Frey syndrome, also known as Baillarger’s syndrome, auriculotemporal syndrome, Dupuy syndrome, or gustatory hyperhidrosis, is a dysfunction of the auriculotemporal nerve. The auriculotemporal nerve, a branch of the trigeminal nerve, consists of parasympathetic fibers that supply the parotid gland to induce salivary production, and sympathetic fibers that innervate the sweat glands of the face and scalp. When an initial insult to the parasympathetic and sympathetic nerve fibers of the auriculotemporal nerve at the parotid region occurs, the resulting aberrant regeneration of post-ganglionic parasympathetic nerve fibers (responsible for salivary activation) along the pre-existing sympathetic pathways to the vessels and sweat glands of the skin, leads to the development of Frey syndrome.
Patients often present with facial warmth, flushing, and sweating in the territory of the auriculotemporal nerve overlying the parotid gland, which may include the preauricular skin, the temporal skin, the scalp, and the temporomandibular joint region. Symptoms occur during meals, especially with spicy and sour foods. It most commonly arises as a complication of parotidectomy, but can also be associated with submandibular gland surgery, repair of mandibular fractures, temporomandibular joint injury, parotid surgery, radical neck dissection, infection, and traumatic injury to the parotid region.
The first report of Frey syndrome was in 1853 by Dr. Jules Baillarger, who described two patients that underwent incision and drainage for parotid abscesses. The patients later developed facial sweating during meals. At that time, he misinterpreted the facial fluid as saliva overflowing through the skin due to a blocked Stenson’s duct. Prior to this, Dupuy had described gustatory sweating over the cheek area in relation to experimental sectioning of cervical sympathetic nerves in horses around 1816. Then, in 1897, Weber described bilateral gustatory sweating and flushing in a patient who had undergone bilateral parotid abscess drainage, representing the first case of reported bilateral Frey syndrome.
It was not until 1923 that the first accurate description of this phenomenon was provided by Dr. Lucja Frey, a Polish physician and one of the first female academic neurologists in Europe. She described a 25-year-old female who sustained a gunshot wound to the parotid region with subsequent development of facial flushing and sweating 5 months afterward. She accurately identified the autonomic innervation of the parotid gland and the auriculotemporal nerve as the link between gustatory stimulation and facial sweat production. In 1927, Dr. Andre Thomas theorized that the pathophysiology of the disease was due to aberrant nerve regeneration. Lastly, in 1932, Dr. Peter Bassoe reported the first case of Frey syndrome after a parotidectomy, which has since been accepted as the most common cause of Frey syndrome.
In adults, Frey syndrome usually occurs with auriculotemporal nerve injury secondary to surgical intervention or trauma in the parotid region.
The auriculotemporal nerve consists of two roots. The superior somatosensory root arises from the mandibular branch of the trigeminal nerve, providing innervation to the auricle, external auditory canal, temporomandibular joint, external tympanic membrane, and the temple. The inferior parasympathetic root arises from the postganglionic fibers at the otic ganglion, which originate from the glossopharyngeal nerve. It is responsible for the visceral secretomotor actions of the parotid gland.
After the two roots are united, the auriculotemporal nerve travels posterior to the mandible and parotid where it gives off the secretomotor parotid branch before coursing across the superior border of the mandibular condyle below the temporomandibular joint and terminating in the temporal region. Frey syndrome can occur if the auriculotemporal nerve proximal to the parotid branch or the parotid branch itself is injured. It has most recently also been shown to have a rare variant characterized by symptoms distal to the parotid region in the temporoparietal scalp even when the injury occurs in the parotid region.
Salivary gland neoplasms comprise 3%-10% of all head and neck tumors, with up to 86% of tumors located in the parotid gland. Parotidectomy is the first-line treatment in patients with salivary gland neoplasms and the most common etiologic cause of Frey syndrome in adults. Other complications after parotidectomy include facial nerve paralysis, face contour asymmetry, scarring, salivary fistula, first bite syndrome, pain and discomfort, xerostomia, and hypoesthesia of the skin innervated by the great auricular nerve. Larger parotid tumors are associated with more extensive dissection, parasympathetic nerve fibers exposure, and damage, thereby resulting in higher risk for Frey syndrome.
Aside from parotidectomy, other causes of Frey syndrome include direct trauma to the parotid region, mandibular condyle fractures, temporomandibular joint fractures, infection, submandibular gland excision, and radical neck dissections.
In children, Frey syndrome is less common and may occur during early infancy with no prior history of surgery or in the setting of post-birth trauma. Symptoms usually occur around the age of 5 months and can be misdiagnosed as food allergies since it occurs during the same time as food diversification. It can be distinguished from allergies especially if there is a history notable for instrumented vaginal delivery, quick onset after a meal compared with allergy reactions, occurrence with specific foods (sweet and sour) not related to common food allergens, rapid recovery without treatment, specific and persistent location, and absence of other atopic symptoms. In traumatic instrumentation delivery using forceps and spatula, the auriculotemporal nerve is usually crushed rather than severed during delivery, resulting in less aberrant nerve regeneration, absence of sweating in certain patients, and the possibility of recovery in a few patients.
Bilateral symptoms are more likely idiopathic in origin. Familial bilateral Frey syndrome has been described in the literature for patients without a history of trauma, leading to the hypothesis of a congenital dysfunction of the auriculotemporal nerve.
The incidence rate of Frey syndrome after parotidectomy ranges widely from 4% to 96%. The diverse incidence rate reported in the literature is a reflection of the heterogeneity in patient symptom severity, reporting, and diagnosis.
The incidence of Frey syndrome approached 80% in parotidectomy patients based on Minor’s starch-iodine test, but ranged from 30% to 60% based on subjective patient reports, signifying a population of asymptomatic Frey syndrome patients or patients with non-bothersome symptoms.
The risk of Frey syndrome also differs depending on the location of surgery. Avinçsal et al. showed that 50% of patients undergoing surgery involving the deep parotid lobe developed Frey syndrome compared to 18% of patients undergoing surgery at the upper neck. Linkov et al. showed Frey syndrome was associated with surgery of the deep parotid lobe in 38.4%, parapharyngeal space surgery in 22.4%, and sympathetic chain sacrifice in 48.6%.
There do not appear to be age or gender predilections for the development of Frey syndrome.
Frey syndrome is theorized to result from injured parasympathetic nerve branches of the auriculotemporal nerve undergoing aberrant nerve regeneration.
The parasympathetic nerve fibers, which originate from the inferior salivary nucleus and glossopharyngeal nerve, branch into the inferior petrosal nerve and synapse at the otic ganglion. From there, the postganglionic parasympathetic fibers join with the auriculotemporal nerve, being responsible for the secretomotor responses of the parotid gland. Postganglionic parasympathetic nerve fibers are cholinergic and activated by acetylcholine during gustatory stimuli. The sympathetic nerve fibers are responsible for the vasomotor and sweat gland innervation of the surrounding skin. Although most postganglionic sympathetic fibers are adrenergic and activated by noradrenaline, the postganglionic sympathetic fibers supplying the sweat glands are activated by a substance resembling acetylcholine and are considered cholinergic in nature.
Both parasympathetic and sympathetic nerve branches of the auriculotemporal nerve can be damaged in trauma or surgical procedures such as parotidectomy. Aberrant nerve regeneration can occur, resulting in the postganglionic parasympathetic fibers growing along the sympathetic nerve axon pathways to cross-innervate the vessels and sweat glands of the face. This causes vessel dilation and sweat gland production in response to gustatory stimulation. Since this complication requires time for nerves to undergo regeneration, this would also explain the delayed presentation of Frey syndrome, often occurring 6 to 18 months after surgery.
In a similar fashion, Frey syndrome can occur after submandibular excision and neck dissection due to aberrant nerve regeneration after damage to the postganglionic parasympathetic nerve fibers to the submandibular gland, postganglionic parasympathetic fibers to the sublingual gland, or postganglionic parasympathetic fibers arising from the cervical sympathetic ganglia to innervate the sweat glands of the skin.
Another theory on the development of Frey syndrome is that damaged sympathetic nerve fibers result in increased sweat glands sensitivity and are stimulated by acetylcholine released from adjacent parasympathetic fibers. This theory is appealing in cases where gustatory sweating occurs shortly after surgery when nerve regeneration would have yet to occur.
There is a paucity in the literature of histopathologic studies on Frey syndrome. The best effort that appears to be available was put forward by Redleaf and McCabe of the University of Iowa, where they describe a rare case of Frey syndrome of the external auditory canal.
A 36-year-old patient had presented with a 6-month history of left watery otorrhea, eventually deciphered to be sweat, that occurred only with eating. Resection of the membranous canal skin with split-thickness skin graft reconstruction led to the resolution of the symptoms. Histopathologic analysis of the canal skin on hematoxylin and eosin staining revealed markedly-thickened canal skin (4.2mm compared to 0.08mm for normal bony canal skin) with hyperplasia and hypertrophy of sweat glands, which are not present in normal bony canal skin. The latter was postulated to be due to aberrant parasympathetic influence.
Patients with Frey syndrome often have a history of prior parotid surgery, neck surgery, trauma, or infection to the parotid region, although idiopathic and infantile presentations may also occur. They report unilateral sweating, flushing, neuralgia, pruritis, and warmth over the preauricular and temporal areas after gustatory stimuli, especially with sour and spicy foods. The severity of symptoms can range from non-bothersome to mild annoyance to social anxiety and avoidance. Symptoms can appear weeks, months, or even years after the initial damage. The physical exam may show signs of prior surgical intervention or trauma in the parotid region.
Historically, Frey syndrome was a clinical diagnosis based on patients' self-report of symptoms through standardized questionnaires. Today, objective methods such as the Minor starch-iodine test serve as more sensitive ways of confirming Frey syndrome.
During the Minor test, the patient's post-surgical facial area is painted first with iodine. Once dry, starch is applied over the painted area, and the patient is presented with a salivary stimulus. If the gustatory stimulus causes activation of the sweat glands, the starch will become moist and turn blue/brown in the presence of iodine.
The main preventative strategy for Frey syndrome is the creation of a barrier system to hinder the aberrant nerve regeneration between the parasympathetic secretomotor fibers and the sweat glands at the time of surgery in the parotid region. Several methods have been described in the literature with risks, including the creation of a donor site, prolonged operative time, mixed efficacy in reducing the incidence of Frey syndrome, wound infection, rejection, or postoperative complications.
Medical therapies for Frey syndrome have included topical antiperspirants and local injections using alcohol, atropine, scopolamine, glycopyrrolate, or botulinum toxin A (BTA). Since the sweat glands are innervated by the postganglionic cholinergic pathways, treatment has traditionally involved anticholinergics.
Surgical management of Frey syndrome after its onset is rarely indicated and is reserved for refractory cases where conservative or medical therapies are no longer effective. Options for surgical management include transection of the auriculotemporal nerve, tympanic nerve, glossopharyngeal nerve, greater auricular nerve, or excision of the affected skin with grafting for the defect.
Sectioning of the auriculotemporal nerve in a previously operated field can be technically challenging and poses a risk to the facial nerve. In addition, the auriculotemporal nerve is capable of regeneration, which may annul any initial benefits obtained. The risk of an intracranial procedure to divide the glossopharyngeal nerve has been considered unjustified for a benign entity such as Frey syndrome. Excision of the affected skin can create an unacceptable cosmetic defect for patients.
Dai et al. reported a study of 17 patients with Frey syndrome who underwent SCM and temporalis fascia transposition (after the onset of Frey syndrome) with 53% of patients showing complete convalescence on starch-iodine testing as well as a reduction in the affected skin surface area from 12.80 cm2 to 1.32 cm2. However, disadvantages include the need for a second operation, flap failure, poor cosmesis, and risk to the facial nerve.
Jacobson’s neurectomy, which involves resection of the tympanic nerve (a branch of the glossopharyngeal nerve), can be performed by raising a tympanomeatal flap inferiorly and identifying Jacobson’s nerve as it emerges from the inferior tympanic canaliculus, coursing across the promontory anterior to the round window. The nerve is sectioned, and the canaliculus is obliterated to prevent the regeneration of the nerve fibers. Limited studies have shown relief of gustatory sweating in up to 82% of cases without complete elimination. It is believed that other parasympathetic pathways to the parotid occur and are responsible for this incomplete response. Two potential pathways postulated include (1) a connection between the chorda tympani and the otic ganglion or a facial nerve and (2) a connection between the greater superficial petrosal nerve to the lesser petrosal nerve. Resection of the chorda tympani, in addition to Jacobson’s neurectomy, does increase the rate of gustatory sweating control but results in unilateral denervation of the major salivary glands and xerostomia. Thus, the division of the chorda tympani should only be offered to patients with debilitating, persistent gustatory sweating after Jacobson’s neurectomy.
Frey syndrome usually occurs from parotid surgery. Asymptomatic patients do not require any intervention. Prevention is first-line and high-risk patients, including those with large (>4 cm) parotid tumors or extensive parotid area injury, should have prophylactic barrier reconstruction. Patients who present with postoperative gustatory sweating should be initially treated with conservative medical management. Topical antiperspirant and anticholinergic ointments can provide symptomatic relief with minimal systemic side effects but do require frequent applications.
Serial botulinum toxin injections can provide an extended duration of control without the need for frequent re-applications, as seen with antiperspirant and anticholinergic ointments. If patients have persistent or refractory symptoms to medical management, surgical options including Jacobsen’s neurectomy, chorda tympani resection, muscle flap reconstruction, or excision of involved skin with graft reconstruction may be offered to the patient. Patients should be counseled that surgical intervention has a higher risk of complications such as xerostomia, facial nerve injury, flap rejection, and cosmetic defects.
Although topical anticholinergic use has been found to have no significant side effects, anticholinergic agents can be extremely toxic if ingested. Symptoms may include delirium, hallucinations, and coma. In addition, their use is contraindicated in patients with narrow-angle glaucoma.
Botulinum toxin use may result in facial muscle weakness/paralysis, eyelid ptosis, localized pain, edema, erythema, and ecchymosis. It is contraindicated in patients with motor neuron disease, myasthenia gravis, Eaton-lambert syndrome, neuropathies, psychological instability, history of an allergic reaction to the toxin or albumin, pregnancy, and infection at the affected skin site.
Frey syndrome is a benign condition and rarely progresses. Asymptomatic patients are rarely treated and investigated only for academic purposes. The majority of patients who present with symptoms can be effectively treated with conservative medical management, including topical antiperspirants, anticholinergics, and botulinum toxin. Those with severe or refractory cases can be treated with surgery.
In children, symptom regression occurred in 69% of unilateral forms. Bilateral forms are usually not related to postnatal trauma and resolve during the first year in 58% of patients.
Although there are no significant medical complications associated with Frey syndrome, it can significantly impair patients’ quality of life. Subjective perception and discomfort associated with Frey syndrome can persist beyond 5 years after surgery. Quality of life questionnaires showed a statistically significant correlation in social functioning, economic difficulties, speech defect, reduced sexuality, and poor oral nutrition with Frey syndrome.
Frey syndrome is a complication that results from aberrant neurological regeneration impacting the salivary glands and integumentary system with a variety of pathophysiological underpinnings between adults and children. Diagnosis and management would need to consist of an interprofessional team, including an otolaryngologist, plastic reconstructive surgeon, dermatologist, neurologist, primary clinician, an allergy specialist, and a pharmacist.
Frey syndrome is often seen as a minor complication and frequently underestimated by surgeons. When surveyed, many patients do not recall being properly educated on the risk of developing Frey syndrome after parotid surgery. This can result in a lack of preoperative patient counseling, postoperative surveillance, and formal diagnosis. Hence, preoperative counseling and education of Frey syndrome to patients is critical during the informed consent process to ensure a timely diagnosis and initiate proper management. Symptoms of facial warmth, flushing, and sweating in the setting of acidic or spicy foods should be reported to the operating surgeon.
The social impact of Frey syndrome should not be overlooked. In a questionnaire for patients who underwent parotidectomy for benign salivary diseases, gustatory sweating was identified as the most serious and concerning complication. Patients reported a reduction in quality of life, pain during eating, drinking, or daily activities, difficulty enjoying meals, and self-perceived discomfort that worsened over time. Early patient education and timely diagnosis and treatment are key to alleviating and addressing the associated social concerns.
Patients with Frey syndrome should be managed in consultation with an interprofessional team comprising otolaryngologists, plastic surgeons, dermatologists, neurologists, primary clinicians, pharmacists, and allergy specialists. Patients who are at high risk for Frey syndromes, such as those with large parotid tumors or extensive traumatic damage to the parotid region, can benefit from prophylactic surgical reconstruction by plastic surgeons to prevent aberrant nerve regeneration. Children with early-onset gustatory sweating should be closely followed and evaluated by primary clinicians and allergy specialists to rule out food allergies.
As Frey syndrome can have a delayed onset up to years after the initial surgery, primary clinicians must remain vigilant for its development and refer patients back to the operating surgeon in a prompt manner. Collaboration between dermatologists, otolaryngologists, and plastic surgeons can provide patients with first-line conservative medical treatment such as topical antiperspirants, anticholinergics, and botulinum toxin injections. Finally, since patients may develop social anxiety and avoidance due to the visible presentation of their disease, especially in public settings, formal peer support groups can aid patients in addressing their concerns.
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