Psychogenic disease

Psychogenic disease also called psychogenic illness or psychogenic disorder was formerly known as ‘hysterical’ illness, are somatic complaints for which there is no apparent physiologic cause ¹. The term psychogenic usually implies that psychological factors played a key causal role in the development of the illness. Psychogenic disease may look very similar to genetic diseases of the nervous system or to illnesses caused by damage to the nerves, brain or muscles. Psychogenic diseases can result in many severe symptoms, such as painful cramps or paralysis. However, unlike organic diseases, psychogenic diseases do not have any apparent physical cause, making them difficult to diagnose and even more difficult to treat ².

Features consistent with psychogenic disorders include ³:

1. Presence of associated psychiatric disorders;
2. Lack of concern (la belle indifference) or an exaggerated emotional response;
3. Disease manifesting only when observed, and not when alone or thought to be unobserved;
4. Bizarre or inconsistent signs;
5. Presence of emotional or situational triggers;
6. Multiple inexplicable physical symptoms;
7. Failure to respond to therapy;
8. Presence of a medical background; and
9. Disease is triggered or ameliorated by placebo.

Management of psychogenic disorders is difficult, as these patients often have an underlying organic disease ⁴. Psychogenic disorder prognosis for functional recovery is generally poor, and successful management requires a multi-disciplinary approach featuring the psychiatrist in a pivotal role ⁵. Empathy and a non-judgemental manner should be used, and it is often helpful to invoke a neurobiological explanation of the symptoms in order to foster trust, acceptance, understanding and recovery ⁶.

Psychogenic fever

Psychogenic fever also called “neurogenic fever” ⁷, is one of the most common psychogenic disorders. Patients with psychogenic fever have acute or persistent core body temperature above normal range (up to 41°C or 105.8°F) in psychologically stressful situations ⁸, whereas others show persistent low-grade high core body temperature (98.6 – 100.4°F or 37–38°C) during situations of chronic stress, lasting months and even years, either during or after situations of chronic stress ⁹. Certain forms of psychogenic fever have been given additional labels, e.g., prolonged low-grade high core temperature in nervous patients has been termed “habitual hyperthermia” ¹⁰ and abrupt increases in core temperature in hysterical patients was previously called “hysterical fever” ¹¹. Psychogenic fever is bothersome for both patients and physicians because, although many patients consider the fever to be disabling, there is no abnormal finding to account for their high core temperature and antipyretic drugs do not reduce their fever. Moreover, there are still physicians who do not recognize the fact that psychological stress can cause high core temperature.

Despite numerous case reports on psychogenic fever have been published, the mechanisms by which psychological stress increases core temperature are not yet fully understood, and epidemiological studies are limited. However, clinical case reports demonstrate that psychogenic fever is not reduced by antipyretic drugs, but by psychotropic drugs that display anxiolytic and sedative properties or by resolving patients’ difficulties via natural means or psychotherapy ¹². Animal studies have demonstrated that psychological stress increases core body temperature via mechanisms distinct from infectious fever (which requires proinflammatory mediators) and that the sympathetic nervous system, particularly β3-adrenoceptor-mediated non-shivering thermogenesis in brown adipose tissue, plays an important role in the development of psychological stress-induced hyperthermia ¹². Acute psychological stress induces a transient, monophasic increase in core body temperature. In contrast, repeated stress induces anticipatory hyperthermia, reduces diurnal changes in core body temperature, or slightly increases core body temperature throughout the day. Chronically stressed animals also display an enhanced hyperthermic response to a novel stress, while past fearful experiences induce conditioned hyperthermia to the fear context. The high core body temperature that psychogenic fever patients develop may be a complex of these diverse kinds of hyperthermic responses.

The age of psychogenic fever patients ranged from 3 to 56 years old and the male: female ratio was 1:1.19 ¹³. Psychogenic fever is seen especially in adolescence in Japan ¹³.

Psychogenic fever is diagnosed when (1) there is no organic disease that accounts for the fever and (2) the fever develops in a psychologically stressful situation or (3) emotionally stressful stimuli induce acute or persistent increases in core temperature above the upper limit of normal body temperature (37°C) ¹³.

Figure 1. Psychogenic fever

Footnote: Prominent psychogenic fever observed in a 15-year-old schoolgirl. She was referred from a pediatrician to my outpatient clinic because she repeatedly developed antipyretic drug-resistant fever of unknown causes. I asked the patient to record her axillary temperature (Ta) using an electrothermometer 4 times a day (8 a.m., 12 a.m., 4 p.m., and 8 p.m.) and the events of the day in a “fever diary” to better understand mind (stressor)-body (temperature) relationships. I also asked her mother and school nurse to make sure the temperature she recorded was accurate. The fever diary demonstrated that she developed a high axillary temperature (Ta) up to 39°C only on the days when she went to school (underlined black bar).

[Source ¹² ]

Psychogenic fever causes

Animal studies have demonstrated that many, but not all, types of acute psychological stress increase core temperature. For example, exposing rats or mice to stressors such as being placed into an unfamiliar space or an open field (novelty stress) ¹⁴, changing home cages (cage-change stress or cage switch stress) ¹⁵, restraint/immobilization ¹⁶, removing cage-mates (cage-mate removal stress) ¹⁷ and exposure to dominant animals (social defeat stress) ¹⁸ or an intruder ¹⁹ increases core temperature. Social defeat stress, i.e., exposing rats to a dominant conspecific, increases core temperature by up to 2°C within 30 minutes ²⁰. As represented by this model, a single exposure to psychological stress induces a transient, monophasic increase in core temperature, known as psychological stress-induced hyperthermia (psychological stress-induced hyperthermia). Existence of psychological stress-induced hyperthermia has been observed not only in rats and mice but also in rabbits, tree shrews, sheep, squirrels, chimpanzees, impalas, Peking ducks and pigeons ¹².

Animal studies have demonstrated that psychological stress increases core temperature via prostaglandinE2- and proinflammatory cytokine-independent mechanisms. This seems to be the case in patients with psychogenic fever. First, nonsteroidal antiinflammatory drugs (NSAIDs) do not attenuate the high core temperature in these patients. Second, stress interview-induced hyperthermia is not associated with changes in blood levels of prostaglandinE2 or proinflammatory cytokines ⁸.

In rodents, brown adipose tissue thermogenesis plays a crucial role in the development of psychological stress-induced hyperthermia. In humans, brown adipose tissue is distributed exclusively in an interscapular region in infants ²¹ and in thyroid/tracheal, mediastinal, paracervical/supraclavicular, parathoracical, supra- and peri-renal regions in adults ²². As in rodents, brown adipose tissue induces non-shivering thermogenesis when humans are exposed to a cold environment. Therefore, it is possible that psychological stress increases core temperature via sympathetic nerve-mediated non-shivering thermogenesis in brown adipose tissue in humans as well. Recently, Lkhagvasuren et al ²³ found that patients with psychogenic fever exhibit greater heart rate response to orthostatic stress and increased prevalence of postural orthostatic tachycardia syndrome, one form of orthostatic intolerance, compared with healthy subjects, suggesting a heightened sympathetic response to stress in patients with psychogenic fever. This might account for prominent hyperthermic responses to stressful events in patients with psychogenic fever. However, a role of brown adipose tissue in psychological stress-induced hyperthermia in healthy subjects or high core temperature in patients with psychogenic fever has not yet been elucidated.

Psychological or emotional stress increases core temperature via mechanisms that are distinct from fever that animals develop when they suffer from infectious and inflammatory diseases ²⁴. Infection- and inflammation-induced fever is induced when prostaglandinE2 acts on neurons in the preoptic area of the hypothalamus (preoptic area of the hypothalamus) ²⁵. When animals suffer from infectious diseases, fever is initiated by the release of brain-permeable prostaglandinE2 from hepatic and pulmonary macrophages ²⁶. Macrophages also release proinflammatory cytokines such as interleukin-1β and interleukin-6 and these cytokines stimulate synthesis and release of acute phase proteins such as C-reactive protein from hepatocytes. Furthermore, macrophage-derived proinflammatory cytokines stimulate synthesis of prostaglandinE2 from endothelial cells of the brain vessels ²⁷ or perivascular cells ²⁸ and cause prolonged fever ²⁹. Activation of the dorsomedial hypothalamus–medullary raphe region (including the rostral raphe pallidus and adjacent raphe magnus nuclei)–sympathetic (hypothalamic-medullary-sympathetic, hypothalamic-medullary-sympathetic) axis increases core temperature by activating β3-adrenoceptor-mediated non-shivering thermogenesis in brown adipose tissue and α-adrenoceptor-mediated peripheral vasoconstriction to inhibit heat loss ³⁰. Stimulation of the dorsomedial hypothalamus and the medullary raphe region also induces shivering thermogenesis in skeletal muscles ³¹. Usually, the preoptic area of the hypothalamus sends tonic inhibitory input to the hypothalamic-medullary-sympathetic axis. prostaglandinE2 causes fever by inhibiting the preoptic area of the hypothalamus neurons, i.e., by disinhibiting the hypothalamic-medullary-sympathetic axis ³². Consequently, fever is attenuated by nonsteroidal antiinflammatory drugs (NSAIDs), which block prostaglandinE2 synthesis.

By contrast, recent studies have demonstrated that acute psychological stress also activates the hypothalamic-medullary-sympathetic axis and increases core temperature ¹⁸, albeit via proinflammatory cytokine- and prostaglandinE2-independent mechanisms ¹⁸. Therefore, systemic administration of cyclooxygenase inhibitors, such as indomethacin, do not inhibit psychological stress-induced hyperthermia ¹⁷, while anxiolytic drugs such as diazepam or 5-hydroxytryptamine1A agonists ³³ and β3-adrenoceptor antagonists, such as SR59230A, do attenuate psychological stress-induced hyperthermia ²⁰. Other brain regions, such as the prefrontal cortex ³⁴, the preoptic area of the hypothalamus ³⁵, the medial amygdala ³⁶, or the lateral habenula ³⁷, in addition to orexin neurons ³⁸ are also suggested to be involved in the development of psychological stress-induced hyperthermia. However, so far, it is not fully understood how psychological stress activates dorsomedial hypothalamus neurons or how other brain regions affect the hypothalamic-medullary-sympathetic axis during psychological stress.

Regardless of the source of stress, acute psychological stress-induced hyperthermia is represented by a transient, monophasic increase in core temperature, and the high core temperature returns to baseline levels within several hours if the stressor is terminated. In contrast, repeated or chronic exposure to psychological stress has complex effects on core temperature. First, repeated exposure to uncontrollable stressors such as daily confrontation with a dominant rat at fixed time intervals induces anticipatory or learned hyperthermia, i.e., core temperature becomes higher during the hour preceding the scheduled time of stress application or during the hour when animals have been exposed to dominant rats even if they are kept in their home cages without stress exposure ³⁹. Second, repeated application of stressors (for more than several weeks) either reduces diurnal changes in core temperature, mostly by increasing core temperature in the light (inactive) period ⁴⁰, or slightly increases core temperature (around 0.2–0.3°C) throughout the day ⁴¹. Third, repeated or chronic stress enhances the magnitude of the hyperthermic effect induced by a novel stressor ⁴² or intravenous administration of noradrenaline ⁴³. Fourth, these rats display depressive-like behavior rather than increased anxiety-like behavior ⁴⁴. Fifth, these changes can be observed even several days after cessation of the final stress exposure ⁴¹.

Hyperthermic responses in rats exposed to repeated or chronic stress do not seem to be induced by exactly the same mechanisms as acute psychological stress-induced hyperthermia. First, the hyperthermic response during conditioned fear does not appear to involve activation of brown adipose tissue ⁴⁵. Contextual conditioned fear does not induce the expression of Fos, a marker of neuronal activation, in the dorsomedial hypothalamus, but does increase Fos in spinally projecting neurons in the perifornical area of the hypothalamus ⁴⁶. Second, after repeated immobilization, the magnitude of the noradrenaline-induced increase in core temperature, interscapular brown adipose tissue temperature, and oxygen consumption become greater in stressed rats versus controls ⁴³. As repeated immobilization stress induces interscapular brown adipose tissue hyperplasia ⁴⁷ and increases uncoupling protein 1 (UCP-1), a protein that generates heat according to its expression and function in brown adipose tissue, these changes may lead to prominent psychological stress-induced hyperthermia ⁴⁷. Thirdly, psychological stress induces microglial activation ⁴⁸ and subsequent proinflammatory cytokine production ⁴⁹ in the central nervous system. As brain-derived cytokines also increase core temperature ⁵⁰ and induce depressive-like behavior ⁵¹, there is a possibility that hyperthermia and depressive-like behaviors in rats exposed to chronic stress are mediated, at least in part, by activated microglia and subsequent proinflammatory cytokines within the brain. However, additional studies are necessary to make sure if this is the case.

As in laboratory animals, psychological stress increases the core temperature in healthy humans. Previous studies have demonstrated that core temperature just before emotional events is higher than core temperature after these events or at the same hour of the day under non-stressful conditions ⁵². For example, the mean oral temperature before boxing contests (37.55°C) in 12 school boys (12–14 years old) was 0.8°C higher than that taken at home at the same hour of the day (36.75°C) ⁵³. The mean oral temperature on movie-watching days in separate groups of females in their teens and twenties (37.55°C and 37.46°C) was 0.53°C and 0.27°C higher than that of the same hour on preceding or following days (37.03°C and 37.19°C), respectively ⁵⁴. The hyperthermic effect of examination stress is reported to be weaker than the effects of the emotional events described above. For example, the mean oral temperature of 40 subjects immediately before taking a nurses’ registration examination (37.17°C) was 0.34°C higher than observed after the examination (36.83°C) ⁵⁵. The mean axillary temperature of 22 residents (26 – 33 years old), 10 to 15 min before a yearly university examination (37.00°C), was 0.6°C higher than the temperature taken 2 to 3 weeks later after having sat and relaxed for at least 30 min (36.40°C) ⁵⁶. The mean oral temperature of 108 medical students (18 – 27 years old) immediately before examination (37.4°C) was 0.18°C higher than what was taken at the same hour of the day 3 days after the exam (37.22°C) ⁵⁷. The mean oral temperature of medical students (17 – 19 years old) 5 – 7 days before examination (36.91°C) was 0.17°C higher than that at the same time 5 – 7 days after the examination (36.74°C) ⁵². In contrast, one study demonstrated that exposing healthy subjects to a standardized laboratory stress task (the Trier Social Stress Test) did not change temporal artery temperature and also decreased intestinal temperature, both of which are assumed to reflect core temperature ⁵⁸.

Psychogenic fever symptoms

Patients with psychogenic fever have acute or persistent core body temperature above normal range (up to 41°C or 105.8°F) in psychologically stressful situations ⁸, whereas others show persistent low-grade high core body temperature (98.6 – 100.4°F or 37–38°C) during situations of chronic stress, lasting months and even years, either during or after situations of chronic stress ⁹.

The clinical significance of high core temperature in patients with psychogenic fever is different from psychological stress-induced hyperthermia in healthy subjects in several ways ⁵⁹. Remarkable differences include the magnitude of increase in core temperature and the associated symptoms. First, in healthy subjects, although emotional events increase core temperature, its magnitude is <1°C and the maximal core temperature they show is <37.5°C in most cases ⁵². By contrast, in some patients with psychogenic fever, emotional events increase core temperature to 39–41°C ⁶⁰. Such differences may arise according to the severity of stressors. However, as was shown in animal studies, it is also possible that chronic stressors that the patient has experienced cause the induction of a prominent hyperthermic response when the patient is exposed to emotional events. Second, healthy subjects do not complain of symptoms even when they exhibit high core temperature. By contrast, although some patients have no complaints except for the high core temperature, others complain of numerous symptoms in addition to high core temperature. These symptoms include insomnia, fatigue, headache, nausea, and/or abdominal pain. As increases in core temperature are frequently associated with these symptoms, patients consider the high core temperature disabling. Some patients are neurotic and have high anxiety ⁷. Psychogenic fever is also observed in patients who have traumatic experiences in their early lives ¹¹ and with psychiatric disorders such as anxiety (panic and post-traumatic stress) disorders ⁶⁰, mood (depressive and bipolar) disorders ⁶¹, somatoform (conversion) disorders ¹¹, catatonia ⁶² and borderline personality disorders ⁶³. For these reasons, they worry about their high core temperature and may consult their physicians asking for treatment.

Psychogenic fever diagnosis

There are no standard tests for psychogenic fever. Diagnosis usually involves assessment of existing symptoms and ruling out any infectious or other medical condition that could cause the symptoms.

Psychogenic fever treatment

Previous clinical case reports have demonstrated that patients who exhibit persistent low-grade high core temperature were treated successfully with drugs that produce sedative effects such as opium ¹⁰ or phenobarbital ⁶³, serotonergic tricyclic antidepressants such as amitriptyline and clomipramine ⁶⁴, selective serotonin reuptake inhibitor (SSRI) such as paroxetine ⁶⁵ or serotonin 1A receptor agonists such as tandospirone ⁶⁶. Furthermore, relaxation training ⁶⁰, solving their difficulties, and psychotherapy to ventilate suppressed negative emotion and conflicts verbally ⁶³ or non-verbally ⁶⁷ are also helpful strategies.

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