Frey`s syndrome - School of Medicine

Bridget Hopewell, MD and Robert Zitsch, MD
FREY’S SYNDROME
HISTORY
1757- described by
Duphoenix
 1923- published by
Lucja Frey

 Gunshot
victim who
developed abscess
 Gustatory sweating 1
month after I&D

Named “Frey’s
syndrome in 1925 by
Higier
Grzybowski A, Sak J. Lucja Frey (1889-1942): life destroyed by the
Holocaust--on the 70th anniversary of her death. Clinics in
dermatology 2012;30(3):355-9.
HER DESCRIPTION
Precisely described the syndrome
 Experimented with sympathetic and
parasympathetic stimulation and the effects on
saliva production
 Diagramed the anatomy, explained the
pathogenesis and proposed treatment

 Including
the reasons for delay in symptoms
LUCJA FREY
Medical school in 1917
 Worked as a
nueropsychiatrist
 Head of neurology at
Warsaw
 Extensively published- 38
papers
 “ant-like diligence” and
precision

Grzybowski A, Sak J. Lucja Frey (1889-1942): life destroyed by the
Holocaust--on the 70th anniversary of her death. Clinics in
dermatology 2012;30(3):355-9.
June 1941- forced to live in Lvov Ghetto
 Worked at the hospital in the ghetto
 Ghetto evacuated to concentration camps,
remainder of medical patients and staff killed

Grzybowski A, Sak J. Lucja Frey (1889-1942): life destroyed by the Holocaust--on the 70th
anniversary of her death. Clinics in dermatology 2012;30(3):355-9.
BY ANY OTHER NAME…
Auriculotemporal syndrome
 Gustatory sweating
 Frey’s syndrome
 Baillarger’s syndrome
 Dupuy’s syndrome
 705.22 ICD-9

PATHOPHYSIOLOGY
Parasympathetic nerve fiber regrowth that
originally innervated the parotid gland after
neuronal injury
 Regenerating fibers cause innervation of sweat
glands and blood vessels in the facial skin

SYMPTOMS
Flushing, heating
 Sweating
 When eating
 Occurs most often after parotidectomy

 At
least 6 weeks after surgery
EPIDEMIOLOGY

After parotidectomy, very prevalent
 2-96%

1997 in Laryngoscope- 759 patients,
retrospective arm and prospective arm
 43%
of prospective patients symptomatic within 1
year
 5-10% severely bothered
Linder TE, Huber A, Schmid S. Frey's syndrome after parotidectomy: a retrospective and prospective analysis. The Laryngoscope
1997;107(11 Pt 1):1496-501.
Linder TE, Huber A, Schmid S. Frey's syndrome after parotidectomy: a retrospective and prospective analysis. The Laryngoscope
1997;107(11 Pt 1):1496-501.
DIAGNOSTIC TESTING
Subjective symptoms
 Minor’s Starch Iodine Test
 Infrared Thermography
 Several variants developed to attempt to
quantitate amount of sweating

 Used
mostly in research
SUBJECTIVE SYMPTOMS
Facial flushing
 Pain
 Sweating after eating
 when symptoms first
appeared
 How these are
affecting daily life

MINOR’S STARCH IODINE TEST
Usually considered “gold standard”
 Not quantitative
 No statistical information

 No
sensitivity or specificity has been developed
MINOR’S




Apply alcohol-iodine-oil solution to skin- allow drying time
Apply starch powder to the skin
Gustatory stimulus given- eg, lemon candy for 10 minutes
Positive tests turn *blue
Parotid.net
ATTEMPTS TO QUANTIFY
Apply tissue paper to face, wets with sialogogue
 Apply blotting paper to face, apply sialogogue
and weigh it pre- and post-stimulation
 Iodine-impregnated paper to face that changes
color when wet- stencil the area

INFRARED THERMOGRAPHY
Pts placed in a room at a controlled temperature
with no wind or exterior light
 Given sialogogue
 Measure skin temperature- compare to
unaffected side

Choi HG, Kwon SY, Won JY, et al. Comparisons of Three
Indicators for Frey's Syndrome: Subjective Symptoms, Minor's
Starch Iodine Test, and Infrared Thermography. Clinical and
experimental otorhinolaryngology 2013;6(4):249-53.
COMPARISON OF DIAGNOSTIC TESTING
Choi et al 2013
 59 pts who underwent unilateral parotidectomy

 Evaluated
12 months after surgery
 Subjective symptoms
 Minor’s iodine test
 Thermography
Choi HG, Kwon SY, Won JY, et al. Comparisons of Three Indicators for Frey's Syndrome: Subjective Symptoms, Minor's Starch Iodine Test,
and Infrared Thermography. Clinical and experimental otorhinolaryngology 2013;6(4):249-53.
SUBJECTIVE SYMPTOMS
35.6% (21/59) had subjective symptoms
 28.8% (17/56) reported symptoms did not
affect daily life
 5.1% (3/56) reported symptoms caused a
large degree of frustration

MINOR’S
50.8% (30/56) had a positive Minor’s starch
iodide test
 Of the 21 patients with subjective symptoms,
19 had a positive Minor’s test
 Of the 38 patients with no symptoms, 11 had a
positive Minor’s test

COMPARISON
+ Iodine
- Iodine
Total
+ symptoms
19
2
21
- symptoms
11
27
38
Total
30
29
59
Table modified from: Choi HG, Kwon SY, Won JY, et al. Comparisons of Three Indicators for Frey's Syndrome: Subjective Symptoms, Minor's
Starch Iodine Test, and Infrared Thermography. Clinical and experimental otorhinolaryngology 2013;6(4):249-53.
INFRARED THERMOGRAPGY
Prior to gustatory stimulation, operated site had
a lower temperature than unoperated site
 After gustatory stimulation, the operated site
had a higher temperature than the unoperated
site
 Neither was statistically significant
 Highest temperature difference was
1.16degreesC

ANALYSIS OF INFRARED
Divided patients into 7 groups based on the
temperature difference between operated and
unoperated site
 0.3degrees difference in each group
 Compared to symptoms and Minor’s

Choi HG, Kwon SY, Won JY, et al. Comparisons of Three
Indicators for Frey's Syndrome: Subjective Symptoms, Minor's
Starch Iodine Test, and Infrared Thermography. Clinical and
experimental otorhinolaryngology 2013;6(4):249-53.
TEMPERATURE VS SYMPTOMS
Choi HG, Kwon SY, Won JY, et al. Comparisons of Three Indicators for Frey's Syndrome: Subjective Symptoms, Minor's Starch Iodine Test,
and Infrared Thermography. Clinical and experimental otorhinolaryngology 2013;6(4):249-53.
TEMPERATURE VS MINOR’S
Choi HG, Kwon SY, Won JY, et al. Comparisons of Three Indicators for Frey's Syndrome: Subjective Symptoms, Minor's Starch Iodine Test,
and Infrared Thermography. Clinical and experimental otorhinolaryngology 2013;6(4):249-53.
PERCEPTION OF TESTS
Useful to quantitate effects of treatment in
research
 Less important to actually use these all on
patients
 In some cases, may decide it would be helpful
to demonstrate pre- and post- treatment
quantification
 Many times, it is unnecessary to do extensive
diagnostic testing

TREATMENTS
External beam radiation*
 Tympanic neurectomy*
 Topical or systemic anticholinergics*
 Antiperspirants
 Botox
 Revision surgery


*use not frequently recommended at present
EXTERNAL BEAM RADIATION
Fairly effective
 Morbidity too great to treat FS
 If indicated for malignancy, will improve
symptoms

TYMPANIC NEURECTOMY

Advocated in 1960s and 1970s
 Frey’s
 Parotitis
 Sialorrhea
 Aural
pain
 Crocodile tears

Transient relief
Friedman WH, Swerdlow RS, Pomarico JM. Tympanic
neurectomy: a review and an additional indication for
this procedure. The Laryngoscope 1974;84(4):568-77.
TOPICAL ANTICHOLINERGICS
Scopolamine cream
 Glycopyrrolate
 Antiperspirants

 Aluminum
chloride
 Aluminum chlorohydrate
 Aluminum-zirconium
SCOPOLAMINE CREAM
Anticholinergic
 Tertiary amine- penetrates skin and blood brain
barrier
 Side effects

 Hallucinations
 CNS
toxicity
 Peripheral anticholinergic symptoms: Dry mouth,
blurred vision, tachycardia, difficult micturition
GLYCOPYRROLATE
Quaternary ammonium (does not cross blood
brain barrier)
 Absorbed more slowly
 Advocated in 1978 as an alternative to
scopolamine due to less side effects, and more
favorable therapeutic index

Hays LL. The Frey syndrome: a review and double blind evaluation of the topical use of a new anticholinergic agent. The Laryngoscope
1978;88(11):1796-824.
CAUTIONS
Must have intact healthy skin
 No glaucoma
 Prosthetic hypertrophy, pyloric obstruction

ANTIPERSPIRANTS
Simple, commercially available
 Often effective
 Little risk of complications

 Must

keep out of eyes
Must frequently apply
BOTOX
Introduced by Drobik in 1995
 Use starch-iodine to identify areas
 Effective in 48-72 hrs
 At least 3 months

REVIEW OF TRIALS 2007
10 trials
 Follow up usually 6
months 2 years
 Consistently highly
effective
 Recurrences
presented 3mo2years

Effective, #pts (%)
Recurrence (%)
3/3 (100)
0/3 (0)
12/15 (80)
2/15 (13)
45/45 (100)
0/45 (0)
18/18 (100)
8/18 (44)
16/16 (100)
33/33 (100)
32/33 (97)
7/7 (100)
0/7 (0)
8/8 (100)
11/13 (85)
10/13 (77)
11/11 (100)
1/11 (9)
Table adapted from: de Bree R, van der Waal I, Leemans CR. Management
of Frey syndrome. Head & neck 2007;29(8):773-8.
TECHNIQUE
Divide into squares
 Inject into each square

de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
REPEAT INJECTIONS
22 patients
 Injected as shown
 Told to follow-up when symptoms recurred
 Followed for 6 years
 All received at least 3 treatments, some up to 7

de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
REPEAT INJECTIONS
Decreased affected area by Minor’s test
 Increased interval between injections

de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
TIME INTERVAL BETWEEN TREATMENTS
de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
AFFECTED AREA BY SIZE
de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
CRITIQUE OF STUDY

Not scheduled follow-up intervals
 Only
repeated if patients requested it
 Intolerance to injections is not success though both
types of patients would not come to follow-up
de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
TECHNIQUES IN PREVENTION
Limited resection
 Thicker flap
 SCM flap
 SMAS flap
 Temporoparietal flap
 Implants
 Fat grafting

SCM FLAP
Easy to rotate into the parotid region
 Long enough to cover all branches of the facial
nerve
 Decrease depression of the surgical area
 Low risk of necrosis
 Low risk of complications
 Systematic review in 2011

Sanabria A, Kowalski LP, Bradley PJ, et al. Sternocleidomastoid muscle flap in preventing Frey's syndrome after parotidectomy: a systematic
review. Head & neck 2012;34(4):589-98.
PRONE TO BIAS
Publication bias
 Significant differences in methods of studies
 Difference in follow-up time

 If
too short, pts have not yet developed it- perhaps
it just takes longer to develop with SCM flap, not
preventing it all together
 If too long, may not be as bothered by it
SMAS FLAP
RCT published 2013 from Turkey
 30 patients randomized into subcutaneous flap
and sub-SMAS skin elevation
 Flap thickness measured at time of surgery
 Assessed at 10 months post-op

 Subjective
questions
 Minor’s test
Durgut O, Basut O, Demir UL, Ozmen OA, Kasapoglu F, Coskun H. Association between skin flap thickness and Frey's syndrome in parotid
surgery. Head & neck 2013;35(12):1781-6.
SUB-SMAS WAS THICKER
Durgut O, Basut O, Demir UL, Ozmen OA, Kasapoglu F, Coskun H. Association between skin flap thickness and Frey's syndrome in parotid
surgery. Head & neck 2013;35(12):1781-6.
SUBJECTIVE SYMPTOMS
2/15 patients in the subcutaneous group had
subjective complaints
 0/15 patients in the sub-SMAS group had
subjective complaints

Durgut O, Basut O, Demir UL, Ozmen OA, Kasapoglu F, Coskun H. Association between skin flap thickness and Frey's syndrome in parotid
surgery. Head & neck 2013;35(12):1781-6.
MINOR’S TEST RESULTS

Median dimension of discoloration in subQ
group was larger compared with the subSMAS
group: 7.5cm vs. 0.5cm
Patients
Negative
Mild
Moderate
severe
subQ
2
4
1
8
subSMAS
3
5
2
5
Table adapted from: Durgut O, Basut O, Demir UL, Ozmen OA, Kasapoglu F, Coskun H. Association between skin flap thickness and Frey's
syndrome in parotid surgery. Head & neck 2013;35(12):1781-6.
ALSO NOTED
One of the patients was severely bothered by
symptoms
 Given one treatment with botox and had
complete resolution of symptoms
 Minor’s test also became negative

CRITIQUE

Follow-up time
 Did
subSMAS really prevent development or simply
delay it?

Small number of patients
TEMPOROPARIETAL FLAP
Superficial facia, deep facia, muscle layer or
various combinations have been described
 Based on superficial temporal artery
 Thin, pliable
 Inconspicuous donor site
 Tedious dissection
 Scalp alopecia
 Frontal branch of CN VII at risk

Ahmed OA, Kolhe PS. Prevention of Frey's syndrome and volume deficit after parotidectomy using
the superficial temporal artery fascial flap. British journal of plastic surgery 1999;52(4):256-60.
BETTER THAN SMAS?
Does not compromise
tumor margins
 Bulkier than SMAS
 Well-defined, wellvascularized fascial
layers

Ahmed OA, Kolhe PS. Prevention of Frey's syndrome and volume deficit after
parotidectomy using the superficial temporal artery fascial flap. British journal
of plastic surgery 1999;52(4):256-60.
RESULTS
Symptoms
TP flap
No flap
None
22
13
Mild
1
2
Moderate
1
6
Severe
0
2
Table adapted from: Ahmed OA, Kolhe PS. Prevention of Frey's syndrome and volume deficit after parotidectomy using the superficial
temporal artery fascial flap. British journal of plastic surgery 1999;52(4):256-60.
ALLODERM
Acellular dermal
matrix
 Molded to fill defectfolded, thick graft
used
 sutured to masseter,
zygomatic arch, SCM,
tragal perichondrium,
mastoid

Sinha UK, Saadat D, Doherty CM, Rice DH. Use of AlloDerm implant to prevent frey syndrome after parotidectomy. Archives of facial plastic
surgery 2003;5(1):109-12.
COMPARED TO SMAS
10 patients with AlloDerm
 10 patients with no interpositional barrier
 10 patients with SMAS flap
 Evaluated after 1 year

 Symptoms
and Minor’s
Sinha UK, Saadat D, Doherty CM, Rice DH. Use of AlloDerm implant
to prevent frey syndrome after parotidectomy. Archives of facial
plastic surgery 2003;5(1):109-12.
RESULTS
2 patients with FS in AlloDerm group
 8 patients with FS in control group
 0 patients with FS in SMAS group

Sinha UK, Saadat D, Doherty CM, Rice DH. Use of AlloDerm
implant to prevent frey syndrome after parotidectomy.
Archives of facial plastic surgery 2003;5(1):109-12.
COMPLICATIONS
2 patients in AlloDerm group developed
transient seroma or sialocele
 3 patients in SMAS group developed transient
seroma or sialocele
 All resolved with conservative management

Sinha UK, Saadat D, Doherty CM, Rice DH. Use of AlloDerm implant to prevent frey syndrome after
parotidectomy. Archives of facial plastic surgery 2003;5(1):109-12.
FREE FAT GRAFT
Used in conjunction with SMAS flap to provide
well-vascularized envelope
 Can achieve volumetric symmetry
 Good viability even in setting of radiation
 1/31 patients in one series developed Frey’s (8
of these had malignant tumors and underwent
radiation)

2 had wound infection
at fat graft site
 They recommend MRI 3
months post radiation (6
months post-op) and at
6 month intervals
thereafter
 For high-grade path,
baseline PET as well

REGARDING FLAPS AND IMPLANTS
Improves cosmesis
 Post-operative tumor surveillance is impaired
via physical exam
 May require MRI for tumor surveillance rather
than just physical exam

SUBMANDIBULAR GLAND EXCISION

Incidence reported
at 1%
Lee JW, Yoon YH. Gustatory sweating after submandibular gland excision. Otolaryngology--head and neck surgery : official journal of
American Academy of Otolaryngology-Head and Neck Surgery 2010;143(6):845-6.
IN CHILDREN
Forceps delivery
 Central nervous system abnormalities
 Subclinical intrauterine infections
 May mimic food allergies

CASE REPORT
Breast-fed infant, born
vaginally with forceps
 6 months of age developed
unilateral erythema after
eating.
 Allergy testing showed
nothing
 Oral provocation showed it to
nearly everything

Ott H, Brost H, Poblete-Gutierrez P, Schroder CM, Frank J. Auriculotemporal syndrome in childhood. Acta dermato-venereologica
2004;84(2):160-1.
DIABETIC AUTONOMIC DYSFUNCTION
Seen in long-standing diabetics with other
sequelae of autonomic dysfunction
 Portends a poor prognosis
 Associated with nephropathy

 Reported
to reverse with renal transplantation
 Also seen in pts without diabetic neuropathy

No improvement with tighter glycemic control
Blair DI, Sagel J, Taylor I. Diabetic gustatory sweating. Southern medical journal 2002;95(3):360-2.
REFERENCES
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1.
Ott H, Brost H, Poblete-Gutierrez P, Schroder CM, Frank J. Auriculotemporal syndrome in childhood. Acta dermato-venereologica
2004;84(2):160-1.
2.
Reich SG, Grill SE. Gustatory sweating: Frey syndrome. Neurology 2005;65(11):E24.
3.
Blair DI, Sagel J, Taylor I. Diabetic gustatory sweating. Southern medical journal 2002;95(3):360-2.
4.
Linder TE, Huber A, Schmid S. Frey's syndrome after parotidectomy: a retrospective and prospective analysis. The Laryngoscope 1997;107(11
Pt 1):1496-501.
5.
Lee JW, Yoon YH. Gustatory sweating after submandibular gland excision. Otolaryngology--head and neck surgery : official journal of American
Academy of Otolaryngology-Head and Neck Surgery 2010;143(6):845-6.
6.
Choi HG, Kwon SY, Won JY, et al. Comparisons of Three Indicators for Frey's Syndrome: Subjective Symptoms, Minor's Starch Iodine Test, and
Infrared Thermography. Clinical and experimental otorhinolaryngology 2013;6(4):249-53.
7.
Hays LL. The Frey syndrome: a review and double blind evaluation of the topical use of a new anticholinergic agent. The Laryngoscope
1978;88(11):1796-824.
8.
Friedman WH, Swerdlow RS, Pomarico JM. Tympanic neurectomy: a review and an additional indication for this procedure. The Laryngoscope
1974;84(4):568-77.
9.
de Bree R, van der Waal I, Leemans CR. Management of Frey syndrome. Head & neck 2007;29(8):773-8.
10.
de Bree R, Duyndam JE, Kuik DJ, Leemans CR. Repeated botulinum toxin type A injections to treat patients with Frey syndrome. Archives of
otolaryngology--head & neck surgery 2009;135(3):287-90.
11.
Sanabria A, Kowalski LP, Bradley PJ, et al. Sternocleidomastoid muscle flap in preventing Frey's syndrome after parotidectomy: a systematic
review. Head & neck 2012;34(4):589-98.
12.
Durgut O, Basut O, Demir UL, Ozmen OA, Kasapoglu F, Coskun H. Association between skin flap thickness and Frey's syndrome in parotid
surgery. Head & neck 2013;35(12):1781-6.
13.
Ahmed OA, Kolhe PS. Prevention of Frey's syndrome and volume deficit after parotidectomy using the superficial temporal artery fascial flap.
British journal of plastic surgery 1999;52(4):256-60.
14.
Sinha UK, Saadat D, Doherty CM, Rice DH. Use of AlloDerm implant to prevent frey syndrome after parotidectomy. Archives of facial plastic
surgery 2003;5(1):109-12.
15.
Grzybowski A, Sak J. Lucja Frey (1889-1942): life destroyed by the Holocaust--on the 70th anniversary of her death. Clinics in dermatology
2012;30(3):355-9.