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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 18-August-2006, Vol 119 No 1240

Botulinum toxin type-A (Botox-A) injections for treatment of sialorrhoea in adults: a New Zealand study
Subhaschandra Shetty, Patrick Dawes, Dean Ruske, Mohannad Al-qudah, Brett Lyons
Abstract
Aim We report our initial experience using Botox-A injection to the salivary glands to control sialorrhoea.
Methods Eight adult patients with significant sialorrhoea were referred from an inpatient rehabilitation unit, GP referral, and internal medicine department. All subjects underwent bilateral submandibular gland injections and, in addition, one patient (the first) also had intraparotid injections. Injections were performed with ultrasound guidance at Dunedin Hospital, New Zealand. Six patients received a total of 30 Units and two patients received 60 Units in the submandibular glands without any complications. Outcome was assessed using a drooling scale and VAS self report of sialorrhoea.
Results Of the eight patients treated, six reported a marked reduction in salivation following treatment, and one patient improved partially. One patient did not find the Botox injection helpful in controlling sialorrhoea and was offered escalation of the Botox dose with a subsequent partial response. No serious adverse events occurred, and no procedure-related complications were noted.
Conclusions Our initial experience suggests that injection of Botox-A injected at a relatively low dose to the submandibular glands can be used to achieve desired results for the treatment of sialorrhoea. This is an easily performed procedure with low morbidity and can be recommended as a first-line intervention in the treatment of adult sialorrhoea.

Sialorrhoea is an important clinical, social, and emotional issue, which contributes to poor quality of life and carer burden. It is associated with a wide range of disorders,1 as shown in Table 1.
Salivary gland secretion is controlled by the autonomic nervous system, mediated by adrenergic and cholinergic nerve endings, but primarily under parasympathetic cholinergic control. The major salivary glands (the paired parotid, submandibular, and sublingual) are responsible 95% of the 1.5 L of saliva secreted daily. In the unstimulated (basal) state, 70% of saliva is secreted by the submandibular salivary glands.2
Sialorrhoea is defined as saliva emanating beyond the lip margins. The physical and psychosocial complications (associated with sialorrhoea) range from mild and inconvenient symptoms to severe problems that can have a significant negative impact on quality of life.3–5
Various treatments are described for sialorrhoea, each having their own side effects.3 Systemic anticholinergics are often ineffective, produce blurred vision, urinary retention, and in 40% of cases, cardiac arrhythmia.5
Surgical intervention may involve either rerouting of the submandibular ducts, excision of salivary tissue, or in uncommon situations (when voice function is lost) laryngectomy.5.
Each surgery carries complications both specific to the procedure as well as to the general condition of the patient. Radiotherapy has been used to reduce salivary gland function. This is time consuming, and is associated with mucositis during treatment as well as injury to minor salivary glands caught in the treatment field, so that the end result may be less predictable—resulting in xerostomia.6
Table 1. Aetiology of sialorrhoea
Neuromuscular/sensory dysfunction
Mental retardation
Cerebral palsy
Parkinson's disease
Pseudobulbar*
Bulbar palsy*
Stroke*
Hypersecretion†
Inflammation (teething, dental caries, oral-cavity infection, rabies)
Drug side effects (tranquillizers, anticonvulsants)
Gastro-oesophageal reflux
Toxins (e.g. mercury)
Anatomic‡
Macroglossia
Oral incompetence
Malocclusions
Orthodontic condition
Head and neck (H&N) surgical defect
*Less common; Usually controlled by increased swallowing; Frequently exacerbate existing problems.
Recently, Botulinum toxin-A (Botox-A) intraglandular application has been shown to significantly decrease saliva production and is considered a safe treatment.7,8 Botox-A acts to inhibit salivary production by binding to SNAP-25 (25 kDa synaptosome-associated protein), a cytoplasmic protein involved in the fusion of synaptic vesicles with the presynaptic membrane. This ultimately disrupts the secretory pathway for acetylcholine and produces a chemodenervation.10 Gradual re-innervation occurs as the neurones regenerate SNAP-25.
The Botox-A injection procedure has its own complications—they range from minor (bleeding, pain at site, flu-like symptoms, parotitis, and dry mouth) to severe (dysphagia, aspiration, facial nerve branch palsy, temporomandibular joint [TMJ] dislocation, and vascular injuries)
We present our personal experience treating eight adults with disabling sialorrhoea using Botox-A injections. We used low dosages and favoured bilateral injection of the submandibular glands. Limiting injection to submandibular glands aimed to minimise morbidity associated with xerostomia.

Methods

Patients—Eight adult patients with drooling (attributable to head and neck carcinoma, neurodegenerative diseases, quadriplegia, or idiopathic salivation) were treated by injection of Botox-A into the submandibular glands (and parotid glands in one case) at Dunedin Hospital in New Zealand. Patient demographics and clinical data are shown in Table 2.
Table 2. Demographics and clinical details
Patient number
Age/Sex
Diagnosis
Duration of sialorrhoea
Total Botox-A dose (IU)
Improvement following injection (Global VAS)
1
84/M
Idiopathic sialorrhoea
4 years
30
Marked
2
50/M
Quadriplegia
3 years
30
Marked
3
35/M
Neurodegenerative + Quadriplegia
1 year
30
Marked (Patient died 5 months following injection due to cardiac disease)
4
74/M
Pharyngocutaneous fistula + Idiopathic sialorrhoea
11 months
30
Mild
5
77/F
Idiopathic hypersalivation
2 years
30
Marked
6
64/M
Parkinson’s disease
3 years
45
No change
7
42/M
Quadriplegia
2 years
30
Marked change
8
69/M
Lateral medullary syndrome
1 year
30
Marked change
All patients were informed of the details of therapy and its possible side effects and gave their written consent to undergo treatment and present themselves regularly for follow-up examinations.
During the first outpatient visit, the symptom ‘drooling’ was scored by means of the ‘questionnaire-based semi-quantitative assessment of drooling severity and frequency’ as shown in Table 3 and a VAS estimate of drooling severity.
Table 3. System for assessment of frequency and severity of drooling*
The VAS scale introduced in this series (before and after injection) was a 100 mm horizontal line marked from 0 (normal salivation) up to 100 (worst possible drooling). Patients marked the line at the point they felt represented their current salivation state or rate.
All patients had high severity scores reflecting that clothing, hands, tray, and objects become wet because of drooled saliva. The frequency scores showed that all patients had frequent to constant drooling scores.
Injection technique—Using high-resolution ultrasound, the vascular anatomy, gland location, and size of the submandibular glands were carefully assessed immediately prior to injection. No anaesthesia was used, and the treatment was usually well tolerated. Botox-A® (ALLERGAN, New Zealand) 100 Mouse Units (U) was reconstituted with 0.9% sodium chloride solution to 100 U/4ml.
In the majority of the patients, 15 U (0.6 ml) of Botox-A was injected into each submandibular gland and, in one case, 7.5 U to both parotids. After defining the gland and its blood supply, the ultrasound transducer was positioned in such a way that injections with the needle were possible along the axis of the transducer, thus providing quick and easy visualisation of the needle entering the gland.
The injections were administered after clearly visualising the central part of the parenchyma of submandibular glands in real time mode with avoidance of blood vessels.
All patients were monitored for 1 hour post-injection. Side effects and procedure-related complications were carefully monitored; only pain at the injection site was noted in one patient. In the follow-up period (at 6 weeks and 6 months), all patients were examined and the scores were repeated; global VAS scores were also noted.

Efficacy and Results:

Major side effects were not seen even after repeated doses; in particular neither xerostomia nor dysphagia was seen. The risk for these potential adverse effects may be diminished but certainly cannot be excluded by our limiting the dose and number of treated glands.
Reduction in salivation was first noted 3 days (mean 5 days) after the injection. Seven patients reported substantial reduction of salivation and drooling at their first visit at 6 weeks after injection and the effect was maintained at 6 months in 5 patients—as shown in Figure 1 and Figure 2. One patient (#3) died from cardiac disease 5 months after the Botox-A injection; he had remained symptom-free till death. (His family confirmed his salivation had remained controlled until he died.)
Figure 1. Patients assessment of the level of sialorrhoea, as determined by VAS, at baseline and the point of maximum benefit after Botox-A injection
Figure 2. Median drooling scores at follow-up periods following Botox injection compared to baseline (pre-injection)
Note: Patient #3 died at 5 months.
One patient, with Parkinson’s disease (patient #6) experienced no improvement after the first injection and proceeded to a second injection with higher dose [30 U], again with little perceived benefit. Patient #4, who had a pharyngocutaneous fistula, showed an initial response for 12 weeks after which his symptoms recurred. He has received further injections at 6 months [30 U/submandibular gland] and is still in follow-up showing gradual improvement in his salivation rate.
Unwanted side effects were assessed at visit 2 and 3 using a 0–4 scale (0=no adverse events; 1=mild or brief; 2=moderate; 3=severe and brief; 4=severe, disabling and long-standing). We asked about dysphagia, chewing and breathing difficulties, and generalised weakness. No serious side effects or procedure-related complications occurred during the treatment. One patient complained of injection site pain, which was considered mild and was controlled with paracetamol.

Discussion

This series represents the preliminary experience gained at Dunedin Hospital with intraglandular injection of Botulinum Toxin-A to reduce drooling in various disorders. Six out of eight patients reported excellent control of drooling.
Early reports describing the use of Botulinum toxin in the management of sialorrhoea described intraparotid injection,7,11 with the reduction in salivation lasting between 4 and 7 months. Overall, the duration of effect is longer than following intramuscular injection of Botulinum toxin, although there is both intra-individual and inter-individual variation.9–11
More recently, Jongius et al12 have recommended injection into the submandibular glands only; their proposal being based on the consideration that the submandibular salivary glands are responsible for 60–70% of basal salivary production. The theoretical benefit being that reducing basal secretion will counteract drooling while allowing secretion from the parotid glands during meals—thus maintaining lubrication for chewing and swallowing as well as reducing the risk of gingivitis, caries, and secondary ascending parotitis.
The reported total dose of Botox-A administered varies from 10 U to 100 U.2,4,11,12 A prospective, double blind, randomised trial has evaluated the efficacy of three different dosages (18.75, 37.5, and 75 U per parotid gland) of intraglandular injection of Botox-A for patients with sialorrhoea. Good control of salivation was achieved with 75 U of Botox-A per side, suggesting this is safe and effective treatment for patients with sialorrhoea.13
A recent placebo-controlled study investigated the highest dosage of Botox-A ever used (450 U) for sialorrhoea; injection was made in to the parotid and submandibular glands and reduced salivation was described for approximately 1 month.14 Pal et al have suggested that accuracy when placing the toxin within the salivary glands plays an important role in dosages required and results.15
We used relatively low dosages of Botox-A (15 U to each gland) and achieved significant effects using an ultrasound-guided technique. Effective low doses of Botox-A may help to prevent development of neutralising antibodies, which is a potential problem in 5–10% of treated patients. An interval of less than 3 months between treatments and high doses of Botox-A are considered risk factors for the development of immunoresistance.16
In late 2004, there was a news report of complications following the use of Botox A for managing sialorhoea in children, the injections having been administered at Starship Hospital (Auckland, New Zealand).17 Specifically, extracapsular spread of the drug had caused paralysis of the pharyngeal muscles resulting in dysphagia for three children. Communication with the ORL-HNS service at Starship indicates that ultrasound was used to identify the submandibular glands; the factors thought most likely to have contributed to the dysphagia were underlying swallowing dysfunction related to cerebral palsy and extravasation of Botox beyond the submandibular gland capsule exacerbated by the use of a larger volume of diluted Botox (Botox-A 100MU diluted in 5 ml saline – 2 ml to each gland). Guidelines have since been developed—Starship now use 100 MU diluted in 1 ml saline, and they inject 30 MU (0.3 ml) to each gland18,19.
Recent literature strongly recommends the use of ultrasound to guide the injection of Botox-A to salivary glands.1,4,9,11–13,15 In our experience, using ultrasound, with real-time needle positioning during infiltration, has made the treatment more precise and helped to avoid inadvertent migration of the toxin. Indeed, this single ultrasound-guided injection not only prevents the morbidity associated with multiple site injection, it is essential for targeting the correct region (intraparenchymal) of the salivary tissue.

Conclusion

The injection of Botox-A in to the submandibular glands is an easily administered, effective treatment for adult drooling, regardless of the underlying cause of the condition; it has few side effects. The use of ultrasound guidance during the injection procedure may enhance efficacy and safety.
Although our results are encouraging, a full clinical trial would be needed to formally evaluate the most effective dosage, risks, and the benefits of Botox-A for palliative treatment of sialorrhoea. Indeed, Botox-A may prove to be a dependable therapeutic option for patients with sialorrhoea.
Author information: Subhaschandra Shetty, MOSS Otolaryngology-Head and Neck Surgeon, Whangarei Base Hospital, Whangarei; Patrick Dawes, Senior Clinical Lecturer and Consultant Otolaryngology-Head and Neck Surgeon, Dunedin Public Hospital, Dunedin; Dean Ruske, Consultant Otolaryngology-Head and Neck Surgeon, Dunedin Public Hospital, Dunedin; Mohannad Al-Qudah, Clinical Fellow in Otolaryngology-Head and Neck Surgery, Department of Otolaryngology-Head and Neck Surgery, Dunedin Public Hospital, Dunedin; Brett Lyons, Clinical Leader and Head of the Department of MR Imaging, Southland Hospital, Invercargill
Correspondence: Subhaschandra Shetty, Otolaryngology-Head and Neck Surgeon, Whangarei Base Hospital, Whangarei. Fax: (09) 430 4127;email: subhash@nhl.co.nz
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