Clinical manifestations

Presentation and course

	• Occasional spontaneous yawning is physiological, but excessive yawning is pathological and may be a sign of neurologic disorder.
	• There are 2 forms of yawning with similar motor action patterns: spontaneous and contagious.

Yawning lasts 5 to 10 seconds and is accompanied by generalized stretching of body musculature, particularly the arms, as well as respiratory muscles. Yawning, like swallowing, is a reflexive phenomenon that is often repetitive and is extremely difficult to modify by voluntary action. Although yawning is considered a stereotyped action pattern, there are substantial variations in this response. Excessive or atypical yawning is linked to neurologic disorders.

Spontaneous yawning. Spontaneous yawning is triggered by physiological mechanisms and follows a circadian pattern. It often occurs just before going to sleep and on waking and is also associated with boring situations. Repetitive yawning is pathological, and the number of yawns per day can exceed 100 (44).

Contagious yawning. Contagious yawning differs from spontaneous yawning because it is an individuals yawn in response to someone else's yawn. Contagious yawning is a common phenomenon affecting more than 60% of healthy humans. A study to verify attentional bias hypothesis showed that the social bond significantly predicted the occurrence of auditory yawn contagion, which was highest between friends and family members (35).

Use of fMRI to assess brain activity during contagious yawning has shown that Brodmann area 9 in the right inferior frontal gyrus, a region of the human mirror neuron system, is activated by visually perceived yawning (24). This finding indicates that contagious yawning is based on the connection between the mirror neuron system and cognitive empathy. Similar conclusions were previously reached by studies of changes in mu oscillations in alpha bandwidth of the EEG (8 to 12 Hz) over sensorimotor areas during the observation of yawns (08). A study using transcranial magnetic stimulation has shown that approximately 50% of the variability in tendency for contagious yawning is determined by cortical excitability and physiological inhibition in the primary motor cortex (04).

Susceptibility to contagious yawning is reduced in patients with disorders that affect the ability for social interaction, such as autism spectrum disorders and schizophrenia. In a double-blind placebo-controlled study on healthy volunteers, intranasal oxytocin, a hormone involved in social behavior and empathy, did not increase contagious yawning as expected but rather appeared to modulate its expression in ways indicative of an enhanced awareness of the social stigma associated with this behavior (14). Only a subset of children with autism spectrum disorder have an impaired contagious yawn response, and this can be predicted as they have lower blood oxytocin levels compared to those not affected by impaired yawning as well as normally developing children (28). Variation in contagious yawning appears to be driven by biased attentional processes and yawn detection rather than emotional sharing as proposed by some authors (13).

Prognosis and complications

Prognosis of yawning depends on that of the associated disorder. Yawning is usually associated with other symptoms, and response to treatment of primary disorders varies on each manifestation. For example, yawning may remain a residual symptom during management of opioid withdrawal with buprenorphine.

Several cases of dislocation of the temporomandibular joint have been reported during yawning. Yawning can also trigger an attack of trigeminal neuralgia in those predisposed to it.

Biological basis

	• Cranial nerve nuclei in the brainstem are the motor centers, but other areas of the brain are also involved in yawning.
	• There is a neuropharmacological regulation of yawning.
	• The pathophysiology of yawning varies according to the associated disorder.

Anatomic localization

Motor centers of the brainstem (nuclei of V, VII, IX, X, XI, and XII cranial nerves) and the spinal cord are involved in yawning, and these are further controlled by the paraventricular nucleus of the hypothalamus (07). A group of oxytocin neurons situated in the parvocellular region of the paraventricular nuclei and extending towards the hippocampus facilitate yawning, in conjunction with the locus coeruleus and the spinal cord. The insula has also been implicated as the brain region for serotonin-mediated yawning.

Pathophysiology

The purpose of yawing is not clear. According to 1 theory, yawning increases circulation of CSF, thereby increasing clearance of somnogenic factors such as prostaglandin D2 and adenosine (43). Yawning has also been considered a manifestation of stress, but the link between yawning, fatigue, and cortisol is not well understood.

Neuropharmacologic regulation of yawning. According to earlier studies, yawning is controlled by the dopaminergic and serotonergic systems, which activate the cholinergic system. Serotonergic activation and dopaminergic inhibition may work together in the event of yawning. Later studies have shown that numerous other neurotransmitters and neurohormones are involved in the mediation of yawning, including acetylcholine, dopamine, glutamate, oxytocin, gamma-aminobutyric acid (GABA), opioids, adrenaline, nitric oxide, adrenocorticotropic hormone (ACTH), and alpha-melanocyte-stimulating hormone. A surge in plasma ACTH levels at night and just prior to awakening from sleep is also associated in humans with yawning.

Yawning and thermoregulation. Brain centers that control yawning are also involved in thermoregulation. According to the thermoregulatory theory of yawning, its function is to cool the brain in part by countercurrent heat exchange with the deep inhalation of ambient air (30). Several studies have confirmed and replicated the specific brain cooling and thermal window predictions derived from the thermoregulatory theory of yawning, and no evidence has been presented contrary to these findings (16). The expression of contagious yawning in humans is altered by seasonal climate variation, pointing to the role of thermoregulation.

Yawning as a symptom of conditions with abnormal thermoregulation. Based on the finding that yawning has a brain cooling function and that excessive yawning may be a useful indicator of abnormal thermoregulation in humans, it has been hypothesized that frequent yawning could be used as an initial signal for fever relief, through measures to relieve high temperature (19). Atypical yawning may be a cooling mechanism in several conditions with thermoregulatory disorder such as migraine, epilepsy, stress, and schizophrenia. Excessive yawning may be a symptom of conditions that increase brain temperature, eg, CNS damage, sleep deprivation, and adverse effects of some serotonin reuptake inhibitors. Yawning has been shown to provide relief of symptoms in patients with multiple sclerosis and sleep problems that have thermoregulatory dysfunction (18). Disturbance of thermoregulation has been offered as a possible mechanism for excessive yawning induced by methylphenidate in treatment of attention deficit hyperactivity disorders as it raises body temperature (17).

Epidemiology

• There are no overall data about prevalence and incidence or absence of yawning, but some figures are available for associated disorders.

Yawning is common in multiple sclerosis patients with brain stem involvement, and figures as high as 37.5% have been reported. In a study, 45.4% of the patients described repetitive yawning during migraine attacks (23). In a series of patients with acute middle cerebral artery stroke, 42.9% had pathological yawning, which was associated with stroke severity, presence of cortical involvement, and insular as well as opercular infarcts (01).

One study showed that none of the children with autism spectrum disorder displayed contagious yawning as compared to 43% of normal controls (10).

Differential diagnosis

Confusing conditions

Yawning is a typical phenomenon that is not confused with other symptoms. The differential diagnosis of pathologic yawning is based on associated disorders.

Associated or underlying disorders

Disorders that are known to be associated with pathologic yawning are shown in Table 1. Characteristic features of these associations help in the differential diagnosis of yawning. Iatrogenic causes should be ruled out, eg, drug-induced yawning.

Table 1. Disorders Known to be Associated With Pathologic Yawning

• Altered states of consciousness • Amyotrophic lateral sclerosis (bulbar form) • Brain tumors • Chiari malformation type I • Drug-induced yawning • Epilepsy • Foix-Chavany-Marie syndrome • Gilles de la Tourette syndrome • Gastrointestinal disorders • Hyperthermia, heat stroke • Intracranial hypertension syndromes • Migraine headaches • Motion sickness • Multiple sclerosis • Multiple system atrophy • Parkinson disease • Progressive supranuclear palsy • Psychogenic neurologic disorders • Schizophrenia • Sleep disorders • Stroke • Traumatic brain injury

Brain tumors. Intractable yawning was associated with mature teratoma of the supramedial cerebellum (39). Yawning was due to a tumor compressing the dorsal side of the junction between the midbrain and pons; yawning disappeared after subtotal removal of the tumor. In 1 case, intractable yawning was caused by foramen magnum meningioma associated with neurofibromatosis type 2 (03). Recurrent yawning resolved completely after total removal of the meningioma. At a previous admission, this patient had undergone a ventriculoperitoneal shunt and radiosurgery for the right vestibular schwannoma, which were not removed due to small size.

Chiari malformation type I. Excessive yawning has been reported as a presenting symptom of Chiari malformation type I in 2 adolescent females, and in both cases, it resolved following foramen magnum decompression (45).

Systemic administration of D2-like dopaminergic-receptor agonists increases yawning. Effects of systemic administration of the D2 agonists and antagonists on yawning behavior have been studied in rats and correlated with the lipid myelin content in the brainstem and other areas in the CNS (11). Dopaminergic D2-like agonists were still able to induce yawning despite the severe myelin loss. Similarly, patients with demyelinating disorders, such as multiple sclerosis, are able to yawn indicating that drugs can trigger neurons that elicit this innate behavior. Extension of the Thompson Cortisol Hypothesis proposes that the stress hormone, cortisol, is responsible for yawning and fatigue, particularly in persons with incomplete innervation such as in multiple sclerosis (42).

Yawning is a side effect of both nonselective and selective serotonin reuptake inhibitors. Yawning has been reported as a dose-dependent side effect of escitalopram and resolved following reduction of the dose (38). History of drug use helps to differentiate drug-induced yawing from that associated with various diseases, and it can be confirmed by relief from yawning by discontinuation of the offending drug.

Epilepsy. Excessive yawning has been reported in the peri-ictal period preceding or following seizures. Yawning has been reported as an ictal sign in a patient affected by drug-resistant focal epilepsy and might be considered a rare automatic behavior, like other automatisms frequently reported in epileptic seizures (41). Impairment of consciousness and paroxysmal excessive yawning in an elderly patient was hypothesized to be an autonomic seizure originating from diencephalic/brainstem structures (34). Yawning has been reported in a patient with intractable epilepsy during depth electrode stimulation of insula and putamen as part of presurgical epilepsy evaluation (25). Because of the role of the putamen in motor control and its extensive connections to cortical and brainstem regions, these findings suggest that it plays a key role in motor movements necessitated by yawning.

Hashimoto encephalopathy, a steroid-responsive encephalopathy associated with autoimmune thyroiditis (STREAT), manifests as epileptic seizures and psychocognitive disorders associated with EEG alterations. An atypical presentation with repetitive forceful yawning as ictal phenomenon and a rare EEG pattern has been described (05). The presence of antithyroperoxidase antibodies in the CSF and response to steroids confirmed the diagnosis of Hashimoto encephalopathy in this case.

Foix-Chavany-Marie syndrome. Automatic yawning is 1 of the manifestations of this cortical form of pseudobulbar palsy. Due to bilateral anterior opercular lesions, there is a dissociation of motor function of lower cranial nerves.

Gastrointestinal disorders. Dyspepsia and slow digestion, as well as an irritable colon, are often associated with excessive yawning.

Hyperthermia. Yawning frequency increases significantly during hyperthermia and is associated with reduction of symptoms (29).

Hypothalamo-pituitary disorders. Excessive yawning may be the result of excessive release of oxytocin as the result of a hypothalamo-pituitary disorder. Clinical examination should try to detect pituitary/hypophyseal endocrine anomalies.

Migraine. Environmental and genetic factors, as well as dysfunction in dopaminergic transmission, are important factors in the pathophysiology of a migraine attack. The dopaminergic system also plays a role in the headache phase by participating in nociceptive pathways, as well as by intervening in the regulation of cerebral arterial circulation. Yawning also acts as an aura before a migraine attack, which ends with repeated yawning accompanied by drowsiness. An open study has shown that migraine patients with dopaminergic symptoms are characterized by a full-blown, more disabling migraine, leading to the recommendation that dopaminergic system modulation should be considered in these individuals for both acute and preventive treatments in future studies (02).

Motion sickness. Yawning occurs frequently during motion sickness. A study has shown that subjects who yawned in motion demonstrated increased severity of motion sickness and drowsiness (31). Yawning may be considered a behavioral biomarker for recognizing the onset of soporific effects and concomitant reduction in cognitive performance.

Multiple sclerosis. A polygraphic study has shown that yawning is increased in multiple sclerosis patients and safe swallowing during yawning suggests that brain stem mechanism and oropharyngeal reflexes are intact (12).

Parkinson disease. Excessive daytime sleepiness is a frequent complaint in patients suffering from Parkinson disease, and it is accompanied by an increase in yawning. One likely explanation is that a quick succession of yawns represents an effort by these patients to remain alert and awake (21).

Psychogenic neurologic disorders. Atypical yawning has been linked to functional disorders such as anxiety, stress, or hyperventilation syndrome and is associated with thermoregulatory disturbance.

Sleep disorders. The most common cause of yawning is sleep deprivation. A prospective clinical study on snorers suspected to have sleep apnea evaluated the relation of yawning with excessive daytime sleepiness (06). Although there was no correlation of yawning frequency with duration of the non-REM phases and mean oxygen saturation, it was positively correlated with increased scores on Epworth sleepiness scale, indicating yawning as a manifestation of sleep deprivation.

Stroke. Deficits in vigilance accompanied by yawning occur during a cerebral ischemic or hemorrhagic episode and could be due to rise of intracranial pressure. Repetitive yawning is a premonitory sign of herniation. Associated movements in hemiplegic limbs occur during yawning in stroke due to ischemia or hemorrhage in the internal capsule region, and their pattern indicates return of ancestral function observed in quadrupeds (32). An MRI/DWI mapping study on patients with acute anterior circulation stroke correlated the intensity of stroke lesions of the common overlapping regions in the insula and the caudate nucleus with duration of abnormal yawning (27).

Drug-induced yawning. Yawning may be an adverse reaction to drugs, but it is rarely serious and is not usually listed in drug summaries (37). Several drugs are reported to induce yawning, and these are listed in Table 2.

Table 2. Drugs that Induce Yawning

• Barbiturates: intravenous thiopental • Benzodiazepines • Dopamine and dopaminergic-receptor agonists: levodopa, apomorphine hydrochloride • Methylphenidate • Opioids and withdrawal from use • Oxytocin • Physostigmine • Antidepressants: serotonin reuptake inhibitors: citalopram, fluoxetine, sertraline, venlafaxine, duloxetine, escitalopram

Dopamine and dopaminergic-receptor agonists. Systemic administration of D2-like dopaminergic-receptor agonists increases yawning. Effects of systemic administration of the D2 agonists and antagonists on yawning behavior have been studied in rats and have been correlated with the lipid myelin content in the brainstem and other areas in the CNS (11). Dopaminergic D2-like agonists were still able to induce yawning despite the severe myelin loss. Similarly, patients with demyelinating disorders, such as multiple sclerosis, can yawn, indicating that drugs can trigger neurons that elicit this innate behavior. Extension of the Thompson Cortisol Hypothesis proposes that the stress hormone, cortisol, is responsible for yawning and fatigue, particularly in persons with incomplete innervation such as in multiple sclerosis (42).

Antidepressants. The relationship between antidepressants and yawning is unclear but may be related to the effects of many different neurotransmitters. Yawning is a side effect of both nonselective and selective serotonin reuptake inhibitors. Yawning has been reported as a dose-dependent side effect of escitalopram and is resolved following reduction of the dose (38). History of drug use helps to differentiate drug-induced yawing from that associated with various diseases, and it can be confirmed by relief from yawning by discontinuation of the offending drug. In one patient on fluoxetine, discontinuation of antidepressants led to the cessation of yawning within a few days (26).

Diagnostic workup

• Diagnostic procedures depend on the suspected cause or associated disease.

Brain imaging studies are indicated for localization of suspected intracranial lesions. Drowsiness or sleep debt might require investigations for sleep disorders, eg, detection of sleep apnea. Appropriate laboratory tests should be done if an endocrine/pituitary disorder is suspected.

Management

	• Nonpharmacological approaches are initially considered for the management of excessive yawning.
	• Treat the cause, if possible. In the case of drug-induced yawning, the offending drug is discontinued.
	• There is no approved drug for excessive yawning, but some drugs with an indirect mechanism of action have been considered.

Nonpharmacological approaches. Atypical yawning due to functional disorders should be treated with nonpharmacological approaches, such as psychological support and relaxation techniques. Behavioral cooling methods of nasal breathing and forehead cooling are effective for excessive yawning. Acupuncture and repeat transcranial stimulation have been used for treatment of excessive yawning, but no controlled clinical studies have been done.

Pharmacological approaches. In the case of drug-induced yawning, the suspected medication may be discontinued, if possible. Prior intravenous administration of either a calcium channel blocker or a beta blocker can greatly reduce thiopental-induced yawning (36).

There is no evidence-based pharmacologic treatment for excessive yawning. Propranolol, a beta blocker, has been found to reduce the severity of yawning, likely through its thermoregulatory effect (20).

Graded physical activity was shown to disrupt complex pathophysiological mechanisms leading to yawning and fatigue in an old man suffering from recurrent attacks of yawning-fatigue-syndrome, triggered by mild exercise of his right leg since a lumbar disc herniation 9 years previously, which was initially treated with the oral µ-opioid-receptor agonist tilidine (09). In the following few months of treatment, exercise was increased in a graded manner to alleviate the yawning-fatigue-syndrome without opioid medication.