Treatment with Type A Botulinum Toxin
Jens J. von Lindern, M.D., D.M.D.
Bernd Niederhagen, M.D., D.M.D.
Stefan Berge ´, M.D.
Georg Ha ¨gler, M.D.
Rudolf H. Reich, M.D., D.M.D., Ph.D.
Department of Maxillofacial Surgery, University of
Bonn, Bonn, Germany.
Address for reprints: Jens J. von Lindern, M.D.,
D.M.D., Department of Oral and Maxillofacial Sur-
gery, University of Bonn, Sigmund-Freud-Strasse
25, D-53105 Bonn, Germany; Fax: 011-228-287-
4334; E-mail: firstname.lastname@example.org
Received January 7, 2000; revision received June
19, 2000e; June 19, 2000.
BACKGROUND. Frey syndrome was first described by Baillarger in 1853. Frey pro-
vided 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.
METHODS. 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.
RESULTS. In the current study, seven patients with severe, symptomatic Frey
syndrome after parotidectomy were treated successfully with type A botulinum
CONCLUSIONS. The method of local, intracutaneous treatment with type A botuli-
num toxin for patients with Frey syndrome is effective, virtually side-effect free,
and minimally invasive. Cancer 2000;89:1659–63.
© 2000 American Cancer Society.
KEYWORDS: Frey syndrome, Frey–Baillarger syndrome, gustatory sweating, auricu-
lotemporal syndrome, sudation parotidenne, botulinum toxin.
vative parotidectomies and occasionally after radical and partial ex-
cision of the parotid gland. The incidence depends on the size of the
glandular compartment removed and on the intensity of the diagnos-
tic procedures used to verify the presence of the syndrome. Frey
syndrome occurs less frequently after purulent parotitis, tumors,
trauma, typhoid fever, and irritation of the auriculotemporal nerve by
dislocated temporomandibular fractures.1–3
Frey syndrome becomes symptomatic when undesirable sweat-
ing occurs in the cheek and in the retroauricular and temporal regions
after eating. Symptoms can also occur in the distribution of the
greater auricular nerve. There can be flushing and warmth with over-
heating of the affected areas of the skin that, in some patients, is
associated with pain. Pain also can occur initially as a preliminary
sign or can be the only symptom present. Typically, the symptoms
occur several weeks or months after surgery.
Gustatory sweating can be verified using the iodine-starch test,4
which reveals the phenomenon on the basis of a color reaction.
Follow-up examinations show that approximately 30–50% of postpa-
rotidectomy patients experience the symptoms described, and ap-
proximately 15% of these patients rate their symptoms as severe.5
rey syndrome is a well known sequela of operative procedures in
the region of the parotid gland. It occurs frequently after conser-
© 2000 American Cancer Society
The precise pathophysiology of Frey syndrome re-
mains unclear. Hypothetical explanations are based on
the dense parasympathetic innervation in the region of
the parotid.7Parasympathetic secretory fibers from the
glossopharyngeal nerve to the parotid gland pass
through the tympanic nerve, superficial petrosal nerve,
and otic ganglion (Jacobson anastomosis) to the auricu-
lotemporal nerve, which branches off the trunk of the
mandibular nerve. Frey syndrome can be explained by
local terminal inhibition of the physiologic reflex1,3or by
malinnervation due to misdirection of the parasympa-
thetic fibers of the auriculotemporal nerve for the pa-
rotid gland in the process of postoperative regeneration.
In the latter situation fibers, follow the sympathetic
nerve paths and attach to the proximal sweat glands of
the skin (crossed reinnervation).1,3,6
MATERIALS AND METHODS
In response to targeted questioning, 30–50% of
postparotidectomy patients report having the typical
symptoms. The minor iodine-starch test4provides re-
liable verification of hyperhydrosis. In this test, the
skin in the distribution of the auriculotemporal nerve
is covered with tincture of iodine and then with starch
powder. The entire preauricular region up to the hair-
covered temporal region and also the retroauricular
skin must be covered completely. After chewing a
stimulant food, a bluish-black color change ensues as
sweat secretion increases.4
The treatment of patients with Frey syndrome has
been unsatisfactory. In addition to surgical measures,
such as excision of the affected skin or the interposi-
tion of fascia lata, muscle flaps (platysma), or silastic
sheeting (temporary), there are also drug treatments
involving the systemic or topical application of anti-
cholinergics or antihydrotics.5,7–10Table 1 provides an
overview of the current treatment options.
Use of type A botulinum toxin
The specific action of botulinum toxin on peripheral
cholinergic synapses has long been known due to the
symptoms associated with botulism. The primary ef-
fect is a receptor-mediated endocytosis in the region
of the synapses followed by selective proteolysis of the
vesicular synaptomal-associated protein. This pre-
vents the release of acetylcholine in the neuromuscu-
lar synaptic gap.11The secretion of acetylcholine sim-
ilarly is blocked at the cholinergic synapses of the
autonomic nervous system.11,12In this context, acetyl-
choline is the transmitter of the nerve innervation to
the salivary and perspiratory glands. The fact that dry
mouth is a primary symptom of botulism suggests the
use of botulinum toxin for the treatment of patients
with Frey syndrome. Early case studies referred to the
use of botulinum toxin in the treatment of patients with
Frey syndrome, whereas later studies addressed treat-
ment techniques and medium-term experience.13–15
Seven patients with symptomatic Frey syndrome were
treated with type A botulinum toxin. In all patients,
local resection of the parotid gland, conservative pa-
rotidectomy, or radical parotidectomy was the accom-
plished cause of gland adenoma or adenocarcinoma.
The patients’ daily routines were particularly dis-
turbed by the hyperhydrosis, and they avoided eating
in public whenever possible. Topical treatment with
anticholinergics (scopolamine ointment, 0.1–0.3%)
summary of the patient data is provided in Table 2.
An iodine-starch test was performed that con-
firmed gustatory sweating regularly in the posterior
aspect of the cheek and the neck and, in three cases, in
an area approximately 2 cm in width in the retroau-
ricular region (Fig. 1). The borders were marked with a
felt-tipped pen before removing the iodine-starch
mixture and cleaning the skin. The area was then
divided evenly into roughly 2 cm ? 2 cm sections, and
the fields were numbered on a diagram to provide an
overview (Fig. 2). It was necessary to divide the area
into fields to ensure the uniform and complete diffu-
sion of the botulinum toxin after injection. The use of
type A botulinum toxin for focal dystonia has shown
that the area of diffusion of the toxin in muscle is
roughly 3 cm.12The patients were given oral and writ-
ten information on the fundamental principles of the
therapy with type A botulinum toxin and also received
a patient information sheet describing the potential
Treatment Options for Patients with Frey Syndrome
Transection of Jacobson anastomosis
Transection of the glossopharyngeal nerve (intracranial)
Excision of the affected skin areas
Interposition of fascia lata
Interposition of muscle flaps
Interposition of silastic sheeting (temporary)
Systemic and topical anticholinergics (e.g., scopolamine, glycopyrronium
Topical antihyperhidrotics (e.g., dialuminium chloride)
1660CANCER October 15, 2000 / Volume 89 / Number 8
To prepare the ready-for-use solution, 2.625 mg of
dry substance (type A botulinum toxin; Dysport) were
dissolved in 2.5 mL NaCl. This corresponds to a con-
centration of 20 U/0.1 mL. After proper surface disin-
fection, 0.1 mL of this solution was injected subcuta-
neously into each field using a 1-mL insulin syringe
(Fig. 3). Uniform distribution was achieved within the
fields by turning the syringe. A separate needle was
used for each injection to prevent skin infection. A
total dose of ?350 U of type A botulinum toxin was
used for the entire area.
At the first examination 10 days later, the patients
reported that there had been a major improvement in
Overview of the Treated Patients
Operative treatment of the
Dose of type A
botulinum toxin (MU)
1 32MaleConservative parotidectomyGustatory
2 56Female Conservative parotidectomy 280 19Yes
3 46Male Conservative parotidectomy250 23Yes
428 Female Local resection28021No
542Female Conservative parotidectomy38019 Yes
6 36MaleConservative parotidectomy 24021Yes
754 MaleConservative parotidectomy 32017Yes
FIGURE 1. View of a patient showing the results of the iodine-starch test
prior to botulinum toxin injection. There is pronounced hyperhydrosis.
FIGURE 2. View of a patient showing the division of the area into fields of 2
cm ? 2 cm for the systematic injection of botulinum toxin.
Frey Syndrome and Type A Botulinum Toxin/von Lindern et al. 1661
the symptoms about 1 week after injection. In the
patients’ opinion, the redness, warmth, and sweating
had disappeared almost completely. In the subjective
opinion of the patient, even meals with intense gus-
tatory stimulants did not trigger any typical symp-
toms. In all patients, no systemic or local side effects
relating to weakening of the mimetic or masticatory
muscles or systemic botulism were reported.
The iodine-starch test was conducted again, and
there was a substantial decrease in sweating in the
affected area compared with the previous examination
(Fig. 4). In two patients, a slight color change was
noted only in the region of the anterior border to the
masseter muscle and in the hair-covered temporal
region. These regions were treated again with botuli-
num toxin in the manner described above. A second
examination after 3 weeks revealed that sweating also
had stopped in this region and could no longer be
detected in the entire area. Further examinations con-
ducted in the same manner 3 months and 8 months
after the last injection also showed no change in the
symptoms. No patient required a reinjection of type A
botulinum toxin in the medium or long term observa-
tion period (up to 23 months).
To date, numerous methods have been used to treat
patients with Frey syndrome. These methods have
shown varying degrees of effectiveness and basically
are divided into surgical methods and noninvasive
drug treatments.5,7–10The surgical methods used in-
volve excision of the affected areas of skin and the
interposition of fascia lata or regional muscle and
fascia flaps. The literature also mentions transection
of Jacobson anastomosis and intracranial transection
of the glossopharyngeal nerve. These methods are de-
scribed with success rates of up to 60% based on a
small series of patients or on individual patients.16
Methods of this kind also are indicated as a pro-
phylactic measure for avoiding Frey syndrome after
primary surgery.2,6,16–21The drug treatment strategies
involve the topical and systemic administration of an-
ticholinergics; however, topical application can lead to
skin irritation, and systemic administration in the re-
quired dose can cause side effects (accommodation
difficulty, onset of glaucoma, tachycardia).16In addi-
tion to causing skin irritation, topical treatment with
antihyperhydrotics also has proven to be problematic
and unpleasant for patients due to its ineffectiveness
despite frequent application.
If the patient is informed beforehand, then Frey
syndrome can be considered relatively harmless, al-
though it can greatly restrict a patient’s social life due
to the localized symptoms and pain. For this reason, a
type of treatment must be used that can produce
permanent suppression of the symptoms while offer-
ing a good success rate, minimal invasiveness, and few
FIGURE 3. View of a patient showing the injection off type A botulinum toxin
using a 1-mL insulin syringe.
FIGURE 4. View of a patient showing the iodine-starch test 3 weeks after
botulinum toxin injection. The excessive sweating has stopped completely.
1662CANCER October 15, 2000 / Volume 89 / Number 8
side effects. Under this premise, treatment with type A Download full-text
botulinum toxin represents a promising therapeutic
approach. It has been used successfully for years as a
local muscle relaxant in the field of focal dystonia.
Long term experience also has been gathered in the
treatment of blepharospasm, spasmodic torticollis,
and hemifacial spasm.12The range of applications for
botulinum toxin is increasing steadily due to its reli-
able effect and ease of administration.
Initial tests of the treatment of Frey syndrome
with type A botulinum toxin were described from 1994
to 1997.13–15In those studies, the first success of the
treatment with type A botulinum toxin was described
in some cases. The methods and principles are the
same aside from the medication (Dysport? instead of
botox). No recurring symptoms were described. In the
current study, we were also unable to find any evi-
dence, either clinically or with the iodine-starch test,
of recurring symptoms after an observation period of
23 months. Patients subjectively reported that the pre-
vious symptoms had been suppressed consistently.
This is contrary to experience with botulinum toxin in
the field of focal dystonia, in which there is usually a
complete reversal of the effect after 2–3 months, and
repeated injections are necessary.12A possible expla-
nation is the nonexistent or poor regeneration of
postsynaptic, parasympathetic fibers compared with
the axons in the region of the neuromuscular pathway,
some of which make the paralysis reversible by form-
ing collaterals. Even if recurrence should become ev-
ident in the medium or long term, the treatment can
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