Botulinum Toxin: A Breakthrough Treatment for Frey Syndrome

How can Frey's syndrome be prevented or treated following parotid surgery?

Frey's syndrome is a rare disorder, the symptoms of which include sweating, flushing and warming over the preauricular and temporal areas following a gustatory stimulus. It often occurs in patients who have undergone parotidectomy, submandibular gland surgery, radical neck dissection, infection and traumatic injury in the parotid region, and is caused by the aberrant regrowth of facial autonomic nerve fibres. Currently there are several options used to treat patients with Frey's syndrome; for example, the topical application of anticholinergics and antiperspirants, and the intradermal injection of botulinum toxin. It is uncertain which treatment is most effective and safe. To assess the efficacy and safety of different interventions for the treatment of Frey's syndrome. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials. The date of the search was 28 April 2014. We included randomised or quasi-randomised controlled trials (RCTs) in participants diagnosed with Frey's syndrome using a clinical standard such as Minor's starch-iodine test. We planned to include trials in which participants received any intervention versus no treatment (observation) or an alternative intervention, with or without a second active treatment. Our primary outcome measures were success rate (as assessed clinically by Minor's starch-iodine test, the iodine-sublimated paper histogram method, blotting paper technique or another method) and adverse events. Our secondary outcome measure was success rate as assessed by patients (disappearance or improvement of symptoms). We used the standard methodological procedures expected by The Cochrane Collaboration. We identified no RCTs or quasi-RCTs that fulfilled the inclusion criteria. Our searches retrieved eight potentially relevant studies, but after assessment of the full-text reports we excluded all of them due to the absence of randomisation or because the patients did not have Frey's syndrome. We excluded one randomised controlled trial that compared two different doses of botulinum toxin in patients with Frey's syndrome because the comparator was not an alternative treatment. We are unable to establish the efficacy and safety of the different methods used for the treatment of Frey's syndrome.RCTs are urgently needed to assess the effectiveness of interventions for the treatment of Frey's syndrome. Future RCTs should include patients with Frey's syndrome of different ranges of severity and report these patients separately. Studies should investigate all possibly effective treatments (such as anticholinergics, antiperspirants and botulinum toxin) compared to control groups using different treatments or placebo. Subjective assessment of Frey's syndrome should be considered as one of the outcome measures.

The effectiveness of botulinum toxin injections for the management of Frey's syndrome was studied. Botulinum toxin A (approximately 0.5 Units/cm2) was injected intracutaneously into the affected skin area as determined by Minor's starch iodine test. Gustatory sweating in the treated skin area ceased completely within 1 week and has not reappeared (12 months follow up until now in the first treated case). There have been no side effects. It is concluded that local botulinum toxin injections are a highly effective and safe treatment for Frey's syndrome. Additional study is required to evaluate the duration of the therapeutic effect.

Gustatory sweating is a common complication of parotid surgery. Injection of botulinum toxin A has been reported as a safe and effective treatment option for patients with Frey's syndrome. A total of 69 patients who had undergone superficial parotidectomy because of adenoma were evaluated with respect to the incidence of Frey's syndrome and treatment interest. Minor's iodine starch test was used to detect the affected skin area. Affected skin areas were documented using a digital camera; skin areas were evaluated morphometrically. A single injection of Botox per 1 cm(2) skin field was administered to those patients interested in treatment. Of 43 patients (62%) with gustatory sweating, 33 patients requested treatment. The affected skin area varied from 16 cm(2) to 81 cm(2). The individual Botox dosage ranged from 16 to 80 IU. All relevant clinical symptoms of sweating disappeared within 1 week after a single injection. Treatment was well tolerated with no side effects. Botox A injection is a safe and effective treatment with long-lasting effects for patients with extensive gustatory sweating.

ObjectivesTo correlate Frey's syndrome with subjective symptoms, Minor's starch iodine test results, and infrared thermography measurements, and to discuss the utility of thermography as a quantitative diagnostic method.MethodsThis study included 59 patients who underwent unilateral parotidectomy. A subjective clinical questionnaire and an objective Minor's starch iodine test were performed to evaluate the incidence of Frey's syndrome. Infrared thermography was performed, and the subjects were divided into seven groups according to the temperature differences between operated and unoperated sites. The thermal differences were correlated with the results from Minor's starch iodine test and the subjective symptoms questionnaire.ResultsOf the 59 patients, 20 patients (33.9%) reported subjective symptoms after eating; 30 patients (50.8%) tested positive for Minor's starch iodine test, 19 patients (63.3%) of which reported subjective symptoms. Of the 29 patients who were negative for the iodine test, 2 patients (6.9%) reported subjective symptoms. Thus, subjective symptoms were well correlated with Minor's starch iodine test (r=0.589, P<0.001). As the thermal differences with infrared thermography increased, the number of patients with subjective symptoms increased (χ2=22.5, P<0.001). Using infrared thermography, the mean temperature difference in the positive group for the iodine test was 0.82℃±0.26℃, and that in the negative group was 0.10℃±0.47℃. With increased thermal differences, more patients showed positivity in the iodine test (χ2=29.9, P<0.001).ConclusionSubjective symptoms, Minor's starch iodine test, and infrared thermography are well correlated with one another. Quantitative thermography provides clues for the wide variation in the incidence of Frey's syndrome, and could be a useful method for diagnosing and studying Frey's syndrome.

To compare the duration of effect of two dosage regimes of botulinum toxin A to treat patients with Frey's syndrome. Prospective study of two unselected cohorts of 20 patients each. The dimension of the affected skin area was determined with Minors iodine-starch test. The skin was infiltrated with botulinum toxin type A (Dysport, Ipsen Pharma, Ettlingen, Germany) using an interinjection distance of 1 cm. In the first group, a concentration of 10 mount units (MU)/0.1 mL and in the second group a concentration of 20 MU/0.1 mL was used. At each injection site, 0.1 mL of the respective solution was injected. The outcome measures were the time of reappearance of gustatory sweating, and the results of an iodine-starch test 10 and 20 months after treatment. Using the lower concentration, the mean duration of effectiveness was 8.3 +/- 2 months (mean +/- standard deviation). Using the higher concentration, the effect was much longer at 16.5 +/- 6 months. Eighty-five percent of the first group but only 5% of the second had a positive Minor's iodine-starch test 10 months after treatment. After 20 months four patients in the second group still had a negative iodine-starch test. In both groups, the amount of required botulinum toxin for the second treatment after recurrence of Frey's syndrome was the same as for the first treatment. Using a higher concentration of botulinum toxin type A (20 MU Dysport/0.1 mL) is more effective than a lower concentration (10 MU Dysport/0.1 mL) in the treatment of Frey's syndrome.

Frey syndrome was first described by Baillarger in 1853. Frey provided a detailed analysis and description as "auriculotemporal syndrome" in 1923. According to the literature, even the most recent therapeutic measures described for the treatment of patients with Frey syndrome have little chance of success and a high incidence of side effects. Thus, a type of treatment is desirable that can suppress the symptoms of Frey syndrome and can offer a good success rate, minimum invasiveness, and few side effects. The experience of the authors and data from the literature confirmed the efficacy of type A botulinum toxin treatment for patients with Frey syndrome up to a maximum observation period of 3 years. In the current study, seven patients with severe, symptomatic Frey syndrome after parotidectomy were treated successfully with type A botulinum toxin. The method of local, intracutaneous treatment with type A botulinum toxin for patients with Frey syndrome is effective, virtually side-effect free, and minimally invasive.

Introduction: Frey‘s syndrome (SF), auriculotemporal syndrome, is an often neglected complication occurring in 6–96% of patients after parotid gland surgery according to recent studies. It arises on the basis of aberrant ingrowth of parasympathetic fi bers into the sheaths of denervated sweat glands after auriculotemporal nerve damage. The syndrome is characterized by a triad of symptoms: sweating, redness and burning or even pain in connection with food intake. Diagnosing these problems is not a time-consuming process and there are a number of therapeutic options. However, the vast majority of approaches, whether surgical or non-surgical, have only a short-term effect and carry a number of complications. The application of botulinum toxin A (BTXA) represents a relatively simple, effective and safe treatment option consisting of intradermal application of the solution according to a predetermined Frey syndrome activation map. Objectives: Presentation and evaluation of pilot results of therapeutic application of BTXA in patients dia gnosed with Frey‘s syndrome. Material and methods: Retrospective analysis of a group of 5 patients who underwent parotid gland surgery of various extents at the Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital at St. Anny in Brno between 2006 and 2019, in whom there was a signifi cant manifestation of SF symptoms on the basis of which BTXA was therapeutically applied. Results: Evaluating the subjective manifestations of SF in all patients in our cohort, after the application of BTXA, showed that the problems signifi cantly decreased from “annoying and reducing their quality of life” to “never” or “almost never” occurring. Objective results of the Minor test interpreted by SketchAndCalc showed a decrease in SF activation of 91.6% on average. Only two patients required re-administration of BTXA at 6 and 19 months intervals. No adverse reactions to BTXA were reported or observed with any of the patients. Conclusion: BTXA is an eff ective and safe way to treat patients with Frey‘s syndrome. Keywords: parotidectomy – Frey syndrome – auriculotemporal syndrome – gustatory sweating – botulinum A toxin

Parotidectomy complications. New techniques for their objective evaluation, prevention and treatment

Several therapeutic approaches exist to treat gustatory sweating (Frey's syndrome) following parotidectomy. Because of the lack of effective treatment, a new therapeutic modality using botulinum toxin injections was presented previously by our group. The duration of the demonstrated positive effect was essentially unknown so far. Based on our experiences using this technique since December 1993, the purpose of this clinical investigation was to make an up-to-date report and demonstrate the duration of effect of BOTOX injections in patients with severe gustatory sweating. Nineteen patients with severe gustatory sweating have been treated with BOTOX by intracutaneous injections into the affected skin areas. The maximal follow-up time was 33 months. The results were obtained by interviews and controls using Minor's starch iodine test. In all treated cases (n = 19 patients, 22 treated sides) gustatory sweating ceased completely within 2 days. Side effects were absent. In 12 patients gustatory sweating reappeared. The mean duration of effect was 17.3 months (subjective personal communication of 18 patients). Findings show that intracutaneous injection of BOTOX is a highly effective, safe, and minimally invasive treatment of Frey's syndrome with long-lasting therapeutic effect.

Graft interposition for preventing Frey's syndrome in patients undergoing parotidectomy.

Frey's syndrome is present in almost all patients after parotidectomy. Gustatory sweating reduces quality of life. Injections of botulinum toxin A have recently been described as effective. This study was designed to evaluate the efficacy of this new treatment. Nineteen patients with severe gustatory sweating following superficial parotidectomy were treated. One unit/cm2 botulinum toxin A was injected intracutaneously into the affected area once. Minor's starch iodine test was performed to prove the outcome of therapy 4 weeks later. Eight patients lost their sweating. However, another seven patients had some blue spots on their cheeks. In four patients whose sweating had extended beyond the hairline, remnants of gustatory sweating showed up. Overall, the affected area of gustatory sweating could be reduced by botulinum toxin A from an average of 31 cm2 before treatment to 4 cm2 after treatment. Although there were some remnants of sweating in a few patients, Frey's syndrome was gone in all cases. No side effects could be observed. Intracutaneous injections of botulinum toxin A are highly effective and safe in treatment of gustatory sweating.

Frey's syndrome, i.e. gustatory sweating on the cheek, is a fairly common embarrassment after parotid gland surgery. New surgical techniques have been proposed to avoid this complication, but are not widely in use. Hence, there is need for treatment of Frey's syndrome. All surgical and topical treatments have drawbacks. This study was set up in order to evaluate a recently described treatment. One hundred and two patients were interviewed after parotidectomy. Thirty-one of them had noticed gustatory sweating and 15 patients underwent Minor's starch iodine test before, and after, treatment with intracutaneous injections of botulinum toxin A (Botox, Allergan Inc., USA). Thirteen of the patients did not experience any gustatory sweating at follow-up (one to 13 months). Minor's starch test showed total disappearance of gustatory sweating in 12 of the 15 treated patients. The only side effect was a discreet, transitory affection of the orbicularis oris muscle in one patient. As this treatment is minimally invasive it could be an attractive treatment for Frey's syndrome if the effect is maintained. Complaints of local hypoaesthesia and pain were also common after parotid surgery.

Frey's syndrome, gustatory sweating in the preauricular area, is an unpleasant phenomenon occurring during meals after surgery on the parotid gland. Recently, botulinum toxin A (BTX) has been shown to reduce the symptoms, but the variation in the reported doses is large. Objective. To quantify the effect of treatment with low-dose BTX in a case of Frey's syndrome over a period of 6 months. Material and methods. A 56-year-old woman was treated with 10 U Botox given as 20 single, intracutaneous injections of 0.5 U, one for each cm2, 3 years after resection of the parotid gland. Before treatment and repeatedly during the 6-month period, the sweating was rated subjectively on a 100-mm visual analog scale (VAS) and by a severity index, and objectively by assessment of the extent of the involved skin area using Minor's iodine-starch test, staining the area of sweating dark. Results. The treatment decreased the involved area from 20 to 5 cm2 and the VAS ratings from 98 to 8 mm. The index showed that treatment affected the sweating intensity, not the frequency. After the 6-month period the patient was still satisfied, but the involved skin area had increased; however, not entirely to pretreatment values. Conclusions. The effect of BTX injections for gustatory sweating obtained in this case was comparable to results reported using higher doses. Low doses of BTX can therefore be used in the treatment of Frey's syndrome, but studies to clarify the dose–response relationship, in terms of both time-course and obtained effect, are needed.

To determine the effectiveness of repeated intracutaneous injections of botulinum toxin A to treat Frey syndrome. Between January 6, 1999, and July 1, 2005, 22 patients with Frey syndrome (12 men and 10 women) received repeated intracutaneous injections of botulinum toxin type A. Before each treatment, the time since the previous treatment; the size of the affected area, as determined by a starch-iodine test; and subjective quantification of symptoms, as assessed by the previously used Frey Questionnaire Card, were recorded. All patients underwent at least 3 treatments. Univariate analysis of variance showed a significant difference (P <.001) in the between-treatment interval. Univariate analysis of variance showed a significant difference in the size of the affected area in accordance with the number of treatments received (P <.001). The mean Frey Questionnaire Card score also decreased with repeated treatments. In patients with Frey syndrome, repeated treatment with intracutaneous injection of botulinum toxin type A lowered subjective symptom scores, decreased the size of the affected area, and increased the duration of the effect.