Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism.

Drooling is a frequent symptom in Parkinson's disease (PD), occurring in almost 75% of all patients. Although it is now well known that drooling in PD is the result of swallowing difficulties rather than excessive saliva production, few treatments have been developed to reduce it. Clinical studies suggest that botulinum toxin A (BTX) injections into salivary glands are effective in decreasing drooling in PD patients. In this double-blind, placebo-controlled study, 20 patients with parkinsonism (idiopathic PD or multiple system atrophy), were randomly assigned to receive 450 U of BTX (Dysport; Ipsen, Berkshire, UK) or 2 ml of placebo, injected into the parotids and submandibular glands under ultrasonographic guidance. Treatment efficacy and safety were assessed at baseline, 1 week and 3 months after BTX injections using clinical scales (Drooling Severity and Drooling Frequency scales) and side effects surveillance. After treatment, the average secretion of saliva in the BTX group was significantly lower than in the placebo group, as appraised by clinical measurements. No side effects were observed in either group. BTX injection into parotids and submandibular glands, under ultrasonographic guidance, is an effective and safe treatment for drooling in parkinsonism.     

Botulinum toxin B reduces sialorrhea in parkinsonism.

We report on our open-label experience with botulinum toxin B for the treatment of severe sialorrhea associated with parkinsonism. Nine adult patients with parkinsonism and medically intractable sialorrhea were treated with botulinum toxin B (1,000 units into each parotid gland using superficial landmarks). After treatment, patients experienced a 61% mean subjective improvement and a 42% mean reduction of quantitative saliva production. There were no adverse effects seen in any subjects. Mean peak benefit from injections lasted 14 weeks. We conclude that denervation of salivary glands with botulinum toxin B produces excellent reduction of excessive salivation associated with parkinsonism.     

Long-term incobotulinumtoxinA treatment for chronic sialorrhea: Efficacy and safety over 64 weeks

BackgroundBotulinum neurotoxin (BoNT) is an effective treatment for chronic sialorrhea; however, reliable and robust evidence supporting long-term efficacy and safety is lacking. This study investigated the efficacy and safety of repeated incobotulinumtoxinA injections for chronic sialorrhea over 64 weeks.MethodsAdults with sialorrhea were randomized (2:2:1) to incobotulinumtoxinA 75 U, incobotulinumtoxinA 100 U (n = 74 each), or placebo (n = 36) in the double-blind, placebo-controlled main period (NCT02091739). Eligible subjects entered the extension period and received dose-blinded incobotulinumtoxinA 75 or 100 U in three further 16±2-week injection cycles. Efficacy and safety assessments in subjects who received incobotulinumtoxinA throughout the study included unstimulated salivary flow rate (uSFR), subjects' Global Impression of Change Scale (GICS), Drooling Severity and Frequency Scale (DSFS), modified Radboud Oral Motor Inventory for Parkinson's Disease (mROMP) drooling, speech, and swallowing symptom scores, and incidence of adverse events (AEs).ResultsIn total, 173/184 subjects (94%) completed the main period and entered the extension period; 141 subjects received incobotulinumtoxinA 75 U (n = 69) or 100 U (n = 72) in both periods. Mean uSFR decreased consistently with repeated incobotulinumtoxinA 75 and 100 U treatment and by −0.16 and −0.17, respectively, at the end-of-study visit. Subjects’ GICS, DSFS, and mROMP drooling scores also improved at all assessments. mROMP speech and swallowing scores remained stable. The most common treatment-related AEs during the extension period were dry mouth (4.4% and 11.1%) and dysphagia (1.5% and 4.2%).ConclusionsData support long-term efficacy and safety of repeated incobotulinumtoxinA treatment for sialorrhea, with no additional safety concerns reported over 64 weeks.     

Long-lasting benefits of botulinum toxin type B in Parkinson’s disease-related drooling

Purpose   To investigate the safety, efficacy and effectiveness of botulinum toxin type-B (BTX-B) injections into the parotid glands to reduce drooling in Parkinson’s disease (PD) subjects. Methods   A double-blind, randomised, placebo-controlled study enrolled 36 advanced phase PD subjects who complained of disabling drooling. Patients received either 4000U BTX-B or placebo. Anatomically guided injections were performed. Outcome measures were chosen to assess both the subjective feeling of improvement (i. e. the Drooling Severity and Frequency Scale, DSFS, visuo-analogic ratings of familial distress, VAS-FD, and social distress, VAS-SD) and objective saliva reduction (saliva production over five minutes was checked by weighing dental rolls). The Global Impression Score (GIS) was also applied, rating improvement from 0 to 3. Results   One month after injections, BTX-B patients showed a meaningful improvement in almost all subjective outcomes. Two-way analysis of variance gave a significant time × treatment effect, F-value being 52.5 (p < 0.0001) for DS-FS, 23.2 (p < 0.0001) for VAS-FD, 29 (p < 0.0001) for VAS-SD, and 28.9 (p < 0.0001) for UPDRSADL drooling item score. All BTX-B subjects declared sialorrhea reduction of any kind (moderate for 44.4 % cases, and dramatic for 33.3 % subjects), at variance with 61.1 % controls who denied any benefit from treatment. (Chi-square = 22.9; p < 0.0001). When present, benefits lasted on average 19.2 ± 6.3 weeks in the BTX-B group compared to 6.7 ± 1.4 weeks in controls (T-value: 26.4; p < 0.0001). Conclusions   BTXB represents a safe and efficacious tool for the management of PDrelated drooling, ensuring a longlasting waning of this disabling symptom.     

Ultrasound-Guided Botulinum Toxin Type A Salivary Gland Injection in Children for Refractory Sialorrhea: 10-Year Experience at a Large Tertiary Children's Hospital

BackgroundSialorrhea is problematic for neurologically impaired children, and botulinum toxin A salivary gland injection has been reported as effective in reducing sialorrhea. This article assesses the success and safety of ultrasound-guided weight-based botulinum toxin A injection for the management of sialorrhea in children.MethodsA total of 111 patients (63 males; 48 females; average age 7 years) with refractory sialorrhea were treated with ultrasound-guided botulinum toxin type A salivary gland injections (144 procedures) from July 1, 2004, to July 1, 2014, using a single weight-based protocol. Patient history, procedural records, and clinical follow-up documents were retrospectively reviewed. Clinical data were compared with reported effectiveness and complications using odds ratios.ResultsA total of 144 procedures were performed in 111 patients with refractory sialorrhea. Cerebral palsy was the most common underlying etiology for sialorrhea (29%), whereas others included encephalopathy (5%), anoxic brain injury (4%), and a variety of chromosomal anomalies (5%). There was a 100% technical success rate. Overall treatment effectiveness was 68%. Repeat injections were not associated with increased clinical success. No procedure-related deaths or major complications were identified; the minor complication rate was less than 2%.ConclusionsThe protocol used for ultrasound-guided injection of botulinum toxin A proved to be safe and effective in children suffering from sialorrhea. Image guidance technique may lead to a reduction in rates of adverse events reported in other series. Subsequent procedures do not improve upon initial efficacy.     

Botulinum toxin type A for drooling in Parkinson's disease: a double-blind, randomized, placebo-controlled study.

To investigate the safety and efficacy of botulinum toxin type A (BoNTX) treatment to reduce sialorrhea in Parkinson's disease (PD), a double-blind, randomized, placebo-controlled study enrolled 32 PD patients complaining of excessive drooling. Patients received either 50 U Botox in each parotid gland or placebo without using ultrasound guidance. Subjects treated with BoNTX experienced a reduction in both drooling frequency and familial and social disability (TimexGroup effect: P<0.01), as well as in saliva production (Time x Group effect: P<0.0001). No adverse events were recorded. BoNTX injections are safe and effective treatment for the management of PD-related drooling.     

Salivary gland botulinum toxin injections for drooling in children with cerebral palsy and neurodevelopmental disability: a systematic review

Aim The aim of this paper was to systematically review the efficacy and safety of botulinum toxin (BoNT) injections to the salivary glands to treat drooling in children with cerebral palsy and neurodevelopmental disability. Method A systematic search of The Cochrane Central Register of Controlled Trials, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), EMBASE, and the Physiotherapy Evidence Database (PEDro) was conducted (up to 1 October 2011). Data sources included published randomized controlled trials (RCTs) and prospective studies. Results Sixteen studies met inclusion criteria. Three outcome measures support the effectiveness of BoNT for drooling. One RCT found an almost 30% reduction in the impact of drooling on patients’ lives, as measured by the Drooling Impact Scale (mean difference ?27.45; 95% confidence interval [CI] ?35.28 to ?19.62). There were sufficient data to pool results on one outcome measure, the Drooling Frequency and Severity Scale, which supports this result (mean difference ?2.71; 95% CI ?4.82 to ?0.60; p<0.001). There was a significant reduction in the observed number of bibs required per day. The incidence of adverse events ranged from 2 to 41%, but was inconsistently reported. One trial was terminated early because of adverse events. Interpretation BoNT is an effective, temporary treatment for sialorrhoea in children with cerebral palsy. Benefits need to be weighed against the potential for serious adverse events. More studies are needed to address the safety of BoNT and to compare BoNT with other treatment options for drooling.     

Randomized double‐blind study of botulinum toxin type B for sialorrhea in als patients

Twenty ALS patients with sialorrhea refractory to medical therapy were enrolled in this double‐blind, randomized study to receive either 2,500 U of botulinum toxin type B (BTxb) or placebo into the bilateral parotid and submandibular glands using electromyographic guidance. Patients who received BTxb reported a global impression of improvement of 82% at 2 weeks compared to 38% of those who received placebo (P < 0.05). This significant effect was sustained at 4 weeks. At 12 weeks, 50% of patients who received BTxb continued to report improvement compared to 14% of those who received placebo. There were no significant adverse events, including dysphagia, in the BTxb group, and there was no significant increase in the rate of decline of vital capacity. Muscle Nerve 39: 137–143, 2009     

Botulinum toxin type A on oral health in treating sialorrhea in children with cerebral palsy: a randomized, double-blind, placebo-controlled study

Intrasalivary gland injection of botulinum toxin type A is known to treat sialorrhea effectively in children with cerebral palsy. However, oral health may be compromised with escalating dose. In this randomized, double-blind, and placebo-controlled pilot trial, the authors aim to determine the therapeutic effect of low-dose, ultrasonography-controlled botulinum toxin type A injection to bilateral parotid and submandibular glands on oral health in the management of sialorrhea. Twenty children diagnosed with cerebral palsy were randomly assigned to 2 groups. The treatment group received botulinum toxin type A injections, whereas the control received normal saline in the same locations. The authors evaluated subjective drooling scales, salivary flow rate, and oral health (salivary compositions and cariogenic bacterial counts). A significant decrease was found in salivary flow rate at the 1- and 3-month follow-up in the botulinum toxin-treated group. The authors suggest that current protocol can effectively manage sialorrhea while maintaining oral health.     

Botulinum toxin treatment of sialorrhea: comparing different therapeutic preparations

In recent years, a number of potential new therapeutic indications of botulinum toxin injections have emerged, amongst which sialorrhea has attracted considerable attention. Based on open‐label and controlled studies, botulinum toxin can be used to improve sialorrhea in patients with Parkinson's disease, parkinsonian syndromes, motor neuron disease and cerebral palsy. The toxin can be injected blindly based on anatomic landmarks of the salivary glands, or localization can be facilitated by use of ultrasound guidance. There are few reported adverse effects. However, many more carefully designed, controlled studies are still required to address the specific questions related to selection of patients, the optimal injection technique, the appropriate dose of botulinum toxin and its long‐term effects.     

Therapie der Clozapin-induzierten Hypersalivation mit Botulinum-Toxin B

Hypersalivation is frequently observed in patients treated with clozapine. Current strategies to counteract sialorrhea include the introduction of antimuscarinergic (anticholinergic) and alpha(2)-agonistic treatment. However, the use of these substances is limited in part by lack of efficacy and by adverse side effects. In cases of intractable sialorrhea, the application of botulinum toxin may be a new and safe therapeutic option. We here present an overview on current treatment strategies for sialorrhea and describe a patient who received botulinum toxin B for clozapine-induced hypersalivation.     

Botulinum toxin A versus B in sialorrhea: A prospective,randomized, double‐blind,crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease

Background: Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions. Methods: Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT‐A) or B (BoNT‐B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re‐treated with the other serotype. Ultrasound‐guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT‐A (Dysport) and 2500 U BoNT‐B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline. Results: Twenty‐seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT‐A and BoNT‐B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT‐B treatments (3.2 ± 3.7 days) compared to BoNT‐A (6.6 ± 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT‐A and BoNT‐B, respectively (P = NS). The only toxin‐related side effect was a change to saliva thickness. Conclusions: Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT‐B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT‐B treatment. © 2011 Movement Disorder Society     

Drooling in Parkinson's disease: A review

Parkinson's disease (PD) is a neurodegenerative disease causing both motor and non-motor symptoms. Drooling, an excessive pooling and spillover of saliva out of the oral cavity, is one of the non-motor symptoms in PD patients that produces various negative physical and psychosocial consequences for patients and their caregivers. At present, the pathophysiology of drooling in PD is not completely certain; however, impaired intra-oral salivary clearance is likely the major contributor. There are neither standard diagnostic criteria nor standard severity assessment tools for evaluating drooling in PD. In accordance with the possible pathophysiology, dopaminergic agents have been used to improve salivary clearance; however, these agents are not completely effective in controlling drooling. Various pharmacological and non-pharmacological treatment options have been studied. Local injection with botulinum toxin serotypes A and B into major salivary glands is most effective to reduce drooling. Future research to explore the exact pathophysiology and develop standard diagnostic criteria and standard severity assessment tools are needed to formulate specific treatment options and improve patient care.     

Drooling in Parkinson’s disease: A randomized controlled trial of incobotulinum toxin A and meta-analysis of Botulinum toxins

IntroductionBotulinum toxins are a therapeutic option for drooling in Parkinson’s Disease (PD). The aims of this study were to: 1. evaluate the efficacy of incobotulinum toxin A for drooling in PD. 2. Perform a meta-analysis of studies of Botulinum toxins for drooling in PD.Methods1. Primary study: Randomized, double blind, placebo controlled, cross over trial. Incobotulinum toxin (100 units) or saline was injected into the parotid (20 units) and submandibular (30 units) glands. Subjects returned monthly for three evaluations after each injection. Outcome measures were saliva weight and Drooling Frequency and Severity Scale. 2. Systematic review of literature, followed by inverse variance meta-analyses using random effects models.Results1. Primary Study: Nine of 10 subjects completed both arms. There was no significant change in the primary outcome of saliva weight one month after injection in the treatment period compared to placebo period (mean difference, gm ± SD: −0.194 ± 0.61, range: −1.28 to 0.97, 95% CI −0.71 to 0.32). Secondary outcomes also did not change. 2. Meta-analysis of six studies demonstrated significant benefit of Botulinum toxin on functional outcomes (effect size, Cohen’s d: −1.32, CI −1.86 to −0.78). The other studies used a higher dose of Botulinum toxin A into the parotid glands.ConclusionsThis study did not demonstrate efficacy of incobotulinum toxin A for drooling in PD, but lacked precision to exclude moderate benefit. The parotid/submandibular dose-ratio may have influenced results. Studies evaluating higher doses of incobotulinum toxin A into the parotid glands may be useful.     

Dysautonomia rating scales in Parkinson's disease: Sialorrhea,dysphagia, and constipation—Critique and recommendations by movement disorders task force on rating scales for Parkinson's disease

Upper and lower gastrointestinal dysautonomia symptoms (GIDS)—sialorrhea, dysphagia, and constipation are common in Parkinson's disease (PD) and often socially as well as physically disabling for patients. Available invasive quantitative measures for assessing these symptoms and their response to therapy are time‐consuming, require specialized equipment, can cause patient discomfort and present patients with risk. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. Six clinical researchers and a biostatistician systematically searched the literature for scales of sialorrhea, dysphagia, and constipation, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated “Recommended” if the scale was used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and clinimetric studies have established that it is a valid, reliable, and sensitive. “Suggested” scales met at least part of the above criteria, but fell short of meeting all. Based on the systematic review, scales for individual symptoms of sialorrhea, dysphagia, and constipation were identified along with three global scales that include these symptoms in the context of assessing dysautonomia or nonmotor symptoms. Three sialorrhea scales met criteria for Suggested: Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale, and Sialorrhea Clinical Scale for PD (SCS‐PD). Two dysphagia scales, the Swallowing Disturbance Questionnaire (SDQ) and Dysphagia‐Specific Quality of Life (SWAL‐QOL), met criteria for Suggested. Although Rome III constipation module is widely accepted in the gastroenterology community, and the earlier version from the Rome II criteria has been used in a single study of PD patients, neither met criteria for Suggested or Recommended. Among the global scales, the Scales for Outcomes in PD‐Autonomic (SCOPA‐AUT) and Nonmotor Symptoms Questionnaire for PD (NMSQuest) both met criteria for Recommended, and the Nonmotor Symptoms Scale (NMSS) met criteria for Suggested; however, none specifically focuses on the target gastrointestinal symptoms (sialorrhea, dysphagia, and constipation) of this report. A very small number of rating scales have been applied to studies of gastrointestinal‐related dysautonomia in PD. Only two scales met “Recommended” criteria and neither focuses specifically on the symptoms of sialorrhea, dysphagia, and constipation. Further scale testing in PD among the scales that focus on these symptoms is warranted, and no new scales are needed until the available scales are fully tested clinimetrically. © 2009 Movement Disorder Society     

Botulinum toxin treatment of social anxiety disorder with hyperhidrosis: a placebo-controlled double-blind trial

OBJECTIVE: Given the often prominent and persistent nature of hyperhidrosis in social anxiety disorder (SAD), to compare botulinum toxin type A to placebo for generalized SAD with hyperhidrosis, in combination with paroxetine. METHOD: Adults with severe axillary hyperhidrosis who met DSM-IV criteria for generalized SAD were randomly assigned to receive 1-time, bilateral, intradermal injections with either botulinum toxin type A or placebo (50 units/axilla). All subjects also received 8 weeks of open-label treatment with paroxetine. The primary outcome measure was the Hyperhidrosis Disease Severity Scale (HDSS). Secondary measures included the Hyperhidrosis Impact Questionnaire, Brief Social Phobia Scale, Liebowitz Social Anxiety Scale, Social Phobia Inventory, and Sheehan Disability Scale. Enrollment occurred from June 2002 to July 2004. RESULTS: Forty subjects were randomly assigned to treatment and included in the analyses. Response rates were 75% (15/20) for botulinum toxin type A versus 15% (3/20) for placebo on the HDSS (p < .001). Botulinum toxin type A produced significantly more improvement in many daily activities that had been limited (p < .01), as well as greater improvement in work and social functioning and in overall disability (p < .05). Botulinum toxin type A was well tolerated, as was paroxetine. CONCLUSION: Botulinum toxin is effective in reducing hyperhidrosis disability and limitations in everyday activities when given in association with paroxetine to subjects with SAD. While further assessment of botulinum toxin type A in SAD is recommended, including a trial of botulinum toxin type A monotherapy, the results suggest that this well-tolerated treatment deserves further consideration in overall management of SAD accompanied by hyperhidrosis.     

A randomized trial of botulinum toxin A for treatment of drooling

The authors compared the efficacy of three different doses (18.75, 37.5, and 75 MU per parotid gland) of botulinum toxin A (BTX-A; Dysport, Ipsen Pharma, Germany) injections vs vehicle in patients with sialorrhea (n = 32) using a single-center, prospective, double-blind, placebo-controlled dose-finding study. The primary endpoint was achieved with 75 MU BTX-A without treatment-related adverse events, suggesting BTX-A is a safe and effective treatment for patients with sialorrhea.     

Quantitative reduction of saliva production with botulinum toxin type B injection into the salivary glands

Drooling is common in patients with neurological disorders. Recently, botulinum toxin type B has been shown to be effective in the treatment of drooling. The authors present a unique case of a 57-year-old man with a history of a brainstem stroke and severe drooling. The patient's parotid and submandibular glands were injected under ultra-sound guidance with botulinum toxin type B. Saliva was collected and quantified before and after the injections by 2 different collection methods: suctioning and dental rolls. Total saliva production decreased by 23.8% after injection of the parotid glands and by 85.8% after submandibular injection compared to the preinjection level. The 2 methods demonstrated similar results. In addition, the patient experienced less drooling and increased participation in therapies without any side effects. This case demonstrates that saliva secretion and drooling can effectively be treated by injections of botulinum toxin type B into the salivary glands.     

Sialorrhea in Parkinson's disease: a review.

A significant number of patients with Parkinson's disease (PD) experience sialorrhea. This problem can cause social embarrassment, and because saliva pools in the mouth, may lead to aspiration pneumonia. Sialorrhea in PD is thought to be caused by impaired or infrequent swallowing, rather than hypersecretion. Oral medications, botulinum toxin injections, surgical interventions, radiotherapy, speech therapy, and trials of devices may be used to treat sialorrhea in PD, but few controlled trials have been published. This article reviews current knowledge regarding the frequency, etiology, assessment, and treatment of sialorrhea in PD.     

Quantitative assessment of parkinsonian sialorrhea and results of treatment with botulinum toxin

Aim: To assess quantitatively sialorrhea in Parkinson's disease (PD) and the efficacy of botulinum toxin (BOTOX) in its treatment.

Material: 11 patients with a clinical diagnosis of idiopathic PD and drooling were assessed at least two points on the UPDRS Part II and 14 control subjects.

Methods: Salivation was measured by weighing dental rolls before, and 2 min after, insertion at six points of highest secretion of saliva in the mouth (buccal vestibule, and sublingual area). PD patients were assessed before and 1 week after injections of five units of BOTOX into each parotid salivary gland and the results were compared to the salivation production of controls.

Results: Average secretion of saliva in PD patients was significantly higher than in controls—0.39±0.4 g/2 min. (range: 0.02–1.82) vs 0.19±0.16 g/2 min. (range: 0.02–0.98) (P=0.03). After treatment, the average secretion of saliva in PD patients decreased to 0.25±0.26 g/2 min. (range: 0.004–0.99) and did not differ significantly from controls. Nine patients improved also according to UPDRS. No side effects were observed in any of the patients injected.

Conclusion: Botulinum toxin may be an effective and safe treatment of parkinsonian sialorrhea.