Botulinum Toxin: Treatment for Refractory Chronic Migraine and Red Ear Syndrome

Introduction

Red Ear Syndrome (RES) is an unusual experience described as painful, burning sensations and redness of the ear and surrounding skin. While several more cases have been recounted since its characterization by Lance in 1996, RES pathophysiology and treatment are still debated. Several conditions have presented with RES, including trigeminal neuralgia, trigeminal autonomic cephalalgia, thalamic syndrome, cervical spine disorders, systemic lupus erythematosus, vasculitis, and temporomandibular joint (TMJ) dysfunction, but seems most consistently to appear in patients with chronic migraine; RES may also be a subtype of erythromelalgia, a comparable erythema and pain of the hands and feet.^{1, 2} Because its underlying mechanism is uncertain, RES remains resistant to most treatment options which consist of routine medications used for migraine: NSAIDs (indomethacin), tricyclic antidepressants (amitriptyline), calcium channel blockers (verapamil), beta-blockers (propranolol), antiepileptic drugs (gabapentin), cervical nerve blocks, and botulinum toxin.^2-4

At the neuromuscular junction, the botulinum toxin is known to cleave SNARE proteins, preventing acetylcholine release and muscle contraction. However, its mechanism for chronic migraine must be more than reduced muscle tension, as its use is ineffective for tension-type headaches.⁵ Studies suggest that botulinum toxin acts in several ways: inhibiting calcitonin-gene related peptide (CGRP) and substance P release peripherally and centrally due to retrograde axonal transport; reducing surface expression of nociceptive receptors; decreasing the production of inflammatory cytokines; and, stimulating mu-opioid receptors.^{5, 6} Overall, these actions subsequently minimize vasodilation and pain. In our case, botulinum toxin A was used as a treatment for RES and chronic migraine.

Case Report

A 67-year-old female with a past medical history of occipital neuralgia status post multiple ablations, possible Ehlers-Danlos Syndrome, rheumatoid arthritis, Raynaud’s disease, facial basal cell carcinoma, gastroesophageal reflux disease, and nasal septal ulcer, presented in clinic with chronic migraine with aura and unilateral RES.

Previous failed treatments for migraine include amitriptyline, gabapentin, dihydroergotamine, acupuncture, ibuprofen, naproxen, and CBD cream. At this time, her prophylactic treatment included nadolol and galcanezumab, while abortive treatment consisted of sumatriptan. Galcanezumab, a CGRP ligand monoclonal antibody, reduced her headache intensity but did not reduce the frequency from 20 headaches per month. Unrelated to her headache, she reported redness of her right ear several times a week, lasting 1-2 hours. Botulinum toxin A 155 units every twelve weeks was added as a treatment for RES and migraines in addition to her prophylactic galcanezumab and nadolol. Botulinum toxin A was administered based on the PREEMPT protocol ⁷.  On the right temple, treatment was adjusted to inject five units of toxin near the pterion, ten units behind the ear, and five above the TMJ.

With the addition of botulinum toxin A treatment to her regimen, both her RES and migraine symptoms were mitigated about two weeks following the second round. Her headache frequency had decreased to 4-6 per month from the baseline of 20. Additionally, her RES improved significantly with a reduction in frequency and duration to about 12 episodes lasting 30 minutes in three months.

Discussion

One basic proposal for RES pathophysiology revolves around decreased sympathetic activity and increased parasympathetic activity. The trigeminal nerve innervates the middle temporal and posterior auricular arteries which supply the ear. A branch of the trigeminal nerve, the auriculotemporal nerve, innervates the anterior superior ear and TMJ. Lastly, the earlobe is innervated by C2 and C3 nerve roots branches. Nerve signals release calcitonin gene-related peptide (CGRP), substance P, and nitric oxide, which lead to blood vessel dilation, erythema, and pain.^{2, 8, 9}

Clinically, RES commonly occurs in association with chronic migraine; therefore, it has been proposed that RES may be produced by trigeminovascular activation and vasodilation during a migraine.^{2, 9} RES could be related to erythromelalgia; although its pathology is still being studied, it is thought the primary trigger may be hypoxia-induced neuropathy as well as arteriovenous shunting due to atypical distribution of blood vessels.^{2, 10, 11} Erythromelalgia has also been linked to several hematologic disorders where thrombosis or intimal and smooth muscle proliferation may be key contributing factors for attacks.¹¹ Interestingly, botulinum toxin has been shown to effectively treat refractory erythromelalgia, supporting the idea that RES may be an auricular subtype since both respond to these injections.^{12, 13}

Conclusion

No definitive treatment for RES has been determined because of its different clinical presentations and numerous associated conditions. However, botulinum toxin A may be the most effective treatment in RES patients who present with chronic migraine. Furthermore, the success of this treatment may support the classification of RES as a subtype of erythromelalgia and add to the basic understanding of its possible pathophysiology.

References

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