Introduction

Frey Syndrome is a condition most commonly developed after surgery on the paratoid glands, whereby during recovery, irregular connections form between different types of nerves that cause abnormal symptoms. For a long time, the histopathology of this condition was theorised, yet unproven. In this article, we will delve into the actual microscopic changes which occur that eventually lead to Frey Syndrome.

Signs and symptoms of Frey syndrome

Due to the vast nature of the healing spectrum, each person heals differently. As a result, Frey Syndrome caused by surgery can appear in the first year following the surgery as the nerves recover, or can even sometimes appear several years afterwards as the nerves continue to grow and heal¹. It can also occur after a traumatic injury that affects the parotid glands and the regions of the face surrounding it. 

Symptoms include:¹

• Sweating on the cheek: Occurs on the side of the face near the ear and jawline, typically during or after eating (gustatory sweating)
• Flushing or redness: The skin in the same region turns red or flushes when eating, especially with spicy or sour foods
• Heat sensation: Some individuals feel a growing warmth or burning sensation in the affected areas when salivation is triggered
• Tingling or mild discomfort: A tingling or prickling sensation in the skin of the cheek might occur when eating
• Hyperhidrosis: Excessive sweating in the cheek area, especially when consuming foods that stimulate the salivary glands
• Unilateral symptoms: Symptoms are usually one-sided, affecting the side of the face where surgery or trauma occurred

Gross anatomy associated with the parotid glands

Frey syndrome typically arises in adults following damage to the auriculotemporal nerve, often caused by surgery or trauma surrounding the parotid glands. This nerve arises from 2 different points in the brain:²

• (Upper) Somatosensory root: Trigeminal nerve – cranial nerve V
• (Lower) Parasympathetic root: Glossopharyngeal nerve – cranial nerve IX

The sympathetic root divides from the mandibular branch of cranial nerve V, and supplies sensation (pain, heat etc.) to the:²

• Auricle of the ear
• external auditory canal
• temporomandibular joint
• lateral eardrum
• temporal scalp 

It also is the nerve branch which is responsible for sweat induction in these areas of the head. 

On the other hand, the parasympathetic nerve root branches from the otic ganglion downstream of the cranial nerve IX. This goes on to provide the secretary function for the parotid glands.

Figure 1: Cranial nerve (IX) and its involvement in the production of saliva. Cranial nerve (VII), the facial nerve, is also included for its contribution to the ventral tongue, though it is not directly implicated in Frey Syndrome.⁴

The two nerve roots combine to form the auriculotemporal nerve that provides motor and sensory control to the parotid gland. The nerve then continues through the jaw joint (temporomandibular joint) and terminates on the sides of the head near the temples. 

Microscopic changes in Frey Syndrome

Historically, Frey Syndrome was only accurately described as recently as 1923, with very few cases of histopathology being described in literature. 

One case has attributed a case of Frey Syndrome affecting the ear to sudomotor gland hyperplasia³. This condition refers to the abnormal increase in the number of sweat glands (sudomotor glands) in a specific area of the skin. This condition is characterised by an excessive cell division that makes up these glands, leading to an overproduction of sweat when thinking about food. After surgical excision, haematoxylin and eosin staining confirmed this division, which is ordinarily absent in healthy ears². This points to the possibility that in most cases the parotid gland may compensate for damage or loss of parotid tissue with a growth response, although the tissue may extend beyond the normal healthy parameters where it is normally found.³ 

Another more common cause occurs when small branches of the auriculotemporal nerve are severed during surgery/ trauma, and as they slowly heal, the nerve fibres fuse incorrectly with other nerve fibres. As a result, when the auriculotemporal nerve is stimulated, saliva is produced alongside sweat as the stimulation passes along the entire auriculotemporal nerve, including the parts that are bound to the sweat-producing sympathetic fibres.¹ 

In rare cases, this aberrant fusion may be present from infancy caused by issues during pregnancy or damage to the auriculotemporal nerve during birth with forceps. However, there haven’t been any cases of this syndrome being genetic.⁵ The incidence rate for Frey Syndrome is unknown due to the relatively rare nature of its occurrence, and there is still a lot of uncertainty about its exact pathology¹. 

Conditions that can cause Frey syndrome²

Surgery on the parotid gland

• Parotidectomy: Caused by the removal of the parotoid gland if nearby nerves are disrupted 
• Tumour excision: Operations to remove tumours in or around the parotid gland can also affect the auriculotemporal nerve

Facial injuries

• Trauma to the face, particularly around the ear and jaw, can damage the nerve and potentially result in Frey syndrome

Surgeries involving the face or skull

• Cosmetic procedures: Surgeries such as facelifts or reconstructive surgeries may accidentally damage the nerves near the parotid gland
• Jaw surgeries: Operations on the jawbone near the temporomandibular joint might also impact the auriculotemporal nerve

Infections

• Abscesses or infections in the parotid area or nearby can lead to nerve damage and contribute to Frey syndrome

Radiation treatment

• Radiation therapy for cancers of the head or neck can sometimes damage the parotid gland and surrounding nerves, leading to Frey syndrome

Developmental or congenital factors

• Some rare instances of Frey syndrome are linked to congenital or developmental anomalies affecting nerve pathways in the parotid region

Less common causes

• Jaw joint surgeries or disorders may occasionally result in nerve damage and Frey syndrome
• Trauma to the temporoparietal area, while less common, can also lead to symptoms extending beyond the usual parotid area

Forcep Delivery During Birth

• A rare cause of Frey syndrome in infants after the auriculotemporal nerve becomes injured in the newborn child during delivery⁵

In these scenarios, the nerve regeneration process can go awry, causing nerves meant for saliva production to mistakenly activate sweat glands during eating or chewing.

Treatments and management

Generally, the symptoms of Frey syndrome can be tolerated by the patients and no treatment is required. However, in some cases, a solution is required. Drugs that can be applied to the affected skin region include anticholinergics that block the neurotransmitter that activates the sweat glands. Another option is antihidrotics, which prevent sweating allowing for a temporary but ineffective relief. However, frequent application of either of these can also cause side effects.

Surgical practices have been adjusted to try and prevent this in the first place, with a corrective muscle flap being placed between the parasympathetic and sympathetic parts to try to prevent crossover. However, once Frey Syndrome occurs, it can be risky to reverse this issue. Another option is botox: the injection of botulinum toxin A, an effective and minimally invasive procedure. However, to provide sustained relief from Frey Syndrome, the procedure needs to be repeated every year as the toxin is naturally broken down in the body, like normal botox. 

Depending on age, comorbidities and general physiology, a different treatment could be necessary. It is important to see a healthcare physician to discuss your needs to make the best decision. Further research and clinical trials for better treatments are currently underway.¹

Summary 

Frey Syndrome is a condition which causes sweating when saliva production is initiated, which can be during food consumption. This can be accompanied by flushing and heat in the affected areas of the face and neck. The main cause is atypical connections between the sympathetic and parasympathetic branches of the auriculotemporal nerve after traumatic injury, as well as incorrect cell division of the parotid tissue. Current treatments are temporary and improvement is ongoing, with preventative procedures in place to prevent this condition from occurring during surgery. 

References

1. Frey syndrome - symptoms, causes, treatment | nord [Internet]. [cited 2024 Sep 16]. Available from: https://rarediseases.org/rare-diseases/frey-syndrome/.
2. Young A, Okuyemi OT. Frey syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Sep 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK562247/.
3. Redleaf MI, McCabe BF. Gustatory otorrhea: frey’s syndrome of the external auditory canal. Ann Otol Rhinol Laryngol [Internet]. 1993 Jun [cited 2024 Sep 16];102(6):438–40. Available from: https://journals.sagepub.com/doi/10.1177/000348949310200606.
4. Cassady CL. A new concept in the treatment of frey’s syndrome: The use of interpositional dermal grafts. an experimental study in the dog. The Laryngoscope [Internet]. 1977 Jun [cited 2024 Sep 16];87(6):962–74. Available from: https://onlinelibrary.wiley.com/doi/10.1288/00005537-197706000-00014.
5. Sekerel, B.E.Coexistence of Frey Syndrome and Cutaneous Mastocytoma. Asthma Allergy Immunol 2019;17:166-168. [cited 2024 Sep 16]. Available from: https://aai.org.tr/uploads/pdf_77.pdf.