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.[4][29] The severity of symptoms can range from non-bothersome to mild annoyance to social anxiety and avoidance.[30] Symptoms can appear weeks, months, or even years after the initial damage.[3][33][34] 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.[18] 

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.[30]

Preventative Techniques

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.[23][25] 

1. Thickened skin flap. Increasing the thickness of the skin flap raised over the parotid gland during surgery can theoretically protect the sweat glands and their nerve fibers from being exposed. This is because the sweat glands reside in the skin at the layer akin to the hair follicles, and so a thickened flap would reduce the chance of their exposure to aberrant regenerating parasympathetic nerves. While some recent studies have shown that increased flap thickness did not appear to significantly lower the incidence of Frey syndrome, there was a tendency towards a decrease in the total skin surface area affected, as well as the overall severity of the symptoms.[35][36]
2. Acellular dermal matrix (ADM). Acellular dermal matrix is an extracellular connective tissue matrix graft formed by a decellularization process where the cellular components of the matrix are removed. It provides a scaffold for donor site cells to incorporate, leading to tissue regeneration and revascularization. As a result, ADMs can function as a biologic barrier between the transected parotid/parotid bed and the overlying skin. In Zeng et al. ADM was utilized as a biologic barrier between the skin and the transected parotid gland, resulting in a reduction of Frey syndrome by 85% on objective starch-iodine test and 68% on subjective assessment of symptoms.[17] However, other studies have found their effectiveness in reducing clinical symptoms and positive starch-iodine tests to be mixed.[30][37] Although large-scale studies are still lacking, the use of barrier methods to prevent Frey syndrome may be considered for high-risk patients.[18]
3. Autologous fat implantation. Fat implantation is a technique that is commonly used to decrease postsurgical contour defects and improve cosmesis in many parts of the body. Some studies that reviewed the efficacy of abdominal fat implantation to prevent Frey syndrome have shown it to be effective,[16][38] whereas others have failed to substantiate its efficacy.[30] Furthermore, the disadvantages of an additional donor site on the abdomen for fat harvest with risks of donor site morbidity (including hematoma, infection, and seroma) may influence its selection for use in preventing Frey syndrome.
4. Superficial muscular aponeurotic system (SMAS) flap. The SMAS is a broad sheet of fascia interdigitating with the facial muscles, extending from the neck to the forehead, that is responsible for facial expression. During a parotidectomy, the SMAS flap can be harvested separately from the underlying parotid fascia and the overlying dermis, then sutured tightly to the ear perichondrium and sternocleidomastoid muscle to act as a physical barrier to the development of Frey syndrome. It can also help improve contour deformities when used in this fashion. Bonanno et al. found this technique effective in preventing Frey syndrome.[39] Although other studies using the SMAS flap have failed to reproduce these results, others have shown a significant decrease in symptom severity and total skin surface area affected.[40][41][42][43]
5. Temporoparietal fascia (TPF) flap. This is a vascularized fascial flap supplied by branches of the superficial temporal artery. The prophylactic placement of TPF between the skin and defect aims to serve as a physical barrier to the development of Frey syndrome. Sultan et al. found that the use of the TPF flap not only improved the contour deformity after parotid surgery but also decreased the incidence of Frey syndrome from 17% to 4%.[44] Disadvantages of this technique include an extended skin incision towards the temple, risk to the temporal branch of the facial nerve during flap harvest, and increased operative time.[30]
6. Sternocleidomastoid muscle (SCM) flap. The SCM is supplied by the occipital artery, superior thyroid artery, and suprascapular artery.[45] Its efficacy in preventing Frey syndrome is ambiguous, given the heterogeneity of results between studies.[16] Filho et al. demonstrated that 24 parotidectomies with SCM flap reconstruction resulted in 0% cases of Frey syndrome compared to 52.6% and 63.2% by clinical and starch-iodine testing respectively in a control group without SCM flap reconstruction.[46] A 2009 meta-analysis published by Curry et al. also concluded that SCM flaps decrease the incidence of Frey syndrome after parotidectomy.[47] However, other studies have shown that the SCM muscle flap is ineffective at preventing Frey syndrome.[48][49]

Medical Treatment

Medical therapies for Frey syndrome have included topical antiperspirants and local injections using alcohol, atropine, scopolamine,[50] glycopyrrolate, or botulinum toxin A (BTA).[51][52] Since the sweat glands are innervated by the postganglionic cholinergic pathways, treatment has traditionally involved anticholinergics.[28]

1. Topical antiperspirants have been shown to be ineffective in completely controlling gustatory sweating. Studies have shown that less than 50% of patients report any benefits, and for those who do, the duration of improvement lasts less than a day.[53]
2. Injection of alcohol to the otic ganglion has historically been proposed, but can result in anesthesia to the mandibular branch of the trigeminal nerve and cause even more bothersome symptoms than Frey syndrome.[54] Systemic atropine is not effective in preventing sweating. If anhidrosis occurs with its use, it is usually a sign of atropine overdose, which can also present with other undesirable side effects such as tachycardia, blurred vision, disorientation, respiratory distress, and coma.[50][54] Periodic topical application of scopolamine hydrobromide or glycopyrrolate cream to the affected skin has been found to be effective without significant side effects, but can be particularly inconvenient for patients.[53][55][56]
3. Currently, botulinum toxin is the most widely used agent for local injection with dosing between 1.9 and 2.5 U/cm2 in the involved area.[57][58][59] Botulinum toxin acts as an anticholinergic and blocks acetylcholine release at the neuromuscular junction by breaking down synaptosomal-associated protein 25 (SNAP-25).[60][61] This produces chemical denervation and paralysis of both striated muscles and sweat glands.[62][63] Peak effects are apparent within 4 to 7 days, and patients report improvement in gustatory sweating, flushing, and overall quality of life.[59][63][64][65] However, the chemical denervation could be reversed if there is the absorption of denatured SNAP-25 and recombination of the nerve ending and the lamina terminalis.[61][66] Thus, repeat injections are often necessary as symptoms can recur in 27% and 92% of patients at 1 and 3 years, respectively.[67] Repeat injections are safe, decrease the area of the affected skin, and increase the symptom-free duration.[59][68][69]

Surgical Treatment

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.[56]

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.[50][54][70] The risk of an intracranial procedure to divide the glossopharyngeal nerve has been considered unjustified for a benign entity such as Frey syndrome.[50][54][70] Excision of the affected skin can create an unacceptable cosmetic defect for patients.[56]

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.[71] 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.[54][56] Limited studies have shown relief of gustatory sweating in up to 82% of cases without complete elimination.[53][56] 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.[70] 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.

1. Food allergy. In children, Frey syndrome can present during early infancy at the same time as food diversification and be mistaken for food allergies. It can be distinguished from allergies in the setting of a history of instrumentation during birth, quicker onset after a meal compared with allergy reactions, specific food triggers (sweet and sour) unrelated to common food allergens, rapid recovery without allergy treatment, symptoms localized to the parotid region, and absence of other atopic symptoms.[3]
2. General hyperhidrosis. Primary hyperhidrosis is an autonomic disorder that affects 0.6%-1% of the population.[72] The majority of cases have an unknown etiology, and patients usually present with at least 6 months of excessive bilateral and symmetrical sweating, age younger than 25 years old, positive family history, or cessation of sweating during sleep.[73][74] Secondary hyperhidrosis can be induced by drugs, toxins, thyroid dysfunction, pituitary dysfunction, metabolic disorders, malignancy, central nerve disorders, or congenital disorders (such as Riley-Day syndrome).[73][75]
3. Emotional sweating is activated by emotional stimuli and affects primarily the palms, soles, and sometimes the axilla. It does not occur when the patient is sleeping or sedated.[75]
4. Compensatory hyperhidrosis is a complication after thoracic sympathectomy. Sympathectomy is initially used to treat primary hyperhidrosis but can result in disruption of the thermoregulatory function of the sympathetic nervous system. This results in uncontrolled sweating in untreated areas, usually below the severed level of sympathectomy.[75]
5. Gustatory tearing (crocodile tears syndrome) presents with unilateral tearing when given a gustatory stimulus. It is commonly associated with Bell’s palsy, Duane syndrome, and trauma. It is theorized that damage to the facial and glossopharyngeal nerve fibers leads to aberrant nerve regeneration of the postganglionic parasympathetic secretomotor nerve fibers along the greater superficial petrosal nerve which innervates lacrimation. Treatment involves subtotal lacrimal gland excision, anticholinergics, transection of the facial or glossopharyngeal nerves, injection of alcohol to the sphenopalatine ganglion, and botulinum toxin injection into the lacrimal gland.[76][77]
6. Gustatory rhinorrhea has a similar etiology as gustatory tearing. After trauma, the postganglionic parasympathetic secretomotor fibers that innervate the parotid undergo aberrant regeneration and grow along the greater superficial petrosal nerve and Vidian nerve, which innervates not only the lacrimal glands but also the glands of the nasal and palatine mucosa. This results in patients presenting with unilateral rhinorrhea when given a gustatory stimulus.[78]

Frey syndrome usually occurs from parotid surgery. Asymptomatic patients do not require any intervention.[18] 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.[18][25] 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.[53][56]

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.[59][67] 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.[23][56][71]

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.[53]

Botulinum toxin use may result in facial muscle weakness/paralysis, eyelid ptosis, localized pain, edema, erythema, and ecchymosis.[79] 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.[80]

Frey syndrome is a benign condition and rarely progresses. Asymptomatic patients are rarely treated and investigated only for academic purposes.[18] 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.[30]

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.[3]

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.[81] 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.[82]

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.[18] 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.[18][81] 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.