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Critical Review: Does treatment with levodopa improve swallowing function
in patients with Parkinson’s Disease?
University of Western Ontario: School of Communication Sciences and Disorders This critical review examines the evidence regarding the effects of levodopa on the swallowing function of persons with Parkinson’s disease in seven studies. Study designs include: mixed design, single and counterbalancing repeated measures pre-posttest designs, critical reviews, systematic review and meta-analysis. Overall, research supporting the ability of levodopa to improve swallowing function in patients with Parkinson’s disease is lacking and the findings are inconclusive. More research is required to examine this relationship. Recommendations for future research and clinical implications are provided. Introduction
in patients with PD. The secondary objective is to provide recommendations for clinical practice and Dysphagia has been reported to be the main cause of pulmonary infection and death in patients with Parkinson’s disease (PD) (Melo & Monteiro, Methods
2012). It is present in more than 90% of PD patients and it is symptomatic in up to 50% of these patients (Hunter et al., 1997). Swallowing dysfunction in PD Computerized databases, including CINAHL, patients is multifactorial with abnormalities possible PubMed, and PsychINFO, were searched using the in all phases of swallowing (Hunter et al., 1997). While Parkinson’s disease is defined as a ((Parkinson’s disease) OR (parkinsonian)) dopaminergic nigrostriatal disorder, not all symptoms of the disease show improvement when treated with dopamine replacement strategies (Menezes & Melo, The search was limited to articles written in 2009). While levodopa improves the motor English between 1989 and 2013. References from symptoms of PD, symptoms such as pain, cognitive selected articles were examined to identify articles impairment, and dysautonomia do not show improvement after treatment with levodopa (Sutton, 2012). The ability of levodopa to improve swallowing function in particular is not well Studies selected for inclusion in this critical review paper were required to examine the effect of Professionals working in the area of clinical levodopa on swallowing function of individuals with dysphagia need to know whether or not PD patients Parkinson’s disease. The selection criteria for being treated with levodopa are at risk for aspiration primary journal articles required each individual to due to swallowing dysfunction. This knowledge is serve as their own control by having their swallowing vital given that many patients with PD and dysphagia are asymptomatic for swallowing difficulties, which administration. No limits were set on the age, sex, makes them prone to silent aspiration (Sutton, 2012). etiology, stage, or severity of PD, or the The role of levodopa in restoring swallowing function is currently unclear in the literature, hence this study seeks to examine the evidence regarding its Results of the literature search yielded seven articles that were consistent with the selection Objectives
criteria: mixed design (nonrandomized clinical trial and single repeated measures pre-posttest design) (1), The primary objective of this paper is to single repeated measures pre-posttest designs (2), critically evaluate existing literature regarding the counterbalancing repeated measures design (1), impact of levodopa treatment on swallowing function critical reviews (2), and a systematic review and In addition, the rater was only partially blinded and the ratings were qualitative and subjective in nature. Results
Hughes (1997) examined the effects of dopaminergic Mixed Design and Single Repeated Measure Designs stimulation on swallowing abnormalities in patients Bushmann, Dobmeyer, Leeker and Perlmutter with PD. They studied the effects of oral levodopa (1989) examined the swallowing abnormalities and and subcutaneous apomorphine on swallowing their response to treatment with levodopa in 20 function separately. The effects of subcutaneous subjects with PD. They also compared the presence apomorphine will not be discussed in this review. of swallowing abnormalities in patients with PD to This study consisted of 15 patients with PD and those of healthy controls. For the purposes of this predetermined symptomatic dysphagia. All patients article, only the swallowing abnormalities of the had been taking levodopa therapy chronically. patients with PD and their response to levodopa will Swallowing function was evaluated using an MBS before and after levodopa, and rated objectively by two blinded speech-language pathologists. Pre- modified barium swallow (MBS) both on and off levodopa and post-levodopa swallowing variables levodopa, and rated by two speech-language (transit time, aspiration, penetration and vallecular pathologists, one of whom was blinded, using an pooling) were analyzed using a non-parametric objective protocol. Appropriate analysis using the Wilcoxon signed rank test. The results showed a kappa statisitc revealed strong inter-rater reliability reduction in the length of the oral preparatory phase for assessment of all swallowing behaviours. Results with semisolids and thin fluids (p < 0.05), and an showed abnormal swallows in 15 patients off unexpected increase in the oral phase time and total levodopa. Of those, five showed mild to dramatic initial swallow time with the solid bolus (p < 0.05). improvement (decreased residue and transit time) on No statistically significant differences were found levodopa, and one showed deterioration. No when analyzing the data at the level of the individual. statistical analysis was completed on the MBS This study provided a high level of evidence findings that were performed both before and after (level 2b). The researchers included the use of scales and protocols to help decrease the subjectivity, and This study provided a high level of evidence they performed statistical analysis of the MBS (level 2b) which included experimenter blinding and findings. However, only one of two rater’s data was interrater statistical analysis. However, there was no analyzed and no interrater reliability statistics were statistical analysis performed on the pre and post Lim, Leow, Huckabee, Frampton, and Anderson (2008) examined the effect of levodopa on characteristics of swallowing abnormalities in PD swallowing and respiratory function. For the patients. For the purposes of this review, only the purposes of this review, only the effects of levodopa changes in swallowing function in response to on swallowing function will be discussed. This study consisted of 10 patients who were This study included 19 patients, 5 of which had currently being treated with levodopa. Nasendoscopy never been treated with levodopa. These 5 patients was used to evaluate swallowing function both on demonstrated responsiveness to levodopa during the and off levodopa during two sessions spaced at least study. Swallowing function was evaluated with an a week apart. Participants were randomly allocated to MBS, on and off levodopa. Rating was performed by two groups of 5 subjects, with group one being ‘on’ one of the researchers of the study who was partially levodopa in the first session and ‘off’ levodopa in blinded and whose professional designation was not their second session, and group two being assessed in reported. The results showed that 12 of 19 PD the reverse order in order to control for potential bias. patients had abnormal swallows on the MBS. Six of One of the 10 participants did not perform the 12 patients showed improvements (oral phase, qualitative swallowing assessment due to discomfort aspiration, decreased residue) after levodopa, with from the endoscopy. Qualitative analysis of one of these patients showing improvement in one swallowing dysfunction examining the incidence of phase of swallowing and deterioration in another. aspiration, penetration, residue, spillage and vocal This study provided a relatively high level of fold bowing revealed no significant changes or evidence (level 2b), however no statistical analysis was performed on the ‘on’ levodopa MBS findings. This study provided a moderately high level of Discussion
evidence (level 2b), which included controlling for an oder bias and performing statistical analysis of the When examining the primary journal articles nasendoscopy findings. However, the endoscopy comprehensively, two of the four studies did not perform statistical analysis on any of their data relating to swallowing abnormalities observed on and off levodopa (Bushmann et al., 1989; Fuh et al., Menezes and Melo (2009) selected five studies 1997). Only a descriptive, qualitative, and subjective to include in their systematic review assessing the analysis of MBS results was performed. It is very role of levodopa in swallowing function. They difficult to draw significant conclusions that can examined the outcomes of oral transit time and assist with making practice decisions from studies pharyngeal transit time for thin fluids and solids, and that have not performed statistical analysis and that aspiration in subsets of these five studies. No single outcome measure was available to be pooled across Statistical anlaysis to examine the effects of all five studies. The researchers transformed the possible confounding variables such as age, sex, descriptive statistics presented in three of the studies comorbidities, additional medications, disease into a mean +/- standard deviation when comparing severity, complaints of dysphagia symptoms, and the patients’ swallowing abnormalities in the ‘on’ and duration of disease was not reported in any of these ‘off’ levodopa states. Given that two of these three studies. None of the studies reported attempts to studies reported descriptive data only, statistical control for any of these variables, although the study meta-analysis was limited to mean comparisons only. by Lim et al. (2008) did report controlling for an Their results showed that none of the dysphagia order bias. Two of the studies examined the parameters evaluated in their meta-analysis relationship between patient complaints of dysphagia demonstrated significant improvement after treatment and the presence of swallowing abnormalities on the MBS, but only when off levodopa (Bushmann et al., 1989; Fuh et al., 1997). The study by Fuh et al. (1997) included patients that had never taken Sutton (2012) wrote a critical review paper that levodopa before, and no statistical analysis was examined the role of levodopa in swallowing performed to control for this variable. None of the function. He supported levodopa-induced swallowing studies examined the chronic effects of levodopa on improvement by describing the relationship of swallowing and the length of time that each patient dysphagia and mortality in PD patients while had been previously taking levodopa was not comparing the pre and post levodopa era, and by controlled for. These two variables may have a discussing case reports that demonstrated swallowing significant impact on the effects that levodopa has on improvements in response to levodopa therapy. He swallowing function, and they should be examined also identified and addressed many flaws that were present in the meta-analysis performed by Menezes They study by Bushmann et al. (1989) was the and Melo (2009), which included mislabeled figures, only study to perform statistical analysis on interrater incorrect source statistics and flaws in study selection reliability, and present data from two independent raters. Fuh et al. (1997) chose to eliminate the data collected from one of their MBS raters without presenting a thorough explanation, which introduces Monteiro (2012) summarized the results of eight a source of bias. Blinding occurred fully in two studies that examined swallowing function in patients studies (Bushmann et al., 1989; Hunter et al., 1997), with PD. Five of these studies also examined the role partially in another (Fuh et al, 1997), and was not of levodopa in swallowing function. These five discussed in the study by Lim et al. (2008). The studies comprise a fair representation of the available blinding of all raters should have occurred in all research addressing this topic. Their review provides studies as it is feasible and serves to eliminate rater an overview of study results that pertain to each bias. The professional designation, and hence phase of swallowing, and concludes that there is no qualification of the raters was clear in only two of the evidence that levodopa consistently improves studies reviewed (Bushmann et al., 1989; Hunter et al., 1997). Using qualified raters strengthens the level The variability in levodopa dose amongst the studies is concerning. Some of the studies had patients take ‘their regular amount’ of levodopa (Bushmann et al., 1989; Lim et al., 2008), while applicable to clinical practice. The small number of others used a fixed amount of levodopa (Fuh et al., included studies and measured parameters, and the 1997; Hunter et al., 1997). A fixed dosage is easier to minimal statistics available to analyze limits the examine statistically in order to control for dosage clinical usefulness of the results of this meta-analysis. effects. Further research using a fixed amount of When examining the critical reviews, Sutton’s (2012) levodopa would allow for more appropriate overall conclusion suggesting that dysphagia is comparisons amongst studies and stronger conclusive responsive to levodopa lacks research-based evidence and is largely anecdotal. He claims that recent pilot The reviewed studies often examined different studies, referring to the studies reviewed in this swallowing behaviour measures. This made it review and in the meta-analysis performed by difficult to compare outcomes from one study to Menezes and Melo (2009), neither strengthen nor another. Pharyngeal residue and aspiration were the weaken his point of view. However, these ‘pilot only two measures found to be common amongst all studies’ are the only experimental studies available in of the studies. This is largely due to the fact that one the literature. The evidence that he refers to involves of the studies used a nasendoscope instead of an observations and case studies only. This implies that MBS to examine patients’ swallowing. The his point of view is based on observations and nasendoscope does not allow for visualization of the nonexperimental studies only, which do not hold a lot oral preparatory or oral phase, the swallow initiation, of merit in the scientific community. In the critical or the esophageal phase whereas an MBS does. The review produced by Melo and Monteiro (2012), there nasendoscope is however, more efficient at detecting is little, if any, critiquing of the studies or penetration and aspiration than the MBS (Singh et al., comprehensive analysis that brings the study results 2009). In addition, none of the studies examined the together. It would have been beneficial for this esophageal phase of swallowing, however, abnormal review to have included a thorough critique of each esophageal peristalsis and gastric reflux are study’s results, as opposed to just stating the results commonly observed swallowing abnormalities in patients with PD (Edwards, Quigley & Pfeiffer, 1992; Conclusions
The sample sizes used in all studies were relatively small; a larger number of subjects may In summary, research support for levodopa- have assisted with identifying meaningful results and induced swallowing improvement in patients with PD achieving statistical significance. All of these studies is lacking and the overall findings are inconclusive. used a study design that results in a relatively high Two of the reviewed studies showed qualitative level of evidence (level 2b). These studies did not use improvements in swallowing function in up to fifty a randomized control trial, which is the gold standard, likely due to the fact that this design is not abnormalities, suggesting an individualized benefit realistic for this type of study as it is unethical to from taking levodopa. However, these studies did not withhold levodopa medication from PD patients. perform any statistical analyses which diminishes the Further methodological flaws in these studies validity of their results. The other two reviewed diminish the level of evidence that they provide. As studies showed limited significant changes. Some of previously discussed, these studies were descriptive the significant changes found in these studies actually in nature, they often did not control for confounding demonstrated a deterioration in swallowing after variables, and statistical analysis was not performed levodopa administration. In addition, the critical in all studies. The results of these studies must reviews and meta-analysis provide conflicting results. therefore be interpreted with caution when attempting While an individual benefit of levodopa on swallowing function is possible, more studies When evaluating the meta-analysis and the involving quantitative research and statistical analysis critical reviews, many weaknesses limit the clinical are needed to resolve the conflicting findings in the usefulness of their conclusions. The majority of the statistical comparisons in the meta-analysis performed by Menezes and Melo (2009) were Recommendations
performed on only two studies, which limits the comprehensiveness of this review. In addition, one of Future research should focus on the following in the included studies used healthy individuals as order to provide more compelling evidence: controls, while the remaining studies the individuals with PD served as their own controls. This makes opposed to using only descriptive subjective their comparisons and analyses less appropriate and findings in order to strengthen the validity of References
Performing appropriate statistical analysis Bushmann, M., Dobmeyer, S. M., Leeker, L., & abnormalities and their response to treatment in Parkinson's disease. Neurology, 39, 1309-1314. variables through statistical analysis or Edwards, L. L., Quigley, E. M., & Pfeiffer, R. F. Using two or more qualified blinded raters, presenting the data from all raters, and performing interrater statistical analysis to pathophysiology. Neurology, 42, 726-732. Performing studies using a fixed amount of Fuh, J. L., Lee, R. C., Wang, S. J., Lin, C. H., Wang, levodopa for all subjects to allow for more P. N., Chiang, J. H., & Liu, H. C. (1997). Swallowing difficulty in Parkinson's disease. Clinical Neurology and Neurosurgery, 99, 106- Performing studies that examine the chronic effects of levodopa on swallowing function, as opposed to only the short-term effects. Hunter, P. C., Crameri, J., Austin, S., Woodward, M. Using larger sample sizes to assist with the identification of more meaningful results. C., & Hughes, A. J. (1997). Response of Parkinsonian swallowing dysfunction to Examining similar swallowing behaviour measures to those examined in existing Dopaminergic stimulation. Journal of Neurology, Neurosurgery, and Psychiatry, 63, Examining the effects of levodopa on the Lim, A., Leow, L., Huckabee, M. L., Frampton C., & Anderson, T. (2008). A pilot study of respiration and swallowing integration in Parkinson's Clinical Implications
disease: "on" and "off" levodopa. Dysphagia, The conflicting results of these reviewed studies suggest that clinicians should exercise caution when Melo, A., & Monteiro, L. (2012). Swallowing implementing study results to their clinical practice. The findings of these studies allude to certain idiopathic Parkinson's disease: Lack of evidence. implications that clinicians should consider when Parkinsonism & Related Disorders, 1-3. assessing and treating dysphagia in PD patients who are taking levodopa. Firstly, it is important for Menezes, C., & Melo, A. (2009). Does levodopa clinicians to remember that the effects of levodopa on improve swallowing dysfunction in Parkinson's swallowing function are highly individualized. disease patients? Journal of Clinical Pharmacy Beneficial effects from taking levodopa cannot be assumed, and some patients may actually show worsening effects after levodopa administration. Singh, V., Berry, S., Brockbank, M. J., Frost, R. A., Patients should be assessed as individuals with no Tyler, S. E., & Owens, D. (2009). Investigation preconceived notions regarding the effects of levodopa on their swallowing function. Secondly, it videofluoroscopy. European Archives of Oto- would be beneficial for clinicians to initially assess PD patients when they are both on and off their levodopa medication. This would assist with the Stroudley, J., & Walsh, M. (1991). Radiological development of a comprehensive plan for each assessment of dysphagia in Parkinson's disease. patient’s diet that accounts for any differences in The British Journal of Radiology, 64, 890-893. their swallowing function when on or off this Sutton, J. P. (2012). Dysphagia in Parkinson's disease is responsive to levodopa. Parkinsonism &

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