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REVIEW ARTICLE Table of Contents  
Ahead of print publication
Treatment of sialorrhea in Parkinson’s disease


 Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

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Date of Submission15-Feb-2022
Date of Decision15-Apr-2022
Date of Acceptance16-May-2022
Date of Web Publication28-Jul-2022
 

  Abstract 

Sialorrhea is a common disabling nonmotor symptom of Parkinson’s disease. It can lead to several ill effects such as poor orodental hygiene, speech and feeding difficulty, depressive symptoms, poor quality of life, and aspiration pneumonia. It most likely occurs secondary to swallowing dysfunction due to a combination of factors such as lingual bradykinesia, oropharyngeal dysphagia, and esophageal dysmotility, leading to impaired salivary clearance. Various tools are available for its objective assessment to assess drooling in patients with Parkinson’s disease. The treatment options include use of anticholinergic medications and optimization of dopaminergic therapy. However, their use is limited due to the occurrence of adverse effects. Botulinum toxin injections into the parotid and submandibular glands is the most effective and safest treatment available at present.

Keywords: anticholinergics, botulinum toxin, glycopyrrolate, Parkinson’s disease, sialorrhea


How to cite this URL:
Mehta S, Lal V. Treatment of sialorrhea in Parkinson’s disease. Ann Mov Disord [Epub ahead of print] [cited 2022 Dec 7]. Available from: https://www.aomd.in/preprintarticle.asp?id=352658





  Introduction Top


Sialorrhea is defined as excessive production or overflow of saliva, and drooling refers to excessive pooling of saliva in the oral cavity due to impaired salivary clearance.[1] It is a disabling symptom associated with many neurological illnesses, the most common being Parkinson’s disease (PD), amyotrophic lateral sclerosis, cerebrovascular accident, cerebral palsy, and other atypical parkinsonian disorders. The prevalence of sialorrhea in PD ranges from 10% to 84% across various studies.[2] It is commonly assessed in routine clinical practice using Part II (2.2) of the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (UPDRS) and is graded from normal to severe. In PD, sialorrhea most likely occurs secondary to swallowing dysfunction and flexed head posture and not due to hypersecretion as demonstrated in several previous studies.[3] The impairment of salivary clearance can occur secondary to lingual bradykinesia, oropharyngeal dysphagia, and upper esophageal dysmotility.[4] It can cause social embarrassment, poor orodental hygiene, impaired quality of life, depressive symptoms, and speech and feeding difficulty. In addition, it can increase the risk of aspiration pneumonia, leading to increased morbidity.

The three pairs of major salivary glands are the parotid, submandibular, and sublingual glands; approximately, 90% of the saliva is produced by these major salivary glands. Most of the saliva produced by the submandibular gland occurs in the resting state. However, the contribution of the parotid gland increases under stimulated conditions.

Subjective and objective assessment tools are available to assess drooling in patients with PD. The three commonly used rating scales in various trials include the Sialorrhea Clinical Scale for PD (SCS–PD), Drooling Rating Scale, and Drooling Severity and Frequency Scale.[5]


  Treatment options Top


  • 1. The first step is to withdraw medications that may aggravate drooling, if possible, such as antipsychotics (clozapine or quetiapine) and cholinesterase inhibitors (donepezil and rivastigmine).[6],[7]


  • 2. The second step is optimization of dopaminergic treatment or use of invasive therapies such as deep brain stimulation, if clinically indicated and justified.


  • 3. The third step is to begin specific adjunctive treatment as described below:
    • A. Anticholinergics: Anticholinergics reduce salivary secretion by inhibiting the binding of acetylcholine to muscarinic receptors (especially M3) in the salivary glands. The commonly used drugs from this class include oral glycopyrrolate, oral trihexyphenidyl, sublingual atropine, and sublingual ipratropium bromide. The potential adverse effects with these medications include confusion, hallucinations, urinary retention, and constipation. Since glycopyrrolate is a quaternary ammonium compound, it does not readily cross the blood–brain barrier and has less potential to induce the abovementioned side effects. It can be used at a dose of 1–2 mg two or three times daily. Arbouw et al.[8] demonstrated a >30% improvement on the sialorrhea rating scale at 4 weeks in their double-blind placebo-controlled trial. Mestre et al.[9] recently demonstrated the efficacy of glycopyrrolate for sialorrhea-related disability and severity in PD (mean duration 10 years) up to 3 months at a dose of 4.5 mg/day. The results were statistically significant (p < 0.05) at 6 weeks of treatment. Adverse effects occurred with a dose of >3 mg/day. In addition, sublingual atropine drops can be used in doses of 0.5 mg twice daily; however, the evidence is scarce.[10]


    • B. Adrenergic receptor agonists: At present, there are no recommendations on using these drugs to treat drooling in PD. However, studies with small sample sizes have demonstrated the beneficial effects of clonidine (0.15 mg daily) and modafinil (100 mg daily) on drooling in PD.[11]


    • C. Dihydroergotoxin mesylate: It is a selective alpha adrenergic blocking agent with some affinity to dopaminergic and serotonin receptors. A dose of 2.5 mg twice daily is generally administered after meals. In a single-center study with a sample size of 30 patients, Cheng et al.[12] demonstrated significant decrease in sialorrhea using SCS–PD with a response rate of 60% (defined as at least 30% reduction in the SCS–PD score) at 3 weeks in the open-label phase. In addition, a significant improvement with a response rate of 55% was observed at 6 weeks in the second phase of this crossover trial. No major adverse effects were observed. However, further research is needed to establish the efficacy of this drug in routine clinical practice.


    • D. Botulinum toxin injections: Botulinum toxins A and B have shown to be effective in the treatment of drooling in PD.[13],[14],[15],[16] The mechanism of action involves presynaptic inhibition of acetylcholine release in the parasympathetic and sympathetic cholinergic ganglia, leading to reduced salivary secretion. Botulinum toxin can be injected using anatomical landmarks or under ultrasound guidance. The landmark for the parotid gland injection is the midpoint of an imaginary line extending from the tragus to the angle of the mandible. The anatomical landmark for the submandibular gland is a one finger-breadth medial to the midline of an imaginary line along the length of the body of the mandible starting from the mandibular angle to the tip of the chin ([Figure 1]). Ultrasound guidance may aid in efficacy and accuracy. The onset of the botulinum toxin injection usually starts at 1 week and may last for approximately 3–5 months. The dose administered in various studies range from 10 to 50 units of onabotulinum toxin per each parotid gland and 5 to 15 units per each submandibular gland.[13],[14],[15] The doses for abobotulinum toxin range from 18.75 to 146.25 units and 18.75 to 78.75 units per each parotid and submandibular gland, respectively.[16],[17] The adverse effects include transient dryness of the mouth and mild dysphagia. Ondo et al.[18] used 1000 units and 250 units of botulinum toxin B in each parotid and submandibular gland, respectively. In a randomized controlled trial, Jost et al.[19] recently demonstrated the long-term efficacy and safety of incobotulinum toxin for chronic sialorrhea over 64 weeks. In their study, 70% of the patients had PD, and 75 units and 100 units of incobotulinum toxin were administered into the bilateral parotid and submandibular glands, respectively. There was improvement in the unstimulated salivary flow rate, modified Radboud Oral Motor Inventory for PD drooling scores, global impression of change scale, and Drooling Severity and Frequency Scale with every cycle. There was no difference between the ultrasound-guided versus blinded injections using anatomical landmarks. Similarly, statistically significant improvement was observed with rimabotulinum toxin (botulinum toxin B) at 4 weeks in another randomized controlled trial.[20]


    • E. Deep brain stimulation: Bilateral subthalamic nucleus deep brain stimulation has been shown to reduce sialorrhea; therefore, it demonstrates a modest level of benefit.[21],[22]


    • F. Nonpharmacological approaches: Speech and behavioral therapy under the guidance of otolaryngologists and neuropsychologists, respectively, can be helpful. Behavioral modifications such as chewing gum or hard candy may serve as a tactile clue to swallow more frequently. In addition, in certain scenarios it may serve as a time-locked reminder to the patient to swallow saliva at regular intervals of 30 minutes each day.[23]


    • G. Other therapies: The other treatments mentioned in the literature include radiotherapy and surgical options such as sectioning of the chorda tympani nerves known as neurectomy, ligation or relocation of the salivary duct, and excision of the gland itself. These are more invasive procedures that can lead to the potential complications of aspiration pneumonia, loss of taste, dry mouth, and dental caries. Postma et al.[24] studied the long-term efficacy and safety of radiotherapy to major salivary glands in 28 patients with  Parkinsonism More Details (22 with PD). A total dose of 12 Gy was administered to the parotid gland and a part of the submandibular gland bilaterally. There was remarkable improvement in sialorrhea at 1 month, and this effect was persistent at 1 year. In their study, 75% of the patients experienced transient side effects in the form of loss of taste and dry mouth. In addition, the efficacy and safety of irradiation to the parotid and submandibular glands have been demonstrated in recent randomized clinical trials.[25]


Figure 1: Anatomical landmarks for botulinum toxin injection for the parotid (A) and submandibular glands (B) (adapted from Srivanitchapoom et al.[4])

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  Conclusion Top


Sialorrhea is a disabling symptom of PD with negative impact on the patient’s quality of life. At present, botulinum toxin is the most efficacious treatment and can be used in conjunction with oral therapy (glycopyrrolate), wherever tolerable. Furthermore, optimization of dopaminergic treatments plays a major role in the management of drooling in patients with PD. A recent 2019 Movement Disorder Society evidence-based review on nonmotor therapies in PD recommended botulinum toxins A and B as clinically useful and oral glycopyrrolate as possibly useful in the treatment of sialorrhea in PD.[26][Table 1] summarizes the major studies focusing on various interventions used in the management of sialorrhea in PD.
Table 1: Summary of major studies focusing on various interventions used for sialorrhea in Parkinson’s disease

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Author contributions

Sahil Mehta- Concept, Drafting of manuscript and review of literature

Vivek Lal- Revision of Manuscript

Acknowledgements

We would like to acknowledge Shasha Verma for helping us in making [Figure 1] of the manuscript

Ethical compliance statement

Nil.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Dand P, Sakel M. The management of drooling in motor neurone disease. Int J Palliat Nurs 2010;16:560-4.  Back to cited text no. 1
    
2.
Kalf JG, de Swart BJ, Borm GF, Bloem BR, Munneke M. Prevalence and definition of drooling in Parkinson’s disease: A systematic review. J Neurol 2009;256:1391-6.  Back to cited text no. 2
    
3.
Proulx M, de Courval FP, Wiseman MA, Panisset M. Salivary production in Parkinson’s disease. Mov Disord 2005;20:204-7.  Back to cited text no. 3
    
4.
Srivanitchapoom P, Pandey S, Hallett M. Drooling in Parkinson’s disease: A review. Parkinsonism Relat Disord 2014;20:1109-18.  Back to cited text no. 4
    
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Perez Lloret S, Pirán Arce G, Rossi M, Caivano Nemet ML, Salsamendi P, Merello M. Validation of a new scale for the evaluation of sialorrhea in patients with Parkinson’s disease. Mov Disord 2007;22:107-11.  Back to cited text no. 5
    
6.
Chen SY, Ravindran G, Zhang Q, Kisely S, Siskind D. Treatment Strategies for clozapine-induced sialorrhea: A systematic review and meta-analysis. CNS Drugs 2019;33:225-38.  Back to cited text no. 6
    
7.
Freudenreich O. Drug-induced sialorrhea. Drugs Today (Barc) 2005;41:411-8.  Back to cited text no. 7
    
8.
Arbouw ME, Movig KL, Koopmann M, Poels PJ, Guchelaar HJ, Egberts TC, et al. Glycopyrrolate for sialorrhea in Parkinson disease: A randomized, double-blind, crossover trial. Neurology 2010;74:1203-7.  Back to cited text no. 8
    
9.
Mestre TA, Freitas E, Basndwah A, Lopez MR, de Oliveira LM, Al-Shorafat DM, et al. Glycopyrrolate improves disability from sialorrhea in Parkinson’s disease: A 12-week controlled trial. Mov Disord 2020;35:2319-23.  Back to cited text no. 9
    
10.
Hyson HC, Johnson AM, Jog MS. Sublingual atropine for sialorrhea secondary to Parkinsonism: A pilot study. Mov Disord 2002;17:1318-20.  Back to cited text no. 10
    
11.
Serrano-Dueñas M. Tratamiento de la sialorrea de enfermos parkinsonianos con clonidina. Estudio comparativo doble ciego, frente a placebo [Treatment of sialorrhea in Parkinson’s disease patients with clonidine. Double-blind, comparative study with placebo]. Neurologia 2003;18:2-6. Spanish.  Back to cited text no. 11
    
12.
Cheng YQ, Ge NN, Zhu HH, Sha ZT, Jiang T, Zhang YD, et al. Dihydroergotoxine mesylate for the treatment of sialorrhea in Parkinson’s disease. Parkinsonism Relat Disord 2019;58:70-3.  Back to cited text no. 12
    
13.
Pal PK, Calne DB, Calne S, Tsui JK. Botulinum toxin A as treatment for drooling saliva in PD. Neurology 2000;54:244-7.  Back to cited text no. 13
    
14.
Lagalla G, Millevolte M, Capecci M, Provinciali L, Ceravolo MG. Botulinum toxin type A for drooling in Parkinson’s disease: A double-blind, randomized, placebo-controlled study. Mov Disord 2006;21:704-7.  Back to cited text no. 14
    
15.
Friedman A, Potulska A. Quantitative assessment of parkinsonian sialorrhea and results of treatment with botulinum toxin. Parkinsonism Relat Disord 2001;7:329-32.  Back to cited text no. 15
    
16.
Mancini F, Zangaglia R, Cristina S, Sommaruga MG, Martignoni E, Nappi G, et al. Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism. Mov Disord 2003;18:685-8.  Back to cited text no. 16
    
17.
Lipp A, Trottenberg T, Schink T, Kupsch A, Arnold G. A randomized trial of botulinum toxin A for treatment of drooling. Neurology 2003;61:1279-81.  Back to cited text no. 17
    
18.
Ondo WG, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson’s disease. Neurology 2004;62:37-40.  Back to cited text no. 18
    
19.
Jost WH, Friedman A, Michel O, Oehlwein C, Slawek J, Bogucki A, et al. Long-term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks. Parkinsonism Relat Disord 2020;70:23-30.  Back to cited text no. 19
    
20.
Isaacson SH, Ondo W, Jackson CE, Trosch RM, Molho E, Pagan F, et al. Safety and efficacy of RimabotulinumtoxinB for treatment of sialorrhea in adults: A randomized clinical trial. JAMA Neurol 2020;77:461-9.  Back to cited text no. 20
    
21.
Zibetti M, Torre E, Cinquepalmi A, Rosso M, Ducati A, Bergamasco B, et al. Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. Eur Neurol 2007;58:218-23.  Back to cited text no. 21
    
22.
Rukmini Mridula K, Borgohain R, Jabeen SA, Padmaja G, Bandaru VS, Ankathi P, et al. Comparison of frequencies of non motor symptoms in Indian Parkinson’s disease patients on medical management versus deep brain stimulation: A case-control study. Iran J Neurol 2015;14:86-93.  Back to cited text no. 22
    
23.
Marks L, Turner K, O’Sullivan J, Deighton B, Lees A. Drooling in Parkinson’s disease: a novel speech and language therapy intervention. Int J Lang Commun Disord 2001;36(Suppl): 282-7.  Back to cited text no. 23
    
24.
Postma AG, Heesters M, van Laar T. Radiotherapy to the salivary glands as treatment of sialorrhea in patients with parkinsonism. Mov Disord 2007;22:2430-5.  Back to cited text no. 24
    
25.
Steenbakkers RJHM, van Doornik SP, Vissink A, Kerdijk W, van Laar T. Radiation of parotid or submandibular glands is effective for drooling in patients with parkinsonism; a randomised double-blind placebo-controlled trial. Clin Park Relat Disord 2022;6:100138. doi: 10.1016/j.prdoa.2022.100138.  Back to cited text no. 25
    
26.
SeppiK, Ray ChaudhuriK, CoelhoM, FoxSH, KatzenschlagerR, Perez LloretS, et al; the collaborators of the Parkinson's Disease Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Medicine Committee. Update on treatments for nonmotor symptoms of Parkinson's disease - An evidence-based medicine review. Mov Disord 2019;34:180-98.  Back to cited text no. 26
    

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Correspondence Address:
Sahil Mehta,
Associate Professor, Department of Neurology, Post Graduate Institute of Medical Sciences and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None



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