art-Matej-Par
ORAL MEDICINE
PSYCHONEUROIMMUNOLOGY OF ORAL DISEASES – A REVIEW
Review Article
Matej Par1a* , Zrinka Tarle1b*
1
Department of Endodontics and Restorative Dentistry, School of Dental Medicine, University of Zagreb, Zagreb, Croatia
DMD, PhD, Postdoctoral Researcher
a
DMD, PhD, Professor, Dean
b
ABSTRACT DOI: https://doi.org/10.25241/stomaeduj.2019.6(1).art.7
Background: Various oral stimuli that are perceived by the brain as stressful can trigger patterns
OPEN ACCESS This
of neurological activity which then directly influence immune and endocrine response. is an Open Access article
Objective: To analyze the psycho-neuro-endocrine-immunological interactions involved in oral under the CC BY-NC 4.0
license.
diseases and conditions.
Data sources: Web of Science, PubMed, Google Scholar were databases researched for peer Peer-Reviewed
Article
review articles in indexed journals.
Study selection: A literature search limited to peer-reviewed articles in indexed journals published Citation: Par M, Tarle Z.
Psychoneuro-immunology of
before January 2019 was performed using specific keywords. 107 articles were selected. oral diseases – a review.
Data extraction: The aspects related to psycho-neuro-immune interactions relevant for dental Stoma Edu J. 2019;6(1):55-65
practitioners were synthesized and presented in the form of narrative review. Oral diseases and Received: March 14, 2019
Revised: March 21, 2019
conditions in which psychological factors act through neurological, endocrine and immunological Accepted: March 27, 2019
mechanisms are discussed. The following clinical entities were included: periodontitis, oral lichen Published: March 28, 2019
planus, recurrent aphthous stomatitis, temporomandibular disorders, herpes labialis, burning *Corresponding author:
mouth syndrome, and atypical odontalgia. Additionally, the role of psycho-neuro-immunological Dr. Matej Par, DMD, PhD
Gunduliceva 5, Department of
factors on bacterial adherence and oral microbiome is briefly discussed. Endodontics and Restorative
Data synthesis: Various oral diseases and conditions of multifactorial etiology can be influenced Dentistry, School of Dental
Medicine, University of Zagreb,
by psycho-neuro-immunological interactions. In daily practice, clinicians should be aware of the Zagreb, Croatia
interplay between mental and general health and consider addressing psychological disturbances Tel.: +3851 480 2203, Fax:
+3851 4802 203, e-mail:
as a supplement for conventional treatment modalities. Recognizing these interactions should mpar@inet.hr
help to better understand the relationship between mental and physical health. Copyright: © 2019 the
Keywords: Periodontitis; Lichen planus, oral; Stomatitis, aphthous; Temporomandibular joint Editorial Council for the
disorders; Herpes labialis. Stomatology Edu Journal.
1. Introduction that stress-induced immunosuppression, stress-
Psychoneuroimmunology is an interdisciplinary field induced inflammation, and various subtle changes
which represents the convergence of psychology, in the regulation of the endocrine and immune
neuroscience, endocrinology, and immunology. system caused by psychological factors can modify
Various stimuli that are perceived by the brain as the course of different diseases. This review is
stressful can trigger patterns of neurological activity focused on the diseases affected by psycho-neuro-
which then directly influence immune and endocrine immunological factors which occur in the oral cavity.
response. Since many cells of the nervous, immune,
and endocrine systems share common signaling
pathways, these systems do not act as isolated 2. Methodology
functional units, but instead interact with each other A literature search limited to peer-reviewed articles
to yield an integrated response. By recognizing in indexed journals published before January 2019
these interactions, psychoneuroimmunology helps (1983-2018) which were identified by searching
to better understand the relationship between the Web of Science, PubMed (Medline) and
mental and physical health. The idea of the interplay Google Scholar using the following keywords:
between psychological factors and physical health (psychoneuroimmunology OR psychological OR
is not new – its origins can be traced back to Galen, psychiatric OR mental health OR stress OR depression
who in the year 200 presented the observation OR cortisol OR hypothalamic-pituitary-adrenal) AND
that melancholic women are more susceptible to (oral OR dental OR dentistry OR periodontitis OR
breast cancer than sanguine women [1]. Almost oral lichen planus OR recurrent aphthous stomatitis
two millennia later, contemporary studies have OR temporomandibular disorders OR herpes OR
collected a great deal of experimental data and burning mouth syndrome OR atypical odontalgia
clinical evidence which support the hypothesis OR eating disorders OR microbiome). The aspects
Stomatology Edu Journal 55
PSYCHONEUROIMMUNOLOGY OF ORAL DISEASES
– A REVIEW
Review Article Table 1. Systematic division of the cited articles according to the
discussed topics. perpetuation [4]. The effect of periodontitis on
systemic health has been extensively studied and
Topic Reference No.
many connections with illnesses of remote organs
Periodontitis 2-40 have been hypothesized [5, 6]. Many of these
Oral lichen planus 41-54 connections have also been supported by evidence,
Recurrent aphthous stomatitis 55-62 although to varying extents. Rather compelling
Temporomandibular disorders 63-82 evidence exists for the association of periodontitis
with cardiovascular disease [7] and diabetes mellitus
Herpes labialis 83-87
[8]. Obstetric complications, respiratory diseases,
Burning mouth syndrome 88, 89 chronic kidney disease, and cancer have also been
Atypical odontalgia 90 linked to periodontitis [9-12]. Two major mechanisms
Eating disorders 91-97 of systemic action involve (I) invasion of periodontal
pockets bacteria, leading to bacteremia and
Oral microbiome 4, 98-107
dissemination of living bacteria or products of their
decomposition; and (II) excessive production of
of psycho-neuro-immune interactions relevant for long-range pro-inflammatory cytokines, resulting in
dental practitioners were synthesized and presented their elevated systemic levels. The latter mechanism
in the form of a narrative review. clearly represents an immuno-endocrine response,
while the former mechanism is also immunologically-
mediated since the presence of bacterial antigens in
3. Results the bloodstream causes a cross-reactive
Oral diseases and conditions in which psychological immunological response which then leads to the
factors act through neurological, endocrine destruction of host tissues [5]. The relationship
and immunological mechanisms are discussed. between periodontitis and systemic health is often
The following clinical entities were included: bidirectional: a complex immuno-endocrine
periodontitis, oral lichen planus, recurrent aphthous response initiated by the microbiome in periodontal
stomatitis, temporomandibular disorders, herpes pockets modulates various systemic conditions,
labialis, burning mouth syndrome, and atypical while the impaired systemic health, in turn, affects
odontalgia. Additionally, the role of psycho-neuro- the progress of periodontal disease. For example,
immunological factors on bacterial adherence and elevated levels of pro-inflammatory cytokines due to
oral microbiome is briefly discussed. The systematic periodontitis can increase insulin resistance, while
division of referenced articles regarding individual the resulting hyperglycemia and formation of
topics is presented in Table 1. glycosylation end products enhance the destructive
potential of periodontitis [13]. Without going further
3.1. Periodontitis into detailed descriptions of the pathophysiology of
Periodontitis is an inflammatory disease which periodontitis and the related systemic conditions, it
progressively damages periodontal tissues, is evident that many of the interactions stem from
eventually leading to tooth loss. Although the underlying dysregulation of the immune system
periodontitis is clearly associated with the presence and can be affected by psycho-neurological factors.
of certain microbial species, it cannot be regarded as Although the psycho-neurological influence on the
a classical infective disease because the damage to complex interactions between periodontitis and
periodontal tissues results from an inappropriate systemic diseases currently remain unexplored, the
inflammatory reaction and not from the destructive psycho-neurological aspects of periodontitis itself
action of the microbes alone [2]. The pathophysiology have been well documented. Clinical observations
of periodontitis is thus related to a complex interplay and epidemiological studies have indicated that
between the microbial challenge and host immune stress [14], depression [15], and inadequate coping
response [3], while the differences in immunological behaviors [16] are related to the onset and
reactivity and susceptibility to periodontal progression of periodontitis. Psychological factors
destruction between individual persons are have long been known to present a risk factor for
determined genetically. These differences explain acute necrotizing ulcerative gingivitis and
why the presence of a certain microbial community periodontitis – these aggressive forms were the first
can cause an aggressive disease in some individuals, to be related to psychological factors about 50 years
whereas in others the same microbial species may ago [17-20]. A systematic review from the year 2013
not trigger any destructive reaction. Additionally, it analyzed 14 studies and showed that 8 studies
is still unclear whether the bacterial strains found in identified a positive relation between psychosocial
active periodontal pockets truly initiate the disease factors and periodontitis, 4 studies identified a
or these strains simply prefer the new environment positive relation between some characteristics of
created by pocket formation and active inflammation, psychological factors and periodontal disease,
without an active role in its initiation and whereas only 2 studies were unable to identify any
56 Stoma Edu J. 2019;6(1): 55-65 http://www.stomaeduj.com
PSYCHONEUROIMMUNOLOGY OF ORAL DISEASES
– A REVIEW
Review Article
relation [19]. Contrary to early beliefs that stress In any case, a relation between psychological factors
response mediated through catecholamines and and periodontal health has been repeatedly
cortisol is primarily immunosuppressive, the immune observed. In studies on the relation between stress
system may be affected by psychological stress in and periodontitis, it is generally difficult to
both directions. This happens because the individual distinguish between the contribution of stress-
cell or tissue reaction to elevated levels of stress related behavioral factors (poor oral hygiene, poor
hormones depends on the presence or absence of nutrition, smoking, and generally neglected health)
particular receptors [21]. Short-term stress appears from exclusively psychoneuroimmunological stress-
to suppress cellular immunity, whereas chronic related factors which directly affect the progress of
stress leads to a more comprehensive dysregulation the disease, without a behavioral intermediary [15].
of the immune system, affecting both cellular and The psycho-neuro-immunological mechanism is
humoral immunity [15]. Psychological status was evidenced by the role of cortisol and other stress-
found to correlate with salivary levels of cortisol and related hormones. In an experimentally induced
β-endorphin, which were in turn identified as periodontitis in rats which had genetically different
determinants for tooth loss due to periodontal responsiveness of the hypothalamic-pituitary-
disease [22]. Depression has also been associated adrenal axis, the high-responding rats developed
with increased risk and severity of periodontitis. more severe periodontal disease. Additionally, they
Various psychometric factors, such as depression showed elevated corticosterone blood levels due to
and anxiety scores, subjective well-being, somatic a local inflammatory response induced by
complaints, quality of life, and introversion have experimentally enhancing the accumulation of
been correlated with periodontitis [23]. Traumatic subgingival microbiome, indicating a positive
life events such as the loss of a spouse, as well as the feedback loop between the hypothalamic-pituitary-
personality trait of exercising extreme external adrenal axis activation and local periodontal
control were shown to increase the risk for severe inflammation [31]. In a rat model of depression
periodontitis [24]. Stress-related depression and induced by olfactory bulbectomy, the role of psycho-
exhaustion have been associated with increased neuro-endocrine factors has been demonstrated by
levels of cortisol and IL-6 in the gingival crevicular a decreased expression of glucocorticoid receptors
fluid, as well as higher levels of gingival inflammation in the hippocampus, different response to injected
and plaque accumulation [25]. Women on long-term lipopolysaccharide and more extensive periodontal
sick leave for depression had more severe bone loss in depressive animals [32]. The association
periodontitis and elevated levels of IL-6 in gingival between cortisol and periodontitis has also been
crevicular fluid compared to healthy controls [26]. observed in humans; patients undergoing stressful
Patients with rapidly progressing periodontitis life events had higher cortisol levels and more severe
presented significantly higher depression and periodontitis [33]. Other studies have confirmed that
loneliness scores compared to patients with chronic hyperactivation of the hypothalamic-pituitary-
adult periodontitis and healthy controls [27]. adrenal axis and the resulting increase in cortisol
Depression was associated with a more extensive level was positively related to the extent and severity
periodontal breakdown [28]. Psychosocial measures of periodontitis [34]. Psychological stress, depression,
of stress and depression associated with financial and salivary cortisol levels were found to be
strain were shown to be significant risk indicators for positively correlated with the extent of periodontal
severity of periodontitis in adults [16]. The destruction, independent of the level of oral hygiene
effectiveness of coping behavior has also been [35]. In addition to cortisol, levels of another stress-
identified as a modulating factor for periodontitis in related hormone whose secretion is regulated by
patients exposed to psychological stress. Adequate corticotrophin, dehydroepiandrosterone, were also
coping behaviors, such as problem-based coping related to the extent and severity of periodontitis,
were shown to reduce the stress-associated risk [16]. adding to the evidence for the role of hypothalamic-
Conversely, patients with inadequate coping pituitary-adrenal axis hyperactivation in the
techniques (passive coping) were shown to be at pathogenesis of periodontitis [36]. The outcome of
greater risk for severe periodontitis [29]. Ineffective periodontal treatment can be negatively affected by
coping was also associated with poorer responses to stressful life events [37], occupational stress [38], and
nonsurgical periodontal treatment, whereas patients clinical depression [39], indicating that psycho-
with active coping had less severe forms of disease neuro-immunological factors play a role in wound
and better treatment outcomes [30]. Although healing and recovery following an invasive
psychological factors have been identified as risk treatment. From a clinical standpoint, these findings
factors for periodontitis in multiple studies, rigorous indicate that routine periodontal treatments may
analyses highlight the issue of heterogeneity of benefit from an adjunctive stress-management
study designs, methodology and assessment criteria, therapy which would comprise the assessment of
thus claiming that it is not yet possible to regard patient’s stress levels and their ability to cope with
psychological stress as a definitive risk factor [19,21]. stress, followed by implementation of stress-
Stomatology Edu Journal 57
PSYCHONEUROIMMUNOLOGY OF ORAL DISEASES
– A REVIEW
Review Article reduction protocols [40]. Similarly, addressing scores on anxiety and depression tests compared
depression in patients with periodontitis may help to healthy controls [43]. Higher sensitivity to stress
to alleviate the course of periodontitis through perception and reduced capability of coping with
immunologic and behavioral changes conducive of stress was also observed [44]. A study evaluating
periodontal healing [35]. psychological personality profiles of patients with
oral lichen planus found significantly higher scores
3.2. Oral lichen planus for hypochondriasis, depression, and hysteria
Oral lichen planus is a chronic inflammatory disorder compared with controls, whereas the scores at
which clinically manifests on the oral mucosa as other clinical scales (psychopathic deviate, paranoia,
multiple bilateral papular, reticular, erythematous, psychasthenia, schizophrenia, and hypomania)
and erosive lesions. Besides the significant negative were not different from controls [47]. In that study, a
effect on the quality of life due to its chronic course, two-fold increase in serum cortisol levels was found
oral lichen planus lesions have a potential for between patients with erosive lesions and controls,
malignant transformation at an overall frequency whereas patients with reticular lesions had similar
of 0.3-3 % [41]. Although the etiology of oral lichen cortisol levels as controls. Elevated plasma cortisol
planus is unclear, the underlying pathophysiology levels were also found to be associated with more
has been known to involve a dysregulated T-cell aggressive erosive lesions in another study [48],
immune response to an induced antigenic change in suggesting that cortisol levels may be predictive
the oral mucosa. The hypothesized etiologic factors of the severity of the disease. Cortisol levels were
which have the potential to induce that antigenic positively correlated with scores on clinical scales
change include dental amalgam, non-steroid anti- for hysteria, hypochondriasis, and depression [47].
inflammatory drugs, and hepatitis C virus [41]. Conversely, a study on diurnal cortisol production
The association of oral lichen planus with reported that patients with oral lichen planus
psychological stress has generally been had decreased salivary cortisol production in the
acknowledged and reported in multiple studies morning hours compared with healthy controls
[42-45]; however, the causal relationship is less [44]. Despite some inconsistencies in the studies of
clear since chronic discomfort due to persistent cortisol levels, the findings indicate that oral lichen
lesions may itself act as a stressing factor [46]. An planus may be related to the dysregulation of the
interesting approach for evaluating a possible hypothalamic-pituitary-adrenal axis triggered by
etiological role of psychosocial stressors on oral psychological factors. Considering the autoimmune
lichen planus was employed in a double-controlled background of oral lichen planus, additional
study which involved healthy individuals as a evidence for the role of neuro-immune crosstalk for
negative control and patients with burning mouth the systemic immune response is the finding that
syndrome, atypical facial pain, and myofascial pain bilateral transection of glossopharyngeal nerves
dysfunction syndrome as a positive control [45]. can attenuate the dose-dependent febrile response
That study found significantly higher stress, anxiety, to injection of lipopolysaccharide or IL-1-b into
and depression levels in oral lichen planus patients the soft palate of rats [49]. This demonstrates that
and positive control compared to the general the communication between the central nervous
population, whereas no significant differences were system and the immune system is not exclusively
found between the oral lichen planus patients and mediated by cytokines and other humoral pathways,
the positive control group. These results have led but instead requires a local neural route linked to
the investigators to hypothesize that psychological the site at which the antigen was administered.
disturbances in susceptible persons may indeed play The common treatment for oral lichen planus is
a causative role in the pathophysiology of oral lichen symptomatic and involves topical, intralesional, and
planus, probably by acting as a starting point for the systemic administration of corticosteroids, while
initiation of autoimmune reactions. other immunosuppressive agents (cyclosporine
In a study which assessed the psychiatric status of 56 and tacrolimus) or retinoids can also be used in
patients with clinically and histologically verified oral more severe cases [46]. Although the disease can
lichen planus, 52% of patients were diagnosed with be successfully controlled by these medications in
mental disturbances (12 patients with slight, 3 with most cases, the effects of the treatment are usually
moderate, and 14 with severe disturbances); that transient and the side effects of long-term treatment
percentage was significantly higher than in healthy may outweigh the benefits. Addressing the psychical
participants in the control group and the general health as a possible adjunctive therapy in treating
population [42]. In a study on anxiety, depression, oral lichen planus has been suggested decades
and stress in patients with oral lichen planus, no ago [42,47,50], however, no studies evaluating the
differences were found between the acute and effectiveness of this approach have been published
remission stage, while patients diagnosed with up to date. A multidisciplinary approach to the
oral lichen planus reported encountering stressful treatment of oral lichen planus could be beneficial
life events more frequently and received higher because the psychological well-being of patients
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PSYCHONEUROIMMUNOLOGY OF ORAL DISEASES
– A REVIEW
Review Article
with oral lichen planus can be severely affected by the conventional treatment for RAS is symptomatic
the disease itself. Psychological support may help and ineffective in the long-term, a supportive
in breaking the vicious circle formed by the disease psychotherapy may be beneficial for alleviating the
that is both causing and being perpetuated by discomfort that RAS patients experience [56].
impaired psychological status [51]. Oral microbiome
in patients with oral lichen planus has been shown 3.4. Temporomandibular disorders
to be altered in comparison to healthy controls [52]. Temporomandibular disorders (TMD) encompass
Also, different colonization patterns were observed several clusters of symptoms involving chronic pain
at the sites of oral mucosa affected by lesions in the temporomandibular joint and masticatory
compared to healthy control sites within the same muscles, limitations in the range of mandibular
patient [53]. However, it has not yet been clarified movement and sounds occurring during movements.
if the dysbiosis associated with oral lichen planus Pain can be spontaneous or triggered by mandibular
has some causative role, for example by invading movement or palpation of the masticatory muscles.
the epithelial barrier and modifying the immune The etiology of TMD remains poorly understood
response [54]. Alternatively, the dysbiosis may and involves psychological, behavioral and
simply be an epiphenomenon due to the changed environmental factors. TMD usually presents no
oral environment, without having an active role in observable organic pathology and shares many
the immunopathology of oral lichen planus. features with other chronic pain conditions. TMD is
often comorbid with other chronic pain conditions,
3.3. Recurrent aphthous stomatitis such as fibromyalgia, headaches, spinal pain, and
Recurrent aphthous stomatitis (RAS) is a chronic back pain [63]. Although it causes significant distress
disease of unclear etiopathogenesis, characterized to affected patients, TMD is self-limiting and usually
by a recurrent onset of solitary or multiple painful does not lead to a progressive structural or functional
ulcerations and erosions appearing predominantly deterioration [64]. Being predominantly a functional
on unattached oral mucosa. Clinical characterization rather than structural disorder, TMD appears more as
distinguishes three main types of oral lesions: minor, a symptom than a disease.
major and herpetiform. The disease is considered to The inseparable interplay between psychological
be caused by a hyper-reactive immune response, stress and the experience of pain is biologically
which is influenced by genetic predisposition and based on the fact that most of the molecules
modulated by a multitude of factors, some of which which regulate the stress response are the same
include: viral and bacterial infections, nutritional as those involved in pain modulation [65]. As
deficiencies, food allergies, psychological stress, in other chronic pain conditions, psychological
mechanical trauma, and hormonal imbalance factors are generally implicated in the occurrence
[55]. The exacerbation of RAS is often related to of TMD, with the involvement of the hypothalamic-
psychological stress. Higher anxiety levels coupled pituitary-adrenal axis, as well as the serotoninergic
with elevated cortisol levels in plasma and saliva and opioid system [66]. In addition to the psycho-
have been associated with RAS [56]. Exposure neuro-immunological dysregulation, the symptoms
to stressful situations and conditions appears can be aggravated by hyperactivity of masticatory
to be more important for the onset of RAS than muscles which often accompanies TMD. However,
personality profiles and stable psychological traits the stress-induced parafunctional activities are not
[57]. However, some evidence exists that trait necessarily related to muscle pain and [67] and
anxiety may be a predisposing factor for RAS [58]. thus cannot be regarded as the primary source
A study in which 160 RAS patients were followed by of TMD symptoms. This is supported by a study
weekly phone surveys over 1 year found a significant evaluating the association of masticatory muscle
association of stressful life events and exacerbations pain and nocturnal electromyography activity with
of RAS, while a stronger association was found for psychological factors demonstrating that muscle
psychological than physical stressors [59]. However, pain is more related to psychological stress than to
no association of stressful life events with the parafunctional activity [68].
duration of RAS episodes was identified in that study. Studies have indicated that patients with TMD tend
There are also reports of no association of RAS with to present higher levels of anxiety [69], depression
alterations in cortisol levels [60] and psychological and somatization [70]. Stress and emotional
factors (stress and depression) [61], which is in line distress have also been shown to be associated
with the complex and multifactorial etiology of with TMD pain, as well as muscular tension and
RAS. Frequent exacerbations of painful RAS lesions parafunctional habits which can independently
interfere with normal daily activities and negatively contribute to the painful experience [71]. TMD
affect the quality of life [62]. The psychological patients showed higher electromyographic activity
consequences may then influence the course of during experimentally induced stress compared
disease thus forming a vicious circle in a similar to patients with other chronic painful conditions
manner as mentioned for oral lichen planus. Since (e.g. chronic back pain) and healthy controls [72].
Stomatology Edu Journal 59
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Review Article Subjects with maladaptive coping were at greater establishes a latent infection in ganglionic neurons
risk for TMD pain than the subjects with adaptive which can be reactivated under conditions of
coping [73]. A prospective cohort study of 171 impaired immune surveillance, thus causing a
healthy female volunteers identified the first-onset recurrent infection. The potential of psychological
TMD in 8.8% of the participants over the course of stress to exacerbate the recurrence of herpes virus
3 years and demonstrated a high predictive value of infection has been well documented and various
depression, perceived stress, and mood for the onset factors such as short-term stress, stressful life events,
of TMD [74]. Some of the TMD patients showed dysphoria, anxiety, anger, and negative mood were
cortisol hypersecretion in response to stress, which associated with viral reactivation at both oral and
could be regarded as a biological predisposition to genital sites [84]. Since cellular immunity plays
TMD [75]. However, the excessive cortisol secretion an important role in maintaining the infection
may represent a response to a painful stimulus, as in a latent stage, an exacerbation is considered
evidenced in a study which showed that cortisol to occur when the cellular immune response is
hypersecretion occurred mostly while the subjects impaired due to the stress-induced imbalance in
were awake, i.e. aware of pain [76]. the secretion of catecholamines, glucocorticoids,
Sleep disorders may also be implicated in the and pro-inflammatory cytokines (IL-1, IL-6, and
pathophysiology of TMD through increasing central TNF) [85]. For example, it has been demonstrated
sensitivity to pain, but also by being associated with that adrenaline and glucocorticoids can be used
muscular parafunctions leading to myofascial pain to experimentally induce herpes simplex virus
[77]. The relation between sleep bruxism and TMD reactivation in animal models [86]. A longitudinal
is unclear, as it has been shown that not all patients study which evaluated daily mood states and weekly
with parafunctional habits develop myofascial pain levels in neuroendocrine markers found that the
[78]. The cause and effect relation between sleep number of natural killer cells and serum levels of
disorders and related parafunctions of masticatory adrenaline were associated with herpes labialis
muscles are difficult to establish since sleep disorders exacerbations [83]. Additionally, that study found
are commonly accompanied by depression and that adrenaline levels were positively correlated
other psychological disturbances which may to scores of affect intensity. Although the role of
independently influence TMD symptoms [79]. psychoneuroimmunological interaction in the
The usual symptomatic treatment of TMD involves recurrent herpes infections has been well confirmed,
the use of orthopedic appliances which are intended it remains difficult to quantify psychological stress
to improve the biomechanics of temporomandibular and its etiological significance for the onset of the
joint thus reducing muscle activity and joint disease [87].
loading, while simultaneously increasing patient
awareness of parafunctional habits [80]. Due to 3.6. Burning mouth syndrome
multifactorial etiology of TMD, a multidisciplinary Burning mouth syndrome is a chronic pain condition
treatment approach encompassing physiotherapy, of unknown etiology, usually characterized by
biofeedback, and cognitive behavioral therapy burning or stinging sensation coupled with a
seems reasonable [81]. Therapeutic modalities subjective feeling of dryness and altered taste.
targeting psychological factors may be beneficial Besides sensory disorders, clinically no oral lesions or
for reducing painful symptoms and functional other objective signs can be identified. The condition
limitations; however, the level of evidence for their is usually associated with a number of psychological
effectiveness is currently low [82]. In any case, it factors, leading some authors to refer to it as psycho-
appears that combined treatment modalities can stomatodynia [88]. Higher levels of neuroticism,
be more effective and yield longer-lasting results anxiety, depression, exposure to stressful life events
than the conventional treatment which employs have been associated with the syndrome and the
orthopedic appliances alone [81]. Also, as in other involvement of some personality disorders as well as
chronic pain conditions, the TMD pain can in many cortisol dysregulation have been hypothesized [89].
patients be mitigated by antidepressants regardless The treatment should aim at identifying and treating
of their possible comorbidity with depressive underlying psychological disturbances.
disorder [66].
3.7. Atypical odontalgia
3.5. Herpes labialis Atypical odontalgia is persistent idiopathic pain
Most individuals have been exposed to herpes which mimics toothache but lacks any identifiable
simplex virus through their lifetime, as evidenced organic cause. It may occur at a healed extraction
by the presence of antibodies in up to 90% of the site or in a healthy, restored or endodontically
general population. About 75% of the general treated tooth which presents with no evidence of
population is affected by clinically evident herpes pathology on clinical or radiographic examination.
labialis at some time in life [83]. After a primary Etiopathogenesis of atypical odontalgia is unclear
infection on skin or mucosa, herpes simplex virus and the involvement of psychogenic and neuropathic
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Review Article
factors has been proposed, although the primary (e.g. ammonia-producing species which elevate oral
cause remains unclear and thus no causal treatment pH values) and pathogenic (e.g. acidogenic species
exists [90]. which cause tooth caries through demineralization
The symptomatic treatment is generally difficult of dental hard tissues).
and unsuccessful, usually leading to unnecessary In fact, two most frequent diseases in the oral cavity,
extractions of multiple teeth due to patients’ i.e. caries and periodontitis, are caused by complex
persistent requests for treatment driven by changes in the microbial community, rather than by
persistent pain. Thus psychological factors need to infection with a specific pathogen [101]. Especially
be thoroughly considered in patients with atypical in the case of periodontitis, well-known shifts of
odontalgia in order to avoid irreversible iatrogenic microbial ecology in favor of specific bacterial
damage. species are associated with the destructiveness of the
disease. Healthy periodontal tissues express a low-
3.8. Eating disorders: anorexia and bulimia nervosa grade controlled inflammation which represents the
Eating disorders which are characterized by host response to periodontal microbiome, whereas
restricted food intake (anorexia nervosa) or purging the transition towards destructive inflammation
behavior by means of induced vomiting or laxative occurs in susceptible individuals when the microbial
use (bulimia nervosa) are psychiatric disorders dysbiosis occurs [102].
of unclear etiology with probable involvement The primary local beneficial effect of the commensal
of serotoninergic dysregulation in the brain [91]. microbiome is the inhibition of colonization of the
Frequent exposure of dental hard tissues to gastric oral cavity by pathogenic species, the so-called
acid due to vomiting can lead to cumulative colonization resistance [103]. Disbalances of the
demineralization and extensive erosions on enamel commensal microbiome can lead to opportunistic
and dentin. The resulting defects usually require infections by Candida spp. or Staphylococcus
comprehensive restorative or prosthodontic aureus, which are commonly seen as a side-effect
treatment. Eating disorders are associated with of antimicrobial therapy. Oral microbiome also has
elevated levels of pro-inflammatory cytokines some systemic effects, as exemplified by its role in
such as TNF- α and IL-6, indicating a psycho-neuro- the metabolism of nitrates. Nitrate is secreted into
immune interplay [92,93]. the saliva (about 25% of the total ingested amount)
Also, eating disorders are related to psychological and reduced by oral bacteria into nitrite which is then
stress and inadequate coping behaviors and are absorbed through gastric mucosa and converted
often comorbid with other psychiatric disturbances into nitric oxide. Nitric oxide has an important
such as anxiety and depression, with a probable role in regulating vasodilatation and maintaining
bidirectional interaction [94]. The acute phase blood pressure homeostasis. For example, orally
of anorexia nervosa has been associated with ingested nitrates in the form of food supplements
increased levels of salivary cortisol, secretory help to reduce blood pressure by exploiting this
immunoglobulin-A, and alpha-amylase, reflecting mechanism [104]. It is clear that the oral microbiome
dysregulation of hypothalamic-pituitary-adrenal plays a complex role in both local and systemic
axis [95]. Some patients with bulimia nervosa health, whereas its imbalances reach beyond a
have shown changes in the enzymatic activity straightforward infective disease caused by a single
of proteases, collagenase, and pepsin in resting pathogen. However, the effects of psycho-neuro-
and simulated saliva, which contributes to the immunological factors on the oral microbiome
progression of dental erosions [96]. Gut microbiome and the consequences of that interaction on
can also play a role in the regulation of food intake. systemic health have not been extensively studied.
For example, bacterial metabolic products such as Considering the better-established links of
short-chain fatty acids exert a neuroactive effect psycho-neuro-immunological factors with the gut
which affects the host appetite, possibly playing a microbiome, it is plausible that a similar interplay may
role in the pathophysiology of eating disorders [97]. occur in the oral cavity. If the link is to be established
and mechanisms elucidated, the oral microbiome
3.9. The role of the oral microbiome could be altered by using probiotics in a manner
Besides the gut and the skin, as two sites of the similar to what is now commonly accepted for gut
human body that are most heavily populated microbiome [105]. In such a scenario, modifying the
by microbes, the oral cavity is also an important oral microbiome could aid in mitigating the course
habitat for 500-1000 bacterial species [4, 98, 99]. of periodontal destruction through two major
The discrepancy in the number of species which is mechanisms: (I) inhibition of microbial adhesion,
encountered in the literature stems from the fact that colonization, growth, and biofilm formation; and
approximately half of the bacterial species found (II) altering the destructive host response involving
in the mouth cannot be cultured under laboratory inhibition of pro-inflammatory pathways and
conditions [100]. Most of the species present can be inflammation-induced enzymes [106].
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Matej PAR
DMD, PhD, Postdoctoral Researcher
Department of Endodontics and Restorative Dentistry
School of Dental Medicine, University of Zagreb
Zagreb, Croatia
CV
Mater Par, DMD, PhD is a postdoctoral researcher at the Department of Endodontics and Restorative Dentistry, School of Dental
Medicine in Zagreb, Croatia. He is a young researcher who authored 26 original research articles and contributed to 2 textbook
chapters. His primary areas of interest include dental biomaterials and the development of experimental remineralizing resin
composites.
64 Stoma Edu J. 2019;6(1): 55-65 http://www.stomaeduj.com
PSYCHONEUROIMMUNOLOGY OF ORAL DISEASES
– A REVIEW
Questions
Review Article
1. Why should dental practitioners consider psycho-neuro-immune interactions
in their daily practice?
qa. Dental treatment may have a negative long-term effect on the psychological status in susceptible
patients;
qb. Certain oral diseases may be affected by psychological disturbances;
qc. Early signs of some psychiatric disorders can be recognized in the mouth;
qd. Major modifications of dental treatment are needed in patients with some personality disorders.
2. Which of the following is incorrect?
qa. Periodontitis can affect systemic health, and some systemic diseases can influence the course of
periodontitis;
qb. Severity of periodontitis can be affected by stress, depression, and coping behavior;
qc. Some forms of periodontitis can be successfully treated using psychotherapy, without the need for local
periodontal treatment;
qd. Despite considerable amount of evidence, psychological factors cannot be yet regarded as definitive risk
factors for the onset of periodontitis.
3. Which of the following conditions usually does not present with painful
symptoms?
qa. Periodontitis and tooth caries;
qb. Herpes labialis and recurrent aphthous stomatitis;
qc. Temporomandibular disorder;
qd. Burning mouth syndrome.
4. Choose the correct statement:
qa. Oral microbiome consists of 500-1000 bacterial species; diseases such as caries and periodontitis occur
in cases of imbalances in microbiome in which only one bacterial species becomes dominant over others;
qb. Exacerbations of periodontitis and oral lichen planus have been shown to correlate with certain
psychological states but no association of these diseases with stress-related hormones such as cortisol was
observed;
qc. Necrotizing ulcerative gingivitis and periodontitis are the only forms of periodontal disease which are
not associated with psychological factors;
qd. Burning mouth syndrome and atypical odontalgia usually present with no clinical or radiological signs of
organic pathology but the patients affected by these conditions often show some psychological disturbance.
https://www.efcd.eu/conseuro-meeting/9th-conseuro-berlin-2019/
Stomatology Edu Journal 65