J. P. O'Neill¹
C. Condron²
A. Curran¹
M. Walsh¹

¹Department of Otolaryngology, Beaumont Hospital, Dublin
²Department of Surgery, Beaumont Hospital, Dublin

Correspondence to:
Mr JP O'Neill, Department of Otolaryngology, The Royal College of Surgeons in Ireland, The Education and Research Building, Beaumont Hospital, Beaumont, Dublin
Tel: +353 (0)87 798 4680
Email: joneill@rcsi.ie

Background: This article documents an objective review of the neuro-anatomical, diagnostic and clinical implications of the auriculotemporal syndrome (Frey's syndrome). The incidence of Frey's syndrome after parotidectomy as cited in the literature varies. It may also be a sequela to a variety of inflammatory, infective and traumatic aetiologies. Method: An electronic search using the search engine Google, Medline and Pubmed was performed under 'Lucja Frey', 'Gustatory sweating', 'The auriculotemporal syndrome', 'Botulinum toxin'. Relevant papers were systematically reviewed from 1965 to present.
Conclusions: This disorder is important for ENT surgeons and allied specialties. We present the main surgical and cosmetic therapeutic strategies in the literature. We also discuss the fascinating life of Lucja Frey. As one of the first female academic neurologists in Europe, her career and life were tragically altered by the events of World War II.

keywords: frey's syndrome, gustatory sweating, botulinum toxin, Lucja Frey
Surgeon, 1 June 2008 178-81

Frey's syndrome
This disorder is important for all surgeons undertaking procedures in the head and neck region. We present the main surgical and cosmetic therapeutic strategies in the literature. We also discuss the fascinating life of Lucja Frey. As one of the first female academic neurologists in Europe her career and life were tragically altered by the events of World War II.
Frey's syndrome or the auriculotemporal syndrome denotes the well described features of gustatory stimulation, flushing and warmth in the preauricular and temporal areas. Frey's syndrome may develop months or years after parotid surgery, where transection of the parasympathetic and sympathetic fibres occurs. The stimulation for salivation 'such as eating' results in cutaneous flushing and sweating secondary to aberrant regeneration of the parasympathetic fibres and allocation into denervated sympathetic sweat gland and vasodilator fibres over the auriculotemporal distribution. The syndrome was attributed to Lucja Frey given her correct description of its features and derivation of the auriculotemporal involvement.
Most commonly Frey's syndrome has been widely reported to follow parotidectomy.^1-4 It has, however, also been reported following radical neck dissections, carotid endarterectomy, submandibular gland excision, mandibular fracture, surgical approaches to the mandible, clinical neuritis syndrome, herpes zoster infections and obstetrics forceps trauma. It can be a source of great social debilitation to patients, with onset of symptoms usually taking five weeks to one year post-surgery. These patients present a therapeutic challenge. We assess the neuro-anatomical origins, diagnostic aids, the current medical and surgical treatment strategies and the immediate historical background to this disease.

The neuro-anatomical pathway
We must consider parasympathetic supply, sympathetic supply, the mandibular nerve and the auriculotemporal nerve to establish the correct order of origin and dysfunction involved.
Preganglionic parasympathetic fibres originate in the inferior salivatory nucleus in the upper medulla. They travel with the glossopharyngeal nerve crossing the middle ear as Jacobson's nerve and continuing beyond the superior tympanic canaliculus as the lesser petrosal nerve passing extradurally through foramen ovale. The otic ganglion lies beneath and medial to the foramen ovale. Post-synaptic parasympathetic fibres from the ganglion now join one of the posterior divisions of the mandibular nerve, the auriculotemporal nerve. This is a mixed nerve with parasympathetic and sympathetic fibres. It winds around the neck of the mandible to pass laterally then superiorly, lying between the temporomandibular joint and the external auditory meatus deep to the parotid gland. The post-synaptic parasympathetic fibres supply secretomotor fibres to the parotid and surrounding mucus glands, and vasodilator fibres to the vasculature.^5,6
Post-ganglionic sympathetic fibres travel from the superior cervical ganglion joining the external carotid and internal arteries forming a plexus around them. These nerves mainly supply vasculature and sweat glands. Most post-ganglionic sympathetic nerve fibres have norepinephrine as their transmitter substance; however, sweat glands are cholinergic. Branches of these nerves leave the plexus to join the mandibular nerve leading to the auriculotemporal nerve. Sympathetic fibres inhibit salivary stimulation and vasoconstrict. Neural anastomoses occur between the facial nerve and the auriculotemporal nerve in the body of the parotid.

Diagnosis
A complete historical analysis and examination should always be performed. The earliest diagnostic procedure was proposed in 1927 by Minor's iodine-starch test which is easy, reliable, rapid and inexpensive.⁷ Firstly an iodine solution is used to paint the preauricular, infra-auricular and temporal regions. Betadine can be used or a combination of iodine, alcohol and oil. When dry, all areas are then sprinkled with starch powder. A stimulus is then given orally, preferably acidic, e.g. boiled sweet or citrus fruit, for maximum evocation. An established sweating region becomes apparent after 30 seconds. This region may be marked and photographed after a period of 10 minutes. Any presence of purple is considered a positive result and the exact extent of discoloration is measured using a standardised grid.^6,8 The majority of postparotidectomy patients will experience minor signs of gustatory sweating.^6,9,10 Other diagnostic tools proposed include a biosensor method of enzymatic electrodes, enabling the detection of l-lactate on intact skin after stimulus.¹¹ This method is also safe and reliable but not widely used.

Medical management: botulinum toxin therapy
Intracutaneous injection of botulinum toxin (BTX) represents a safe, highly effective and minimally invasive procedure with long-lasting effects for the treatment of Frey's syndrome.^12,13,14 Almost 15% of all patients who undergo parotid gland surgery consider their symptoms severe and desire therapy.¹⁵
BTX was a welcome alternative to the unsuccessful and troublesome topical treatments of 3% scopolamine hydrobromide, 20% aluminium chloride and 1% glycopyrrolate roll-on solution.^9,16,17
BTX consists of a heavy and light chain. The heavy chain correlates with the binding of toxin to peripheral synapses, and the light chain allows the proteolysis of one of the three SNARE proteins (Snap25, Vamp, syntaxin). The SNARE complex has differential involvement in the release of co-transmitters from the same autonomic neurons.¹⁸ Without these proteins, vesicle membrane fusion and the release of acetylcholine cannot take place thereby arresting impulse transmission.¹⁴ A BTX effect on gustatory sweating lasts on average for 17.3 months.¹³
Atropine was identified as an early agent for treating gustatory sweating given the cholinergic nature of sweat glands.^19,20 It does not alleviate the associated flushing as this is not mediated by a cholinergic response. BTX relieves both pathological sweating and flushing indicating its inhibitory influence on another neurotransmitter. The effects of both vasoactive intestinal polypeptide (VIP) and Nitric oxide (NO) have been postulated. The vasodilator effect of VIP in different vascular tissues or species may be due to increases in NO, cyclic GMP and other signaling agents.²¹
It has thus been established BTX also inhibits, at some point, the biochemical relationship between NO and VIP. In human skin, VIP-mediated vasodilatation includes a NO-dependent component; however, the mechanism is not fully elucidated.²² In gastrointestinal smooth muscle presynaptic, VIP and NO can induce each other's release. Evidence was obtained in isolated myenteric ganglia where VIP induced NO release, and NO facilitated VIP release. Postsynaptically, many studies support that VIP and NO are parallel co-transmitters, acting via the cGMP and cAMP pathways.²³
Application of BTX ranges from 20 to 50 units/ml, with most patients not requiring in excess of a total dose of 100 units. Alleviation of symptoms is noted in two days to two weeks and recurrent symptoms may be treated with BTX type B. Pre-treatment with an anaesthetic ointment containing lidocaine and prilocaine as active substances may be used in some patients suffering from pain. This is applied 15 minutes prior to injection to reduce the sensitivity of the skin.
BTX-B is an effective and safe treatment for a variety of movement disorders, as well as drooling and hyperhidrosis. BTX-B has also been shown to be safe for patients who are resistant to BTX-A. BTX-B is an antigenically distinct form of botulinum toxin which has unique physical and clinical properties that distinguish it from BTX-A. It has a more rapid onset and greater diffusion characteristics as well as diminished longevity. The most commonly reported side effects include dry mouth and dysphagia and recently more disturbing reports of parasympathetic visual dysfunction have been associated with BTX-B use.²⁴

Surgical management
In 1932, Bassoe recognised the potential sequelae of gustatory sweating post-parotidectomy.^6,25 In a recent paper discussing a severity score evaluation for Frey's syndrome no significant differences were found between patients treated with partial vs total parotidectomy or between patients treated with or without adjuvant radiotherapy.²⁶ Within these patient populations there is a high subclinical incidence of gustatory sweating given the apparent difference between the majority of patients testing positive for gustatory sweating (90%), those who volunteer admission of symptoms upon questioning (30-50%) and those complaining of symptoms (10%).^8,10 Patient distress correlates with the objective severity of sweating.
Many differing surgical approaches and strategies have been proposed with varying success. Surgical correction of Frey's syndrome may be performed as a primary or secondary procedure. Early corrective techniques include tympanic neurectomy, interrupting parasympathetic fibres crossing the tympanic promontory, with success rates of 80%.^27,28
Optimal surgical intervention has been sought to interrupt the anastomotic potential between post-ganglionic secretomotor fibers intended for the parotid and the adjacent sweat glands by interposition of a tissue barrier. An interposing flap derived from preauricular cheek fascia in continuity with platysma muscle developed through sharp dissection from the parotid gland was first proposed in 1976. This superficial musculoaponeurotic system (SMAS) acts as an interposing flap and a cosmetic enhancement by reduction of the retromandibular depression.^29,30 Prevention of the onset of Frey's symptoms following this procedure were reported at 100%; however, dissection of the SMAS in parotid surgery is only indicated in tumours not extending to the parotid capsule.³¹ Another similar interposing flap with cosmetic reconstructive merit is the vascularised temporoparietal fascial flap between the parotid bed and overlying skin immediately after complete superficial parotidectomies to successfully prevent Frey's syndrome and contour defects.²⁹ Dermal fat reportedly demonstrates success, improving facial contour cosmesis and preventing misdirected regenerating nerve fibres by acting as a barrier. More recently acellular dermis has been employed but complicated by significant rates of seroma accumulation.⁴³
Four types of sternocleidomastoid (SCM) flap have been described: the muscle flap, the myocutaneous flap, the myoperiosteal flap and the myosseus or osteomuscular flap. The SCM muscle flap has been used in the prevention of Frey's syndrome. The use of a sternomastoid muscle pedicle has received mixed opinion in the literature.³² An overall complication rate of this flap reported at 11% and results of one study suggest SCM reconstruction does not alter the incidence of Frey's syndrome and does not significantly improve facial aesthetics or contour.^33,34

Lucja Frey
The auriculotemporal syndrome not only highlights a fascinating pathological and neuro-anatomical process but also a tragic story of a very talented, determined neurologist during a very evil period of religious persecution.
Lucja Frey was born on 3 November 1889, a Jew in Lwow, then part of the Austro-Hungarian empire, now part of Russia. She began her academic career studying mathematics under Professor Smoluchowski in Lwow, a university dating back to 1661. It would appear she changed to the department of philosophy where she studied from 1907 to 1913. She sat a secondary school teaching examination in mathematics and science in 1913. Four years later in 1917 she read medicine at the University of Lwow. During the war between Ukraine and Poland for Eastern Galicia (November 1918 to July 1919) Lucja suspended her studies, became a Polish citizen and, it is suggested, gave birth to a baby boy, Jakub.
She became acquainted with Kazimierz Orzechowski, an eminent Polish neurologist and worked, or was affiliated, with his department from 1921 to 1928.³⁵ This was facilitated by her move to the University of Warsaw where she qualified on 2 June 1923.
Her bibliography contains 43 articles written between1923 and 1928. Her Polish biographer cites her most important work, including papers such as anatomical changes in Charcot's joints, a case of aneurysm of the plexus of the medulla and First steps in learning the topography of the brain.^36-38 She deduced from her pathological examinations and research that multiple sclerosis was more than just a disease of the myelin, also involving axonal degeneration.
Her landmark paper was published in 1923, in Polish, Zespol nerwu uszno-skroniowego and then in French, the more quoted Le syndrome du nerf auriculo-temporal.³⁹ Lucja had by now become one of the first female academic neurologists in Europe. She presented a systematic investigation of the symptoms and completed neurological pathway of gustatory sweating by putting into perspective the relevant role of the auriculotemporal nerve. She attributed auriculotemporal nerve involvement to invasion and irritation of healing tissue. The theory of misdirected functional nerve regeneration was proposed at a later date.^40,41,42
Lucja moved back to Lwow in 1929 and married a lawyer called Marek Mordekhai-Meir Gottesman. They celebrated the birth of their baby daughter, Danuta, in 1930. Lucja now worked in the prestigious Hospital of the Jewish Religious Commune in Rappaporta Street as a neurology consultant.
Her life was destined for tragedy as Nazi religious and academic persecution intensified. It has now been established that Lucja Frey was most likely shot along with all of the staff and patients at the Hospital of the Jewish Religious Commune (400 people) on 20 August 1943.³⁵ To date there is no evidence that any of her family survived the war.

Conclusion
Frey's syndrome remains a fascinating complication of interrupted and aberrant regeneration of the parasympathetic supply to the auriculotemporal distribution. Primary prevention in the post-parotidectomy patient can be achieved, assuming the patient's pathology does not preclude using a SMAS flap. A temporoparietal fascial flap is another successful alternative. BTX-A is a well established, effective, minimally invasive treatment which can be applied according to the particulars of the patient. It has long-lasting effects for patients with extensive gustatory sweating and has an excellent safety profile.
Our knowledge and treatment strategies of this condition have progressed rapidly since the work of Lucja Frey. She represents true scientific inspiration during a historical period of mass cruelty and oppression.

Copyright © 29 November 2007

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