Indomethacin-responsive idiopathic red ear syndrome: A pediatric case

First described in 1994,1 red ear syndrome (RES) remains a pathophysiologic mystery.2 Proposed criteria include at least 20 attacks of external ear pain and redness lasting up to 4 h at least once per day with two of the following: burning quality, unilateral location, mild to moderate severity, and triggered by cutaneous or thermal stimulation of the ear.3 Epidemiology is unknown, likely owing to lack of questioning, but the reported male:female ratio in children is 3:1.4 Treatment remains challenging.2 We report a child with isolated RES involving either or both ears and face treated successfully with indomethacin. This may help shed light on the underlying mechanisms of disease. The parent consented and patient assented to publication of this report. This 11-year-old male presented with 2 years of burning pain with associated redness of the right, left, or both ears. Discomfort and redness often extended to the cheeks and mandibular region. Episodes occurred daily to multiple times per day and were 30 min to 8 h in duration. Episodes were triggered by concentration, stress, and indoor heat. Touch did not trigger attacks but exacerbated existing pain. Episodes were most common and severe in the evening in bed. Cold compress and fanning the ears provided mild relief but ibuprofen was ineffective. He denied other head and facial pain, nausea, vomiting, photophobia, phonophobia, and other autonomic symptoms during or between attacks. Past history was positive for anxiety and sleeping difficulty but negative for head/neck trauma. Birth was complicated by supplemental oxygen requirement but the patient was discharged after 48 h and development was normal. Family history was positive for “headaches” in his father and migraine with aura and Raynaud's syndrome in his mother. Maternal uncle reported history of “post-coital cephalalgia.” Physical and neurologic exams were normal including no allodynia or signs of temporomandibular joint dysfunction. Attacks could not be triggered by palpation over the greater or lesser occipital nerves or the ears and these areas were nontender. Brain MRI with and without contrast showed mild dilatation of the right lateral ventricle with normal third and fourth ventricles and borderline prominent extra-axial fluid spaces without signs of obstruction, suspected to be developmental. MRI brain visualized no upper cervical spine abnormalities. Indomethacin 50 mg (1.1 mg/kg) twice daily resulted in complete resolution of attacks within 24 h but dose was decreased to 25 mg BID due to drowsiness and dizziness, then discontinued after 2 weeks due to gastric upset despite famotidine. There was a single severe unilateral attack throughout 2 weeks of treatment and attacks returned for 1 h, once daily on 15 days/month after discontinuation. Due to this improvement, the parent opted to wait prior to attempting further prevention but gabapentin, amitriptyline, and non-invasive vagus nerve stimulation were discussed. RES in children is likely more common than reported. Though erythromelalgia can present similarly, symptoms are usually present in the hands and feet. Side-alternating and bilateral attacks are common, and may be associated with cheek involvement so our patient is not atypical in those regards.4 A pediatric review of RES identified only two patients without a comorbid primary headache disorder and no effective therapy for these was reported.4 A recent report described an adolescent male with RES isolated to both ears 2–3 times per week for 30–45 min responsive to indomethacin.5 An adult male with bilateral idiopathic RES was similarly treated with indomethacin with sustained remission 3 months after weaning off.6 Often those with a primary headache disorder experience RES attacks in isolation4 but treatment of a primary headache disorder may be effective in relieving RES as well.2 Pathophysiology of RES remains unclear given the multiple neuronal and vascular distributions involved in patients such as ours with erythema extending to the cheeks and mandibular region. The earlobe is innervated by the C2 and C3 roots via the greater auricular nerve whereas the anterosuperior ear is supplied by the third branch of the trigeminal nerve via the auriculotemporal nerve and the concha is supplied by the auricular branch of the vagus nerve.2 The cheeks and mandibular regions are supplied by the second and third divisions of the trigeminal nerve, respectively. In addition, ear erythema is under sympathetic control whereas facial erythema is predominantly controlled by parasympathetic fiber activation.3 Proposed theories include peripheral and central mechanisms. A peripheral theory is problematic in the setting of entire ear and cheek involvement, though may account for secondary cases and those isolated to the pinnae. The peripheral nerves involved converge to form the trigeminocervical complex within the brainstem and may represent a common location of dysfunction. The trigemino-autonomic reflex originating in this region has been proposed as the mechanistic connection between RES, migraine, and trigeminal autonomic cephalalgias (TACs), including paroxysmal hemicrania and hemicrania continua.2 In RES, indomethacin may inhibit parasympathetic neuronal activation from the trigeminocervical complex similar to TACs. However, this would not account for the ear erythema which is under sympathetic control. Perhaps parasympathetic activation induces downregulation of sympathetic tone. Alternatively, indomethacin's inhibition of the potent vasodilator nitric oxide production might explain its efficacy in RES.3 Interestingly, our patient had a family history of migraine with aura and autonomic dysfunction (Raynaud's syndrome) in his mother, so likely has genetic predisposition to migraine and migraine-like syndromes and possibly to autonomic dysfunction. However, the patient reported no headaches which is a unique difference compared to other reports. His maternal uncle was also diagnosed with what we suspect represents primary headache associated with sexual activity, another indomethacin-responsive disorder. The genetic relationship between these disorders is unknown but the uncle's disorder was one reason for trialing indomethacin. Given melatonin's structural similarity to indomethacin, this may be another reasonable option and may also aid the patient's sleep difficulty. RES is a rare and fascinating syndrome with many challenges. Isolated RES without comorbid headache disorders is rarely reported in children. We show that indomethacin could be a therapeutic option in such a patient, even with widespread involvement. Study of this disorder will remain challenging until criteria are included within formal classification systems and further detailed cases are reported. Study concept and design: Daniel N. Lax. Acquisition of data: Daniel N. Lax, Kelly Sitterle. Analysis and interpretation of data: Daniel N. Lax, Kelly Sitterle, Joanne Kacperski, Andrew D. Hershey, Marielle Kabbouche. Drafting of the manuscript: Daniel N. Lax. Revising it for intellectual content: Daniel N. Lax, Kelly Sitterle, Joanne Kacperski, Andrew D. Hershey, Marielle Kabbouche. Final approval of the completed manuscript: Daniel N. Lax, Kelly Sitterle, Joanne Kacperski, Andrew D. Hershey, Marielle Kabbouche. D. N. Lax and K. Sitterle report no conflicts. M. Kabbouche serves as site PI and SubPI for studies sponsored by Amgen, Biohaven, Lilly, and Teva, receives research support from NIH, serves on the board for Impel, and is a consultant for Theranica. J. Kacperski has received research funding to her institution for participation in ongoing studies sponsored by Amgen, Eli-Lilly, Teva, Biohaven, and Currax, serves as site PI for a study sponsored by Currax; there is no other potential conflict of interest for this manuscript. A. D. Hershey has received support paid to Cincinnati Children for an advisory role to AbbVie, Amgen, Biohaven, Lilly, Lundbeck, Teva, Theranica, and Upsher-Smith, serves as site PI on studies sponsored by Amgen, Biohaven, Theranica, and Upsher-Smith, has research grants from NIH (NINDS and NICHDS), and received honorariums from Lundbeck, Theranica, and Up-to-Date.