Periodontics
Rajkumar Parwani Simran R Parwani
Does Stress Predispose to Periodontal Disease? Abstract: The relationship of a sound mind to the maintenance of a healthy body has been recognized throughout most of recorded history. The term ‘stress’ is used to describe adverse emotions or reactions to unpleasant experiences. Individuals with high levels of stress and poor coping skills experience twice as much periodontal disease as compared to those with minimal stress and good coping skills. Although stress may predispose an individual to more destruction from periodontitis, the presence of periodontal pathogens remains the essential aetiologic factor. This review presents a summary of stress, discussing how it can predispose an individual to periodontal disease. Clinical Relevance: Stress, which is a universal phenomenon, is implicated to have various systemic effects besides being a risk factor for periodontal disease. This article elucidates the relationship between psycho-social stress and destructive periodontal disease. Dent Update 2014; 41: 260-272
The relationship of a sound mind to the maintenance of a healthy body has been recognized throughout most of recorded history. The ancient Romans and Greeks discussed the importance of the patient’s mental attitude and temperament in the treatment of physical disease.1 Stress can be best understood as part of a complex and dynamic system of transaction between individuals and their environment. It is a part of the human condition which is universally present but to varying degrees and with different effects on individuals.2 Stress is compatible with good health, the latter being necessary to cope with the challenges of everyday life. Problems start when the stress response is inappropriate for the size of the challenge.
Rajkumar N Parwani, Professor, MDS, Department of Oral and Maxillofacial Pathology and Simran R Parwani, MDS, Senior Lecturer, Department of Periodontics, Modern Dental College and Research Centre, Indore, India.
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What is stress?
The term ‘stress’ is used to describe adverse emotions or reactions to unpleasant experiences. It is ‘a state of physiological or psychological strain caused by adverse stimuli, physical, mental or emotional; internal or external, that tend to disturb the functioning of an organism and which the organism naturally desires to avoid’.3 Thus, ‘stress’ can be viewed as a process with both psychological and physiological components.4 Psychological definition: A stressor is any stimulus, situation or circumstance with the potential to induce stress reactions.5 Physiological definition: Stress can result in the de-regulation of the immune system mediated primarily through the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes.6 Whether or not a subject exhibits a stress response depends on a myriad of factors, including coping behaviours, genetic predisposition, concomitant stressors, levels of social support and other lifestyle factors. Potential effects of the stress response that may be observed or measured include anxiety, depression, impaired cognition and altered self-esteem.4
Riley7 demonstrated that stress can be induced in animals by factors such as noise, increased population density, male-female proximity, handling by animal keepers and deliberate trauma. In a low-stress environment also, the stress levels (measured by plasma corticosteroid levels) were significantly increased by a single, slightly stressful stimulus and these increased levels adversely affected the immune response of the animals. These effects may stimulate a variety of neuroimmunologic phenomena in multiple organs and tissues.
Biologic impact of stress Anxiety, as well as other emotional or psychological stresses, produce well characterized neuroendocrine and biochemical changes in experimental animals. The physiological consequences of these stress-mediated changes have been shown to have significant adverse effects on the proper functioning of the immune system.7 Activation of the hypothalamopituitary-adrenal axis by stress results in the release of an increased concentration of corticotropin-releasing hormone from April 2014
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Periodontics
the hypothalamus. The pituitary gland is connected to the hypothalamus by the infundibulum, a stalk of tissue that contains nerve fibres and small blood vessels. Corticotropin-releasing hormone in turn acts on the anterior pituitary, resulting in the release of adreno-cortico-tropic hormone (corticotropin). The adrenocortico-tropic hormone then acts on the adrenal cortex and causes the production and release of glucocorticoid hormones (predominantly cortisol) into the circulation. The glucocorticoids then produce a myriad of effects throughout the body, such as suppressing the inflammatory response, modifying cytokine profiles, elevating blood glucose levels and altering levels of certain growth factors.8,9 (Figure 1). Importantly, it has been established that pro-inflammatory cytokines, such as interleukin-1 can also activate the hypothalamo-pituitary-adrenal axis, leading to a feedback loop.10 Immune function plays a critical role early in the wound healing cascade. Pro-inflammatory cytokines, such as interleukin-1 and tumour necrosis factor, are two of the essential cytokines in this regard. It has been speculated that success in the later stages of healing is critically dependent on these early events. In an experimental study where blister wounds were inflicted in human subjects, it was found that women with higher levels of stress produced fewer cytokines than those with lower levels of stress. In addition, the individuals exhibiting greater stress had higher salivary cortisol levels.11 The second major pathway to be activated is the sympathetic nervous system. A well-known example of this is the so-called ‘flight or fight’ response to potentially harmful stimuli. Stress activates the nerve fibres of the autonomic nervous system, which innervate the tissues of the immune system. The adrenal medulla is actually a modified sympathetic ganglion. Its nerve bodies, instead of possessing axons, secrete their products directly into the bloodstream. The release of catecholamines results in the hormonal secretion of nor-epinephrine and epinephrine from the adrenal medulla, which results in a range of effects that may act to modulate immune responses. Catecholamines released during stress contribute to the development of hyperglycemia by directly stimulating glucose production and interfering with the tissue disposal of glucose.8 In addition, the sympathetic nervous system has a role in April 2014
Major life events
Psychological factors
Daily hassles Systemic illness
Environmental influences
STRESS
Poor coping strategies
Hypothalamus
Autonomic Nervous System
Corticotropin-releasing hormone Anterior Pituitary Adreno-corticotropic hormone Health impairing behaviours
Adrenal Medulla
Adrenal Cortex Increased epinephrine and Nor-epinephrine secretion
Increased cortisol secretion
-Suppressed inflammatory response -Poor oral hygiene -Increased blood glucose levels -Increased blood glucose levels -Cigarette and alcohol -Altered immune cell function -Altered growth factor levels consumption -Altered cytokine levels -Disturbed sleeping patterns -Poor nutritional intake -Forgetfulness
Increased susceptibility to periodontal destruction
Figure 1. Flow chart of ‘Patho-physiology of Stress Response’. (Courtesy of Boyapati et al, 2007.)
regulating immune cell activities.12 From the above discussion, it is apparent that the response of the human body to stressful stimuli is both helpful and therapeutic, but a potentially harmful imbalance occurs when the stressful stimuli are prolonged, eg chronic anxiety states.13,14
Stress and systemic disease General adaptation syndrome
The composite of the systemic reactions that results from continued exposure to stress is termed the General Adaptation Syndrome (GAS), which was DentalUpdate 261
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Periodontics
described by Selye in 1946. This syndrome is a generalized group of physiologic mechanisms which represents an attempt of the body to resist the damaging effects of stress. The changes involved are: Enlargement of the adrenal cortex with increased secretion of adrenocorticoid hormones; Involution of lymphatic organs; Hyalinization and inflammatory changes in blood vessels with hypertension; Gastrointestinal ulceration; Malignant nephrosclerosis.15,16 This syndrome develops in three stages. The first phase of the GAS (Alarm Reaction) activates adrenal cortex to release corticosteroids better to prepare the body to adapt to and resist a stressful incident (Resistance Stage). If the causative stressful event is not suppressed, the third stage of GAS occurs (Exhaustion Stage). At this point, the body’s ability to resist is overwhelmed and damage occurs to target tissues. This response is further modified by extraneous factors such as the patient’s immunologic and nutritional status, medications, age and the presence/ absence of co-existent systemic diseases.17-19
factors as well as induce negligence in oral hygiene procedures, increased smoking and alcohol use, decreased salivary flow and bruxism.23 Personality traits
Certain personality traits and psychiatric disturbances have also been implicated.23-28 Gastric ulceration
This can occur in stressed subjects because mucosal defences fail when mucosal blood flow drops. Cigarette smoking induced as a result of stress impairs mucosal blood flow and healing of mucosal epithelium. Alcohol has not been proved to cause peptic ulceration directly, but alcoholic cirrhosis is associated with increased incidence of peptic ulcers. Cortisteroids in high dose and with repeated use also promote ulcer formation.29 Activation of monocytes and macrophages, with release of tumour necrosis factor, interleukin-1 and reactive oxygen metabolites could also be reasons for ulceration.30
Depression
Poor coping skills to combat stress are often manifested as depression.22 Depression may affect host resistance
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Rheumatoid arthritis
Studies have also demonstrated a relationship between psychological stress and inflammatory diseases such as rheumatoid arthritis and periodontitis.37 This may be attributed to influence on immune activities directly or indirectly via neuroendocrine (hormone) messenger substances (neurotransmitters and neuropeptides).38 Other effects
Effects of hormonal secretion
Stress-induced stimulation of the hypothalamo-pituitary adrenal axis and sympatho-adrenal medullary system causes stimulation of the adrenal cortex and medulla and leads to: Release of insulin, androgens, thyroid hormones, cortisol and catecholamines, causing protein degradation, increased glucose synthesis, lipolytic action, sodium retention and inhibition of new bone formation leading to osteoporosis and tetany.20 Eosinopenia, thrombocytosis and decreased clotting time.20 Release of substance-p which is a neurotransmitter which transmits pain signals, causes vasodilation and increased blood flow to gingival and periodontal capillaries.21 Stimulation of most immune cells via specific receptors, enhancing the phagocytic activity of leukocytes and macrophages and stimulating T-cell proliferation and antibody production from B cells.21
Stress-induced changes in sIgA levels are the result of an increased adrenergic output.34 Development of viral respiratory tract infection in stressed subjects could also be attributed to low NK cell activity,35 and/or a decreased specific T-cell killing of Epstein-Barr Virus (EBV) infected cells, as well as decreased lymphokine production. This was associated with an increase in antibody titer to EBV, suggesting reactivation of the latent, endogenous virus.36 This finding proved the relationship between life stress, seroconversion to EBV and development of infectious mononucleosis.
Involvement of other systems
Mental, physical and biological stresses also have an impact on the body’s ability to resist diseases, resulting in a number of diseases including coronary heart disease and breast cancer.31 There have also been reports linking psychosocial factors to other malignancies, autoimmune and infectious diseases,13 because the natural killer (NK) cells, which play a key role in immune surveillance preventing the development of cancer, are lowered in stress.32 In a large, 6-month prospective study, Graham et al33 examined the relationship between stress and upper respiratory tract infection. In a multivariate analysis model, the authors observed that both intra-study as well as the pre-study stress was significantly associated with more episodes of respiratory illness and more symptom days. The effect of stress on levels of immunoglobulin A in saliva (sIgA) in relation to upper respiratory infections has also been studied, where an increased frequency of infection periods was found in subjects with high levels of stress. This was accompanied by low levels of sIgA.
Stress is also associated with certain masochistic habits like lip-biting or cheek-biting and habitual grinding of teeth. Traumatic ulcers, aphthous ulcers,39 lichen planus40 have known stress as the aetiology. Overeating is also linked to stress.41
Stress and periodontal disease In 1976, De Marco42 presented a series of case reports describing severe alveolar bone loss in 11 soldiers who had experienced severe war-time emotional stress. He proposed that, in the absence of other obvious causative factors, these cases represented a disease entity that he called ‘Periodontal Emotional Stress Syndrome’. Acute necrotizing ulcerative gingivitis
Psychological stress has been implicated as a risk indicator for periodontal disease.43 The most notable example is the documented relationship between stress (eg experienced by soldiers at war or by students during examinations) April 2014
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Periodontics
and acute necrotizing ulcerative gingivitis (NUG). In individuals with NUG, primarily, the neuro-endocrine mechanism is activated under stressful conditions. Stress-induced vasoconstriction may also induce local tissue ischaemia and predispose the periodontal tissues to microbial invasion. Both these effects could be enhanced by tobacco smoking, which is a nearly universal habit among individuals with NUG.44
Chronic periodontitis
Several clinical studies have documented the relationship between psycho-social stress and chronic forms of periodontal disease. Croucher et al45 found that, in case-controlled studies, individuals with stable lifestyles (based on family structure and employment status) and minimal negative life events had less severe periodontal disease than individuals with less stable lifestyles (eg unmarried, unemployed) and more negative life events. The effect is not simply a matter of the presence of stress versus a lack of stress but rather the type of stress and the ability of the individual to cope with it that correlates with destructive periodontal disease. All individuals experience stress, but these events do not invariably result in destructive periodontitis. The types of stress that lead to periodontal destruction appear to be more chronic or long term and less likely to be controllable by the individual. Life events such as the loss of a spouse or family member, a failed relationship, loss of employment and financial difficulties are examples of stressful life events that are typically not controllable by the individual or not perceived by the individual as being under his or her control, rendering the person with a feeling of ‘helplessness’. The duration of the stressful life event will also have an influence on the total impact of the stress-induced disease destruction. Financial stress is an example of a long-term, constant pressure that may exacerbate periodontal destruction in susceptible individuals. Genco et al22 found that individuals with high levels of financial stress and poor coping skills had twice as much periodontal disease as those with minimal stress and good coping skills. Psychological tests were used to identify and weigh the causes of stress, such as children, spouse, finances, single life and work; and to measure individual coping skills. Individuals April 2014
with problem-focused (practical) coping skills fared better than individuals with emotionfocused (avoidance) coping skills with respect to periodontal disease. The researchers also found that chronic stress and inadequate coping could lead to changes in daily habits, such as poor oral hygiene, clenching and grinding, decreased salivary flow and suppressed immunity. Individual life events, such as divorce and bereavement increased stressful events and led to a greater prevalence of periodontal disease.46 Psychologically depressed human subjects who also smoked had high titers of IgG against T. forsythia. These subjects were found to have more severe and extensive chronic periodontitis which was due to the negative influence of depression on the immune system.47 Pro-inflammatory cytokine levels were also increased in stressed subjects.48 Stress-induced periodontal destruction
The following observations have been reported in stressed experimental animals. In the alarm reaction,49 no significant changes; in the late stage of the stress syndrome, osteoporosis of alveolar bone,50 epithelial sloughing, degeneration of the periodontal ligament and reduced osteoblastic activity.51 In chronic stress, osteoporosis of alveolar bone, apical migration of junctional epithelium and formation of periodontal pockets occur.52 Stress results in delayed healing of the connective tissue and bone in artificially induced gingival wounds but does not affect the epithelium.53 Chronic periodontitis patients resistant to therapy were also found to be more stressed than those who responded well.54 Monteiro da Silva et al21 failed to find association between psychological factors and periodontal disease. They identified depression and smoking as marginally significant in the aggressive periodontitis group. These relationships may be difficult to elucidate because the aetiology and pathogenesis of periodontal diseases are multi-factorial and the role of individual factors (eg stress) is difficult to define.55 Pathogenesis of stress-induced periodontal disease
The impact of stress on periodontal wound healing may be
influenced by factors that can be classified into the following two broad categories. ‘Health-impairing behaviours’,56 such as poor oral hygiene and factors that have pathophysiological effects, such as altered cytokine profiles. Health-impairing behaviours include neglecting oral hygiene practices,57 increased consumption of cigarettes,21 and alcohol and disturbed sleeping patterns. Other behaviours potentially harmful to the periodontium are bruxing, anxietyinduced forgetfulness and difficulty in concentrating.58 Depression has consistently been associated with smoking.59 This provides a strong link between depression and periodontal disease as smoking is a well-established risk factor for periodontal disease.60 Smoking could lead to increased periodontal destruction by influencing host response and tissue reactions, eg smokers have depressed numbers of T-helper lymphocytes and tobacco smoke can also impair chemotaxis and phagocytosis of oral and peripheral phagocytes.61 Among further effects of tobacco, nicotineinduced secretion of epinephrine, resulting in gingival vasoconstriction, has been proposed as one possible mechanism by which smoking may influence tissue susceptibility.62 In addition, smoking has been shown to impair collagen synthesis and increase matrix metalloproteinase-8 levels in blister wounds, compared with non-smoking controls.63 Smoking and diabetes, both known risk factors, act as physical stressors capable of activating the stress-immune system. Stress management has even been shown to be a novel means of improving glycaemic control in Type II diabetes.64 Disturbed sleep patterns, as a result of stress, could result in a reduction of growth hormone, which may act to downregulate the tissue repair response.65 This, in addition to poor nutritional intake because of unhealthy eating habits and excessive alcohol and cigarette consumption, could further impair tissue wound healing. Therefore, it is possible that correlations between stress and an impaired healing response could be secondary to stressinduced changes in health behaviours, which themselves act to down-regulate an individual’s immune response.66 Cortisol, produced by the adrenal cortex, can exert potential antiDentalUpdate 263
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Periodontics
inflammatory and immuno-suppressive effects.67 Increased levels of plasma glucocorticoid (cortisol) may also provoke an inappropriate T helper 2 cell response.68 A dominant T helper 2 cell response increases susceptibility to infectious diseases.69 Infact, T helper 1 cell responses may actually be protective against periodontitis, whereas a T helper 2 cell response may increase periodontal breakdown.70 In an experimental study, two genetically distinct types of rats, which differed in response to stress, were compared.69 One group of rats was high cortisone-responding and the other was low cortisone-responding. Ligature-induced periodontitis was produced around the maxillary right second molars of all rats and was measured using digital radiographic and histological examinations. The high cortisone-responding rats exhibited greater alveolar bone loss and more loss of connective tissue fibres. Kavelaars et al71 also demonstrated that, in comparison to low cortisone-responding rats, the high cortisone-responding group generates a stronger T helper 2 cell response to infectious agents. These data lend weight to the contention that a shift to the T helper 2 cell immune response may be more destructive. Glucocorticosteroids also exert powerful effects on a wide variety of metabolic events occurring in the metabolism of carbohydrate, protein and fat. Fibroblasts are known to be important target tissues of cortisol; these steroids can cause morphological changes in fibroblasts in vivo. Thus, they inhibit wound healing, both through suppression of fibroblast proliferation and the inflammatory response and through inhibition of the synthesis of collagen and glycosaminoglycans.72 Systemic administration of cortisone in experimental animals resulted in osteoporosis of alveolar bone; capillary dilatation and engorgement, with haemorrhage in the periodontal ligament and gingival connective tissue; degeneration and reduction in the number of collagen fibres of the periodontal ligament and increased destruction of the periodontal tissues associated with inflammation caused by local irritation.73 The effects of corticosteroids and inflammation on monolayer cultures of connective tissue have been reviewed by
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Nacht and Garzon.74 Cortisol and cortisone exerted a dichotomous effect, depending on the concentration utilized; cell growth was stimulated at low dosages while higher ones were inhibitory. Corticosteroids also affect the synthesis of collagen; cortisol, at a concentration of l g/ml added to monolayer cultures of fibroblasts derived from synovial membrane, caused a significant inhibition of collagen formation. Steroids inhibit chemotaxis,75 as well as the phagocytic and killing ability of polymorphonuclear leukocytes.76 In addition, these agents dramatically decrease host immunologic responses.77 Thus, not only do the corticosteroids inhibit inflammation, they also compromise the host’s ability to combat infection. This effect may be contributory in causing damage to the periodontium in conditions such as acute necrotizing ulcerative gingivitis, where stress plays an important role in its aetiology.78 Increased cortisol secretion (by stress) suppresses the immune response directly through suppression of neutrophil activity, IgG production and salivary IgA secretion. All these immune responses are critical for the normal immunoinflammatory response to periodontal pathogens. The resulting ‘stress-induced’ immunosuppression increases the potential for destruction by periodontal pathogens. Stress may also affect the cellular immune response directly through an increased release of neuro-transmitters, including epinephrine, nor-epinephrine, neurokinin and substance-p, which interact directly with lymphocytes, neutrophils and monocytes/ macrophages via receptors, causing an increase in their tissue-destructive function. Patients with stress also exhibit greater levels of nitric oxide (NO, a reactive oxygen species).79 Increased levels of salivary NO are responsible for more inflammation and signs of matrix degradation in the periodontal tissues. This was also correlated with the presence of increased bleeding on probing as biological activity of NO plays a role in vasodilatation and inhibition of platelet adhesion and aggregation. NO is also responsible for greater amounts of alveolar bone loss seen in patients with periodontitis.80 It is important to remember that, although stress may predispose an individual to more destruction from periodontitis, the
presence of periodontal pathogens remains the essential aetiologic factor.55 Release of stress hormones impairs the host defence, which helps in the growth of opportunistic organisms in the gingival sulcus.81 Stressinduced elevation of corticosteroid and catecholamine levels may reduce gingival microcirculation and salivary flow and enhance nutrition of Prevotella intermedia and also depress neutrophil and lymphocyte functions which facilitate bacterial invasion and damage.82
Stress assessment Defining stress ranges from subjective assessments of stressful situations, such as during examinations or military service, to physiological measurements, such as plasma cortisol levels, cytokine profiles and heart rate. A major limitation is that these parameters all show divergent reaction patterns, both within an individual at different time points and between different individuals.83 Detailed case history and current medical status for assessment of subjective symptoms include: depressed mood most of the day (feeling sad, empty, appearing tearful); diminished interest or pleasure in all activities; significant weight loss or weight gain; insomnia or hypersomnia; psychomotor retardation or agitation; fatigue; feeling of worthlessness; indecisiveness; and suicidal tendencies.84 Generalized anxiety disorders may be associated with three or more of the following six symptoms (with some symptoms present for at least six months): 1. Restlessness; 2. Being easily fatigued; 3. Difficulty concentrating; 4. Irritability; 5. Muscle tension; 6. Sleep disturbance.85 Patients who develop anxiety after exposure to extreme traumatic events, such as the threat of personal death/injury or the death of a loved one, demonstrate disturbances with clinically significant distress or impairment in social, occupational or other important areas of functioning.85
Physiological measurements
Measurement of serum, salivary and urinary cortisol levels has often been April 2014
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Periodontics
used in the assessment of stress in relation to periodontal disease or its treatment. Corticosteroid levels in urine were found to be higher in necrotizing ulcerative gingivitis patients.28 Significant elevation of 17-hydroxy-corticosteroids was found in necrotizing ulcerative gingivitis patients which correspondingly decreased when the disease resolved.86 Other methods of assessment of stress are as follows: The Beck Depression Inventory87 focuses on effective, cognitive, somatic and behavioural aspects of depression. This 21-item inventory rates each category from 0−3 in terms of intensity and the total score ranges from 0−63. The State-Trait Anxiety Inventory88 assesses both state and trait anxiety. State anxiety is characterized by subjective feelings, such as tension, apprehension and nervousness and is regarded as having a transitory nature. Trait anxiety refers to relatively stable individual differences in anxiety proneness. The stronger the anxiety trait, the more probable it is that the individual will experience elevations in state anxiety in threatening situations. Both the State anxiety scale and the Trait anxiety scale consist of 20 items, which are scored on four-point intensity scales. The Perceived Stress Questionnaire89 emphasizes cognitive perceptions more than emotional states or specific life events. It was developed to measure general stress perceived over the preceding year or two, and is a 30-item questionnaire. The items are scored from 1−4, and a Perceived Stress Questionnaire Index is derived from the total raw score.
Management of stressed periodontitis patient90 A careful history needs to be taken for checking any underlying stress or psychological disorder.54 There are four basic approaches to dealing with stress:91 1. Removal/alteration of the source of stress; 2. Learning to change way of perceiving stressful events; 3. Reducing the effect of stress on the body; 4. Learning alternative ways of coping − proactive coping. Dealing with stress in advance by the following methods: - Jacobson’s progressive muscle relaxation (JPMR);86 April 2014
- Breathing exercises/meditation; - Guided imagery; - Drug therapy: antidepressants and benzodiazepines;45 - Supportive psychotherapy. History-taking
Care should be taken by the dentist to ensure that the patient receives information in such a way that it does not cause him/her to become defensive and that proper access to the disease is established.21,92 Proactive coping
Patients may then be advised to participate in stress management seminars where they would be able to analyse their stress coping strategies and thus get to know themselves better. This could be an important and integral aspect of comprehensive periodontal treatment in cases of advanced disease and might have a positive effect on a putative risk factor for severe forms of adult periodontal disease. The stress coping strategy, as a behaviour variable, plays a very important role, especially in cases of failure or relapse. This factor should be given more attention in prevention programmes.21,92 Guided imagery
Imagination is recommended as one of several cognitive coping strategies. Here, the person imagines how the smoking toxins erode his lungs (aversive imagination) or how the overjoyed family congratulates him on his decision to stop smoking (positive imagination).21,92 Supportive psychotherapy and drugs
Acute stress reactions are usually self-limited and treatment typically involves short-term use of benzodiazepines and supportive/ expressive psychotherapy. Propranolol given during the acute stress period may have beneficial effects in preventing the development of recurrence. The chronic and recurrent nature of stress disturbance, however, requires a more complex approach employing drug and behavioural treatments. Trazodone, a
sedating antidepressant, is frequently used at night to help with insomnia (50−150 mg qhs). Psychotherapeutic strategies for post-traumatic stress disorders help the patient overcome avoidance behaviours and demoralization and master fear of recurrence of trauma. Therapies that encourage the patient to dismantle avoidance behaviours through stepwise focusing on the experience of the traumatic event are the most effective.93 Endocannabinoid anandamide (AEA) has been used in experimental periodontitis with restraint stress, since this system is known to modulate the hypothalamo-pituitary-adrenal axis as well as immune functions and has been found in human gingival tissues. Local injection of AEA (10(-8) M, 30 µl) decreased corticosterone plasma levels and the content of the cytokines (TNF-α and IL-1β) in gingival tissues with stress-induced periodontitis groups.94
Conclusion Stress-induced vasoconstriction and smoking may induce local tissue ischaemia and predispose the periodontal tissues to microbial invasion and lead to necrotizing ulcerative gingivitis. Individuals with high levels of stress and poor coping skills experience twice as much periodontitis as those with minimal stress and good coping skills. Although stress may predispose an individual to more destruction from periodontitis, the presence of periodontal pathogens remains the essential aetiologic factor. Patients who are in stress should be recognized and advised about the harmful effects of stress on the periodontium if the level of stress is not lowered. A prudent dentist should have holistic knowledge of supportive psychotherapy and drugs which can reduce the levels of stress, along with the therapeutic measures required for periodontal treatment. In addition, all stress-induced risk factors for periodontal disease should be minimized, promoting good oral hygiene and smoking cessation. To live a stress-free life, it is important for a person to develop good coping skills. Meditation and breathing exercises may also play vital roles in reducing dayto-day stress. DentalUpdate 267
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Kumar V, Abbas AK, Fausto N, eds. India: Saunders, 2004: pp797−876. McHenry L Jr, Vuyyuru L, Schubert ML. Helicobacter pylori and duodenal ulcer disease: somatostatin link? Gastroenterology 1993; 104: 1573−1575. Cooper CL, Davies R, Cooper EB, Faragher A. A prospective study of the relationship between breast cancer and life events, Type A behavior, social support and coping skills. Stress Medicine 1986; 4: 271−277. Roitt IM. Essential Immunology 8th edn. Oxford: Blackwell Scientific Publications, 1988. Graham NMH, Douglas RM, Ryan P. Stress and acute respiratory infection. Am J Epidemiol 1986; 124: 389−401. McClelland DC, Ross G, Patel V. The effect of an academic examination on salivary norepinephrine and immunoglobulin levels. J Human Stress 1985; 11: 52−59. Dorian BJ, Garfinkel PE, Keystone EC, Gorezynski R, Darby P. Stress, immunity and illness. Psycho Med 1986; 48: 304−305. Glaser R, Rice J, Sheridan J et al. Stressrelated immune suppression: health implications. Brain Behav Immun 1987; 1: 7−20. Hilgert JB, Hugo FN, Bandeira DR, Bozzetti MC. Stress, cortisol and periodontitis in a population aged 50 years and over. J Dent Res 2006; 85: 324−328. Breivik T, Thrane PS, Murison R, Gjermo P. Emotional stress effects on immunity, gingivitis and periodontitis. Eur J Oral Sci 2007; 104: 327−334. Rennie JS, Reade PC, Hay KD, Scully C. Recurrent aphthous stomatitis. Br Dent J 1985; 159: 361−367. Conklin RJ, Blasberg B. Oral lichen planus. Dermatol Clin 1987; 5: 663−673. Johnson BD, Engel D. Acute necrotizing ulcerative gingivitis. A review of diagnosis, etiology and treatment. J Periodontol 1986; 57: 141−150. De Marco T. Periodontal emotional stress syndrome. J Periodontol 1976; 47: 67−68. Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996; 67(Suppl): 1041−1049. Loesche W. Periodontal disease as a April 2014
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risk factor for heart disease. Compend Contin Educ Dent 1994; 15: 976−991. Croucher R, Marcenes WS, Torres MC et al. The relationship between life-events and periodontitis: a case-control study. J Clin Periodontol 1997; 24: 39−43. Green LW, Tryon WW, Marks B, Huryn J. Periodontal disease as a function of life events stress. J Human Stress 1986; 12: 32−36. Moss ME, Beck JD, Kaplan BH et al. Exploratory case-control analysis of pychosocial factors and adult periodontitis. J Periodontol 1996; 67: 1060−1069. Deinzer R, Forster P, Fuck L, Herforth A, Stiller-Winkler R, Idel H. Increase of crevicular interleukin-1beta under academic stress at experimental gingivitis sites and at sites of perfect oral hygiene. J Clin Periodontol 1999; 26: 1−8. Shklar G, Glickman I. The periodontium and the salivary glands in the alarm reaction. J Dent Res 1953; 32: 773−778. Gupta OP, Blechman H, Stahl SS. The effects of stress on the periodontal tissues of young adult male rats and hamsters. J Periodontol 1960; 32: 413−417. Ratcliff PA. The relationship of the general adaptation syndrome to the periodontal tissues in the rat. J Periodontol 1956; 27: 40–43. Shklar G. Periodontal disease in experimental animals subjected to chronic cold stress. J Periodontol 1966; 37: 377–383. Stahl SS. Healing gingival injury in normal systemically stressed young male rats. J Periodontol 1961; 32: 63–73. Axtelius B, Soderfeldt B, Nilsson A, Edwardsson S, Attstrom R. Therapy resistant periodontitis. Psychosocial characteristics. J Clin Periodontol 1998; 25: 482–491. Klokkevold PR, Mealey BL. Influence of systemic disorders and stress on the periodontium. In: Carranza’s Clinical Periodontology 10th edn. Newman MG, Takei HH, Klokkevold PR, Carranza FA, eds. St Louis, Missouri: Saunders, 2006; pp284–311. Wiebe DJ, McCallum DM. Health practices and hardiness as mediators in the stress-illness relationship. Health Psychol 1986; 5: 425–438.
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57. Kurer JR, Watts TL, Weinman J, Gower DB. Psychological mood of regular dental attenders in relation to oral hygiene behavior and gingival health. J Clin Periodontol 1995; 22: 52–55. 58. LeResche L, Dworkin SF. The role of stress in inflammatory disease, including periodontal disease: review of concepts and current findings. Periodontol 2000 2002; 30: 91–103. 59. Alati R, Lawlor DA, Najman JM, Williams GM, Bor W, O’Callaghan M. Is there really a ‘J-shaped’ curve in the association between alcohol consumption and symptoms of depression and anxiety? Findings from the MaterUniversity Study of Pregnancy and its outcomes. Addiction 2005; 100: 643–651. 60. Bergstrom J, Preber H. Tobacco use as a risk factor. J Periodontol 1994; 65: 545−550. 61. Eichel B, Shahrik HA. Tobacco smoke toxicity: loss of human oral leukocyte function and fluid cell metabolism. Science 1969; 166: 1424−1428. 62. Schwartz DM, Baumhammers A. Smoking and periodontal disease. Periodontal Abstracts 1972; 20: 103−106. 63. Knuutinen A, Kokkonen N, Risteli J et al. Smoking affects collagen synthesis and extra-cellular matrix turnover in human skin. Br J Dermatol 2002; 146: 588−594. 64. Christensen NJ, Jensen EW. Sympathoadrenal activity and psychosocial stress. The significance of aging, long term smoking, and stress models. Ann N Y Acad Sci 1995; 771: 640−647. 65. Rose M, Sanford A, Thomas C, Opp MR. Factors altering the sleep of burned children. Sleep 2001; 24: 45−51. 66. Ebrecht M, Hextall J, Kirtley LG, Taylor A, Dyson M, Weinman J. Perceived stress and cortisol levels predict speed of wound healing in healthy male adults. Psychoneuroendocrinology 2004; 29: 798−809. 67. Goforth P, Gudas CJ. Effects of steroids on wound healing: a review of the literature. J Foot Surg 1980; 19: 22−28. 68. Brevik T, Thrane PS, Murison R, Gjermo P. Emotional stress effects on immunity, gingivitis and periodontis. Eur J Oral Sci 1996; 104: 327−334. 69. Breivik T, Sluyter F, Hof M, Cools A. Differential susceptibility to
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periodontitis in genetically selected Wistar rat lines that differ in their behavioral and endocrinological response to stressors. Behav Genet 2000; 30: 123−130. Seymour GJ, Gemmell E, Kjeldsen M, Yamazaki K, Nakajima T, Hara K. Cellular immunity and hypersensitivity as components of periodontal destruction. Oral Dis 1996; 2: 96−101. Kavelaars A, Heijnen CJ, Ellenbroek B, van Loveren H, Cools A. Apomorphinesusceptible and apomorphineunsusceptible Wistar rats differ in their susceptibility to inflammatory and infectious diseases: a study on rats with group-specific differences in structure and reactivity of hypothalamicpituitary-adrenal axis. J Neurosci 1997; 17: 2580−2584. Chaudhuri SK. The suprarenal glands. In: Concise Medical Physiology. Chaudhuri SK, ed. India: New Central Book Agency (P) Ltd, 1999: pp303−313. Hojer JA. Studies on scurvy. Acta Paediatr 1924; 3(Suppl): 29−38. Nacht S, Garzon P. Effects of corticosteroids on connective tissue and fibroblasts. In: Advances in Steroid Biochemistry and Pharmacology 4. Briggs MH, Christie GA, eds. London: Academic Press Inc Ltd, 1974: pp157−187. Ward P. The chemo-suppression of chemotaxis. J Exp Med 1966; 124: 209−225. Mandell G, Rubin W, Hood E. The effect of NADH oxidase inhibitor (hydrocortisone) on PMN leukocyte bacterial activtity. J Clin Invest 1970; 49: 1381−1388. Schreiber A, Parsons J, McDermott P, Cooper R. Effect of cortisteroids on the human monocytes, IgG and complement receptors. J Clin Invest 1975; 56: 1189−1197. Sooriyamoorthy M, Gower DB. Hormonal influences on gingival tissue: relationship to periodontal disease. J Clin Periodontol 1989; 16: 201−208. Das D, Bandyopadhyay D, Bhattacharjee M, Banerjee RK. Hydroxyl radical is the major causative factor in stress induced gastric ulceration. Free Radic Biol Med 1997; 23: 8−18. Parwani SR, Chitnis PJ, Parwani RN. Salivary nitric oxide levels in DentalUpdate 271
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inflammatory periodontal disease − a case-control and interventional study. Int J Dent Hygiene 2012; 10: 67−73. Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress. Metabolism 2002; 51: 5−10. Johnson BD, Engel D. Acute necrotizing ulcerative gingivitis. A review of diagnosis, etiology and treatment. J Periodontol 1986; 57: 141−150. Miller SM. When is a little information a dangerous thing? Coping with stressful events by monitoring vs. blunting. In: Coping and Health. Levine S, Ursin H, eds. New York: Plenum Press, 1980: pp145−169. Reus VI. Medical management of major depressive disorders. In: Harrison’s Principles of Internal Medicine II 17th edn. Fauci, Braunwald, Kasper, Hauser, Longo, Jameson, Loscalzo, eds. New York: McGraw Hill
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Medical, 2008: pp2717−2725. 85. Diagnostic and Statistical Manual of Mental Disorders 4th edn. Washington, DC: American Psychiatric Association, 2000. 86. Maupin C, Bell B. Relationship of 17-hydroxycorticosteroid to acute necrotizing ulcerative gingivitis. J Periodontol 1975; 46: 721−722. 87. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988; 8: 77−100. 88. Spielberger CD. Manual for the StateTrait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, 1983. 89. Levenstein S, Prantera C, Varvo V et al. Development of the Perceived Stress Questionnaire: a new tool for psychosomatic research. J Psychosom Res 1993; 37: 19−32. 90. Sharma N, Gujjari SK, Kanagotagi S. Stress and the periodontium.
J Contemp Dent 2012; 2: 28−30. 91. Shannon IL, Kilgore WG, O’Leary T. Stress as a predisposing factor in necrotizing ulcerative gingivitis. J Periodontol 1969; 40: 240−242. 92. Smith SE, Warnakulasuriya KA, Feyerabend C et al. A smoking cessation programme conducted through dental practices in the UK. Br Dent J 1998; 185: 299−303. 93. Reus VI. Mental disorders. In: Harrison’s Principles of Internal Medicine II 17th edn. Fauci, Braunwald, Kasper, Hauser, Longo, Jameson, Loscalzo, eds. New York: McGraw Hill Medical, 2008: pp2710−2723. 94. Rettori E, De Laurentiis A, Zorrilla Zubilete M, Rettori V, Elverdin JC. Anti-inflammatory effect of the endocannabinoid anandamide in experimental periodontitis and stress in the rat. Neuroimmunomodulation 2012; 19: 293−303.
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Rajkumar Parwani Simran R Parwani
Does Stress Predispose to Periodontal Disease? Abstract: The relationship of a sound mind to the maintenance of a healthy body has been recognized throughout most of recorded history. The term ‘stress’ is used to describe adverse emotions or reactions to unpleasant experiences. Individuals with high levels of stress and poor coping skills experience twice as much periodontal disease as compared to those with minimal stress and good coping skills. Although stress may predispose an individual to more destruction from periodontitis, the presence of periodontal pathogens remains the essential aetiologic factor. This review presents a summary of stress, discussing how it can predispose an individual to periodontal disease. Clinical Relevance: Stress, which is a universal phenomenon, is implicated to have various systemic effects besides being a risk factor for periodontal disease. This article elucidates the relationship between psycho-social stress and destructive periodontal disease. Dent Update 2014; 41: 260-272
The relationship of a sound mind to the maintenance of a healthy body has been recognized throughout most of recorded history. The ancient Romans and Greeks discussed the importance of the patient’s mental attitude and temperament in the treatment of physical disease.1 Stress can be best understood as part of a complex and dynamic system of transaction between individuals and their environment. It is a part of the human condition which is universally present but to varying degrees and with different effects on individuals.2 Stress is compatible with good health, the latter being necessary to cope with the challenges of everyday life. Problems start when the stress response is inappropriate for the size of the challenge.
Rajkumar N Parwani, Professor, MDS, Department of Oral and Maxillofacial Pathology and Simran R Parwani, MDS, Senior Lecturer, Department of Periodontics, Modern Dental College and Research Centre, Indore, India.
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What is stress?
The term ‘stress’ is used to describe adverse emotions or reactions to unpleasant experiences. It is ‘a state of physiological or psychological strain caused by adverse stimuli, physical, mental or emotional; internal or external, that tend to disturb the functioning of an organism and which the organism naturally desires to avoid’.3 Thus, ‘stress’ can be viewed as a process with both psychological and physiological components.4 Psychological definition: A stressor is any stimulus, situation or circumstance with the potential to induce stress reactions.5 Physiological definition: Stress can result in the de-regulation of the immune system mediated primarily through the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes.6 Whether or not a subject exhibits a stress response depends on a myriad of factors, including coping behaviours, genetic predisposition, concomitant stressors, levels of social support and other lifestyle factors. Potential effects of the stress response that may be observed or measured include anxiety, depression, impaired cognition and altered self-esteem.4
Riley7 demonstrated that stress can be induced in animals by factors such as noise, increased population density, male-female proximity, handling by animal keepers and deliberate trauma. In a low-stress environment also, the stress levels (measured by plasma corticosteroid levels) were significantly increased by a single, slightly stressful stimulus and these increased levels adversely affected the immune response of the animals. These effects may stimulate a variety of neuroimmunologic phenomena in multiple organs and tissues.
Biologic impact of stress Anxiety, as well as other emotional or psychological stresses, produce well characterized neuroendocrine and biochemical changes in experimental animals. The physiological consequences of these stress-mediated changes have been shown to have significant adverse effects on the proper functioning of the immune system.7 Activation of the hypothalamopituitary-adrenal axis by stress results in the release of an increased concentration of corticotropin-releasing hormone from April 2014
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the hypothalamus. The pituitary gland is connected to the hypothalamus by the infundibulum, a stalk of tissue that contains nerve fibres and small blood vessels. Corticotropin-releasing hormone in turn acts on the anterior pituitary, resulting in the release of adreno-cortico-tropic hormone (corticotropin). The adrenocortico-tropic hormone then acts on the adrenal cortex and causes the production and release of glucocorticoid hormones (predominantly cortisol) into the circulation. The glucocorticoids then produce a myriad of effects throughout the body, such as suppressing the inflammatory response, modifying cytokine profiles, elevating blood glucose levels and altering levels of certain growth factors.8,9 (Figure 1). Importantly, it has been established that pro-inflammatory cytokines, such as interleukin-1 can also activate the hypothalamo-pituitary-adrenal axis, leading to a feedback loop.10 Immune function plays a critical role early in the wound healing cascade. Pro-inflammatory cytokines, such as interleukin-1 and tumour necrosis factor, are two of the essential cytokines in this regard. It has been speculated that success in the later stages of healing is critically dependent on these early events. In an experimental study where blister wounds were inflicted in human subjects, it was found that women with higher levels of stress produced fewer cytokines than those with lower levels of stress. In addition, the individuals exhibiting greater stress had higher salivary cortisol levels.11 The second major pathway to be activated is the sympathetic nervous system. A well-known example of this is the so-called ‘flight or fight’ response to potentially harmful stimuli. Stress activates the nerve fibres of the autonomic nervous system, which innervate the tissues of the immune system. The adrenal medulla is actually a modified sympathetic ganglion. Its nerve bodies, instead of possessing axons, secrete their products directly into the bloodstream. The release of catecholamines results in the hormonal secretion of nor-epinephrine and epinephrine from the adrenal medulla, which results in a range of effects that may act to modulate immune responses. Catecholamines released during stress contribute to the development of hyperglycemia by directly stimulating glucose production and interfering with the tissue disposal of glucose.8 In addition, the sympathetic nervous system has a role in April 2014
Major life events
Psychological factors
Daily hassles Systemic illness
Environmental influences
STRESS
Poor coping strategies
Hypothalamus
Autonomic Nervous System
Corticotropin-releasing hormone Anterior Pituitary Adreno-corticotropic hormone Health impairing behaviours
Adrenal Medulla
Adrenal Cortex Increased epinephrine and Nor-epinephrine secretion
Increased cortisol secretion
-Suppressed inflammatory response -Poor oral hygiene -Increased blood glucose levels -Increased blood glucose levels -Cigarette and alcohol -Altered immune cell function -Altered growth factor levels consumption -Altered cytokine levels -Disturbed sleeping patterns -Poor nutritional intake -Forgetfulness
Increased susceptibility to periodontal destruction
Figure 1. Flow chart of ‘Patho-physiology of Stress Response’. (Courtesy of Boyapati et al, 2007.)
regulating immune cell activities.12 From the above discussion, it is apparent that the response of the human body to stressful stimuli is both helpful and therapeutic, but a potentially harmful imbalance occurs when the stressful stimuli are prolonged, eg chronic anxiety states.13,14
Stress and systemic disease General adaptation syndrome
The composite of the systemic reactions that results from continued exposure to stress is termed the General Adaptation Syndrome (GAS), which was DentalUpdate 261
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described by Selye in 1946. This syndrome is a generalized group of physiologic mechanisms which represents an attempt of the body to resist the damaging effects of stress. The changes involved are: Enlargement of the adrenal cortex with increased secretion of adrenocorticoid hormones; Involution of lymphatic organs; Hyalinization and inflammatory changes in blood vessels with hypertension; Gastrointestinal ulceration; Malignant nephrosclerosis.15,16 This syndrome develops in three stages. The first phase of the GAS (Alarm Reaction) activates adrenal cortex to release corticosteroids better to prepare the body to adapt to and resist a stressful incident (Resistance Stage). If the causative stressful event is not suppressed, the third stage of GAS occurs (Exhaustion Stage). At this point, the body’s ability to resist is overwhelmed and damage occurs to target tissues. This response is further modified by extraneous factors such as the patient’s immunologic and nutritional status, medications, age and the presence/ absence of co-existent systemic diseases.17-19
factors as well as induce negligence in oral hygiene procedures, increased smoking and alcohol use, decreased salivary flow and bruxism.23 Personality traits
Certain personality traits and psychiatric disturbances have also been implicated.23-28 Gastric ulceration
This can occur in stressed subjects because mucosal defences fail when mucosal blood flow drops. Cigarette smoking induced as a result of stress impairs mucosal blood flow and healing of mucosal epithelium. Alcohol has not been proved to cause peptic ulceration directly, but alcoholic cirrhosis is associated with increased incidence of peptic ulcers. Cortisteroids in high dose and with repeated use also promote ulcer formation.29 Activation of monocytes and macrophages, with release of tumour necrosis factor, interleukin-1 and reactive oxygen metabolites could also be reasons for ulceration.30
Depression
Poor coping skills to combat stress are often manifested as depression.22 Depression may affect host resistance
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Rheumatoid arthritis
Studies have also demonstrated a relationship between psychological stress and inflammatory diseases such as rheumatoid arthritis and periodontitis.37 This may be attributed to influence on immune activities directly or indirectly via neuroendocrine (hormone) messenger substances (neurotransmitters and neuropeptides).38 Other effects
Effects of hormonal secretion
Stress-induced stimulation of the hypothalamo-pituitary adrenal axis and sympatho-adrenal medullary system causes stimulation of the adrenal cortex and medulla and leads to: Release of insulin, androgens, thyroid hormones, cortisol and catecholamines, causing protein degradation, increased glucose synthesis, lipolytic action, sodium retention and inhibition of new bone formation leading to osteoporosis and tetany.20 Eosinopenia, thrombocytosis and decreased clotting time.20 Release of substance-p which is a neurotransmitter which transmits pain signals, causes vasodilation and increased blood flow to gingival and periodontal capillaries.21 Stimulation of most immune cells via specific receptors, enhancing the phagocytic activity of leukocytes and macrophages and stimulating T-cell proliferation and antibody production from B cells.21
Stress-induced changes in sIgA levels are the result of an increased adrenergic output.34 Development of viral respiratory tract infection in stressed subjects could also be attributed to low NK cell activity,35 and/or a decreased specific T-cell killing of Epstein-Barr Virus (EBV) infected cells, as well as decreased lymphokine production. This was associated with an increase in antibody titer to EBV, suggesting reactivation of the latent, endogenous virus.36 This finding proved the relationship between life stress, seroconversion to EBV and development of infectious mononucleosis.
Involvement of other systems
Mental, physical and biological stresses also have an impact on the body’s ability to resist diseases, resulting in a number of diseases including coronary heart disease and breast cancer.31 There have also been reports linking psychosocial factors to other malignancies, autoimmune and infectious diseases,13 because the natural killer (NK) cells, which play a key role in immune surveillance preventing the development of cancer, are lowered in stress.32 In a large, 6-month prospective study, Graham et al33 examined the relationship between stress and upper respiratory tract infection. In a multivariate analysis model, the authors observed that both intra-study as well as the pre-study stress was significantly associated with more episodes of respiratory illness and more symptom days. The effect of stress on levels of immunoglobulin A in saliva (sIgA) in relation to upper respiratory infections has also been studied, where an increased frequency of infection periods was found in subjects with high levels of stress. This was accompanied by low levels of sIgA.
Stress is also associated with certain masochistic habits like lip-biting or cheek-biting and habitual grinding of teeth. Traumatic ulcers, aphthous ulcers,39 lichen planus40 have known stress as the aetiology. Overeating is also linked to stress.41
Stress and periodontal disease In 1976, De Marco42 presented a series of case reports describing severe alveolar bone loss in 11 soldiers who had experienced severe war-time emotional stress. He proposed that, in the absence of other obvious causative factors, these cases represented a disease entity that he called ‘Periodontal Emotional Stress Syndrome’. Acute necrotizing ulcerative gingivitis
Psychological stress has been implicated as a risk indicator for periodontal disease.43 The most notable example is the documented relationship between stress (eg experienced by soldiers at war or by students during examinations) April 2014
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and acute necrotizing ulcerative gingivitis (NUG). In individuals with NUG, primarily, the neuro-endocrine mechanism is activated under stressful conditions. Stress-induced vasoconstriction may also induce local tissue ischaemia and predispose the periodontal tissues to microbial invasion. Both these effects could be enhanced by tobacco smoking, which is a nearly universal habit among individuals with NUG.44
Chronic periodontitis
Several clinical studies have documented the relationship between psycho-social stress and chronic forms of periodontal disease. Croucher et al45 found that, in case-controlled studies, individuals with stable lifestyles (based on family structure and employment status) and minimal negative life events had less severe periodontal disease than individuals with less stable lifestyles (eg unmarried, unemployed) and more negative life events. The effect is not simply a matter of the presence of stress versus a lack of stress but rather the type of stress and the ability of the individual to cope with it that correlates with destructive periodontal disease. All individuals experience stress, but these events do not invariably result in destructive periodontitis. The types of stress that lead to periodontal destruction appear to be more chronic or long term and less likely to be controllable by the individual. Life events such as the loss of a spouse or family member, a failed relationship, loss of employment and financial difficulties are examples of stressful life events that are typically not controllable by the individual or not perceived by the individual as being under his or her control, rendering the person with a feeling of ‘helplessness’. The duration of the stressful life event will also have an influence on the total impact of the stress-induced disease destruction. Financial stress is an example of a long-term, constant pressure that may exacerbate periodontal destruction in susceptible individuals. Genco et al22 found that individuals with high levels of financial stress and poor coping skills had twice as much periodontal disease as those with minimal stress and good coping skills. Psychological tests were used to identify and weigh the causes of stress, such as children, spouse, finances, single life and work; and to measure individual coping skills. Individuals April 2014
with problem-focused (practical) coping skills fared better than individuals with emotionfocused (avoidance) coping skills with respect to periodontal disease. The researchers also found that chronic stress and inadequate coping could lead to changes in daily habits, such as poor oral hygiene, clenching and grinding, decreased salivary flow and suppressed immunity. Individual life events, such as divorce and bereavement increased stressful events and led to a greater prevalence of periodontal disease.46 Psychologically depressed human subjects who also smoked had high titers of IgG against T. forsythia. These subjects were found to have more severe and extensive chronic periodontitis which was due to the negative influence of depression on the immune system.47 Pro-inflammatory cytokine levels were also increased in stressed subjects.48 Stress-induced periodontal destruction
The following observations have been reported in stressed experimental animals. In the alarm reaction,49 no significant changes; in the late stage of the stress syndrome, osteoporosis of alveolar bone,50 epithelial sloughing, degeneration of the periodontal ligament and reduced osteoblastic activity.51 In chronic stress, osteoporosis of alveolar bone, apical migration of junctional epithelium and formation of periodontal pockets occur.52 Stress results in delayed healing of the connective tissue and bone in artificially induced gingival wounds but does not affect the epithelium.53 Chronic periodontitis patients resistant to therapy were also found to be more stressed than those who responded well.54 Monteiro da Silva et al21 failed to find association between psychological factors and periodontal disease. They identified depression and smoking as marginally significant in the aggressive periodontitis group. These relationships may be difficult to elucidate because the aetiology and pathogenesis of periodontal diseases are multi-factorial and the role of individual factors (eg stress) is difficult to define.55 Pathogenesis of stress-induced periodontal disease
The impact of stress on periodontal wound healing may be
influenced by factors that can be classified into the following two broad categories. ‘Health-impairing behaviours’,56 such as poor oral hygiene and factors that have pathophysiological effects, such as altered cytokine profiles. Health-impairing behaviours include neglecting oral hygiene practices,57 increased consumption of cigarettes,21 and alcohol and disturbed sleeping patterns. Other behaviours potentially harmful to the periodontium are bruxing, anxietyinduced forgetfulness and difficulty in concentrating.58 Depression has consistently been associated with smoking.59 This provides a strong link between depression and periodontal disease as smoking is a well-established risk factor for periodontal disease.60 Smoking could lead to increased periodontal destruction by influencing host response and tissue reactions, eg smokers have depressed numbers of T-helper lymphocytes and tobacco smoke can also impair chemotaxis and phagocytosis of oral and peripheral phagocytes.61 Among further effects of tobacco, nicotineinduced secretion of epinephrine, resulting in gingival vasoconstriction, has been proposed as one possible mechanism by which smoking may influence tissue susceptibility.62 In addition, smoking has been shown to impair collagen synthesis and increase matrix metalloproteinase-8 levels in blister wounds, compared with non-smoking controls.63 Smoking and diabetes, both known risk factors, act as physical stressors capable of activating the stress-immune system. Stress management has even been shown to be a novel means of improving glycaemic control in Type II diabetes.64 Disturbed sleep patterns, as a result of stress, could result in a reduction of growth hormone, which may act to downregulate the tissue repair response.65 This, in addition to poor nutritional intake because of unhealthy eating habits and excessive alcohol and cigarette consumption, could further impair tissue wound healing. Therefore, it is possible that correlations between stress and an impaired healing response could be secondary to stressinduced changes in health behaviours, which themselves act to down-regulate an individual’s immune response.66 Cortisol, produced by the adrenal cortex, can exert potential antiDentalUpdate 263
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inflammatory and immuno-suppressive effects.67 Increased levels of plasma glucocorticoid (cortisol) may also provoke an inappropriate T helper 2 cell response.68 A dominant T helper 2 cell response increases susceptibility to infectious diseases.69 Infact, T helper 1 cell responses may actually be protective against periodontitis, whereas a T helper 2 cell response may increase periodontal breakdown.70 In an experimental study, two genetically distinct types of rats, which differed in response to stress, were compared.69 One group of rats was high cortisone-responding and the other was low cortisone-responding. Ligature-induced periodontitis was produced around the maxillary right second molars of all rats and was measured using digital radiographic and histological examinations. The high cortisone-responding rats exhibited greater alveolar bone loss and more loss of connective tissue fibres. Kavelaars et al71 also demonstrated that, in comparison to low cortisone-responding rats, the high cortisone-responding group generates a stronger T helper 2 cell response to infectious agents. These data lend weight to the contention that a shift to the T helper 2 cell immune response may be more destructive. Glucocorticosteroids also exert powerful effects on a wide variety of metabolic events occurring in the metabolism of carbohydrate, protein and fat. Fibroblasts are known to be important target tissues of cortisol; these steroids can cause morphological changes in fibroblasts in vivo. Thus, they inhibit wound healing, both through suppression of fibroblast proliferation and the inflammatory response and through inhibition of the synthesis of collagen and glycosaminoglycans.72 Systemic administration of cortisone in experimental animals resulted in osteoporosis of alveolar bone; capillary dilatation and engorgement, with haemorrhage in the periodontal ligament and gingival connective tissue; degeneration and reduction in the number of collagen fibres of the periodontal ligament and increased destruction of the periodontal tissues associated with inflammation caused by local irritation.73 The effects of corticosteroids and inflammation on monolayer cultures of connective tissue have been reviewed by
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Nacht and Garzon.74 Cortisol and cortisone exerted a dichotomous effect, depending on the concentration utilized; cell growth was stimulated at low dosages while higher ones were inhibitory. Corticosteroids also affect the synthesis of collagen; cortisol, at a concentration of l g/ml added to monolayer cultures of fibroblasts derived from synovial membrane, caused a significant inhibition of collagen formation. Steroids inhibit chemotaxis,75 as well as the phagocytic and killing ability of polymorphonuclear leukocytes.76 In addition, these agents dramatically decrease host immunologic responses.77 Thus, not only do the corticosteroids inhibit inflammation, they also compromise the host’s ability to combat infection. This effect may be contributory in causing damage to the periodontium in conditions such as acute necrotizing ulcerative gingivitis, where stress plays an important role in its aetiology.78 Increased cortisol secretion (by stress) suppresses the immune response directly through suppression of neutrophil activity, IgG production and salivary IgA secretion. All these immune responses are critical for the normal immunoinflammatory response to periodontal pathogens. The resulting ‘stress-induced’ immunosuppression increases the potential for destruction by periodontal pathogens. Stress may also affect the cellular immune response directly through an increased release of neuro-transmitters, including epinephrine, nor-epinephrine, neurokinin and substance-p, which interact directly with lymphocytes, neutrophils and monocytes/ macrophages via receptors, causing an increase in their tissue-destructive function. Patients with stress also exhibit greater levels of nitric oxide (NO, a reactive oxygen species).79 Increased levels of salivary NO are responsible for more inflammation and signs of matrix degradation in the periodontal tissues. This was also correlated with the presence of increased bleeding on probing as biological activity of NO plays a role in vasodilatation and inhibition of platelet adhesion and aggregation. NO is also responsible for greater amounts of alveolar bone loss seen in patients with periodontitis.80 It is important to remember that, although stress may predispose an individual to more destruction from periodontitis, the
presence of periodontal pathogens remains the essential aetiologic factor.55 Release of stress hormones impairs the host defence, which helps in the growth of opportunistic organisms in the gingival sulcus.81 Stressinduced elevation of corticosteroid and catecholamine levels may reduce gingival microcirculation and salivary flow and enhance nutrition of Prevotella intermedia and also depress neutrophil and lymphocyte functions which facilitate bacterial invasion and damage.82
Stress assessment Defining stress ranges from subjective assessments of stressful situations, such as during examinations or military service, to physiological measurements, such as plasma cortisol levels, cytokine profiles and heart rate. A major limitation is that these parameters all show divergent reaction patterns, both within an individual at different time points and between different individuals.83 Detailed case history and current medical status for assessment of subjective symptoms include: depressed mood most of the day (feeling sad, empty, appearing tearful); diminished interest or pleasure in all activities; significant weight loss or weight gain; insomnia or hypersomnia; psychomotor retardation or agitation; fatigue; feeling of worthlessness; indecisiveness; and suicidal tendencies.84 Generalized anxiety disorders may be associated with three or more of the following six symptoms (with some symptoms present for at least six months): 1. Restlessness; 2. Being easily fatigued; 3. Difficulty concentrating; 4. Irritability; 5. Muscle tension; 6. Sleep disturbance.85 Patients who develop anxiety after exposure to extreme traumatic events, such as the threat of personal death/injury or the death of a loved one, demonstrate disturbances with clinically significant distress or impairment in social, occupational or other important areas of functioning.85
Physiological measurements
Measurement of serum, salivary and urinary cortisol levels has often been April 2014
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used in the assessment of stress in relation to periodontal disease or its treatment. Corticosteroid levels in urine were found to be higher in necrotizing ulcerative gingivitis patients.28 Significant elevation of 17-hydroxy-corticosteroids was found in necrotizing ulcerative gingivitis patients which correspondingly decreased when the disease resolved.86 Other methods of assessment of stress are as follows: The Beck Depression Inventory87 focuses on effective, cognitive, somatic and behavioural aspects of depression. This 21-item inventory rates each category from 0−3 in terms of intensity and the total score ranges from 0−63. The State-Trait Anxiety Inventory88 assesses both state and trait anxiety. State anxiety is characterized by subjective feelings, such as tension, apprehension and nervousness and is regarded as having a transitory nature. Trait anxiety refers to relatively stable individual differences in anxiety proneness. The stronger the anxiety trait, the more probable it is that the individual will experience elevations in state anxiety in threatening situations. Both the State anxiety scale and the Trait anxiety scale consist of 20 items, which are scored on four-point intensity scales. The Perceived Stress Questionnaire89 emphasizes cognitive perceptions more than emotional states or specific life events. It was developed to measure general stress perceived over the preceding year or two, and is a 30-item questionnaire. The items are scored from 1−4, and a Perceived Stress Questionnaire Index is derived from the total raw score.
Management of stressed periodontitis patient90 A careful history needs to be taken for checking any underlying stress or psychological disorder.54 There are four basic approaches to dealing with stress:91 1. Removal/alteration of the source of stress; 2. Learning to change way of perceiving stressful events; 3. Reducing the effect of stress on the body; 4. Learning alternative ways of coping − proactive coping. Dealing with stress in advance by the following methods: - Jacobson’s progressive muscle relaxation (JPMR);86 April 2014
- Breathing exercises/meditation; - Guided imagery; - Drug therapy: antidepressants and benzodiazepines;45 - Supportive psychotherapy. History-taking
Care should be taken by the dentist to ensure that the patient receives information in such a way that it does not cause him/her to become defensive and that proper access to the disease is established.21,92 Proactive coping
Patients may then be advised to participate in stress management seminars where they would be able to analyse their stress coping strategies and thus get to know themselves better. This could be an important and integral aspect of comprehensive periodontal treatment in cases of advanced disease and might have a positive effect on a putative risk factor for severe forms of adult periodontal disease. The stress coping strategy, as a behaviour variable, plays a very important role, especially in cases of failure or relapse. This factor should be given more attention in prevention programmes.21,92 Guided imagery
Imagination is recommended as one of several cognitive coping strategies. Here, the person imagines how the smoking toxins erode his lungs (aversive imagination) or how the overjoyed family congratulates him on his decision to stop smoking (positive imagination).21,92 Supportive psychotherapy and drugs
Acute stress reactions are usually self-limited and treatment typically involves short-term use of benzodiazepines and supportive/ expressive psychotherapy. Propranolol given during the acute stress period may have beneficial effects in preventing the development of recurrence. The chronic and recurrent nature of stress disturbance, however, requires a more complex approach employing drug and behavioural treatments. Trazodone, a
sedating antidepressant, is frequently used at night to help with insomnia (50−150 mg qhs). Psychotherapeutic strategies for post-traumatic stress disorders help the patient overcome avoidance behaviours and demoralization and master fear of recurrence of trauma. Therapies that encourage the patient to dismantle avoidance behaviours through stepwise focusing on the experience of the traumatic event are the most effective.93 Endocannabinoid anandamide (AEA) has been used in experimental periodontitis with restraint stress, since this system is known to modulate the hypothalamo-pituitary-adrenal axis as well as immune functions and has been found in human gingival tissues. Local injection of AEA (10(-8) M, 30 µl) decreased corticosterone plasma levels and the content of the cytokines (TNF-α and IL-1β) in gingival tissues with stress-induced periodontitis groups.94
Conclusion Stress-induced vasoconstriction and smoking may induce local tissue ischaemia and predispose the periodontal tissues to microbial invasion and lead to necrotizing ulcerative gingivitis. Individuals with high levels of stress and poor coping skills experience twice as much periodontitis as those with minimal stress and good coping skills. Although stress may predispose an individual to more destruction from periodontitis, the presence of periodontal pathogens remains the essential aetiologic factor. Patients who are in stress should be recognized and advised about the harmful effects of stress on the periodontium if the level of stress is not lowered. A prudent dentist should have holistic knowledge of supportive psychotherapy and drugs which can reduce the levels of stress, along with the therapeutic measures required for periodontal treatment. In addition, all stress-induced risk factors for periodontal disease should be minimized, promoting good oral hygiene and smoking cessation. To live a stress-free life, it is important for a person to develop good coping skills. Meditation and breathing exercises may also play vital roles in reducing dayto-day stress. DentalUpdate 267
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