The Laryngoscope

© 2018 The American Laryngological,

Rhinological and Otological Society, Inc.

Management and Follow-up Results of Salivary Fistulas Treated

With Botulinum Toxin

Thorsten Send, MD; Mattis Bertlich, MD, BSc; Klaus W. Eichhorn, MD;
Friedrich Bootz, MD, PhD; Mark Jakob, MD, PhD

Objectives/Hypothesis: Salivary fistulas are a common minor complication of parotid surgery. botulinum toxin has
repeatedly been reported to be an adequate treatment of this entity. To date, there is little scientific evidence for clinical deci-
sion making after appearance of a salivary fistula.
Study Design: Retrospective chart analysis of 16 patients who had been treated with botulinum toxin for salivary fistula.
Methods: All patients who had been treated for salivary fistula at a tertiary referral hospital from 2010 to 2016 were
included. Patient files were used to obtain characteristics of patients, treatment, and follow-up.
Results: Sixteen patients with salivary fistula received 27 injections of botulinum toxin. Nine patients required one injec-
tion for the fistula to heal, five patients needed two injections, and one patient needed three and four injections, respectively.
No patient underwent additional surgery or radiotherapy. We observed no adverse effects in any patient treated with botuli-
num toxin.
Conclusions: In most cases of salivary fistula, injections of botulinum toxin are a valid treatment. If the initial injection is
not successful, injections may be repeated once. Otherwise, revision surgery should be considered. In general, treatment with
botulinum toxin should be commenced in an earlier stage and with higher dosages.
Key Words: Parotid surgery, salivary fistula, botulinum toxin.
Level of Evidence: 4
Laryngoscope, n/a:1–6, 2018

INTRODUCTION has been used to treat salivary fistulas. By permanently

A sialocutaneous fistula is a relatively rare, yet very
unpleasant and impairing wound healing disorder in the
head and neck region. The most common cause for sialocu-
taneous fistula is previous parotid surgery.1–4 Apart from
parotid surgery, fistulas may also occur after facial trauma5
and as part of neoplasms of the head and neck region.6
Although very minor fistulas have the tendency to
heal quickly and without residual defects, medium to
larger-sized fistulas used to be a considerable challenge
for physicians.7 Often, conservative therapy with antibi-
otics, wound dressings, and suppression of salivary flow
by anticholinergics is not successful and revision surgery
is needed.
In the past decade, the botulinum toxin A neurotoxin
(BoNT), derived from Clostridium botulinum, is marketed
under various brand names (Botox, Dysport, Xeomin) and
From the Department of Otorhinolaryngology–Head and Neck
Surgery (T.S., K.W.E., F.B.), University Hospital Bonn, Bonn, Germany;
Department of Otorhinolaryngology–Head and Neck Surgery (M.B., M.J.),
University Hospital Munich, Munich, Germany
Editor’s Note: This Manuscript was received on January 26, 2018,
revised on April 4, 2018 and May 13, 2018, and accepted for publication
on June 6, 2018.
T.S. and M.B. contributed equally to this work.
The authors have no funding, financial relationships, or conflicts of
interest to disclose.
Send correspondence to Mark Jakob, MD, Department of
Otorhinolaryngology–Head and Neck Surgery, University Hospital
Munich, Marchioninistrasse 15, 81377 Munich, Germany. E-mail: mark.
jakob@med.uni-muenchen.de
DOI: 10.1002/lary.27416
blocking the glandular innervation and thus salivary
secretion for a period of several months, direct intra-
glandular application of BoNT reduces the permanent
inflammation to the surrounding tissue, allowing scar tis-
sue to close the defect. However, systematic evidence of
the effectiveness of this treatment is scarce in scientific
literature, and most articles are limited to single case
reports. In our study, we retrospectively analyzed 27 injec-
tions of BoNT in 16 patients for salivary fistulas for its
efficacy and safety.
MATERIALS AND METHODS
Ethics
This study was registered with the ethics committee of the
University of Bonn under the ongoing file number 209/17. The
need for informed consent was waived by the committee because
the study was limited to a strictly retrospective analysis.
Data Collection
The patient files for all patients who had received parotid
surgery (International Classification of Diseases codes 5.262-0,
5.262-1, 5.262-2) from 2010 to 2016 at the University Hospital of
the University of Bonn were screened for potential postoperative
salivary fistula. Additionally, all files of patients who were trea-
ted with Botox, Xeomin, or Dysport, in the ear, nose and throat
department were included in the screening list. All patients who
were identified from the file who had developed a salivary fistula
were included in the study.

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 The following data were obtained from the patient files: age,
gender, histology, type of previous surgery, dates of the individual
injections, the type and amount of BoNT that was injected, and
the duration until the closing of the fistula. The latter was calcu-
lated starting from the day of the first injection up until the closure
of the fistula. Additionally, the digital routine photodocumentation
of the fistulas were reviewed by the authors, and an individual
assessment of the size of the fistula was established.
Differentiation of Fistulas
Fistulas were generally divided into four classes: small,
large, and planar fistulas as well as sialocele. Small fistulas were
characterized by a singular small opening the size of a few milli-
meters with salivary flow from the opening. Where the opening
was significantly larger than that or dehiscence of the sutures
together with salivary flow was present, the fistula was consid-
ered to be large. Sialoceles were clinically identified by painless
swelling in the area of the parotid gland where surgery was per-
formed as well as ultrasound confirmation of subcutaneous fluid
retention. If several openings were visible, the fistula was consid-
ered to be planar. When in doubt, samples of the fluid from the
fistula or sialocele were tested for presence of amylase.
Clinical Treatment of Patients
All patients presented with an early onset fistula. Once the
diagnosis of a fistula was confirmed, antimicrobial agents (rou-
tinely cefuroxime-HCl 1.5 g intravenously three times a day or
cefuroxime axetil 500 mg two times a day for outpatients until
microbial cultures were available) were started if concomitant
infection was present. BoNT therapy was offered to patients as
early as the fistula presented. However, if closure of the fistula
was not achieved by pressure dressings (or sole surgical drainage
in cases of sialoceles), injections of BoNT were recommended to
the patients. These were done according to the following scheme.
In small fistulas, injections of small amounts of 10 to 15 IU of
BoNT were injected straight into the tissue surrounding the fis-
tula. If the fistula was considered large or a sialocele was pre-
sent, ultrasound-guided injections into the remaining glandular
tissue of 20 to 40 IU to reduce salivary flow was performed as
per recommendation by previous authors.1,8,9 In fistulas present-
ing as a sialocele, the sac was drained surgically prior to BoNT
injections. During the follow-up visits, the attending physician
decided upon the clinical impression of the fistula whether addi-
tional injections were necessary. If closure of the fistula was not
achieved after the second injection, revision surgery (microscopic
excision of the fistula where possible and debridement of the
wound margins) with concomitant BoNT injections were dis-
cussed with the patient.
Calculation of Doses
Either Dysport (abobotulinumtoxin A) or Xeomin (incobotu-
linumtoxin A) were used in the patients presented in this study.
The doses of Dysport were calculated into Xeomin doses by 3:1
according to the recommendations made by Scaglione.10 Due to
the very few cases treated with Dysport, we did not perform sep-
arate analysis for each BoNT formulation.
Differentiation of Early and Late Fistulas
In the scientific literature available addressing this topic,
authors tend to differentiate between early- and late-onset fis-
tula.1,5,8 Although the definition of the early fistula is fairly
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straightforward, the question of when a salivary fistula is to be
considered late or chronic is not uniform in the available scien-
tific literature to this date. In our analysis, fistulas that appeared
after more than 30 days after initial surgery were considered to
be late fistulas. This is somewhat higher than in comparable lit-
erature, and our experience has shown that under conditions like
protracted wound healing (as is the case in inflammation), sali-
vary fistulas may even appear weeks after the initial surgery but
before wound healing has been completed.
RESULTS
Demographic Data of the Patients
This study included nine males and seven females
who were on average 55.1 ± 10.3 years of age. The fistu-
las appeared six times on the right-hand side and
10 times on the left-hand side. (Table I)
Surgical Procedures, Timeline, and Histological
Features Obtained From the Patients
All patients included in this study had received par-
tial lateral parotidectomy for unknown masses in the
parotid gland. Histology revealed eight cases of cystade-
nolymphomas, five cases of pleomorphic adenomas, two
cases of chronic sialadenitis, and one case of an enlarged
intraglandular lymph node.
Fistulas appeared on average 6.3 ± 3.0 days after ini-
tial surgery, with all of the cases being early fistula. Eight
fistulas were considered small, three were considered
large, three were considered to be planar, and two
appeared as sialoceles. In three cases, concomitant infec-
tion was observed with the appearance of the fistula. Ini-
tial injections were performed on average 30.3 ± 58.2 days
after initial diagnosis of postoperative sialocutaneous
fistula.
Adverse Effects During Treatment
No adverse effects such as distant spreading of the
injected BoNT, postinjection onset of sarcoidosis lesions,11
local inflammation, or hematoma were reported after the
application of BoNT.
Injections of Botulinum Toxin
Overall, 16 patients who received 27 injections of
BoNT were included in this study. The amount of BoNT
injected into the gland ranged from 10 to 40 IU of Xeo-
min, depending on the amount of remaining glandular
tissues. The doses of Dysport were converted according to
actual recommendations. On average, 20 ± 8.4 IU of Xeo-
min were injected. The average cumulated dose of BoNT
was 32.6 ± 20.9 IU.
Efficacy of Botulinum Toxin Injections
In nine cases, one injection was sufficient for closure
of the fistula. Five patients needed two injections, and
one patient needed three or four injections, respectively.
The average time until the fistula closeure was
Send et al.: Botulinumtoxin for Salivary Fistulas
 TABLE I.
Clinical Features of Patients Included in the Study With Salivary Fistula
Days Days
Patient Age at Postoperative Fistula to No. of Overall Days to Size of
No. Surgery, yr Gender Side Histology to Fistula First Injection Injections Dose (IU) Dose (IU) Cost (€) Formulation Closure Fistula Infection

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1 59 Male Right CAL 4 21 1 10 10 40.68 Xeomin 11 Small No
2 70 Female Left CAL 5 5 1 10 10 32.83 Dysport 17 Small No
3 68 Female Left PMA 5 39 2 15 30 122.04 Xeomin 19 Planar Yes
15 Xeomin
4 65 Male Left CAL 3 7 3 40 75 305.09 Xeomin 40 Planar Yes
15 Xeomin
20 Xeomin
5 58 Male Left CAL 7 5 2 30 60 244.07 Xeomin 20 Large No
30 Xeomin
6 55 Female Right CAL 13 15 2 20 35 114.91 Dysport 4 Sialocele No
15 Dysport
7 45 Male Left PMA 3 7 2 27 47 154.31 Dysport 18 Planar Yes
20 Dysport
8 64 Male Right CAL 4 19 1 40 40 162.72 Xeomin 10 Small No
9 51 Male Right CSA 6 29 2 10 20 73.51 Xeomin 8 Small N/A
10 Dysport
10 43 Male Left HLN 4 6 1 30 30 122.04 Xeomin 12 Large No
11 55 Female Left PMA 10 0 1 15 15 61.02 Xeomin 11 Small No
12 43 Male Left CAL 8 60 1 20 20 81.36 Xeomin 7 Small No
13 57 Male Left CAL 7 8 1 10 10 40.68 Xeomin 10 Small No
14 45 Female Right CSA 12 248 4 20 75 305.09 Xeomin 73 Large No
15 Xeomin
20 Xeomin
20 Xeomin
15 35 Female Left PMA 5 6 1 25 25 101.70 Xeomin 12 Sialocele No
16 69 Female Right PMA 5 10 1 20 20 81.36 Xeomin 25 Small No
P
/ 55.1 ± 10.3 9 male, 6 right, 8 CAL, 5 PMA, 6.3 ± 3.0 30.3 ± 58.2 27 20.0 ± 8.4 32.6 ± 20.9 127.71 ± 84.83 21 Xeomin, 18.5 ± 16.3 8 small, 3 yes,
7 female 10 left 2 CSA, 1 HLN 6 Dysport 3 large, 12 no
3 planar,
2 sialocutaneous

CAL = cystadenolymphoma; CSA = chronic sialadenitis; HLN = hyperplastic lymphatic node; N/A = not available; PMA = pleomorphic adenoma.

3
Send et al.: Botulinumtoxin for Salivary Fistulas

Fig. 1. Clinical examples of successful botulinum neurotoxin ther-
apy in minor fistula before (A) and after (B) injection, as well as in
large fistulas (C, D) and in sialoceles before (E) and after drainage
and botulinum neurotoxin injections (F). [Color figure can be viewed
in the online issue, which is available at www.laryngoscope.com.]
18.5 ± 16.3 days, with all but two fistulas closing within
25 days following injection. The average time between
the injection and the closure of the fistula was
12.7 ± 5.0 days in the group that required only one injec-
tion. Additionally, all fistulas closed under conservative
treatment. Revision surgery or additional measures were
not necessary or favored by the patients in any of the
cases reviewed (Fig. 1).
Costs of Injections
One IU of Xeomin was calculated to cost 4.07€
(406.79€ for 100 IU). One IU of Dysport was calculated to
cost 3.28€ (328.33€ for 300 IU of Dysport, equivalent to
100 IU of Xeomin). The average cost of an injection was
127.71€ ± 84.83€.
DISCUSSION
Botulinum Toxin acts as a proteolytic enzyme in pre-
synaptic axon terminals, targeting the SNARE complex
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(soluble NSF [N-ethylmaleimide-sensitive factor] attach-
ment protein receptor), thus preventing the presynaptic
vesicles of the neurotransmitter acetylcholine to be
released and eventually rendering the axon terminal
inert.12 In muscles, it prevents the contraction from tak-
ing place; in salivary glands, it eliminates stimulation of
the gland and thus production of saliva.
Because saliva is relatively aggressive and causes
chronic inflammation, the constant flow of saliva in postop-
erative sialocutaneous fistulas poses a considerable prob-
lem. Earlier strategies have also aimed at reducing
salivary flow, but applied systemic medication like glyco-
pyrrolate that may coincide with systemic side effects.13
Another approach is the transdermal, oral, or intravenous
application of scopolamine, also known as hyoscine, like
glycopyrrolate, an anticholinergic that prevents the pro-
duction of saliva in the salivary glands.14 Compared with
BoNT therapy, application of scopolamine or glycopyrro-
late wields the advantages of easy handling and low over-
all costs. However, when scopolamine or glycopyrrolate are
applied systemically, possible side effects include typical
anticholinergic effects such as blurred vision, xerostomia,
accommodation deficit, sleepiness, constipation, urinary
retention, tachycardia, erythema, and dizziness.14
The local application of BoNT, on the other hand, is
a safe and secure way to locally control salivary secretion,
as underlined by the results presented here. Controlling
salivary secretion then reduces the constant chemical and
mechanical irritation to the tissue around the fistula,
allowing scar tissue to form and eventually close the fis-
tula. Additionally, reducing salivary flow from the fistula
decreases the social stigma of a salivary fistula, because
saliva draining from the fistula during meals has been
reported to cause considerable social discomfort.1,9
We observed considerable interindividual differences
in the time between the appearance of a fistula and the
beginning of BoNT therapy. This phenomenon might be
explained by the strategy that was applied in treatment;
even though BoNT was offered to the patients as early as
the fistula appeared and recommended if pressure dress-
ings proved ineffective, patients were informed in great
depth about the experimental nature of the procedure.
This might have caused a certain reserve against the
treatment in patients.
Nonetheless, we have been able to show that every
fistula could be treated conservatively. It has been
reported by Laskawi et al.1 that high rates of closures
under conservative management, starting with BoNT
therapy, can be achieved. In this respect, our results are
in line with previous literature. However, in the cohort
analyzed by Laskawi et al.,1 three patients eventually
underwent surgery and/or radiotherapy, resulting in a
75% closure rate by injecting patients with BoNT a maxi-
mum of two times.
In the cohort at hand, we discussed revision surgery
with concomitant BoNT injections as recommended by
Laskawi et al.1 with two patients after their fistulas per-
sisted after a second injection of BoNT (patients 4 and
14). However, both patients were unwilling to undergo
revision surgery and opted for additional injections. Both
of these patients showed by far the longest time for the
Send et al.: Botulinumtoxin for Salivary Fistulas
Fig. 2. Flowchart for clinical decision making when treating salivary fistulas. Adapted from Laskawi et al.1 BoNT = botulinum neurotoxin.
fistula to heal, underlining the limits of BoNT therapy.
We therefore recommend revision surgery whenever clo-
sure of the fistula cannot be achieved with two BoNT
injections. In very severe cases, radiotherapy of salivary
fistulas to achieve closure may be considered.1,15
We also found that the average time until reaching
fistula closure is relatively short, with an average period
of 18.5 days. The average time in those patients who only
needed one injection was even lower at 12.7 days. We
therefore suggest for clinical practice that when it comes
to reevaluating the success of an injection, and an addi-
tional injection is considered, this decision may be taken
after 8 to 10 days.
Another aspect of BoNT therapy in salivary fistulas
that has to be addressed are the costs associated with the
therapy. With the toxin itself being relatively costly, the
average costs of this therapy are considerable, with some
patients requiring BoNT worth several hundred euros.
These costs might be covered by the clinic treating the
patient. Nonetheless, safety, the efficacy, and the fast
effects of BoNT therapy in salivary fistulas should war-
rant early and decisive use in these entities. Additionally,
a persistent salivary fistula causes considerable periods
of sick leave that may be reduced by BoNT therapy.
Comparing the dosages of BoNT therapy for salivary
fistulas to those for other indications such as drooling,2 it
may appear that the dosage is relatively high, bearing in
mind the postoperatively reduced amount of glandular
tissue. However, considering the different aims in BoNT
therapy for drooling and managing salivary fistulas, these
differences appear logical. Fittingly, the dosages we
injected in each individual setting were comparable to
those used in the aforementioned study1 and several case
reports.5,6,9
Bearing the two main facts in mind that 1) we were
able to achieve closure under conservative BoNT therapy
in every single case and 2) we observed not a single
adverse effect, we recommend that BoNT should be com-
menced at an earlier stage and with higher dosages. In
the case of small fistulas, we recommend injections of
20 IU into the surrounding tissue. This method and dos-
age has proven to be very effective. Additionally, this
easy-to-handle approach allows lower dosing and thus
risk- and cost-effective management of minor fistulas.
This is due to the fact that adverse effects in BoNT
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therapy would be expected to rise as dosage increases,
and the costs for BoNT need to be covered by the
hospital.
In the case of large or planar fistulas, we recom-
mend ultrasound-guided injections into the remaining
glandular tissue of 50 IU. This recommendation for
BoNT may be higher than what the authors have
applied up to now. However, these fistulas persisted the
longest and required the most injections; this may be
caused by the high costs and little available evidence for
dosing in BoNT therapy for salivary fistulas. Treatment
for persisting sialoceles should generally be as described
for large or planar fistulas. Small sialoceles do not need
any treatment. However, prior to commencing BoNT
therapy, the sac of the sialocele needs to be drained sur-
gically (Fig. 2)
Finally, concerning the point in time when BoNT
therapy is considered, one has to consider prolonged sick
leave as well as the social stigma associated with salivary
fistula. Bearing in mind that in the data at hand, BoNT
therapy is a highly effective and safe treatment for sali-
vary fistula, and it should be considered as early as the
fistula appears.
CONCLUSION
Overall, we have been able to confirm that botuli-
num toxin is a save and efficient treatment for salivary
fistula. In comparison with previous literature, we recom-
mend that injection of botulinum toxin may be com-
menced as early as the fistula appears, and if a large or
planar fistula or a sialocele appears, dosage of BoNT
should be considerably higher than what has been
applied to date. Injections may be repeated once. In
refractory cases, surgical revision and eventually even
radiotherapy may be considered.
Acknowledgments
The authors thank Dr. Julian B. Pump of the Johan-
niterkrankenhaus in Bonn, Germany for valuable aid in
the data collection. Additionally, the authors thank Jen-
nifer Lee Spiegel of the ear, nose, and throat department
of the Ludwig Maximilians University for critical proof-
reading of the manuscript.
Send et al.: Botulinumtoxin for Salivary Fistulas
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