skin lesions 16 0 <0.0001 14 0.692 45 <0.0001
Global body
dysthermia 14 0 <0.0001 6 0.236 8 0.258
* These data result from the clinical analysis of 150 consecutive clinically evaluable cases issued from the database
including an already published series of EHS and/or MCS patients who were investigated for biological markers [
10
].
Symptoms in EHS self-reported patients were compared with symptoms obtained from a series of 50 apparently
normal subjects used as controls. These symptoms were also compared to those occurring in MCS and EHS/MCS
self-reported patients. Percentage of patients with symptoms were compared by using the chi-square independence
test. ** Statistical difference between EHS self-reported patients and normal controls. *** Statistical difference between
EHS self-reported patients and MCS self-reported patients. **** Statistical difference between EHS self-reported
patients and EHS/MCS self-reported patients.
Table 3reveals that between EHS and MCS there is no statistically significant difference in
types and frequencies of clinical symptoms for headache, myalgia and arthralgia, balance disorder,
concentration/attention deficiency, emotivity and irritability, skin lesions and global body dysthermia,
whereas dysesthesia, ear heat/otalgia, tinnitus, hyperacusis, dizziness, loss of immediate memory,
insomnia and fatigue as well as depression tendency and suicidal ideation appear to be statistically
more frequent in EHS than in MCS. Moreover, in the case of EHS associated with MCS, most of
the symptoms—such as headache, dysesthesia, myalgia and arthralgia, tinnitus, and, above all,
cognitive capability, including loss of immediate memory, concentration/attention deficiency, and
tempo-spatial confusion—were found to be significantly more frequent than in EHS alone, suggesting
that the presence of an additional chemical intolerance component to the intolerance attributed to EMF
exposure is associated with a more severe pathology. This was especially the case for skin lesions
which were found in 45% of the cases, as well as for physical and mental suffering and depressive
tendency with underlying suicidal ideation in 40%.
Note that cutaneous lesions were more frequent on the superior members than on the inferior
members of the patients, and more frequent on the hands, particularly on the hand which held the
mobile phone (as exemplified in Figure 1A). Note also that the cutaneous lesions were not only more
frequent in the group of patients with EHS- and MCS-associated disorders (45%) than in the group of
Int. J. Mol. Sci. 2020,21, 1915 5 of 20
patients with only EHS (16%), but also that they were more extensive and persistent in the cases of
both associated disorders than in the case of EHS alone (Figure 1B).
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 5 of 21
tempo-spatial confusion—were found to be significantly more frequent than in EHS alone,
suggesting that the presence of an additional chemical intolerance component to the intolerance
attributed to EMF exposure is associated with a more severe pathology. This was especially the case
for skin lesions which were found in 45% of the cases, as well as for physical and mental suffering
and depressive tendency with underlying suicidal ideation in 40%.
Note that cutaneous lesions were more frequent on the superior members than on the inferior
members of the patients, and more frequent on the hands, particularly on the hand which held the
mobile phone (as exemplified in Figure 1A). Note also that the cutaneous lesions were not only more
frequent in the group of patients with EHS- and MCS-associated disorders (45%) than in the group
of patients with only EHS (16%), but also that they were more extensive and persistent in the cases
of both associated disorders than in the case of EHS alone (Figure 1B).
Figure 1. Examples of skin lesions observed on the hand of an EHS-bearing patient (A) and of an
EHS/MCS-bearing patient (B). (Photographs are issued from the database).
These clinical observations strongly suggest that EHS and EHS/MCS are objective somatic
disorders, which can neither be claimed as originating from some psychologic or psychiatric-related
conditions, nor from nocebo effects [11] (see further).
4. Identification of Biomarkers
On the basis of previously published experimental data, we selected and identified several
biomarkers in the peripheral blood and urine of EHS and/or MCS patients which can allow
physicians to objectively characterize EHS and MCS as true somatic pathological disorders [10],
discounting the hypothesis that EHS and MCS could be caused by a psychosomatic or nocebo-related
process [11]. As indicated in Table 4, there is a similar increase in mean level values of low-grade
inflammation-related biomarkers in the peripheral blood of patients with EHS, MCS, or both
associated disorders. In addition, as far as frequency is concerned, we found hypersensitive C reactive
protein (hs-CRP) to be increased in 12–15% of the cases, histamine in 30% to 40%, immunoglobulin E
(IgE) in 20% to 25%, and heat-shock protein 27 (Hsp 27) and Hsp 70 in 12% to 30%. Note that, among
these markers, IgE and histamine were found to be increased in patients with no proven allergy; thus,
in the case of no associated allergy, histamine appears to be the most frequently involved biomarker
in EHS, as well as in MCS, suggesting a low-grade inflammatory process is involved in the genesis
of these two disorders. Consequently, it is believed that, as an inflammation mediator, histamine
Figure 1.
Examples of skin lesions observed on the hand of an EHS-bearing patient (
A
) and of an
EHS/MCS-bearing patient (B). (Photographs are issued from the database).
These clinical observations strongly suggest that EHS and EHS/MCS are objective somatic
disorders, which can neither be claimed as originating from some psychologic or psychiatric-related
conditions, nor from nocebo effects [11] (see further).
4. Identification of Biomarkers
On the basis of previously published experimental data, we selected and identified several
biomarkers in the peripheral blood and urine of EHS and/or MCS patients which can allow physicians
to objectively characterize EHS and MCS as true somatic pathological disorders [10], discounting the
hypothesis that EHS and MCS could be caused by a psychosomatic or nocebo-related process [
11
].
As indicated in Table 4, there is a similar increase in mean level values of low-grade inflammation-related
biomarkers in the peripheral blood of patients with EHS, MCS, or both associated disorders. In addition,
as far as frequency is concerned, we found hypersensitive C reactive protein (hs-CRP) to be increased in
12–15% of the cases, histamine in 30% to 40%, immunoglobulin E (IgE) in 20% to 25%, and heat-shock
protein 27 (Hsp 27) and Hsp 70 in 12% to 30%. Note that, among these markers, IgE and histamine
were found to be increased in patients with no proven allergy; thus, in the case of no associated allergy,
histamine appears to be the most frequently involved biomarker in EHS, as well as in MCS, suggesting
a low-grade inflammatory process is involved in the genesis of these two disorders. Consequently, it is
believed that, as an inflammation mediator, histamine could play a major key contributing role in the
physiopathologic mechanism which may account for the occurrence of the two disorders [
11
,
14
] (see
further). Note also that, with the exception of Hsp 70, which was found to be less frequently increased
in the MCS group, there was no significant difference between the three groups of patients for the
percentage of patients with values above normal, nor any significant difference in mean increased
values in comparison with normal values for all biomarkers in the three groups studied, meaning that
EHS, MCS, and the association of both disorders may share a common low-grade inflammation-related
physiopathologic mechanism for genesis.
Int. J. Mol. Sci. 2020,21, 1915 6 of 20
Table 4.
Increase in low-grade inflammation-related biomarker mean blood level values in the
peripheral blood of patients with EHS and/or MCS, according to References [
9
,
10
]. SE—standard error;
hs-CRP—hypersensitive C reactive protein; IgE—immunoglobulin E; Hsp—heat-shock protein.
Patient Groups
Marker Normal Values EHS Mean
±SE
Above
Normal
(%)
MCS Mean
±SE
Above
Normal
(%)
p*EHS/MCS
Mean ±SE
Above
Normal
(%)
p**
hs-CRP <3 mg/L 10.3 ±1.9 15 5.3 ±1.7 12 0.50 6.9 ±1.7 14.3 0.36
Histamine <10 nmol/L 13.6 ±0.2 37 23.5 ±4.5 33 0.91 13.6 ±0.4 41.5 0.52
IgE <100 UI/mL 329.5 ±43.9 22 150.9 ±18.3 20 0.23 385 ±70 24.7 0.53
Hsp 70 <5 ng/mL 8.2 ±0.2 18.7 5.9 ±0.5 12 0.03 8 ±0.3 25.4 0.72
Hsp 27 <5 ng/mL 7.3 ±0.2 25.8 6.8 ±0.1 6 *** 0.59 7.2 ±0.3 31.8 0.56
* Comparison between the EHS and MCS groups of patients for marker mean level values was done using the
two-tailed t-test. Except for Hsp 70, there is no statistically significant difference between EHS and MCS patients for
increased mean level values of the different biomarkers analyzed, suggesting that EHS and MCS share a common
physiopathological mechanism for genesis. ** Comparison between the EHS and EHS/MCS groups of patients by
using the two-tailed t-test. There is no statistically significant difference between EHS and EHS/MCS patients for
increased mean level values of the different biomarkers analyzed. *** With the exception of MCS, for which there is a
statistically significantly lower frequency percentage value for Hsp 27, the frequency percentage values obtained in
EHS and EHS/MCS for all the other investigated parameters do not differ significantly on the basis of the chi-square
independence test.
Moreover, as indicated in Table 5, we were able to show that, in peripheral blood, there is
an increase in S100B protein in 15–20% of the patients and an increase in nitrosative stress-related
nitrotyrosine (NTT) in 8–30% in the EHS and/or MCS groups, suggesting that these biomarkers may
reflect opening of the blood–brain barrier (BBB) in these patients, whatever the patient group considered,
since it was shown that S100B protein [
15
,
16
] and nitrotyrosine [
17
–
20
] are markers associated with
BBB opening. In addition, we detected the presence of autoantibodies against O-myelin in about 20%
of all cases, whether EHS, MCS or both; meaning that an autoimmune response against the white
matter of the nervous system occurres in patients; a finding that may in fact be the consequence of the
occurrence of oxidative/nitrosative stress [10,21].
Table 5.
Increase in mean blood level values of peripheral blood S100B protein, nitrotyrosine (NTT),
and O-myelin autoantibodies in EHS and/or MCS patients, according to References [10,11].
Patient Groups
Markers Normal Values EHS Mean
±SE
Above
Normal
(%)
MCS Mean
±SE
Above
Normal
(%)
p*EHS/MCS
Mean ±SE
Above
Normal
(%)
p**
S100B <0.105 µg/L 0.20 ±0.03 14.7 0.25 ±0.05 21.15 0.56 0.17 ±0.03 19.7 0.69
NTT * >0.9 µg/ml 1.36 ±0.12 29.7 1.26 ±0.13 8 0.85 1.40 ±0.12 28.9 0.86
O-myelin (qualitative test) Positive 22.8 Positive 13.6 _ Positive 23.6 _
* Comparison between the EHS and MCS groups of patients using the two-tailed t-test. There is no statistically
significant difference between the two groups of EHS and MCS patients for increased mean level values of the two
different biomarkers analyzed, suggesting that EHS and MCS share a common physiopathological mechanism
for genesis. ** Comparison between the EHS and EHS/MCS groups of patients using the two-tailed t-test. There
is no statistically significant difference between EHS and EHS/MCS patients for increased mean level values of
the different biomarkers analyzed, suggesting here too that EHS and MCS share a common physiopathological
mechanism for genesis.
Moreover, more recently, we measured different oxidative and nitrosative stress-related biomarkers
such as thiobarbituric acid reactive substances (TBARS), oxidized glutathione (GSSG), and NTT in the
peripheral blood of EHS patients. As reported in Figure 2, we found that nearly 80% of EHS patients
presented with an increase in oxidative/nitrosative stress-related biomarkers—more precisely, with
only one of these three studied biomarkers in 43% of the patients, two of these biomarkers in 21% of
them, and all three in 15% [
22
]. This clearly indicates that, in addition to low-grade inflammation
and an anti-white matter autoimmune response, EHS can also be diagnosed by the presence of
oxidative/nitrosative stress.
Int. J. Mol. Sci. 2020,21, 1915 7 of 20
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 7 of 21
Markers
Normal
Values
EHS
Mean ±
SE
Above
Normal
(%)
MCS
Mean ±
SE
Above
Normal
(%)
p * EHS/MCS
Mean ± SE
Above
Normal
(%)
p **
S100B <
0.105 µg/L
0.20 ±
0.03 14.7 0.25 ±
0.05 21.15 0.56 0.17 ± 0.03 19.7 0.69
NTT * > 0.9
µg/ml
1.36 ±
0.12 29.7 1.26 ±
0.13 8 0.85 1.40 ± 0.12 28.9 0.86
O-myelin
(qualitative
test)
Positive 22.8 Positive 13.6 _ Positive 23.6 _
* Comparison between the EHS and MCS groups of patients using the two-tailed t-test. There is no
statistically significant difference between the two groups of EHS and MCS patients for increased
mean level values of the two different biomarkers analyzed, suggesting that EHS and MCS share a
common physiopathological mechanism for genesis. ** Comparison between the EHS and EHS/MCS
groups of patients using the two-tailed t-test. There is no statistically significant difference between
EHS and EHS/MCS patients for increased mean level values of the different biomarkers analyzed,
suggesting here too that EHS and MCS share a common physiopathological mechanism for genesis.
Moreover, more recently, we measured different oxidative and nitrosative stress-related
biomarkers such as thiobarbituric acid reactive substances (TBARS), oxidized glutathione (GSSG),
and NTT in the peripheral blood of EHS patients. As reported in Figure 2, we found that nearly 80%
of EHS patients presented with an increase in oxidative/nitrosative stress-related biomarkers—more
precisely, with only one of these three studied biomarkers in 43% of the patients, two of these
biomarkers in 21% of them, and all three in 15% [22]. This clearly indicates that, in addition to low-
grade inflammation and an anti-white matter autoimmune response, EHS can also be diagnosed by
the presence of oxidative/nitrosative stress.
Figure 2. Percentage of EHS self-reported patients having positive thiobarbituric acid reactive
substances (TBARS), oxidized glutathione (GSSG), and/or NTT oxidative stress biomarkers measured
in the peripheral blood, according to Reference [22]. Corresponds to NTT, TBARS, and GSSG, i.e.,
all three biomarkers measured in 14 of the 32 included patients. Corresponds to TBARS and GSSG
analyzed in all 32 included patients. “Positive” biomarkers correspond to patients having one, two,
or three markers with levels above the upper normal limits, and “total” corresponds to patients
having at least one positive biomarkers, i.e., having one, two, or possibly three positive biomarkers.
Finally, we also found that, in comparison with normal reference values, the 24-h urine 6-
hydroxymelatonin (6-OHMS)/creatinine ratio was normal or significantly decreased in 88% of cases,
while, due to a still unexplained process, it was significantly increased in 12%, whatever the group
Figure 2.
Percentage of EHS self-reported patients having positive thiobarbituric acid reactive
substances (TBARS), oxidized glutathione (GSSG), and/or NTT oxidative stress biomarkers measured
in the peripheral blood, according to Reference [
22
].
Corresponds to NTT, TBARS, and GSSG, i.e.,
all three biomarkers measured in 14 of the 32 included patients.
Corresponds to TBARS and GSSG
analyzed in all 32 included patients. “Positive” biomarkers correspond to patients having one, two, or
three markers with levels above the upper normal limits, and “total” corresponds to patients having at
least one positive biomarkers, i.e., having one, two, or possibly three positive biomarkers.
Finally, we also found that, in comparison with normal reference values, the 24-h urine
6-hydroxymelatonin (6-OHMS)/creatinine ratio was normal or significantly decreased in 88% of
cases, while, due to a still unexplained process, it was significantly increased in 12%, whatever the
group of patients considered. 6-OHMS is a melatonin metabolite. Decrease in melatonin production
as a consequence of prolonged EMF exposure was experimentally evidenced both in animals and in
humans [
23
,
24
]. However, since EMF exposure was also reported not to alter melatonin synthesis and
secretion [
25
], an alternative plausible explanation could be that a decrease in the excretion of 6-OHMS
in the urine may result from a decrease in melatonin metabolic bioavailability due to its increased
intake and utilization of melatonin as a free radical scavenger [
26
,
27
]. This indeed could be the case in
patients with a decrease in the 24-h urine 6-OHMS/creatinine ratio level, since, as shown above, most
EHS patients present with oxidative/nitrosative stress. Thus, a decrease in 6-OHMS in the urine may
in fact be a consequence of the antioxidative stress effect of this hormone rather than its decreased
synthesis in the pineal gland. Consequently, such reduction in bioavailability may contribute not
only to clinical sleep disturbance in these patients, but also to a decrease in host defense mechanisms,
possibly putting these patients at risk of neurodegenerative disease and cancer [28,29].
Moreover, the development of oxidative/nitrosative stress-related autoimmune response may also
contribute to weakening the putative protective health effect of the chaperone proteins Hsp 70 and Hsp
27 [
30
]. There is presently no clear explanation why, in 12% of the cases, instead of having a normal or
significant decrease in the 24-h urine 6-OHMS/creatinine ratio, this ratio was significantly increased
in comparison with normal control values. As indicated in Table 6, this may be due in some cases
to an increased production of serotonin in the brain, since serotonin is a precursor neurotransmitter
of melatonin.
As indicated in Table 6, changes in neurotransmitter levels revealed that EHS is associated with
different abnormal neurotransmitter profiles, confirming EHS is a well-established new brain-related
neurologic disorder.
Int. J. Mol. Sci. 2020,21, 1915 8 of 20
Table 6.
Preliminary unpublished data based on the measurement of neurotransmitters and their
metabolites in the urine of 42 EHS-bearing patients. 3-4 DOPAC—3,4-Dihydroxyphenylacetic acid.
Neurotransmitters Patients %
Dopamine increase 17/42 31
3-4 DOPAC decrease 18/42 43
Noradrenaline increase 11/42 26
Adrenaline increase 8/42 19
Adrenaline decrease 12/42 22
Serotonin increase 4/42 9.5
Serotonin decrease 5/42 12
5. Radiological Identification of Cerebral Neuro-Vascular Abnormalities
Classical brain imaging techniques including brain computerized tomography (CT) scans, brain
magnetic resonance imaging (MRI), and brain angioscans are usually normal in EHS patients and in
MCS or EHS/MCS patients, meaning that the normality of these investigations is not an argument
against the diagnosis of these pathological disorders. Fortunately we have shown that development
and use of other imaging techniques could be greatly helpful to increase our ability of objectively
characterizing EHS and MCS, should they show abnormal function. In fact, as indicated in Table 7,
by using transcranial Doppler ultrasound (TDU) in patients with EHS, we showed a decrease in the
mean pulsatility index in one or both middle cerebral arteries, i.e., for one artery in 25% and 31% of the
cases respectively for the right and left artery, and for both arteries in 50%. Moreover, for the dual
EHS/MCS group of patients, it was for one artery in 20% of the cases and for both arteries in 50%. In
addition, as far as resistance in the blood flow (BBF) is concerned, we found that, in EHS patients, BBF
resistance was increased for one artery in 6.25% of the cases and for both arteries in 18.75%, while in
EHS/MCS patients, it was 5–10% for one artery and 25% for both arteries. Note also that mean blood
flow velocity was below normal values in 9.75% to 40% of the cases, while it was above normal values
in 5% to 18.75%, depending on the EHS and EHS/MCS group considered (see Table 7). This suggests
that, in EHS and/or MCS, BBF may be decreased in one or both of these brain arteries.
Table 7.
Results of resistance index, pulsatility index, and mean flow velocity in comparison with
normal values in the right and left middle cerebral arteries using transcranial Doppler ultrasound in 32
EHS cases and 20 EHS/MCS cases (unpublished data).
EHS n=32
Normal
Value Mean ±SE Below Normal (%) Above Normal (%)
Right
and
Left
Right Left Right
Only
Left
Only Both Right
Only
Left
Only Both
Resistance index <0.75 0.62 ±0.03 0.65 ±0.04 _ _ _ 6.25 6.25 18.75
Pulsatility index >0.60 0.55 ±0.02 0.55 ±0.03 25 31.25 50 _ _ _
Mean flow velocity
62 ±12 59.56 ±5.98 61.35 ±5.27 9.75 9.75 31.25 3.12 9.25 18.75
EHS/MCS n=20
Normal
values Mean ±SE Below Normal (%) Above Normal (%)
Right
and
Left
Right Left Right
only
Left
only Both Right
only
Left
only Both
Resistance index <0.75 0.79 ±0.09 0.64 ±0.04 _ _ _ 5 10 25
Pulsatility index >0.60 0.48 ±0.03 0.61 ±0.02 20 0 65 _ _ _
Mean flow velocity
62 ±12 53.03 ±9.09 51.77 ±7.63 20 20 40 10 10 5
Int. J. Mol. Sci. 2020,21, 1915 9 of 20
Moreover, by using ultrasonic cerebral tomosphygmography (UCTS) applied to the temporal
lobes [
12
], we showed there is a significant decrease in mean pulsometric index in the middle
cerebral artery-dependent tissue areas of these lobes, especially in the capsulo-thalamic area, which
corresponds to the limbic system and the thalamus [
12
]. As exemplified in Figure 3, this tissue
hypo-pulsation—mainly detected in the capsulo-thalamic area of these lobes—suggests that EHS
and/or MCS are associated with a capillary BBF decrease in these two brain structures, thus leading to
the hypothesis that they may be associated with some vascular and/or neuronal dysfunction [
10
–
12
].
Although these abnormalities are not specific, since they may be similar to those found in Alzheimer’s
disease and other neurodegenerative disorders, we recently confirmed that UCTS could presently be
one of the most accurate imaging techniques to be used to diagnose EHS and/or MCS and to follow
objectively treated patients [12].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 9 of 21
values in 5% to 18.75%, depending on the EHS and EHS/MCS group considered (see Table 7). This
suggests that, in EHS and/or MCS, BBF may be decreased in one or both of these brain arteries.
Table 7. Results of resistance index, pulsatility index, and mean flow velocity in comparison with
normal values in the right and left middle cerebral arteries using transcranial Doppler ultrasound in
32 EHS cases and 20 EHS/MCS cases (unpublished data).
EHS n = 32
Normal
Value Mean ± SE Below Normal (%) Above Normal (%)
Right
and Left Right Left Right
Only
Left
Only Both Right
Only
Left
Only Both
Resistance
index <0.75 0.62 ±
0.03
0.65 ±
0.04 _ _ _ 6.25 6.25 18.75
Pulsatility
index >0.60 0.55 ±
0.02
0.55 ±
0.03 25 31.25 50 _ _ _
Mean flow
velocity 62 ± 12 59.56 ±
5.98
61.35 ±
5.27 9.75 9.75 31.25 3.12 9.25 18.75
EHS/MCS n = 20
Normal
values Mean ± SE Below Normal (%) Above Normal (%)
Right
and Left Right Left Right
only
Left
only Both Right
only
Left
only Both
Resistance
index <0.75 0.79 ±
0.09
0.64 ±
0.04 _ _ _ 5 10 25
Pulsatility
index >0.60 0.48 ±
0.03
0.61 ±
0.02 20 0 65 _ _ _
Mean flow
velocity 62 ± 12 53.03 ±
9.09
51.77 ±
7.63 20 20 40 10 10 5
Moreover, by using ultrasonic cerebral tomosphygmography (UCTS) applied to the temporal
lobes [12], we showed there is a significant decrease in mean pulsometric index in the middle cerebral
artery-dependent tissue areas of these lobes, especially in the capsulo-thalamic area, which
corresponds to the limbic system and the thalamus [12]. As exemplified in Figure 3, this tissue hypo-
pulsation—mainly detected in the capsulo-thalamic area of these lobes—suggests that EHS and/or
MCS are associated with a capillary BBF decrease in these two brain structures, thus leading to the
hypothesis that they may be associated with some vascular and/or neuronal dysfunction [10–12].
Although these abnormalities are not specific, since they may be similar to those found in Alzheimer’s
disease and other neurodegenerative disorders, we recently confirmed that UCTS could presently be
one of the most accurate imaging techniques to be used to diagnose EHS and/or MCS and to follow
objectively treated patients [12].
Figure 3.
Examples of diagrams obtained from the database by using ultrasonic cerebral
tomosphygmography (UCTS), exploring the global centimetric ultrasound tissue pulsatility in the
two temporal lobes of a normal subject (
A
) and of an EHS self-reported patient (
B
), according to
References [
11
,
12
]. Measurements are expressed as pulsometric index (PI). Note that, in A and B, mean
values of PI in each explored area are recorded from the cortex to the internal part of each temporal lobe
(i.e., from left to right for the right lobe, and from right to left for the left lobe). In addition, note that, in
A (normal subject), all values are over the median normal PI values, whereas, in B (EHS self-reported
patient), values in the so called capsulo-thalamic areas (the fifth and the second column for the right
and left temporal lobes, respectively) are significantly under the median normal values, suggesting that
the limbic system and the thalamus in each temporal lobe may be involved in EHS, as exemplified in
this patient.
It appears, however, that these brain abnormalities are not restricted to the limbic system and the
thalamus, since, by using TDU as indicated above, we showed that, in EHS and/or MCS patients, BBF in
the middle cerebral arteries may be abnormal. Moreover, by using functional MRI (fMRI) in EHS patients
exposed chronically to extremely low-frequency (ELF) radiation, regional BBF changes were also
reported by Heuser and Heuser, but mainly in the frontal lobes, as an abnormal default mode network
(DMN) (particularly as hyper-connectivity of this DMN), in association with a decrease in cerebral BBF
and metabolic processes in the two so far individualized fragment hyper-connected components [
31
].
For example, in Figure 4, abnormal DMN is represented with fragmented hyper-connectivity of the
anterior component and posterior component, which may lead to decreased BBF and/or metabolism in
the bi-frontal lobes.
Int. J. Mol. Sci. 2020,21, 1915 10 of 20
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 10 of 21
Figure 3. Examples of diagrams obtained from the database by using ultrasonic cerebral
tomosphygmography (UCTS), exploring the global centimetric ultrasound tissue pulsatility in the
two temporal lobes of a normal subject (A) and of an EHS self-reported patient (B), according to
References [11,12]. Measurements are expressed as pulsometric index (PI). Note that, in A and B, mean
values of PI in each explored area are recorded from the cortex to the internal part of each temporal
lobe (i.e., from left to right for the right lobe, and from right to left for the left lobe). In addition, note
that, in A (normal subject), all values are over the median normal PI values, whereas, in B (EHS self-
reported patient), values in the so called capsulo-thalamic areas (the fifth and the second column for
the right and left temporal lobes, respectively) are significantly under the median normal values,
suggesting that the limbic system and the thalamus in each temporal lobe may be involved in EHS,
as exemplified in this patient.
It appears, however, that these brain abnormalities are not restricted to the limbic system and
the thalamus, since, by using TDU as indicated above, we showed that, in EHS and/or MCS patients,
BBF in the middle cerebral arteries may be abnormal. Moreover, by using functional MRI (fMRI) in
EHS patients exposed chronically to extremely low-frequency (ELF) radiation, regional BBF changes
were also reported by Heuser and Heuser, but mainly in the frontal lobes, as an abnormal default
mode network (DMN) (particularly as hyper-connectivity of this DMN), in association with a
decrease in cerebral BBF and metabolic processes in the two so far individualized fragment hyper-
connected components [31]. For example, in Figure 4, abnormal DMN is represented with fragmented
hyper-connectivity of the anterior component and posterior component, which may lead to decreased
BBF and/or metabolism in the bi-frontal lobes.
Figure 4. Abnormal functional MRI brain scan in patients complaining of EHS after long-term
exposure to EMF, according to Reference [31].
6. Diagnostic Criteria
On the basis of the above clinical, biological, and radiological reported investigations, it appears
that there is presently sufficient comprehensive and relevant data allowing the objective
characterization and identification of EHS as a well-defined new neurologic pathological disorder.
As a result, patients who self-report that they suffer from EHS should be investigated utilizing
presently available objective tests, including the use of the above-reported blood and urine
biomarkers and imaging techniques.
At a clinical level, isolated symptoms such as headache, tinnitus, dizziness, or cognitive defects,
although they may be referred by the patients as being due to EMF or chemical exposure, are indeed
not sufficient for the diagnosis to be made, as they may reflect another pathology. Clinical arguments
for EHS could nevertheless be the following: (1) absence of known pathology accounting for the
Figure 4.
Abnormal functional MRI brain scan in patients complaining of EHS after long-term exposure
to EMF, according to Reference [31].
6. Diagnostic Criteria
On the basis of the above clinical, biological, and radiological reported investigations, it appears
that there is presently sufficient comprehensive and relevant data allowing the objective characterization
and identification of EHS as a well-defined new neurologic pathological disorder. As a result, patients
who self-report that they suffer from EHS should be investigated utilizing presently available objective
tests, including the use of the above-reported blood and urine biomarkers and imaging techniques.
At a clinical level, isolated symptoms such as headache, tinnitus, dizziness, or cognitive defects,
although they may be referred by the patients as being due to EMF or chemical exposure, are indeed
not sufficient for the diagnosis to be made, as they may reflect another pathology. Clinical arguments
for EHS could nevertheless be the following: (1) absence of known pathology accounting for the
observed clinical symptoms; (2) characteristic association of symptoms such as those we identified,
with the association of headache, tinnitus, hyperacusis, dizziness, loss of immediate memory, and
attention/concentration deficiency being the most characteristic and reproducible; (3) reproducibility
of symptoms under the said influence of EMFs; (4) regression or disappearance of symptoms in the
case of said EMF avoidance; (5) finally and most importantly, the association with MCS. As we showed
that MCS is associated with EHS in 30% of the cases, and as MCS was well defined during a 1999
international consensus meeting [
32
], this latter association may in fact be the best clinical criterion for
the diagnosis of EHS.
However, because many of these clinical criteria are subjective, they are not sufficient to objectively
prove the disease and, thus, establish the diagnosis. Among biological markers, histamine in the
blood is presently the best available marker in the case of no associated allergy and the easiest to
measure routinely in medical practice. Moreover, detection in the blood of an increase in protein
S100B and oxidative/nitrosative stress-related biomarkers such as GSSG and NTT may also be objective
contributing elements for the diagnosis. Note, however, that, in 30% of the cases, there were no
positive detectable biomarkers in the blood; thus, in addition to the availability of clinical criteria,
the EHS diagnosis could be made by using imaging techniques, such as TDU, fMRI, and, if possible,
UCTS. Overall, by using this approach, we were able to objectively diagnose EHS in about 90% of EHS
self-reported patients.
Int. J. Mol. Sci. 2020,21, 1915 11 of 20
7. Treatment and Prognostic Evolution
There is, at the moment, no recognized standardized treatment of EHS. There are, however,
some treatments that could be indicated, on the basis of biological investigations. We showed, for
example, that patients with EHS present frequently with a profound deficit in vitamins and trace
elements, especially in vitamin D and zinc, which should be corrected [
10
,
11
,
22
]. Anti-histaminics
should also be used in the case of increased histamine in the blood. Furthermore, antioxidants such
as glutathione and, more specifically, anti-nitrosative medications should also be used in case of
oxidative/nitrosative stress. Moreover, as exemplified in Figure 5, we showed that natural products
such as fermented papaya preparation (FPP) and ginkgo biloba can restore brain pulsatility in the
various middle cerebral artery-dependent tissue areas of temporal lobes, thereby improving brain
hemodynamics and, consequently, brain oxygenation [
33
]. Since FPP was shown to possess some
antioxidant, anti-inflammation, and immune-modulating properties [
34
–
36
], we recommend the use of
this widely available natural product.
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 11 of 21
observed clinical symptoms; (2) characteristic association of symptoms such as those we identified,
with the association of headache, tinnitus, hyperacusis, dizziness, loss of immediate memory, and
attention/concentration deficiency being the most characteristic and reproducible; (3) reproducibility
of symptoms under the said influence of EMFs; (4) regression or disappearance of symptoms in the
case of said EMF avoidance; (5) finally and most importantly, the association with MCS. As we
showed that MCS is associated with EHS in 30% of the cases, and as MCS was well defined during a
1999 international consensus meeting [32], this latter association may in fact be the best clinical
criterion for the diagnosis of EHS.
However, because many of these clinical criteria are subjective, they are not sufficient to
objectively prove the disease and, thus, establish the diagnosis. Among biological markers, histamine
in the blood is presently the best available marker in the case of no associated allergy and the easiest
to measure routinely in medical practice. Moreover, detection in the blood of an increase in protein
S100B and oxidative/nitrosative stress-related biomarkers such as GSSG and NTT may also be
objective contributing elements for the diagnosis. Note, however, that, in 30% of the cases, there were
no positive detectable biomarkers in the blood; thus, in addition to the availability of clinical criteria,
the EHS diagnosis could be made by using imaging techniques, such as TDU, fMRI, and, if possible,
UCTS. Overall, by using this approach, we were able to objectively diagnose EHS in about 90% of
EHS self-reported patients.
7. Treatment and Prognostic Evolution
There is, at the moment, no recognized standardized treatment of EHS. There are, however,
some treatments that could be indicated, on the basis of biological investigations. We showed, for
example, that patients with EHS present frequently with a profound deficit in vitamins and trace
elements, especially in vitamin D and zinc, which should be corrected [10,11,22]. Anti-histaminics
should also be used in the case of increased histamine in the blood. Furthermore, antioxidants such
as glutathione and, more specifically, anti-nitrosative medications should also be used in case of
oxidative/nitrosative stress. Moreover, as exemplified in Figure 5, we showed that natural products
such as fermented papaya preparation (FPP) and ginkgo biloba can restore brain pulsatility in the
various middle cerebral artery-dependent tissue areas of temporal lobes, thereby improving brain
hemodynamics and, consequently, brain oxygenation [33]. Since FPP was shown to possess some
antioxidant, anti-inflammation, and immune-modulating properties [34–36], we recommend the use
of this widely available natural product.
Figure 5. Example of diagrams obtained from the database by using UCTS exploring the global
centimetric ultrasound pulsatility in the two temporal lobes of an EHS subject at inclusion (Ti) and
three months later (T3) after fermented papaya preparation (FPP) supplementation (9 g per day in
two divided doses), according to Reference [33].
Figure 5.
Example of diagrams obtained from the database by using UCTS exploring the global
centimetric ultrasound pulsatility in the two temporal lobes of an EHS subject at inclusion (Ti) and
three months later (T3) after fermented papaya preparation (FPP) supplementation (9 g per day in two
divided doses), according to Reference [33].
In the case of no treatment and no protection against environmental stressors such as EMF
and multiple chemicals, EHS may evolve toward some neurodegenerative and psychiatric disorders,
possibly including some seemingly Alzheimer’s disease-related states. However, in treating and
protecting patients as soon as possible, we never observed the occurrence of true Alzheimer’s
disease in any patient included in the database. By contrast, regression and even disappearance
of symptoms of intolerance may occur after treatment and protection of patients. However, in our
experience and to our knowledge, hypersensitivity to EMF and/or MCS-related chemical sensitivity
never disappears, meaning – unlike symptomatic intolerance – EHS and MCS appear to be associated
with some irreversible neurologic pathological state, requiring strong and persistent prevention. So,
contrary to some recent claims, we believe these disorders cannot be merely reduced to some type of
functional impairment.
8. Proposed Physiopathological Mechanism
In its 2005 official statement on EHS, WHO indicated there is “no scientific basis to link EHS
symptoms to EMF exposure” meaning there is no accepted physiopathological mechanism to link
environmental cause to disease. This is no longer the case. The basic low-grade inflammation
and oxidative/nitrosative stress-related states we showed in EHS patients [
10
,
11
,
22
] are remarkable
since they confirm the detrimental health effects of (1) non-thermal or weak thermal non-ionizing
Int. J. Mol. Sci. 2020,21, 1915 12 of 20
radiation, which were proven experimentally in animals [
37
–
39
] and in humans [
11
] exposed to different
environmental stressors including ELF and RF EMFs, and (2) multiple man-made environmental
chemicals [40–42], especially in the brain [43,44].
Figure 6summarizes the different steps of the model we have so far been able to construct from
the presently available published data, including our own. On the basis of the inflammation and
oxidative/nitrosative stress processes which we evidenced in EHS and/or MCS patients, this model
accounts for the mechanisms via which physiopathological effects could take place in the brain and,
consequently, how EHS and/or MCS genesis can occur.
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 13 of 21
Figure 6. EHS/MCS physiopathological model based on low-grade neuroinflammation and
oxidative/nitrosative stress-induced blood–brain barrier disruption, according to Reference [10].
In a first step, there could be an initial local inflammatory response to environmental stressors,
whatever they may be. Resident microglia cells, astrocytes, and mastocytes could be the first cells in
the brain locally involved in the inflammatory process, releasing inflammatory mediators such as
histamine. On the basis of our data [10–12,22,33], it is speculated that histamine is a key mediator
contributing to the induction of oxidative/nitrosative stress and, consequently, to cerebral
hypoperfusion, thereby leading to some local cerebral hypoxia.
In a second step, amplification of inflammation could occur, including oxidative/nitrosative
stress-related BBB disruption, allowing transmigration of circulating inflammatory cells from the
blood to the brain. Finally, neuroinflammation in the brain would occur, mainly involving the
capsulo-thalamic area of temporal lobes, i.e., the limbic system and the thalamus.
The major interest of this comprehensive physiopathological model is that it can explain the
main clinical symptoms occurring in EHS and/or MCS patients, since the limbic system involvement
may account for both the emotional and cognitive pathological alterations (in particular memory
loss), while the thalamic involvement may explain sensibility-related abnormalities, both superficial
and deep. Naturally, the possible extension of neuroinflammation into the frontal lobes and possibly
into the hypothalamus [45] may, in addition, account for the other associated clinical symptoms.
9. Etiopathogenesis and Prevention
The causal origin of EHS is still debated, and the present current institutional message is that
there is no proof that EHS genesis is causally related to EMF exposure. There is, however, great
confusion in the present scientific literature in addressing this problem, since there is presently no
clear distinction between the cause of clinical symptoms occurrence in EHS patients, i.e., after EHS
Figure 6.
EHS/MCS physiopathological model based on low-grade neuroinflammation and
oxidative/nitrosative stress-induced blood–brain barrier disruption, according to Reference [10].
In a first step, there could be an initial local inflammatory response to environmental stressors,
whatever they may be. Resident microglia cells, astrocytes, and mastocytes could be the first cells in the
brain locally involved in the inflammatory process, releasing inflammatory mediators such as histamine.
On the basis of our data [
10
–
12
,
22
,
33
], it is speculated that histamine is a key mediator contributing
to the induction of oxidative/nitrosative stress and, consequently, to cerebral hypoperfusion, thereby
leading to some local cerebral hypoxia.
In a second step, amplification of inflammation could occur, including oxidative/nitrosative
stress-related BBB disruption, allowing transmigration of circulating inflammatory cells from the
blood to the brain. Finally, neuroinflammation in the brain would occur, mainly involving the
capsulo-thalamic area of temporal lobes, i.e., the limbic system and the thalamus.
The major interest of this comprehensive physiopathological model is that it can explain the main
clinical symptoms occurring in EHS and/or MCS patients, since the limbic system involvement may
Int. J. Mol. Sci. 2020,21, 1915 13 of 20
account for both the emotional and cognitive pathological alterations (in particular memory loss),
while the thalamic involvement may explain sensibility-related abnormalities, both superficial and
deep. Naturally, the possible extension of neuroinflammation into the frontal lobes and possibly into
the hypothalamus [45] may, in addition, account for the other associated clinical symptoms.
9. Etiopathogenesis and Prevention
The causal origin of EHS is still debated, and the present current institutional message is that there
is no proof that EHS genesis is causally related to EMF exposure. There is, however, great confusion in
the present scientific literature in addressing this problem, since there is presently no clear distinction
between the cause of clinical symptoms occurrence in EHS patients, i.e., after EHS has already occurred,
and the environmental causal origin of EHS itself. In fact, as reported in Table 8, by querying the
database and analyzing retrospectively previous exposure to EMFs and/or chemicals in EHS- and
EHS/MCS-bearing patients, we found there are presently several direct and indirect arguments which
strongly suggest that EMF exposure and even chemicals may cause or contribute to cause EHS.
Table 8. Clinical analysis of self-reported excessive presumed EMF and chemical exposure preceding
the occurrence of electrohypersensibility (unpublished data). DECT—digital enhanced cordless
telecommunications; RF—radiofrequency; ELF—extremely low frequency.
Sources EHS (%) Frequency Bands
Mobile phone 37
RF
Mobile phone/DECT 8
DECT 7
Cathode-ray screen 9
WiFi 16
Relay antenna towers 3
Energy-saving lamps/mobile phone * 1.4 RF and ELF
High-voltage power lines 2.7
ELF
Power transformer 1.7
Railway 0.8
Chemicals 11
Idiopathic ** 2.4
* Presumed excessive source exposure concern both low frequencies (LF) and radiofrequencies (RF); ** possible
genetic susceptibility.
Moreover, a further distinction should be made between the general term of intolerance,
which refers to the clinical symptoms and/or the biological abnormalities occurring in a particular
environmental situation, and the term hypersensitivity, which should in fact be defined as a particular
endogenous physiopathological state characterized by a decrease in the environmental tolerance
threshold to such a critical point that patients become intolerant to low-dose stressors. Such a distinction
is already made in medicine as, for example, the individualization of atopy in allergic patients.
Thus, if we agree on the distinction between the concept of intolerance and that of EHS, EHS
should be characterized by definition as a particular decrease in the intolerance threshold according to
which patients become intolerant to low-dose-intensity EMF exposure, while MCS (as already indicated
by the MCS consensus meeting report in 1999 in Atlanta) was defined by a similar physiopathological
state in which patients become intolerant to low-dose multiple chemicals [
32
]. This distinction may
explain why most studies using provocation tests aiming to reproduce the clinical symptoms which
may occur under EMF exposure in EHS self-reported patients report negative findings. Indeed, these
negative results may in fact be due to different, unacceptable scientific flaws: (1) the lack of objective
inclusion criteria, because objective biomarkers were not used to define EHS in so-called EHS-self
reported patients; (2) EHS patients may be sensitive to certain frequencies and not necessarily to others;
(3) duration of exposure was generally too short and assessment too early; (4) association with MCS
Int. J. Mol. Sci. 2020,21, 1915 14 of 20
was not considered; (5) as reported above, EHS patients have cognitive defects and, thus, can make
mistakes in distinguishing EMF exposure from sham exposure; (6) and above all, patients may respond
positively in the case of sham exposure because of a decrease in environmental tolerance threshold, as
well as because of psychologic conditioning from their past history of suffering.
Hence, on this basis, and because ofthe experimentalevidenceprovided by studies inanimals [
37
–
39
,
43
,
44
]
and in humans [
11
,
14
,
23
,
24
] have shown the detrimental impact of EMF on health we believe, there
is presently no sufficiently robust scientific data to refute a role of EMF exposure in inducing the
previously described clinical symptoms and biological alterations in EHS patients.
Therefore, the causal origin of EHS should be established with a different scientific approach. RF
and ELF were found to cause persistent adverse biological effects not only in animals [
46
,
47
] but also in
plants [48,49] and microorganisms [50]. Here too, such observations certainly dismiss the hypothesis
of a nocebo effect as the initial cause of EHS. In fact, the inflammation and oxidative/nitrosative states
we showed in EHS patient are remarkable since they confirm the data obtained experimentally
in animals exposed to these two types of non-ionizing frequencies [
37
–
39
], especially in the
brain [43,44]
. Furthermore, the limbic system-associated capsulo-thalamic abnormalities that we
showed to characterize these patients [
12
,
33
] may likely correspond to the hippocampal neuronal
alterations caused by EMF exposure in rats [51–53].
We therefore consider that the biological effects we observed in EHS patients may be due to
both the pulsed and the polarized characteristics of man-made EMF emitted by electric or wireless
technologies, as opposed to terrestrial non-polarized and continuously emitted natural EMFs [
54
–
56
].
In addition, as indicated in Table 9, we showed that, in 30% of the EHS cases, EHS was associated
with MCS, with MCS preceding the occurrence of EHS in 37% of these EHS/MCS-associated cases;
meaning that in this group of patients, EHS evolved toward MCS in 63% of the cases. As reported in
Table 8, we thus speculate that man-made environmental chemicals may also be causally involved in
EHS genesis in around 11% of the cases.
Table 9. Percentage of MCS patients who later suffered from EHS and vice versa.
Total EHS/MCS Patients Total EHS Patients Including
EHS/MCS Patients *
Percentage of MCS patients that
later suffered from EHS 37 11
Percent of EHS patients that later
suffered from MCS 63 19
* EHS/MCS patients represent 30% of the total number of EHS patients.
These various considerations should not be neglected, since to avoid risks, knowledge of them
could lead to protective measures in EHS and/or MCS patients. Such measures should include as much
as possible EMF and chemical avoidance, use of anti-EMF clothes, and earthing-related electric charge
detoxication. In addition, public preventive measures for the most vulnerable people—particularly
pregnant women, infants, children, and adolescents—should be taken by limiting or even totally
avoiding the use of wireless technology in these conditions. Such protective measures should also be
taken and carried out in vulnerable patients, i.e., in cardiac patients with pacemakers, in patients with
auditive prothesis, and in patients with neurodegenerative diseases.
10. The Worldwide Health Plague
Another argument incriminating the role of new wireless technology and possibly man-made
chemicals introduced in the environment [
57
,
58
] is that, as indicated in Table 10, the increase in EHS
prevalence is not restricted to a single country but is presently a worldwide plague, which started as
soon as these industrial technologies became widespread. Prevalence of EHS occurrence is estimated
Int. J. Mol. Sci. 2020,21, 1915 15 of 20
to range from 0.7% to 13.3%, mainly affecting about 3% to 5% of the population in many countries
(Table 10), meaning that millions of people may in fact be affected by EHS worldwide.
Table 10.
Estimated prevalence of people with self-reported EHS in different worldwide countries.
USA—United States of America.
Country Date Sample Size
People
Contribution
Rate (%)
Estimated % of
People with
EHS
References
Sweden 1997 15,000 (19–80) * 73 1.5 Hillert et al., 2002 [59]
Sweden 2010 3406 40 2.7 Palmquist et al., 2014 [60]
Swiss 2004 2048 (>14) * 55.1 5 Schreier et al., 2006 [61]
Swiss 2008 1122
(30–60) * 37 8.6 Roosli et al., 2010 [62]
Swiss 2009 1122
(30–60) * 37 7.7 Roosli et al., 2010 [62]
Germany 2004 30,047 58.6 10.3 Blettner et al., 2009 [63]
Germany 2004 30,047 58.4 8.7 Kowall et al., 2012 [64]
Germany 2006 30,047 58.4 7.2 Kowall et al., 2012 [64]
USA (California) 1998 2072 58.3 3.2 Levallois et al., 2002 [65]
Finland 2002 6121 40.8 0.7 Korpinen et al., 2009 [66]
Great Britain Before 2007 3633 18.2 4 Eltiti et al., 2007 [67]
Taiwan 2007 1251 11.5 13.3 Tseng et al., 2011 [68]
Austria Before 2008 460 88 3.5 Schröttner and Leitgeb, 2008 [69]
Japan Before 2009 2472 62.3 1.2 Furubayashi et al., 2009 [70]
Holland 2011 5789 39.6 3.5 Batiatsas et al., 2014 [71]
Holland Before 2013 1009 60 7 Vabn Dongen et al., 2014 [72]
* When precised, age intervals of included patients are indicated in brackets.
Furthermore, although these reported EHS prevalence figures are only estimations, not critically
evaluated due to a lack of objective criteria to clearly define EHS, it is possible—as speculated in
Figure 7—that the EHS prevalence will continue to grow in the future, in as much as the manufacture
of wireless technology and industrial chemicals will continue to develop.
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 16 of 21
Sweden 2010 3406 40 2.7 Palmquist et a.,
2014 [60]
Swiss 2004
2048
(>14)* 55.1 5
Schreier et al.,
2006 [61]
Swiss 2008
1122
(30–60)* 37 8.6
Roosli et al., 2010
[62]
Swiss 2009
1122
(30–60)* 37 7.7
Roosli et al., 2010
[62]
Germany 2004 30,047 58.6 10.3 Blettner et al.,
2009 [63]
Germany 2004 30,047 58.4 8.7 Kowall et al., 2012
[64]
Germany 2006 30,047 58.4 7.2 Kowall et al., 2012
[64]
USA
(California) 1998 2072 58.3 3.2 Levallois et al.,
2002 [65]
Finland 2002 6121 40.8 0.7 Korpinen et al.,
2009 [66]
Great Britain Before
2007 3633 18.2 4
Eltiti et al., 2007
[67]
Taiwan 2007 1251 11.5 13.3 Tseng et al., 2011
[68]
Austria Before
2008 460 88 3.5
Schröttner and
Leitgeb, 2008 [69]
Japan Before
2009 2472 62.3 1.2
Furubayashi et al.,
2009 [70]
Holland 2011 5789 39.6 3.5 Batiatsas et al.,
2014 [71]
Holland Before
2013 1009 60 7
Vabn Dongen et
al., 2014 [72]
* When precised, age intervals of included patients are indicated in brackets.
Furthermore, although these reported EHS prevalence figures are only estimations, not critically
evaluated due to a lack of objective criteria to clearly define EHS, it is possible—as speculated in
Figure 7—that the EHS prevalence will continue to grow in the future, in as much as the manufacture
of wireless technology and industrial chemicals will continue to develop.
Figure 7. Estimated prevalence (%) of people around the world who consider themselves to be
electrohypersensitive, plotted over time in a normal distribution graph, according to Reference [73].
11. Conclusions
Figure 7.
Estimated prevalence (%) of people around the world who consider themselves to be
electrohypersensitive, plotted over time in a normal distribution graph, according to Reference [73].
11. Conclusions
In summary, we showed that there are presently sufficient clinical, biological, and radiological data
for EHS to be acknowledged as a well-defined, objectively identified, and characterized pathological
neurologic disorder. As a result, patients who self-report they suffer from EHS should be diagnosed
and treated on the basis of presently available biological tests, including the detection of peripheral
blood and urine biomarkers and the use of imaging techniques such as fMRI, TDU, and, when possible,
UCTS. Moreover, because we showed for the first time that EHS is frequently associated with MCS and
that both clinico-biological entities may be associated with a common physiopathological mechanism
for genesis, it clearly appears that they can be identified as a unique neurologic pathological syndrome,
Int. J. Mol. Sci. 2020,21, 1915 16 of 20
whatever their causal origin. Moreover; as it was shown that MCS genesis may be attributed to toxic
chemical exposure, and EHS genesis to potentially excessive EMF and/or chemical exposure; protective
measures against these two environmental stressors should be taken.
Whatever its causal origin and mechanism of action, EHS should therefore be from now on
recognized as a new identified and characterized neurological pathological disorder. As it is already a
real health plague potentially involving millions of people worldwide it should be acknowledged by
WHO, and thus be included in the WHO ICD. As stated during the international scientific consensus
meeting on EHS and MCS that we have organized in 2015 in Brussels, scientists unanimously asked
WHO to urgently assume its responsibilities, by classifying EHS and MCS as separate codes in the
ICD; so as to increase scientific awareness of these two pathological entities in the medical community
and the general public, and to foster research and train medical practitioners to efficiently diagnose,
treat, and prevent EHS and MCS–, which in fact constitute a unique, well-defined, and identifiable
new neurologic disease.
Author Contributions:
Conceptualization: D.B. and P.I.; methodology, D.B.; software, P.I.; validation, D.B. and
P.I.; formal analysis, P.I.; investigation, D.B.; resources, D.B.; data curation, P.I.; writing—original draft preparation,
D.B.; writing—review and editing, D.B. and P.I.; visualization, P.I.; supervision, D.B.; project administration, P.I.
All authors read and agreed to the published version of the manuscript.
Funding:
The present study was supported by ARTAC, a non-profit private research center (Paris, France;
www.artac.info), ECERI (Europe) and partially by Osato Research Institute (Japan).
Acknowledgments:
The authors acknowledge Marie Anne Barros from the ARTAC for clinical assistance, as well
as Sylvie Barbier from Laboratoire Barbier-Metz and Natalio Awaida from Labo XV-Paris for blood collection and
high-quality EHS-related blood marker measurements. They also thank Tony Tweedale from R.I.S.K. (Rebutting
Industry Science with Knowledge) Consultancy in Brussels for his careful scientific and English review of
the manuscript.
Conflicts of Interest:
The authors declare no conflicts of interests. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
Abbreviations
6-OHMS 6-hydroxymelatonin
BBB blood–brain barrier
BBF brain blood flow
CT scan computerized tomography (CT) scan
DECT digital enhanced cordless telecommunications
DMN default mode network
EHS electrohypersensitivity
EHS/MCS electrohypersensitivity and multiple chemical sensitivity
EMF electromagnetic field
ELF extremely low frequencies
fMRI functional magnetic resonance imaging
GSSG oxidized glutathione (GSSG)
Hs-CRP hypersensitive C reactive protein
ICD international classification of disease
IEI-EMF idiopathic environmental intolerance attributed to EMF
IgE immunoglobulin E
IPCS International Program on Chemical Safety
MCS multiple chemical sensitivity
MRI magnetic resonance imaging
NTT nitrotyrosine
PI pulsometric index
RF radiofrequencies
TBARS thiobarbituric acid reactive substances
Int. J. Mol. Sci. 2020,21, 1915 17 of 20
TDU transcranial Doppler ultrasound
UCTS ultrasonographic cerebral tomosphygmography
WHO World Health Organization
WiFi Wireless Fidelity
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