Botulinum Toxin: A Breakthrough Treatment for Frey Syndrome

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of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials.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.

In 1990 the authors reported their preliminary study of the prevention of Frey's syndrome in 55 patients utilizing a superficial musculoaponeurotic system (SMAS) flap in parotid gland surgery. During the past 10 years, numerous studies have supported their original thesis that interposition of living tissue between the resected gland bed and the skin could prevent the development of this complication. The authors have expanded their own patient population and now consider this a definitive study on the prevention of Frey's syndrome. A total of 160 patients are presented with a follow-up period of 5 to 22 years. All patients underwent subtotal or total parotidectomy performed by one of the authors. A history was acquired and testing for Frey's syndrome (Minor's starch iodine test) was performed. As a result of this approach, and in spite of the intensive search for it, no cases of Frey's syndrome were encountered. The hoped-for secondary benefit of preventing the postparotidectomy retromandibular depression was somewhat less satisfactory, although most patients remain satisfied with their appearance. The debilitating symptoms in Frey's syndrome, which is reported to have an incidence of 5% to 50% in the typical parotidectomy patient, can be avoided with thoughtful preoperative planning. The authors favor an aesthetic incision followed by the development of an SMAS flap. The parotidectomy is then performed using the surgeon's preferred technique. The SMAS flap is then placed into the bed of the resected parotid gland. This institutes a protective tissue barrier guarding against the aberrant anastomotic communication between the postganglionic secretomotor fibers intended for the parotid gland, and the now adjacent sweat glands. Their patient population is large enough to provide significant evidence that Frey's syndrome can be prevented, compared with a meta-analysis of parotid patients in multiple other studies in the literature. Assuming the patient's history and pathology does not preclude its use, the SMAS flap should be considered the standard of care for preventing Frey's syndrome in the postparotidectomy patient. If the SMAS flap is not available, a temporoparietal fascial flap has proved to be a good alternative.

The preventive effect of decellularized pericardial patch against Frey's syndrome following the superficial parotidectomy

Primary palmar hyperhidrosis (PPH) constitutes a distressing dermatologic condition that greatly affects patients' quality of life. Its management still needs to be addressed to find a suitable therapeutic modality that is readily available, cost effective, and gives patients a quite long disease-free period. To assess the efficacy of fractional CO2 laser as a delivery method for botulinum toxin-A (BTX-A) and aluminum chloride in treating PPH. Twenty-four subjects with PPH were treated on both hands with fractional CO2 laser followed on the right hand with topical BTX-A and on the left hand with topical aluminum chloride. Minor's starch-iodine test and Hyperhidrosis Disease Severity Scale (HDSS) were used for evaluation of treatment response and for follow-up. There was a significant improvement in HDSS in both groups, but there was no statistically significant difference in the therapeutic response for both modalities. There was a statistically significant longer disease-free period in the BTX-A-treated hands. Fractional CO2 laser-assisted drug delivery (LADD) represents a safe, minimally invasive procedure that enhances the delivery of BTX-A and aluminum chloride, the two most widely used agents for treating PPH, with a comparable anhidrotic response.

The benefit of using a sternocleidomastoid flap following parotidectomy to reduce the incidence of symptomatic gustatory sweating (Frey's syndrome) was reviewed. A retrospective study was undertaken to review subjective and objective symptoms of Frey's syndrome in two groups of patients, one of whom had undergone superficial parotidectomy with a sternocleidomastoid flap rotated at the time of surgery and a second group of patients who had undergone a standard superficial parotidectomy. A total of 22 patients, randomly sampled and willing to attend, were evaluated postoperatively, at a median time from surgery of 42 months (range 23-82 months) in the non-flap group and 44 months (range 14-66 months) in the flap group, by Minor's starch iodine test. In the 11 patients who had a sternocleidomastoid flap rotated, two had evidence of gustatory sweating. Of the 11 that had not undergone sternocleidomastoid flap rotation, nine patients showed evidence of gustatory sweating (P < 0.05, chi 2 test). There were two patients in total who had clinical symptoms of Frey's syndrome and both of these had not undergone flap rotation at the time of parotidectomy.

The role of botulinum toxin as a therapeutic agent is expanding rapidly in otolaryngology. Botulinum toxin is a protease that blocks the release of acetylcholine from nerve terminals. Its effects are transient and nondestructive, and largely limited to the area in which it is administered. These effects are also graded according to dose, allowing for individualized treatment of patients and disorders. Botulinum toxin has been used primarily to treat disorders of excessive or inappropriate muscle contraction. In the field of otolaryngology, these include spasmodic dysphonia, oromandibular dystonia, and blepharospasm; vocal tics and stuttering; cricopharyngeal achalasia; various tremors and tics; hemifacial spasm; temporomandibular joint disorders; and a number of cosmetic applications. Botulinum toxin treatment has recently begun to show some benefit in the control of pain from migraine and tension headache. It may also prove useful in the control of autonomic dysfunction, as in Frey syndrome, sialorrhea, and rhinorrhea. In over 20 years of use in humans, botulinum toxin has accumulated a considerable safety record, and in many cases represents relief for thousands of patients unaided by other therapy.

There are no regional data about the prevalence and use of botulinum toxin (BoNT) in otorhinolaryngology (ORL) departments in Germany. In order to obtain an overview of the current applications of BoNT in ORL departments a survey was carried out. Standardized multi-choice questionnaires were mailed to 150 ORL departments. In the analysis a differentiation was made between university and regional departments. Also an analysis of the whole collective of respondent hospitals was carried out. The most commonly treated indication is the Frey syndrome followed by hypersalivation due to a salivary fistula after parotidectomy, dysphagia, aesthetic application and laryngeal dystonia. The rate of return was 62% and 75% of all responding hospitals use BoNT as a therapeutic option, especially where "off-label-use" indications are concerned (15 out of 20 indications or 75%). BoNT is widely used as a therapeutic option with an increasing trend. Due to different applications a schedule of hospitals would be helpful in order to be able to find the nearest hospital for the appropriate indications.

Twenty-one patients were followed up with a home visit after having parotid surgery at the Westmead Centre between January 1988 and October 1989. Nine of these patients (42.8%) had objective gustatory sweating as proven by Minor's Starch Iodine Test, with three of these (14.3%) having symptoms of Frey's syndrome. Symptoms started an average of 4.3 months after surgery. None of the three were anxious enough about their symptoms to seek medical treatment. Those patients with objective gustatory sweating were more likely to be women. No statistical significance was found in regard to the presence or absence of greater auricular nerve section, facial nerve paresis, age or type of operation (superficial parotidectomy or otherwise). Frey's syndrome is a benign condition and explanation and reassurance are usually adequate therapy.

Benign parotid tumors are increasingly treated with parenchyma-sparing extracapsular enucleation, yet postoperative salivary collections and Frey syndrome can still generate clinically relevant morbidity; we evaluated whether a standardized intraoperative bundle combining intraparotid botulinum toxin A (BTX-A) and bovine collagen membrane interposition is associated with fewer complications than standard enucleation alone. In this retrospective comparative cohort at a tertiary Head and Neck Surgery Unit, consecutive adults undergoing extracapsular enucleation for pleomorphic adenoma or Warthin tumor (2010–2025) were allocated by institutional era-based protocol to Group A (2010–2017, standard enucleation) or Group B (2018–2025, enucleation plus intraoperative intraparotid BTX-A 50 IU and bovine collagen membrane placement over the repaired parotid fascia). Prespecified endpoints were sialocele/salivary fistula, surgical-site infection (SSI) within 30 days, and clinically recorded Frey syndrome within 6 months; effect sizes with 95% confidence intervals were reported. A total of 188 patients were analyzed (94 per group). Sialocele occurred in 20/94 (21.3%) in Group A versus 2/94 (2.1%) in Group B [Relative Risk (RR) 0.10]. SSI occurred in 14/94 (14.9%) versus 2/94 (2.1%) (RR 0.143), and clinically recorded Frey syndrome in 18/94 (19.1%) versus 4/94 (4.3%) (RR 0.222). This combined protocol was associated with lower complication rates through 6 months; prospective controlled studies with standardized Frey assessment and longer follow-up are warranted.

Acellular dermal matrix for prevention of Frey's syndrome after superficial parotidectomy of benign tumors

The Minor's test in Frey syndrome treated with botulinum toxin: Methodology and efficacy

Use of allogenic acellular dermal matrix in prevention of Frey's syndrome after parotidectomy

Purpose: Detrusor sphincter dyssynergia (DSD), a common lower urinary tract condition in patients with suprasacral spinal cord injury (SCI), can lead to urological complications and reduced quality of life. Urethral sphincter botulinum toxin A (BoNT-A) injection has been used to promote spontaneous voiding, albeit with limited success. This study aimed to identify predictive factors for treatment success. Methods: This retrospective analysis included 207 patients (157 males and 50 females) with chronic SCI and varying DSD grades treated with urethral sphincter BoNT-A injection. Each received 100 U of onabotulinumtoxinA via transurethral sphincter injection. The primary outcome was voiding efficiency (VE) and symptom improvement, assessed via global response evaluation 3 months post-treatment. Baseline videourodynamic parameters were used to predict success. Results: Successful outcomes were observed in 33.8% of patients. These patients were older and had higher voiding pressure, maximum flow rate (Qmax), voided volume, bladder contractility index, and VE, as well as lower post-void residual (PVR) volume and bladder outlet obstruction index. Patients with SCI and DSD grade 1 had the highest success rate (65.7%) compared to those with DSD grade 2 (14.3%) or 3 (7.1%). Patients with DSD grade 3 had the highest failure rate (55.8%). Multivariate analysis showed that higher Qmax and lower PVR significantly predicted success, consistent with lower DSD grades. Conclusion: Grade 1 DSD, higher Qmax, and lower PVR were associated with higher success after urethral BoNT-A injection, whereas grade 3 DSD predicted failure. Thus, careful patient selection is essential for effective DSD treatment with urethral BoNT-A injection.

Primary axillary hyperhidrosis is an idiopathic disorder that creates severe psycho-social burden due to excessive uncontrolled sweating. Various therapeutic agents have been described, but each has its own limitations. The use of fractional microneedling radiofrequency has emerged lately with promising results. This study aimed to determine the efficacy and safety of fractional microneedle radiofrequency in comparison to Botulinum toxin-A (BT-A) in patients with primary axillary hyperhidrosis. In this randomized controlled clinical trial, 20 patients (40 sides) were randomized to either fractional microneedle radiofrequency (4 sessions at 3-week intervals) or BT-A (single session), where each side received one of the treatment modalities. Efficacy was measured at 3, 6 and 12 months using Minor’s starch iodine test, HDSS score, Hqol questionnaire, and patient satisfaction. Fractional microneedle radiofrequency, although showed moderate efficacy, is inferior to BT-A regarding longitudinal efficacy at 12 months, as well as patients’ satisfaction. Both treatment modalities showed to be equally safe, but fractional microneedle radiofrequency procedure was substantially more painful. In conclusion, fractional microneedle radiofrequency does not offer a better substitute to BT-A in primary axillary hyperhidrosis. BT-A shows higher efficacy, is less painful, less expensive, and needs a smaller number of sessions.

Not only can botulinum toxin be used for cervical and laryngeal dystonia but in this article its use and complications in the management of oromandibular dystonia, Frey's syndrome, crocodile tears and drooling is described.