Anatomy, physiology and pathophysiology
Any attempt to define the pathophysiology of RES, must explain the burning ear pain along with ear flushing as well as the triggers of tactile stimuli and warmth. For this, an appreciation of the neural and vascular supply of the ear is essential.
The earlobe and the lower external aspect of the ear are innervated by the greater auricular nerve, a superficial branch of the C2-C3 spinal nerves, whereas the tragus and the anterosuperior aspect of the ear are supplied by the auriculotemporal branch of the mandibular division of the trigeminal nerve. The vascular supply of the ear is provided by branches of the middle temporal and posterior auricular arteries, which, as part of the external carotid circulation has sensory innervation of the blood supply from the trigeminal nerve. The dominant mechanism of vasomotor control of the skin of the ear is from variations in sympathetic vasoconstrictor tone, whereas the facial parasympathetic system seems to be only a marginal component accounting mainly for forehead and cheek skin vasodilation [
24]. Importantly, vasodilation of the skin of the ear seems to be provoked by an inhibition of the sympathetic vasoconstrictor fibres as opposed to activation of the facial parasympathetic fibres.
The pathophysiological mechanisms underlying RES are currently unclear. However, several theories have been proposed and can be divided into two main groups namely, peripheral theories with mechanisms involving a dysfunction in cervical spinal nerves (predominantly C3 root) and central theories in which the underlying mechanisms would involve a dysregulation of brainstem trigemino-autonomic circuits.
In his original paper, Lance observed that RES was commonly associated with irritative lesions of the third cervical nerve root and this led him to suggest that, in cases of underlying cervical pathology, an antidromic discharge of impulses along C3 may occur leading to pain and vasodilatation due to release of vasodilator peptides [
2]. Support for this hypothesis appeared to come from the fact that symptoms were temporarily relieved in one patient following local anaesthetic block of the C3 root and permanently relieved in another patient after C3 section. Lance also presented two cases in which attacks were triggered but where the underlying cause was thought to be TMJ dysfunction. In these cases he proposed that a local axon reflex, triggered by non-noxious stimuli such as heat, touch or chewing, might precipitate the antidromic discharge. He postulated that RES might be an example of Angry Back-firing C-nociceptors syndrome, in which the phenomenon of ‘cross-modality threshold stimulation’ occurs, whereby temperature changes alter the threshold for the pain induced by mechanical stimulation [
25]. It was this hypothesis of an antidromic discharge from fibres of the third cervical root causing vasodilation in the referred pain area by discharge of vasodilator peptides, which led Lance to label RES an auriculo-autonomic cephalgia, though the exact mechanism by which C-fibres become “angry” was not specified [
26].
On the basis of the presence of RES features in a patient with paroxysmal hemicrania, Goadsby and Lipton suggested that both conditions may share common pathogenic mechanisms centred on the brainstem connections between the trigeminal nerve and the facial parasympathetic outflow. They suggested a primary role for the dysregulation of brainstem trigemino-autonomic circuits in the pathophysiology of the syndrome [
27]. The anatomical basis of this unifying hypothesis would be the convergence of processing nociceptive information at the level of the trigeminal nucleus caudalis and dorsal horn nuclei of the upper cervical spine, of both trigeminal afferents and C1-C2 spinal afferents. RES has subsequently been described in association with CH [
16] and SUNA [
23], thereby supporting the possible nosological and pathophysiological link between RES and TACs.
Given the frequent association of RES with migraine, Raieli
et al. proposed that symptoms of migraine-associated RES may be due to the trigeminovascular activation during migraine attacks producing extracerebral vasodilatation via direct release of vasodilator substances (substance P, CGRP and nitric oxide) [
5]. The activation of the trigeminovascular system would explain the ear pain that extends beyond the trigeminal distribution to the earlobe, due to the overlap between trigeminal and upper cervical spinal nerves in the trigemino-cervical complex [
28]. The same authors showed that RES was associated with migraine features partially provoked by parasympathetic system activation and concluded that RES could be considered a specific sign of parasympathetic hyperactivation, via the trigemino-autonomic reflex, during migraine, in essence considering RES as a migraine-related phenomenon, sharing activation of pathophysiological mechanisms known to be pivotal in migraine.
However, all these theories concerning a trigemino-autonomic dysregulation as the main mechanism in RES and RES associated with migraine and TACs raise an interesting anatomical inconsistency. The trigemino-autonomic reflex is based on a brainstem connection between the trigeminal nerve and the facial parasympathetic outflow [
27]. According to this hypothesis, the facial nerve parasympathetic outflow fibres that appear to be responsible for the facial autonomic symptomatology in TACs should also be able to produce vasodilation and therefore redness of the skin of the ear in RES. However, unlike other parts of the face, such as the cheek and the nose, the vasodilation of the skin of the ear is mainly under sympathetic vasoconstrictor control and occurs when there is inhibition of the sympathetic vasoconstrictor fibres [
24]. During TACs attacks there is marked trigemino-parasympathetic activation, along with a sympathetic deficit. It may be possible that in cases of RES in conjunction with TACs, the presence of an imbalance between parasympathetic and sympathetic systems in the latter may in turn facilitate the inhibition of the sympathetic tone of the ear giving raise to the red ear phenomenon. However, as it is the sympathetic dysregulation and not a parasympathetic activation that is the predominant mechanism for the ear reddening, it seems less likely that the trigemino-autonomic reflex plays a central role at least in isolated cases of RES. Indeed, other mechanisms may contribute more specifically to the red ear phenomenon.
A further pathophysiological hypothesis is based on the fact that the clinical presentation of RES is strikingly similar to the clinical presentation of erythromelalgia (EM), a dermatological condition characterised by paroxysmal episodes of burning pain and erythema often involving hands and feet. The diagnostic criteria of EM include: burning pain, aggravated by warmth and relieved by coldness, erythema and increased skin temperature [
29]. The pathophysiology of EM is unfortunately unclear but local primary damage of vascular and neuronal structures has been proposed as the main pathophysiological mechanism underlying it. In essence, it is postulated that primary vascular misdistribution leading to skin hypoxia may cause a secondary hypoxic-induced neuropathy. Conversely, primary small-fibre dysfunction may lead to a secondary vascular misdistribution and hypoxia accompanied by secondary capillary proliferation [
30,
31]. Given the clinical similarities, some authors have raised the possibility that RES may be an auricular variant of EM, possibly caused by similar small sensory and sympathetic nerve dysfunction [
19]. Moreover, they stated that since a gene has been identified in hereditary EM caused by mutations of Na 1.7 channels in sensory and sympathetic nerves [
32], sodium-channel blocking drugs may be a reasonable therapeutic option to explore in the management of RES.
Secondary RES
The majority of RES described in the medical literature are primary but secondary RES has been reported (25 cases). Lance originally described the first series of 12 patients with RES. Ten out of these patients had a secondary pathology thought to be responsible for the RE episodes [
2]. Subsequently other authors have reported cases of RES secondary to an underlying pathology (Table
1) [
7,
9,
10,
16].
Table 1
Secondary causes of red ear syndrome
Upper cervical spine
| • Hypertrophy of the ipsilateral C2-C3 facet joint |
• Degeneration of superior facet of C4 |
• Cervical arachnoiditis with posterior column myelomalacia |
• Traction injury of upper cervical roots |
• Narrowing of C4 neural foramen |
• Chari I malformation |
• Chronic whiplash |
• Congenital fusion of C1-C3 vertebrae with enlargement of the cervical spinal canal |
• Neurovascular compression between vertebral artery and C3 root |
Cranial and cervical neuralgias
| • Atypical glossopharyngeal neuralgia |
• Atypical trigeminal neuralgia |
• C3 root neuralgia |
TMJ dysfunction
| |
Thalamic syndrome
|
Herpes zoster
|
Pleomorphic adenoma of carotid body
|
Secondary RES cases can be divided in two main groups: upper cervical spine lesions and temporo-mandibular joint dysfunction (TMJD). Eleven patients with RES secondary to upper cervical spine abnormalities were found in the literature. Different aetiologies have been implicated including cervical spondylosis, infections of the meninges, traction injury, narrowing of the neural foramen at the side of the pain and congenital cervical abnormalities (Table
1). Eleven patients with RES and co-existing TMJD ipsilateral to the side of the pain have been described [
2,
9,
10,
16]. One patient’s RES attacks settled with the use of a dental plate seeming to point to a causal relationship between TMJD and RES in this case [
2].
Other secondary causes of RES include Chiari 1 malformation, thalamic syndrome and a neurovascular compression of the C3 root by the vertebral artery [
2,
9,
21].
Investigations
Due to the association of secondary RES with upper cervical spine pathology and TMJD, an MRI of the cervical spine should be carried out and, when the clinical suspicion for TMJD is high, an orthodontic assessment is warranted. In addition, given the possible link between RES and thalamic lesions [
2,
17], an MRI scan of the brain should be included in the diagnostic work up of RES.
Given the description of a patient with chronic paroxysmal hemicrania (CPH), presenting as RES with unilateral short-lasting, attacks of ear pain and redness, sometimes involving the entire side of the face which responded to indometacin [
3], all patients with short-lasting strictly unilateral side-locked attacks of ear pain and redness occurring more than once a day should have a trial of indometacin up to 225 mg a day [
33], to exclude an indometacin-sensitive headache disorder.
Classification and diagnostic criteria
Given the relatively limited description of RES in terms of aetiology, pathophysiology and treatment, it is currently not included in the ICHD-II [
34] and ICHD-IIIβ [
22]. Some authors have suggested that RES could be considered a form of TAC on the basis that both are a similar phenotype characterized by short-lasting attacks of unilateral pain, occurring once or more times a day associated with cranial autonomic features [
27]. Lance proposed that since symptoms in RES are mostly centred over the earlobe (which derives its sensory supply from C3), RES may be a form of autonomic cephalalgia mediated by the greater auricular nerve rather than the trigeminal nerve, and that therefore, the term “auriculo-autonomic cephalgia” rather than TAC should be used [
26].
RES often appears to occur in associated with migraine without aura. Indeed, 81% (n=60/74) of patients reported in the literature with primary RES had a personal history of migraine [
5,
6,
9,
13‐
16]. Given this striking association, Raieli
et al., suggested that RES be encompassed into the wider clinical spectrum of migraine, with RES episodes considered a migraine related phenomenon when occurring during a migraine attack and an “acephalgic” migraine phenomenon when occurring outside a migraine attack [
5]. Subsequently, the same authors studied a group of 40 young migraineurs with RES and found that RES was significantly associated with some of the migraine associated features, possibly explained by parasympathetic nervous system activation. They concluded that RES could be considered a specific sign of parasympathetic hyperactivation via the trigemino-autonomic reflex, occurring during migraine [
13].
In view of its various possible aetiologies, other authors argued that primary and secondary forms of RES be kept separated. They proposed that primary RES be considered a migraine-related phenomenon, whereas secondary forms considered a neuralgiform radiculopathy involving the C3 root [
7].
Although the pathophysiological mechanisms and consequently the treatment of RES remains unclear, the clinical description in 100 patients provides enough detail to allow us to propose the first set of diagnostic criteria (Table
3). We propose that RES be included in the 4
th Chapter of the IHS Classification, “Other Primary Headache Disorders”, until further understanding regards its pathophysiology and treatment emerges. Since secondary forms of RES are rather frequent, physicians should carefully look for secondary causes of RES, namely a disease of the upper cervical spine and TMJ dysfunction. Secondary RES due to a disorder of the neck or TMJ should be classified within Chapter 11 of the ICHD-IIIβ (Headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cervical structure).
Table 3
Proposed diagnostic criteria for primary red ear syndrome
A.
| At least 20 attacks fulfilling criteria B-E |
B.
| Episodes of external ear pain lasting up to 4 hours. |
C.
| The ear pain has at least two of the following characteristics: |
-Burning quality |
-Unilateral location |
-Mild to moderate severity |
-Triggered by cutaneous or thermal stimulation of the ear. |
D.
| The ear pain is accompanied by ipsilateral redness of the external ear. |
E.
| Attacks occur with a frequency of ≥1 per day, although cases with lower frequency may occur. |
F.
| Not attributed to another disorder. |
Primary versus secondary RES
Although primary and secondary forms of RES share common epidemiological and clinical characteristics, differences in age of onset, clinical presentation and associated conditions have been described. For this reasons, Donnet and Valade proposed to distinguish RES into two separate types - a primary form that occurs in younger people with a personal history of migraine, and a secondary form seen more frequently in older patients with upper cervical spine pathology or TACs [
6]. The analysis of the published cases (Table
4) indicates that patients with primary RES have a younger age of onset compared to those with secondary RES and that whilst both forms show a female preponderance this is more pronounced in secondary RES. Clinically, a higher proportion of patients with the secondary form of RES have daily and triggerable attacks as compared to those with the primary form, a difference that may be attributable to the underlying pathology. As suggested by Donnet and Valade, a higher proportion of patients with primary RES had a personal history of migraine.
Table 4
Characteristics of primary and secondary forms of red ear syndrome (RES)
Number
| 74 | 26 |
Median age of onset
*
| 34 years (range: 5–74) | 45 years (range: 9–76) |
Gender
| Females: 37 (51%) | Females: 17 (65%) |
Males: 36 (49%) | Males: 9 (35%) |
RE episodes: frequency
***
| ≥ 1 attack/day: 17 (53%) | ≥ 1 attack/day: 17 (77%) |
< 1 attack/day: 15 (47%) | < 1 attack/day: 5 (23%) |
RE episodes: duration
**
| <4 hours: 47 (94%) | <4 hours: 13 (68%) |
>4 hours: 3 (6%) | >4 hours: 6 (32%) |
Triggered attacks
| 16/74 (22%) | 18/26 (69%) |
Personal history of migraine
| 60/74 (81%) | 6/26 (23%) |
In summary, the primary form of RES affects younger males and females almost equally and is characterised by short-lasting episodes occurring with a variable frequency. Attacks are usually spontaneous and most patients have a personal history of migraine. The secondary form of RES occurs in older people, with a female preponderance, usually without a personal history of migraine and is characterised by short-lasting, daily attacks, often provoked by specific triggers (Table
3). More clinical and therapeutic data is needed to ascertain if primary and secondary forms show different responses to medical treatments, as suggested by some authors [
10].