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.     

Ipratropium bromide spray as treatment for sialorrhea in Parkinson's disease.

Sialorrhea is a significant problem in advanced Parkinson's disease (PD). Current treatment options include systemic anticholinergics which frequently cause side effects. We hypothesized that sublingual application of ipratropium bromide spray, an anticholinergic agent that does not cross the blood brain barrier, may reduce drooling without systemic side effects. We performed a randomized, double blind, placebo-controlled, crossover study in 17 subjects with PD and bothersome drooling. Patients were randomized to receive ipratropium bromide or placebo (one to two sprays, maximum of four times per day) for 2 weeks followed by a 1 week washout and crossover for further 2 weeks of treatment. The primary outcome was an objective measure of weight of saliva production. Secondary outcomes were subjective rating of severity and frequency of sialorrhoea using home diaries, United Parkinson's Disease Rating Scale (UPDRS) part II salivation subscore, parkinsonian disability using UPDRS, and adverse events. Ipratropium bromide spray had no significant effect on weight of saliva produced. There was a mild effect of treatment on subjective measures of sialorrhea. There were no significant adverse events. Ipratropium bromide spray was well tolerated in subjects with PD. Although it did not affect objective measures of saliva production, further studies in parkinsonism may be warranted.     

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     

Safety and efficacy of botulinum toxin type B for treatment of sialorrhea in Parkinson's disease: a prospective double-blind trial

Sialorrhea (drooling) is a common symptom of Parkinson's disease (PD) that can significantly impair a patient's health and quality of life. Fifty-four PD subjects with troublesome sialorrhea were enrolled using a multicenter, randomized, double-blind, sequential-dose escalation design in which subjects received a single intraglandular treatment with botulinum toxin type B (doses of 1,500 Units [0.3 mL]; 2,500 Units [0.5 ml]; or 3,500 Units [0.7 ml]) or placebo. Postinjection, subjects were followed acutely for 4 weeks and long-term for up to 20 weeks. Safety/tolerability, as assessed by adverse events, was the primary outcome measure. Efficacy, as assessed by the Drooling Frequency and Severity Scale and unstimulated salivary flow rate, was secondary. Gastrointestinal-related adverse events occurred more frequently in the active groups versus placebo group (31% vs 7%), with dry mouth being most common (15%). There were no serious adverse events attributed to botulinum toxin type B or discontinuations due to adverse events from treatment. At 4 weeks postinjection, Drooling Frequency and Severity Scale scores significantly improved versus placebo (-1.3 ± 1.3) in a dose-related manner (-2.1 ± 1.2, P = 0.0191; -3.3 ± 1.4, P < 0.0001; -3.5 ± 1.1, P < 0.0001, respectively) and unstimulated salivary flow rates significantly decreased in all active groups versus placebo (P ≤ 0.0009). Furthermore, treated subjects appeared to have more sustained improvement in sialorrhea than placebo subjects. We conclude that intraglandular injection of botulinum toxin type B was safe, tolerable, and efficacious in treating sialorrhea in PD patients. Additional studies are warranted to further confirm the drug's robust efficacy, as well as evaluate its effect with repeated dosing.     

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.     

Validation of a new scale for the evaluation of sialorrhea in patients with Parkinson's disease.

Sialorrhea is common in Parkinson disease (PD), affecting approximately 70% to 75% of patients. Several tools for measuring saliva volume or production exist, but none are designed specifically for assessing sialorrhea-related discomfort. The objective of this study was to develop and validate a clinical scale for subjective evaluation of sialorrhea in PD. In Phase I, internal consistency of the Sialorrhea Clinical Scale for PD (SCS-PD) was established in 39 PD patients. In Phase II, scale validity was proven through saliva volume measurements obtained in 49 PD patients and 27 healthy volunteers. Internal consistency estimated using Cronbach's alpha was 0.78, indicating none of the original seven items tested needed to be removed. Twenty-one patients complaining of sialorrhea (63%) studied during Phase II, showed higher SCS-PD scores but no differences in saliva volume. SCS-PD scores showed significant correlation with saliva volume (r = 0.41; P = 0.004) and with total Unified Parkinson's Disease Rating Scale Part III (UPDRS III) scores (r = 0.70). Furthermore, saliva volume showed inverse relation to age in PD patients as well as in controls (r = -0.3 and r = -0.4; P < 0.05), but SCS-PD scores did not. The SCS-PD scale showed good internal consistency and validity, providing support for its use in routine clinical sialorrhea-related discomfort evaluation.     

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     

Pathophysiology of diurnal drooling in Parkinson's disease

Drooling is an incapacitating feature of Parkinson's disease. Better pathophysiological insights are needed to improve treatment. In this study, we tested the hypothesis that the cause of drooling is multifactorial. We examined 15 patients with Parkinson's disease with distinct diurnal saliva loss (“droolers”) and 15 patients with Parkinson's disease without drooling complaints (“nondroolers”). We evaluated all factors that could potentially contribute to drooling: swallowing capacity (maximum volume), functional swallowing (assessed with the dysphagia subscale of the Therapy Outcome Measures for rehabilitation specialists), unintentional mouth opening due to hypomimia (Unified Parkinson's Disease Rating Scale item), posture (quantified from sagittal photographs), and nose‐breathing ability. We also quantified the frequency of spontaneous swallowing during 45 minutes of quiet sitting, using polygraphy. Droolers had more advanced Parkinson's disease than nondroolers (Unified Parkinson's Disease Rating Scale motor score 31 vs 22; P = .014). Droolers also scored significantly worse on all recorded variables except for nose breathing. Swallowing frequency tended to be higher, possibly to compensate for less efficient swallowing. Logistic regression with adjustment for age and disease severity showed that hypomimia correlated best with drooling. Linear regression with hypomimia as the dependent variable identified disease severity, dysphagia, and male sex as significant explanatory factors. Drooling in Parkinson's disease results from multiple risk factors, with hypomimia being the most prominent. When monitored, patients appear to compensate by increasing their swallowing frequency, much like the increased cadence that is used to compensate for stepping akinesia. These findings can provide a rationale for behavioral approaches to treat drooling. © 2011 Movement Disorder Society     

The effect of injecting botulinum toxin type a into the calf muscles on freezing of gait in Parkinson's disease: a double blind placebo-controlled pilot study.

OBJECTIVE: To assess the effect on freezing of gait (FOG) of botulinum toxin type A (BTX-A) injections in advanced Parkinson's disease (PD) patients. METHOD: BTX-A 150 IU or normal saline was injected into each leg's calf muscles by a blinded investigator. FOG severity was assessed at set intervals (6-month follow-up). RESULTS: Eleven age- and disease severity-matched PD patients with disabling FOG participated. Six patients received BTX-A and 5 received saline. No improvement was observed in either group over time. Leg weakness and falls lead to early termination. CONCLUSION: BTX-A injections to the legs did not improve FOG and might increase fall risk.     

Cognitive changes in prodromal Parkinson's disease: A review

Although other nonmotor phenomena representing possible prodromal symptoms of Parkinson's disease have been described in some detail, the occurrence and characteristics of cognitive decline in this early phase of the disease are less well understood. The aim of this review is to summarize the current state of research on cognitive changes in prodromal PD. Only a small number of longitudinal studies have been conducted that examined cognitive function in individuals with a subsequent PD diagnosis. However, when we consider data from at‐risk groups, the evidence suggests that cognitive decline may occur in a substantial number of individuals who have the potential for developing PD. In terms of specific cognitive domains, executive function in particular and, less frequently, memory scores are reduced. Prospective longitudinal studies are thus needed to clarify whether cognitive, and specifically executive, decline might be added to the prodromal nonmotor symptom complex that may precede motor manifestations of PD by years and may help to update the risk scores used for early identification of PD. © 2017 International Parkinson and Movement Disorder Society     

Botulinum toxin A may be efficacious as treatment for jaw tremor in Parkinson's disease.

Jaw tremor in Parkinson's disease (PD) may not respond well to conventional treatment. It causes embarrassment and social handicap. We piloted the use of botulinum toxin (BTX) injections in three patients with PD jaw tremor. BTX A (Dysport; mean, 53 U; range, 30-100 U) was given into each masseter muscle. Outcome was assessed by subjective and clinical improvement and by video recording before and 4 to 9 weeks after injections. There was an excellent response in all without side effects. BTX injections into the masseter may effectively improve jaw tremor and be useful in PD and other conditions.     

Autonomic and sensory symptoms and signs in incident,untreated Parkinson's disease: Frequent but mild

Although nonmotor symptoms are increasingly recognized as key features in Parkinson's disease (PD), the occurrence and severity of autonomic and sensory symptoms in patients with very early and untreated PD are poorly documented. Two hundred seven patients with newly diagnosed, untreated PD and 175 controls from the population‐based Norwegian ParkWest study were included. Postural blood pressure and olfactory function were measured and eight autonomic and sensory symptoms assessed using interview‐based rating scales. Autonomic and sensory symptoms were more frequent in patients compared with controls (mean number of symptoms 2.9 vs. 1.1; P < 0.001) and in the postural instability and gait difficulty motor‐subtype vs. tremor dominant subtype (mean 3.3 vs. 2.5; P = 0.008). In the patient group, reduced olfaction (59%), urinary problems (47%), increased saliva or drooling (42%), constipation (39%), and sensory complaints (34%) were the most frequent symptoms. Daily activities were not affected by these symptoms in 58% of the patients, and the influence on daily activities was rated as “mild” or less for all of these symptoms in 90%. A higher Hoehn and Yahr stage was associated with a higher number of autonomic and sensory symptoms and with the occurrence of gastrointestinal symptoms. Autonomic and sensory symptoms are common in patients with untreated, early PD although the severity of these symptoms is mild, with little or no influence on daily activities. The high prevalence of increased saliva or drooling close to the time of diagnosis is noteworthy and not described earlier. © 2010 Movement Disorder Society     

Emotional processing in Parkinson's disease: a systematic review

Parkinson's disease provides a useful model for studying the neural substrates of emotional processing. The striato-thalamo-cortical circuits, like the mesolimbic dopamine system that modulates their function, are thought to be involved in emotional processing. As Parkinson's disease is histopathologically characterized by the selective, progressive, and chronic degeneration of the nigrostriatal and mesocorticolimbic dopamine systems, it can therefore serve as a model for assessing the functional role of these circuits in humans. In the present review, we begin by providing a synopsis of the emotional disturbances observed in Parkinson's disease. We then discuss the functional roles of the striato-thalamo-cortical and mesolimbic circuits, ending with the conclusion that both these pathways are indeed involved in emotional processing.     

Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study.

Sialorrhea is a relatively common symptom in idiopathic Parkinson's disease and related conditions for which most of the accepted treatments are either highly invasive or may cause substantial systemic side effects. This study describes an open-label pilot study of sublingual atropine drops for the treatment of sialorrhea in 7 patients (6 with Parkinson's disease, 1 with progressive supranuclear palsy). Participants demonstrated statistically significant declines in saliva production, both objectively and subjectively. Self-reported drooling severity showed a significant decline between baseline and 180 minutes, t(6) = 3.240 P < 0.025 (eta(2) = 0.636), and between baseline and 1 week, t(6) = 4.583 P < 0.005 (eta(2) = 0.778). Objectively measured saliva production decreased significantly between baseline and the 1-week follow-up, t(6) = 2.711 P < 0.05 (eta(2) = 0.551). Delirium occurred in 1 patient (concurrent with a urinary tract infection), and 2 patients experienced worsening of hallucinations (active hallucinosis was concealed by both individuals to allow participation in the trial). The remaining trial participants did not experience any anticholinergic side effects. This trial shows that, in selected patient populations, sublingual atropine is a simple and inexpensive treatment for sialorrhea associated with parkinsonism.     

Depression in Parkinson's disease: the effectiveness and risk of pharmacotherapy. Clinical review

Parkinson's disease (PD) is a neurological disease with a heterogeneous pattern of neurological symptoms and concomitant psychiatric syndromes. These syndromes are triggered by alterations to neurotransmission that are likely common for both neurological and psychiatric symptoms. Syndromes such as depression, anxiety, or cognitive impairment can precede motor symptoms of PD and delay its diagnosis. Recently, questions related to aetiological factors and treatment strategies of depression in PD have become a growing concern of PD researchers. This article describes the main features of depression in PD and presents current hypotheses on its aetiology and recommended treatment modes.     

Neuroprotection trials in Parkinson's disease: Systematic review

Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design, reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double‐blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO‐B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy in seven. Mean participant age was 62 years, 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest = 806). Follow‐up averaged <16 months in all but two trials. Detailed randomization methods and success of double‐blinding were reported in 20% and 13%, respectively. Based on the investigators' conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes. © 2008 Movement Disorder Society     

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease

Aim: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. Methods: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale – Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale – Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. Results: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. Conclusions: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.     

Prevalence of pain in Parkinson's disease: a systematic review using the modified QUADAS tool

Pain has been studied more intensely as a symptom of Parkinson's disease (PD) in recent years. However, studies on the characteristics and prevalence of pain in PD have yielded conflicting results, prompting us to do a systematic review of the literature. A systematic review of the literature was conducted, using different databases. The last inclusion date was March 15, 2011. The modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used, which is especially designed for judging prevalence studies on their methodological quality. Only articles that met the predefined criteria were used in this review. We found 18 articles, of which only 8 met the methodological criteria. Prevalence frequency ranges from 40% to 85% with a mean of 67.6%. Pain is most frequently located in the lower limbs, with almost one-half of all PD patients complaining about musculoskeletal pain (46.4%). The pain fluctuates with on-off periods. Surprisingly, only 52.4% of PD patients with pain used analgesics, most often nonopioids. PD patients seem to be predisposed to develop pain and physicians should be aware of pain as a common feature of PD. As many as one-half of PD patients with pain may be missing out on a potentially useful treatment, and proper treatment could increase quality of life in PD patients.     

Parkinson's disease and pregnancy: An updated review

Pregnancy does not often occur in the setting of Parkinson's disease (PD) as the most common age of onset is beyond the childbearing years, yet management of these two conditions is crucial for the health of both mother and child. Here we review treatment data of PD during pregnancy, primarily from case reports and drug registries, and focus on available evidence regarding the pregnancy risks for patient and fetus. Historically, it was reported that many women had worsening of symptoms during pregnancy but this may be because anti-parkinsonian medications were not recommended or were under dosed. Levodopa has the best safety data for use in pregnancy and amantadine should be avoided in women who are pregnant or trying to become pregnant. The data for other pharmacological and surgical treatments is less clear. There is no evidence that women with PD have higher rates of birth or fetal complications.