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Botulinum Toxin Treatment for Sialadenitis (OnabotulinumtoxinA - Botox®) (IncobotulinumA - Xeomin®) and (AbobotulinumtoxinA - Dysport®) Salivary Swelling

see also: Botox injection to salivary glands for hypersalivation; Botulinum neurotoxin preparations; case example of gland removal for chronic sialadenitis associated with stricture

Review indicating that:

Management of chronic sialadenitis with botulinum toxin injection is useful - "to avoid excision of the gland, which is often necessary in recurrent chronic sialadenitis" (Ellies 2004)

1. Background - Obstructive Sialadenitis without Sialolithiasis

Recurrent pain and swelling of the salivary glands from inflammation (sialadenitis) may be associated with obstruction to salivary flow from processes other than salivary stones and include: radioiodine treatment, autoimmune disorders (e.g. Sjogren's syndrome), recurrent infections, surgical trauma and 'idiopathic' (Strohl 2021). Chemodernervation through botulinum toxin (BTX) injection 'silences' the gland to diminish salivary secretion and induce atrophy( Graillon 2019, Ellies 2004, Lavato 2017, Kwon 2021) . 

Management is usually initiated by a conservative approach focussed on increasing hydration, stimulating salivation (such as use of sour candy) and gland massage often accompanied by treatment with anti-staphylococcal antibiotics.  Unsuccessful conservative management in the past was commonly followed by removal of the gland (parotidectomy/submandibular gland resection). Other less commonly described options have included tympanic neurectomy and duct ligation to induce atrophy (Guntinas-Lichius 2002, Mandour 1977).

Gland preservation as an alternative to gland removal is now widely available through innovations including sialendoscopysialography and ultrasound to direct dilation of salivary duct stenoses with irrigation (often including steroid infusion)  

However, it has been reported that 50% of more of patients with salivary duct obstruction in the absence of stones fail conservative sialendoscopy management (**Strohl 2021)

A prospective analysis of outcomes following sialendoscopy-assisted salivary duct surgery for obstruction (without stones) Delagnes et al (**Delagnes 2017) assessed a cohort of 20 patients with 37 symptomatic glands employing the COSS (Chronic Obstructive Sialadenitis Symptoms) questionnaire preoperatively and 3 months after sialendoscopy for chronic obstructive sialadenitis without sialolithiasis.

  • During the course of this study balloon dilation was not employed.
  • Surgeon discretion resulted in inconsistent use of stents and insufflation of triamcinolone (40 mg/mL diluted 1:1 with saline)
    • Subsequent comparative analysis suggested value in use of steroid (triamcinolone).
  • Overall statistically significant improvement (measured by reduction in the COSS score) was seen with subgroup analysis identifying:
    • 38% (8 of 21) of glands with radioiodine (RAI) sialadenitis met the criteria for either partial or complete resolution of symptoms  
    • 69% (9/13) with idiopathic sialadenitis met the criteria for either partial or complete resolution of symptoms.
    • 14% (5/37) of symptomatic glands (2 patients)  had ducts that could not be instrumented due to complete stenosis
  • Overall: "Approximately half of the study cohort met criteria for at least partial resolution of symptoms, whereas only 16% reported... complete resolution of symptoms"
  • With the comment that the "value of repeat procedures should be further explored"

2. Rationale for Salivary Gland Chemodenervation with Botulinum Toxin (BTX)

When a neuro-effector junction is exposed to the botulinum protein (BTX) (see mechanism), the neurotoxin inhibits presynaptic acetylcholine release to produce a local chemical blocking with loss of neuronal activity (Lovato 2017). Although the dominant mechanism whereby BTX diminishes salivary gland pain is thought to be an interference to the neurogenic stimulus to salivary secretion resulting in decreased intraductal pressure, the antinociceptive and anti-inflammatory effects of BTX have been supported as possible ancillary benefits to decrease the pain (Graillon 2019). 

Guntinas-Lichius et al. in 2002 reported treatment of a patient with left parotid sialectasis (duct ectasia associated with painful swelling over a ten-year period) with relief of symptoms following parotid injection of 200 IU of Dysport® (20 IU in 10 sites) with swelling episodes stopped after two weeks and no recurrence despite monthly followup for 12 months.

Ellies et al. have been credited with being the first to report salivary BTX injection to manage chronic sialadenitis to cause "a temporary silencing of the gland" (Ellies 2004, Lavato 2017, Kwon 2021).  In a followup publication following a sequence of reports these investigators expanded their use of botulinum toxin (Botox®) beyond success in management of drooling and salivary fistula to include treatment of two patients with chronic sialadenitis (Ellies 2004). Following ultrasound guided Botox® injection both patients identified 'the absence of sialadenitis to date" and a 'reduced feeling of tension in the affected gland"

Delivery of  BTX to the neuroeffector junction of salivary gland is most commonly done via percutaneous intraglandular injection- with many reports recommending use of ultrasound guidance.

Intraductal BTX infusion is an alternative delivery method that we found useful for selected patients.  Intraductal infusion - proposed to more effectively permeate the parenchyma to saturate the neuro-effector junctions - has been reported as successful in addressing excess salivary production and a salivary fistula (Schwalje 2019). This delivery approach may not be as useful when treating obstructive sialadenitis. If the BTX is administered in the course of sialendoscopy, the saline infusion done during the process may saturate the parenchyma to limit the botox delivery to the neuroeffector junction.  Additionally, the risk for extravasation of botox is likely to be higher in the presence of ductal structures. Ductal extravasation of water soluble radiocontrast has been reported to occur at a higher rate (without untoward sequelae) during sialography done in the presence of strictured ducts (Truong 2018). 

3.  Support for Botulinum Toxin Injection to Manage Parotid Sialadenitis

Publication

Dose

Comments

Strohl 2021 

Strohl MP, Chang CF, Ryan WR, Chang JL. Botulinum toxin for chronic parotid sialadenitis: A case series and systematic review. Laryngoscope Investig Otolaryngol. 2021 May 2;6(3):404-413. doi: 10.1002/lio2.558. PMID: 34195360; PMCID: PMC8223475

 

 

 contains excellent systemic review of the literature to supplement their study with overall conclusion:

 

Parotid gland chemodenervation with BTX

  • "minimally invasive treatment option for symptomatic chronic sialadenitis refractory to sialendoscopy and/or medical management" 

  • "alleviates obstructive symptoms of gland pain and swelling and provides an alternative to parotidectomy for recurrent sialadenitis."

Botox® - Onabotulinum toxin - was diluted to 100U per 2 mL employing 1cc syringes with 27g 1.5 inch needless with ultrasound guidance; two separate injections (parotid body and tail parenchyma)

Dose dependent on severity and need for bilateral injections - more severely affected gland:70 to 100 U) and remaining dose (total 100 U delivered) to 'other affected gland if present'

Prospective study of 10 patients with 13 affected glands with recurrent obstructive sialadenitis symptoms after sialendoscopy  -  with injections an average of 6 months after sialendoscopy. Number of treatments ranged from 1 session (4 patients) to 4 sessions (1 patient)                    

Five patients with 8 affected glands had data for 2-3 month f/u post-injection: COSS score statistically improved - gland pain frequency and severity of gland swelling between meals declined significantly postinjection. No increase or change in xerostomia symptoms

Three patients with 4 affected glands had data for 9 to 12 months post-injection: COSS scores remained low - but with insufficient data for statistical significance

None of the patients underwent parotidectomy in the followup period (mean 13 months)

Conclusion: Botulinum toxin alleviates gland pain and swelling associated with salivary obstruction; provides alternative to parotidectomy for recurrent sialadenitis

Kwon 2021

Kwon SY, Chun KJ, Kil HK, Oh KH, Kim C, Jang SJ, Kim MS. Botulinum Toxin Injection for Chronic Parotitis: A Multi-Center and Prospective Trial. Laryngoscope. 2021 Jun;131(6):E1903-E1909. doi: 10.1002/lary.29225. Epub 2020 Oct 28. PMID: 33111982.

 

 

Meditoxin® - Botulinum toxin A

Both parotid gland received 25.00 units fractionated into three 8.33 units   

8.33 units per 1 mL in  three sites:

1. upper pole / 2. lower pole / 3. anterior portion of the gland

with 1 cc 29 gauge insulin syringe; ice pack applied to injection area and reexamined 60 minutes later

 

Prospective study including questionnaires and salivary testing with 6 months followup

Greatest improvement 1 month after BTX injection  - discomfort at 3 and 6 months improved compared to testing prior to injection

BTX injections reduced parotid gland secretion, but did not cause serious drop under lower limit of normal

Conclusion: "BTX can be a viable alternative treatment option in chronic parotitis patients"

Graillon 2019

Graillon N, Le Roux MK, Chossegros C, Haen P, Lutz JC, Foletti JM. Botulinum toxin for ductal stenosis and fistulas of the main salivary glands. Int J Oral Maxillofac Surg. 2019 Nov;48(11):1411-1414.

Xeomin® - IncobotulinumtoinA -

100 IU injected per parotid gland-

  initially distributed between three sites

  finalized as sufficient for two site:

   a. superior pole

   b. inferior pole

50 IU injected per submandibular gland through single injection site

 "echo guided only for non-palpable submandibular glands."

Retrospective study of 22 patients (parotid duct stenosis =14; submandibular duct stenosis = 4; parotid fistula = 4) accrued during years 2014 to 2018. All with salivary duct stenosis had failed treatment with interventional sialendoscopy before use of BTX

No complications

Pain decreased significantly - comparison of visual analog scale grading pretreatment to posttreatment

Average duration of BTX effect was 4.5 months

Concluding BTX injection - following effort at interventional sialendoscopy - "should only be considered as a second-line treatment for salivary duct stenosis" (first line therapy being interventional sialendoscopy if conservative treatment fails)

"Botulinum therapy therefore prevented gland removal"

"Botulinum injections had to be repeated until atrophy of the gland was achieved" (one to nine injections were required)



 

Other reports supporting favorable outcomes after BTX injection for chronic sialadenitis

   

Trapeau C, Foletti JM, Collet C, Guyot L, Chossegros C. Clinical efficacy of botulinum toxin in salivary duct stenosis: a preliminary study of six cases. J Stomatol Oral Maxillofac Surg 2017;118:349–352.

50 units BTX into parotid gland (6 patients)

Mean onset of action: 8 days

Mean duration efficacy: 3.5 months

O’Neil LM, Palme CE, Riffat F, Mahant N. Botulinum toxin for the management of sjogren syndrome-associated recurrent parotitis. J Oral Maxillofac Surg 2016;74:1771-1773

50 units Botox® into each parotid with U/S guidance

65 yo with Sjogrens syndrome requiring antibiotics every two weeks treated initially with BTX injections with 36 month follow-up

"symptoms and antibiotic requirements of our patient were drastically reduced after the first injection of botulinum toxin. Remarkably, she has not required any further courses of antibiotics after the second injection cycle. She requires injections every 4 months to prevent further episodes of parotitis"

 

Guntinas-Lichius O, Jungehulsing M. Treatment of chronic parotid sialectasis with botulinum toxin A. Laryngoscope. 2002;112:586-587.

Dysport® -lyophilized botulinum toxin type A -  was reconstituted with sterile saline solution to a final concentration of 20 IU/mL.

Under ultrasonographic control we injected 200 IU (20 IU were injected into 10 injection sides) into the left parotid gland.

"We suppose that BTXA leads to a long-lasting or perhaps irreversible atrophy of the affect parotid gland acini. Therefore, selective chemodernervation with BTXA is a successful alternative for the treatment of chronic parotid sialectasis"


"The patient was reexamined monthly over 1 year. No toxin side effects were seen. The swelling episodes stopped after 2 weeks and did not reappear during the next 12 months."

Kruegel J, Winterhoff J, Koehler S, Matthes P, Laskawi R. Botulinum toxin: a noninvasive option for the symptomatic treatment of salivary gland stenosis – a case report. Head Neck 2010;32:959–963.

Daniel SJ, Diamond M. Botulinum toxin injection: a novel treatment for recurrent cystic parotitis Sjogren syndrome. Otolaryngol Head Neck Surg 2011;145:180–181.

Capaccio P, Torretta S, Osio M, Minorati D, Ottaviani F, Sambataro G, Nascimbene C, Pignataro L. Botulinum toxin therapy: a tempting tool in the management of salivary secretory disorders. Am J Otolaryngol. 2008 Sep-Oct;29(5):333-8. 

Gillespie MB, Intaphan J, Nguyen SA. Endoscopic-assisted management of chronic sialadenitis. Head Neck. 2011 Sep;33(9):1346-51

   

References

**Strohl MP, Chang CF, Ryan WR, Chang JL. Botulinum toxin for chronic parotid sialadenitis: A case series and systematic review. Laryngoscope Investig Otolaryngol. 2021 May 2;6(3):404-413. doi: 10.1002/lio2.558. PMID: 34195360; PMCID: PMC8223475

Guntinas-Lichius O, Jungehulsing M. Treatment of chronic parotid sialectasis with botulinum toxin A. Laryngoscope. 2002;112:586-587.

**Delagnes EA, Aubin-Pouliot A, Zheng M, Chang JL, Ryan WR. Sialadenitis without sialolithiasis: prospective outcomes after sialendoscopy-assisted salivary duct surgery. Laryngoscope. 2017;127:1073-1079.

Lovato A, Restivo DA, Ottaviano G, Marioni G, Marchese-Ragona R. Botulinum toxin therapy: functional silencing of salivary disorders. Acta Otorhinolaryngol Ital. 2017 Apr;37(2):168-171. doi: 10.14639/0392-100X-1608. PMID: 28516981; PMCID: PMC5463526.

Koch M, Kunzel J, Iro H, Psychogios G, Zenk J. Long-term results and subjective outcome after gland-preserving treatment in parotid duct stenosis. Laryngoscope. 2014;124:1813-1818.

Kwon SY, Chun KJ, Kil HK, Oh KH, Kim C, Jang SJ, Kim MS. Botulinum Toxin Injection for Chronic Parotitis: A Multi-Center and Prospective Trial. Laryngoscope. 2021 Jun;131(6):E1903-E1909. doi: 10.1002/lary.29225. Epub 2020 Oct 28. PMID: 33111982.

Guntinas-Lichius O, Klussmann JP, Wittekindt C, Stennert E. Parotidectomy for benign parotid disease at a university teaching hospital: outcome of 963 operations. Laryngoscope. 2006;116:534-540.

Aubin-Pouliot A, Delagnes EA, Eisele DW, Chang JL, Ryan WR. The Chronic Obstructive Sialadenitis Symptoms Questionnaire to assess sialendoscopy-assisted surgery. Laryngoscope. 2016;126:93-99.

Gillespie MB, O'Connell BP, Rawl JW, McLaughlin CW, Carroll WW, Nguyen SA. Clinical and quality-of-life outcomes following gland- preserving surgery for chronic sialadenitis. Laryngoscope. 2015;125: 1340-1344.

**Delagnes EA, Aubin-Pouliot A, Zheng M, Chang JL, Ryan WR. Sialadenitis without sialolithiasis: prospective outcomes after sialendoscopy-assisted salivary duct surgery. Laryngoscope. 2017;127:1073-1079.

Ellies M, Gottstein U, Rohrbach-Volland S, et al. Reduction of salivary flow with botulinum toxin: extended report on 33 patients with drooling, salivary fistulas, and sialadenitis. LaLaryngoscope 2004;114:1856-60

Truong K, Hoffman HT, Policeni B, Maley J. Radiocontrast Dye Extravasation During Sialography. Ann Otol Rhinol Laryngol. 2018 Mar;127(3):192-199. doi: 10.1177/0003489417752711. Epub 2018 Jan 7. PMID: 29308655.

Schwalje AT, Hoffman HT. Intraductal Salivary Gland Infusion With Botulinum Toxin. Laryngoscope Investig Otolaryngol. 2019 Sep 3;4(5):520-525. doi: 10.1002/lio2.306. PMID: 31637296; PMCID: PMC6793609.

Trapeau C, Foletti JM, Collet C, Guyot L, Chossegros C. Clinical efficacy of botulinum toxin in salivary duct stenosis: a preliminary study of six cases. J Stomatol Oral Maxillofac Surg 2017;118:349–352.

Kruegel J, Winterhoff J, Koehler S, Matthes P, Laskawi R. Botulinum toxin: a noninvasive option for the symptomatic treatment of salivary gland stenosis – a case report. Head Neck 2010;32:959–963.

Daniel SJ, Diamond M. Botulinum toxin injection: a novel treatment for recurrent cystic parotitis Sjogren syndrome. Otolaryngol Head Neck Surg 2011;145:180–181.

O’Neil LM, Palme CE, Riffat F, Mahant N. Botulinum toxin for the management of sjogren syndrome-associated recurrent parotitis. J Oral Maxillofac Surg 2016;74:1771-1773

Capaccio P, Torretta S, Osio M, Minorati D, Ottaviani F, Sambataro G, Nascimbene C, Pignataro L. Botulinum toxin therapy: a tempting tool in the management of salivary secretory disorders. Am J Otolaryngol. 2008 Sep-Oct;29(5):333-8. doi: 10.1016/j.amjoto.2007.10.003. Epub 2008 Jun 16. PMID: 18722890.

Gillespie MB, Intaphan J, Nguyen SA. Endoscopic-assisted management of chronic sialadenitis. Head Neck. 2011 Sep;33(9):1346-51. doi: 10.1002/hed.21620. Epub 2011 Jan 20. PMID: 21254296.

Reddy R, White DR, Gillespie MB. Obstructive parotitis secondary to an acute masseteric bend. ORL J Otorhinolaryngol Relat Spec. 2012;74(1):12-5. doi: 10.1159/000334246. Epub 2011 Dec 8. PMID: 22156562.

Graillon N, Le Roux MK, Chossegros C, Haen P, Lutz JC, Foletti JM. Botulinum toxin for ductal stenosis and fistulas of the main salivary glands. Int J Oral Maxillofac Surg. 2019 Nov;48(11):1411-1414. doi: 10.1016/j.ijom.2019.04.015. Epub 2019 May 6. PMID: 31072799.

Ryan WR, Plonowska KA, Gurman ZR, Aubin-Pouliot A, Chang JL. One-Year symptom outcomes after sialolithiasis treatment with sialendoscopy-assisted salivary duct surgery. Laryngoscope. 2019 Feb;129(2):396-402. doi: 10.1002/lary.27398. Epub 2018 Aug 27. PMID: 30151855.

Plonowska KA, Gurman ZR, Humphrey A, Chang JL, Ryan WR. One-year outcomes of sialendoscopic-assisted salivary duct surgery for sialadenitis without sialolithiasis. Laryngoscope. 2019 Apr;129(4):890-896. doi: 10.1002/lary.27433. Epub 2018 Aug 27. PMID: 30152080.

Mandour MA, Helmi AM, El-Sheikh MM, El-Garem F, El-Ghazzawi E. Effect of tympanic neurectomy on human parotid salivary gland. Histopathologic, Histochemical, and Clinical Study. Arch Otolaryngol. 1977 Jun;103(6):338-41. doi: 10.1001/archotol.1977.00780230060008. PMID: 869767.

Callander JK, Plonowska-Hirschfeld K, Gulati A, Chang JL, Ryan WR. Symptom Outcomes After Sialendoscopy-Assisted Salivary Duct Surgery: A Prospective 6-Year Study. Laryngoscope. 2023 Apr;133(4):792-800. doi: 10.1002/lary.30294. Epub 2022 Jul 18. PMID: 35848880.