Sialorrhea

Drooling is present in 80% of patients with PD and is secondary to disturbances in swallowing the saliva that accumulates in the mouth rather than to increased production.

Marks et al. [1] performed a 4-month, randomized trial in PD patients. Those who had had PD for more than 15 years and presented hypersalivation were divided into three groups for speech/language therapy, therapy with botulinum toxin type A injections in the salivary glands and a control group. In the group treated with speech/language therapy, the basic mechanisms of salivation, functionality and swallowing exercises were explained from a table filled out by the subject about salivation. Separately, this group was given a device that made a sound at a determined time reminding them to swallow. A total of 28 patients were included; however, a significant number withdrew due to a fear of needles in the botulinum toxin group. According to the final results, both the speech/language therapy and the botulinum toxin injections were effective in reducing sialorrhea, the latter being measured by a salivation scale. The strengths of this study are the findings that re-education and a heightened awareness of the mechanics of swallowing are effective in the management of hypersalivation, even though the poor methodological and statistical design of the study, the number of losses of subjects in one of the branches of the study and the small number of recruited participants warrant further studies to corroborate these findings.

Botulinum toxin may reduce saliva production by inhibiting the release of acetylcholine at the parasympathetic autonomic level and at the postganglionic sympathetic level. Mancini et al. [2] performed a 3-month, randomized, double-blinded, placebo-controlled study in 20 subjects (14 with PD and six with multiple-system atrophy [MSA]), which consisted of ultrasound-guided applications of 450 U of botulinum toxin A (Dysport®) or placebo in the parotid and submandibular glands. They were assessed using salivation scales (Drooling Severity Scale, Drooling Frequency Scale and Drooling Score). The patients in both groups had a history of PD of more than 7 years. Improvements in the reduction of sialorrhea lasted 1 month, and there was no significant benefit after 3 months of application. The trial demonstrated the safety and effectiveness of this therapy in the management of drooling. However, the heterogeneity of the tested groups as well as the small size of the sample could have caused biased results.

Lagalla et al. [3] performed a randomized, double-blinded, placebo-controlled study using 50 U of botulinum toxin type A (Botox®) in 32 PD subjects with an average age of 70 and more than 12 years with the disease. Visual analog scales were used to evaluate the severity of hypersalivation. They referenced the frequency of salivation as well as the secondary, frequent familial and social stresses, and the items in the Unified Parkinson’s Disease Rating Scale (UPDRS)-II that evaluate sialorrhea and dysphagia. One month after the injections, a significant difference was observed for all scores except for the item for dysphagia on the UPDRS-II. Eighty-eight percent of the subjects tested with botulinum toxin and 31% of those with placebo were satisfied with the results. An objective evaluation of the quantity of saliva, measured by the weight of five oral cotton rolls placed in the mouth for 5 min without swallowing, demonstrated a significant reduction in cases treated with the toxin compared with those treated with placebo. Although the authors confirmed the benefits of the toxin for hypersalivation associated with PD, the length of the study and a more objective analysis of the target should be improved. In addition, the mental or emotional state of the subjects, which directly affects the responses measured from the visual analog scales, was not reported. Lastly, a higher proportion of the subjects with PD at Hoehn and Yahr stage IV were in the group treated with placebo (25 vs 12%, placebo vs botulinum toxin; respectively), which might unbalance the findings, making the toxin seem more effective in the more disabled subjects than it actually is.

Botulinum toxin type B has also been studied in subjects with PD and sialorrhea, as it is believed to have better selectivity and higher potential at the autonomic level. In 2004, Ondo et al. [4] performed a randomized, double-blinded, placebo-controlled study on 16 patients with PD injecting 2500 U of botulinum toxin type B or placebo in the parotid and submandibular glands. Participants were evaluated using salivation scales (Drooling Severity Scale, Drooling Frequency Scale and Drooling Score), visual analog scales and a global impression of change. The subjects had suffered from PD for more than 12 years. At 1 month after the injection, the majority of the subjects treated with botulinum toxin B showed significant improvements on all applied scales. In addition, they were studied using scintigraphy with ^99mTC-pertechnetate to evaluate saliva production in the salivary glands. They found a greater than 30% reduction in saliva production in four out of six patients treated with the toxin when compared with two out of seven subjects treated with placebo. The weaknesses of the study were the low number of subjects included and the short evaluation time (1 month), as well as significant differences in age, disease duration and UPDRS-II and –III scores. Botulinum toxin type B was similarly effective to what has been reported for type A for the treatment of hypersalivation.

In 2009, Lagalla et al. [5] published another randomized placebo-controlled study in subjects with PD and moderate to severe sialorrhea. They were treated either with 4000 U of botulinum toxin type B (Neurobloc®) or placebo in the parotid glands. Subjects were evaluated at baseline and 1 month after intervention. They were then questioned monthly by telephone to see if the effects were sustained. The participants were evaluated according to the Frequency and Drooling Severity Scale, by similar scales for familial and social stress, a Global Impression Scale and the UPDRS-II items for dysphagia and sialorrhea. Thirty-six subjects with a PD history of more than 12 years were randomly assigned to either the botulinum toxin or placebo (18 per arm). Subjects treated with botulinum toxin type B showed significant favorable changes in practically all of the scales employed 1 month after treatment. Almost 78% of the participants treated with the toxin expressed a moderate to dramatic improvement with sialorrhea, lasting for 19 weeks. This study employed good methodology and demonstrated the effectiveness of botulinum toxin type B for the management of sialorrhea in patients with PD. The type of evaluations utilized were practically the same as those in the study published by the same team in 2006 with botulinum toxin type A, with visual analog scales and two items from the UPDRS-II. It is possible that the data could have been better analyzed by using Fisher’s exact test instead of a χ² test and the beneficial results of the toxin evaluated more objectively by using monthly oral cotton roll test measurements weighing the saliva content.

In 2012, Chinnapongse et al. [6] conducted a randomized, double-blinded, placebo-controlled study in 17 centers in the USA on 54 participating subjects who suffered from PD and problematic sialorrhea. The population was divided into four groups: placebo (15 subjects), and botulinum toxin type B (Myobloc®) of 1500 U (14 subjects), 2500 U (12 subjects) and 3500 U (13 subjects). Toxin was applied to the parotid and submandibular glands (250 U per gland, fixed dose for the latter). The principal objective of the study was to evaluate the safety of the drug, although the main scale for evaluating the effect was the Drooling Frequency and Severity Scale (DFSS). After 8 weeks, there was a significant decrease in saliva in all the subjects treated with botulinum toxin type B when compared with placebo and measured by the DFSS. The effect of the toxin lasted for about 100 days. This study showed the effectiveness of botulinum type B for problematic sialorrhea in patients with PD as well as demonstrating the safety and the duration of the effect lasting over 3 months. The challenge for future studies will be to assess whether the effect is sustained throughout the years with continued use.

There have been other interventions evaluated in the management of sialorrhea associated with PD. In 2007, Thomsen et al. [7] evaluated the safety, tolerability and effectiveness of an ipratropium bromide spray through sublingual administration in subjects with PD. Ipratropium bromide is a muscarinic antagonist that does not cross the blood–brain barrier and, when administered locally, has no systemic side effects. This was a randomized, double-blinded, crossover, placebo-controlled study with intervals of drug/placebo application of no less than 4 h during 2 weeks, followed by 1 week of washout and switch to the other intervention. The primary objective was to assess the reduction of saliva production as measured by three to five cotton dental rolls placed in the mouth for 5 min and weighed. Fifteen subjects were evaluated without finding any significant differences between ipratropium bromide and placebo in either the severity or frequency of sialorrhea. It is possible that the small size of the group and the statistical management of categorical variables as if they were continuous could have affected the final results.

Another anticholinergic that has been tested for the treatment of hypersalivation is glycopyrrolate, a drug that does not cross the blood–brain barrier. Arbouw et al. [8] tested this drug through oral administration (1 mg three times daily) in subjects with PD and problematic sialorrhea in a randomized, double-blinded, placebo-controlled, crossover study that lasted for 4 weeks. Twenty-three subjects were randomly chosen and the effect of the drug was measured on a sialorrhea scale of 9 points. Responders demonstrated a 30% reduction on the sialorrhea scale. Almost 40% of the subjects treated with glycopyrrolate responded to the intervention compared with less than 5% of those treated with placebo. The subjects treated with glycopyrrolate showed an average improvement in the sialorrhea score of 0.8 points. Both results were statistically significant. The rate of adverse effects between one intervention and another did not demonstrate any differences. A larger sample size, validation of the employed scale and an exploratory dosage study are some of the future needs for this kind of therapy.

Recently, Lloret et al. [9] used intraoral tropicamide films in subjects with PD. This was a randomized, double-blinded, placebo-controlled study and was divided into four groups: tropicamide at concentrations of 0.3, 1 or 3 mg, and placebo. A visual analog scale was used together with oral cotton rolls placed in the mouth for 5 min and then weighed, to measure the severity of the sialorrhea. The visual analog scale baseline was the primary measurement of effectiveness at 20 min after treatment. The first phase of the study consisted of 12 subjects receiving treatment on different days separated by a 7-day washout. The second phase objectively measured the content of saliva in the mouth at baseline and at 75 min after treatment. Only six subjects completed the analysis at the second phase of the study. The trial demonstrated significant benefits only when utilizing 1 mg of tropicamide and at 120 min after its application. There was no significant difference observed in neither the tropicamide dosage nor placebo or in the volume of saliva obtained in the other different groups. A small sample size plus large time assessments of a short half-life drug could interfere with the outcomes of this study.

Dysphagia

This complication leads to the principal cause of death in patients with PD: aspiration pneumonia. The hyolaryngeal muscular complex with poor contractions of the submentonian muscles is believed to produce this complication.

In 2010, Troche et al. [10] conducted a randomized, double-blinded, placebo-controlled study with 60 subjects with PD and mild to moderate dysphagia. They employed an expiratory muscle strength training (EMST) device designed to generate equal resistance to expiratory pressure or, for the placebo group, a device that did not produce the resistance. The primary objective of the study was to verify improvements on the Penetration–Aspiration Scale. This was a 4-week study where the participants had to do five sets of five repetitions five times a week. Subjects were examined in a blinded manner by language/speech therapists using videofluoroscopy. There was a significant improvement in the Penetration–Aspiration Scale score for the EMST subjects when compared with those in the placebo group (a 0.57 reduction of points in the scale vs a 0.61 point increase for treated vs not treated, respectively). This scale is categorical, consists of 8 points, where 1 implies no aspiration and 8 demonstrates aspiration and risk in swallowing. The subjects treated with the EMST device had an average baseline of 2.64, which was reduced to 2.07, and those treated with placebo had an average baseline of 2.59, which increased to 3.3. Eleven subjects treated with the EMST device showed score improvements on the Penetration–Aspiration Scale in contrast to the five treated with placebo. It would be interesting to observe whether the results showed positive changes in the subjects who had a greater severity of dysphagia, and whether the score obtained from the scale showed a large divergence from the results. It is possible that the mild grade of severity in the tested subjects did not affect their Penetration–Aspiration Scale score considerably, which caused the minimal numerical results.

Manor et al. [11] published a randomized, double-blinded study that compared video-assisted swallowing therapy (VAST) against conventional rehabilitation swallowing therapy in 42 subjects (21 in each group) with PD and dysphagia. Patients were evaluated by fiber-optic endoscopy and by a speech specialist. Endoscopy qualifies five variables: bolus flow time, bolus location when the swallowing reflex is triggered, residue location, and the penetration and aspiration of food and liquid. The following other swallowing evaluation scales were also employed: swallowing disturbance questionnaire, swallowing quality of life, swallowing quality of care and pleasure of eating. Each group started with five rehabilitation sessions and finished with a sixth, 4 weeks after the fifth intervention. For those treated with VAST, their videoendoscopy was shown to them, informing them about swallowing mechanisms, the problems they had and how to correct them. The most frequent abnormality found was food residue left in the pharynx. This complication diminished in both groups but achieved significant improvement only for the VAST group when compared with the conventional rehabilitation group. There were no statistical differences in the other items that were analyzed by fiber-optic endoscopy. The VAST group also showed more favorable results on the other scales that were employed.

Surface electrical stimulation therapy for treating dysphagia has also been evaluated in two recent open-label studies. The first was by Baijens et al. [12], which consisted of a pilot study with ten subjects with PD and mild to severe dysphagia as well as ten healthy control subjects of the same age and gender. Surface electrical stimulation was applied in three different positions with VitalStim®, using a frequency of 80 Hz and a pulse width of 700 μs. Stimulation was applied on the suprahyoid, infrahyoid or a combination of the two muscles. After 90–120 min from having taken dopaminergic therapy, videofluoroscopic images were captured while the participants were being electrically stimulated. There were no significant differences between the subjects with PD and the control group during the fluoroscopic evaluation. It is possible that the small size of the group, the lack of blindness and an important placebo effect created an inadequate context to reach the formulated hypothesis.

In the second study, Heijnen et al. [13] included three groups of patients with PD and dysphagia. The subjects participated in physical therapy, motor electrical stimulation and electrical stimulation of the suprahyoid muscles. The electrical impulses were performed with VitalStim®, using a frequency of 80 Hz and a pulse width of 700 μs. The evaluations were made according to the Dysphagia Severity Scale, Quality of Life in Swallowing Disorders (SWAL-QOL) and MD Anderson Dysphagia Inventory. The study demonstrated overall benefits for swallowing in the three groups, but there were no significant differences among them. The loss of participants near to 20%, an unblinded study, a nonparametric distribution of the data and the lack of sensitivity to change from the scales employed could all have contributed to a loss in the differentiation for the results obtained from the groups.

Constipation

This disorder is present in 80–90% of the population with PD, and may be secondary to several problems including a decrease in gastric and intestinal motility secondary to dopaminergic and anticholinergic drugs, as well as from the disease, a decline in fluid intake, a reduction in body movements as a result of the disease, anorectal dysfunction and pelvic floor dysinergia, among others.

Sullivan et al. [14] conducted a double-blinded, randomized, placebo-controlled pilot study using tegaserod for the treatment of constipation in PD. Fifteen subjects (eight with tegaserod 6 mg and seven with placebo, three times daily) were evaluated using the Subject’s Global Assessment of Relief for 4 weeks after the initial intervention. Subsequently, a tendency toward a significant statistical improvement for constipation was noted in the tegaserod group (Subject’s Global Assessment of Relief score of 9.1 before treatment and 8.3 after with tegaserod vs a score of 6.2 before treatment and 8.7 after with placebo). The small group size and a gender imbalance among the participants warrant a study on a larger scale to test the effectiveness of this drug.

Zangaglia et al. [15] published a randomized, double-blinded, placebo-controlled study on the use of macrogol in patients with PD and constipation. Subjects took either 7.3 g of macrogol diluted in water or placebo for 8 weeks. The patients filled out a diary with the following information: stool frequency, straining and stool consistency. Fifty-seven subjects were included in the study (29 on macrogol and 28 with placebo), of which 14 did not finish (nine macrogol and five placebo). Stool frequency increased in a significant way in both groups; however, stool frequency was better for the macrogol group (5.6 vs 3.4 at 4 weeks and 6.6 vs 3.7 at 8 weeks for macrogol versus placebo, respectively) when compared over the same time period. Straining improved in both groups at week 4; however, at 8 weeks the study showed no differences between the groups, although there was a tendency toward improvement for the group managed with macrogol. Furthermore, stool consistency improved in a significant way during the two stages of the study for those treated with macrogol when compared with placebo. The use of higher doses and the frequency of the use of laxatives throughout the duration of the study were smaller for the group that was treated with macrogol, although these differences were not statistically significant. A withdrawal rate of greater than 20% and a possible lack of dietary control as well as an arbitrary management of laxatives could mislead the results obtained from this study.

Ondo et al. [16] conducted a randomized, double-blinded, placebo-controlled study of lubiprostone for constipation in PD. The study lasted for 6 weeks. Thirty patients were randomized for the trial of lubiprostone 48 μg daily and 31 for placebo, of which five from the first group and four from the second withdrew. The patients in the lubiprostone group wrote in diaries that showed significant improvements in global impression, stool frequency, visual analog scale score and constipation questionnaires. Although almost 50% of the population displayed stool softening, it did not become a serious problem or cause them to end the treatment.

Weight

Weight change is a documented fact with PD. Some causes that may contribute to the weight loss are: mitochondrial respiratory chain dysfunction, hypothalamic dysfunction, the presence of Lewy bodies on nonmotor circuits, an increase in energy expenditure, early satiety from gastric hypomotility, bulbar dysfunction, olfactory disorders, depression and the loss of the mechanisms related to dopaminergic reward function due to depletion, among others.

To date, there are no direct interventions for the management of weight loss in PD, although there is a subanalysis of the COMPARE (Cognition and Mood in Parkinson Disease in Subthalamic Nucleus Versus Globus Pallidus Interna Deep Brain Stimulation) study [17] that detailed weight changes in patients with PD. From these, 23 patients were treated with globus pallidus interna deep-brain stimulation (GPi-DBS) (10 bilateral, 13 unilateral) and 21 with subthalamic nucleus (STN)-DBS (15 bilateral, six unilateral). Thirty-one evaluated subjects (70%) gained weight 6 months after DBS, 10 subjects (23%) lost weight and three (7%) showed no weight change. When analyzed according to the target, of those who received GPi stimulation, 16 (70%) gained weight (10.65 ± 6.98 lb), six (24%) lost weight (7.77 ± 4.55 lb) and in one participant (4%) there was no change. For those treated with DBS-STN, 15 subjects (71%) gained weight (7.2 ± 5.55 lb), four subjects (19%) lost weight (4.5 ± 2.38 lb) and two participants (10%) did not show changes. There were no significant changes between the groups; however, it is worth noting that the percentage of subjects who received uni- or bilateral treatments within those groups showed a trend for significant differences (P = 0.06). As data was analyzed retrospectively, misclassification bias can occur. The relatively small sample and the lack of DBS unilateral or bilateral stratification for subjects could also have caused biases in this study.

Urinary symptoms

Urinary dysfunction is the most frequent complaint in patients with PD, affecting up to 70% of patients in the early stages of the disease and 90% for those in the advanced stages. They include mainly urinary urgency, nocturia, increased urinary frequency, incontinence, detrusor hyper- or hyporeflex found in urodynamic findings, decreased bladder capacity and anomalies of the external urinary sphincter. There have been some studies done to evaluate the management of these disorders.

Kabay et al. [18] conducted an open study of electrical stimulation on the posterior tibial nerve to improve bladder capacity in 32 subjects with PD who had had almost 7 years with the disease. Cystometric analysis was performed before and after stimulation. The mean volume of the first involuntary detrusor contraction was 145.2 ± 41.1 ml. There was an important change after the stimulation, increasing the average by 244.7 ± 51.7 ml. A greater than 50% volume increase of the first involuntary detrusor contraction was observed in 20 of the 32 participants. Similarly, the maximum cystometric capacity average was 204.8 ± 40.5 ml before stimulation and 301.2 ± 51.5 ml with stimulation. An improvement of greater than 50% for maximum cystometric capacity was observed in 15 of the 32 participants. In addition, stimulation was effective for the relief of detrusor pseudodyssynergia in five of the seven participants. Posterior tibial nerve stimulation proves to be a useful therapy for some urinary complications in patients with PD; however, a double-blinded study with a “sham procedure,” and a larger sample size of the test group are required.

Kulaksizoglu et al. [19] reported an open study using botulinum toxin type A (Dysport®) on 16 patients with PD and an overactive bladder. They were interviewed using the SEAPI (stress incontinence, emptying, anatomy, protection and inhibition) Incontinence Quality of Life Assessment Questionnaire, as well as other urodynamic studies. The caregivers were asked to describe the burden of urinary symptoms in quality of life, as evaluated with a visual analog scale. Five hundred units of the toxin was diluted in 30 ml of saline solution and applied with a flexible fiberscope on 30 points at a depth of 4 mm, respecting the bladder dome. An initial visit was made and then at 3, 6, 9 and 12 months post-application. There was an important improvement on the SEAPI scale as well as in the maximum bladder capacity, lasting for up to 12 months (SEAPI baseline: 32; 3 months: 11, 6 months: 10, 9 months: 16, 1 year: 26; and maximum bladder capacity baseline: 217.8 ml; 3 months: 355.1 ml; 6 months: 399 ml; 9 months: 401.4 ml; 1 year: 295.2 ml). Six subjects presented continuous urinary incontinence, which improved within the first 3–6 months as measured by the number of daily diaper changes. The visual analog scale from the caregiver improved for the first 9 months but reached the same score a year after the application. A double-blinded, placebo-controlled study with a larger number of participants and stratified by other variables including age, gender, the presence of prostate disorders, mental status, diabetes and dopaminergic and/or anticholinergics daily dosage would be helpful for this purpose.

Vaughan et al. [20] conducted an open study that consisted of exercise-based behavioral therapy in PD patients with urinary incontinence. The study included five visits, at 2-week intervals, over 8 weeks. During the visits, it was explained to the patients how to contract and relax the pelvic floor muscles, manage liquid intake and constipation and exercise pelvic floor muscles, and they were given strategies for urge suppression. The primary objective was to observe a weekly change in incontinence. Out of the 24 subjects selected, only 17 completed the study. Of this group, 12 (71%) achieved a greater than 50% reduction in urinary incontinence frequency and seven (41%) were continent by the end of the study. This demonstrates some interesting results because the subjects improved their problems without the help of pharmaceuticals. However, there are various reasons why we should be cautious of the results: there was no control group, the evaluations were not blinded, withdrawal from the study was greater than 20% and there was no formal statistical evaluation due to the number of participants.