ABSTRACT
Background and Objective
The delayed‐on phenomenon (DOP) related to levodopa treatment frequently disturbs quality of life in advanced‐stage Parkinson's disease (PD) patients. The objective of this study was to explore the impact of swallowing dysfunction on the development of DOP.
Methods
Swallowing function was investigated by endoscopic evaluation in 11 PD patients with the DOP and 9 PD patients without the DOP during the on phase. Residual drug in the pharynx after taking the drug in tablet, capsule, and powder forms was also observed.
Results
Residual drug was seen in the pharynx in six cases (30.0%). Pooling of saliva, delayed swallowing reflex, and residual drug were more frequent in the DOP group than in the group without the DOP (P < 0.05). The odds ratios for residual drug in the pharynx, pooling of saliva, and delayed swallowing reflex for the DOP were 42.7 (95% confidence interval, 1.89–962.9), 14.0 (95% confidence interval, 1.25–156.6), and 15.8 (95% confidence interval, 1.75–141.4), respectively.
Conclusions
These results suggest that swallowing dysfunction leading to residual antiparkinsonian drug in the pharynx has substantial impacts on the DOP in PD patients.
Keywords: Parkinson's disease, dysphagia, delayed‐on phenomenon, videoendoscopic swallowing study, levodopa
Motor fluctuations develop frequently during the course of disease progression in Parkinson's disease (PD) patients.1 Of the several types of motor fluctuations, the delayed‐on phenomenon (DOP) is a serious complication, representing an obstacle to PD patients performing activities of daily living.2 Although impaired gastric emptying is thought to be associated with the DOP, the exact mechanisms remain unknown. On the other hand, swallowing dysfunction is a disabling complication of PD and impairs quality of life in patients through the induction of malnutrition, dehydration, aspiration pneumonia, and choking.3, 4, 5 Videofluorographic swallowing studies have demonstrated that PD patients show various disturbances in swallowing food and water.6, 7 However, few studies have evaluated swallowing of tablet‐form drugs in PD patients.8, 9
Fiberoptic endoscopic evaluation of swallowing (FEES), which can directly observe the pharynx and larynx, is useful for evaluating swallowing.10 The aim of this study was to investigate the relationship between disturbances during drug swallowing and the DOP.
Methods
Study Participants
Swallowing function was evaluated in PD patients with various kinds of swallowing problems such as awareness of dysphagia, history of aspiration pneumonia, and/or increased sputum after eating meals. This study was a retrospective and case study of a consecutive series of 25 PD patients who performed drug swallowing for evaluations by FEES at Fukuoka University Hospital, Fukuseikai‐Minami Hospital, or Omuta National Hospital between April 1, 2013 and February 28, 2019. PD was diagnosed according to the U.K. Parkinson's Disease Society Brain Bank Diagnostic criteria,11 and all patients were clinically evaluated by certified neurologists. The DOP was defined as “improvement of parkinsonism taking longer than 30 minutes after a dose.”2, 10, 12 The PD patients were divided into 2 groups, with and without the DOP.
Swallowing Evaluation
Endoscopic examination was performed during the on phase. During the endoscopic examination, the patient sat on a chair or bed in a usual posture for swallowing drugs, and an endoscope (FNL‐10RBS fiberscope; Pentax, Tokyo, Japan) was inserted through the nose until the epiglottis and vocal cords were visible. Endoscopic videos obtained during the examination were recorded, and swallowing was assessed by 2 independent raters. Swallowing function was evaluated using jelly and a drug. The following aspects of swallowing function were assessed: awareness of dysphagia, structural abnormality in the hypopharynx, pooling of saliva, delayed swallowing reflex, residual drug, and the Penetration Aspiration Scale (PAS).13 Awareness of dysphagia was determined by asking the patients whether they were aware of dysphagia before the videoendoscopic swallowing examination. Structural abnormality was assessed by direct observation of the surface anatomy and mucosal abnormalities in the pharynx. Pooling of saliva was assessed by observing whether saliva was not cleared from the pharynx even after repeated swallowing. A delayed swallowing reflex was defined as a food bolus flowing from the epiglottic vallecula into the piriform fossa before the swallowing reflex occurred.14 The PAS was used to assess swallowing of jelly.13 The jelly was visible green and cut into 1 tablespoon of sliced jelly. Swallowing jelly was conducted three times unless there was a risk of aspiration. The worst score in swallowing jelly 3 times was recorded as PAS. A residual drug in the pharynx was assessed with tablets, capsules, and powder. The size of the drug, tablets or capsules, was 10 mm diameter or 18 mm length, and the powder was made by fractured tablets or capsules. The form of the drug each individual ordinarily took was selected because medicines with which patients are not familiar could potentially change swallowing function as forming unusual bolus. The real drug was used for the examination at the time of taking medicine, but the forged drug made of lactose was done when it was difficult to adjust the times. Evaluation of drug swallowing was performed with the drug and a certain amount and viscosity of liquid according to the patient's usual method of drug intake. The liquid was dyed with green food coloring to aid visualization. After the first swallowing reflex before spontaneous clearing swallows, whether a tablet or a capsule remained in the pharynx was checked. If drug stasis was observed in the pharynx, the patient was asked to swallow repeatedly to achieve passage of the drug into the esophagus. For swallowing evaluations with powder, swallowing was defined as finished when half of the total amount of powder administered had disappeared from the pharynx. We did not use anesthetic during FEES for all the patients.
Statistical Analysis
Statistical analyses were performed using SPSS for Macintosh version 21 (SPSS, Chicago, IL). Student's t‐test was used to compare mean age, disease duration, Hoehn and Yahr stage, levodopa‐equivalent dose, and PAS between groups with and without the DOP. The odds ratio (OR) for each swallowing function were analyzed. If there is null included in the cell of a 2‐by‐2 table, the OR were calculated by adding 0.5 to each cell. Values of P < 0.05 were considered significant.
Results
Of the initial 25 PD patients, 5 were excluded because their PD was at an advanced stage, and the presence of the DOP could not be determined. A total of 20 patients with PD were finally included, and the background characteristics of these patients are summarized in Table 1. Of the 20 patients, 9 were categorized in the DOP group, and the other 11 were in the group without the DOP. No significant differences between these 2 groups were seen in age at the time of examination (69.7 ± 15.5 years vs. 68.8 ± 12.2 years; P = 0.88), sex (male:female, 4:7 vs, 5:4; P = 0.65), disease duration (8.5 ± 4.5 years vs. 10.7 ± 6.4 years; P = 0.378), Hoehn and Yahr stage (3.4 ± 0.5 vs. 3.9 ± 1.1; P = 0.16), and levodopa‐equivalent dose (569.4 ± 207.1 mg/day vs. 701.9 ± 380.2; P = 0.36).
Table 1.
Demographic characteristics of PD patients
| Case | Age, y | Sex | Disease Duration, y | Hoehn and Yahr Stage | Awareness of Dysphagia | Abnormal Structure | Pooling of Saliva | Delayed Swallowing Reflex | Drug Residue in Pharynx | Type of Drug | PAS | LED |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patients without the delayed‐on phenomenon (N = 11) | ||||||||||||
| 1 | 79 | M | 5 | 3 | − | − | + | − | − | Tablet | 6 | 650 |
| 2 | 73 | F | 9 | 3 | − | − | − | + | − | Powder | 1 | 200 |
| 3 | 79 | M | 3 | 4 | + | − | + | + | − | Capsule | 2 | 480 |
| 4 | 71 | F | 3 | 3 | − | − | − | − | − | Capsule | 1 | 450 |
| 5 | 76 | F | 7 | 3 | − | − | − | − | − | Tablet | 1 | 460 |
| 6 | 81 | M | 4 | 4 | + | − | + | − | − | Tablet | 1 | 930 |
| 7 | 27 | F | 11 | 3 | − | − | − | − | − | Tablet | 1 | 475 |
| 8 | 62 | F | 16 | 3 | − | − | − | − | − | Tablet | 1 | 500 |
| 9 | 64 | F | 12 | 3 | − | − | − | − | − | Tablet | 1 | 850 |
| 10 | 78 | F | 14 | 4 | − | − | − | − | − | Tablet | 1 | 532 |
| 11 | 77 | M | 9 | 4 | − | − | + | − | − | Tablet | 1 | 736 |
| Mean (SD) | 69.7 (15.4) | 10.7 (6.1) | 3.4 (0.5) | 7 | 11:0 | 7:4 | 9:2 | 9:0 | 1.5 (1.4) | 569.4 (197.4) | ||
| Patients with the delayed‐on phenomenon (N = 9) | ||||||||||||
| 12 | 69 | F | 9 | 3 | − | − | + | + | − | Tablet | 1 | 450 |
| 13 | 83 | M | 5 | 4 | − | − | + | + | + | Powder | 8 | 300 |
| 14 | 48 | F | 6 | 4 | − | − | + | + | − | Tablet | 3 | 600 |
| 15 | 65 | F | 17 | 5 | − | − | + | + | + | Tablet | 6 | 250 |
| 16 | 83 | F | 15 | 5 | + | − | + | + | + | Powder | 2 | 600 |
| 17 | 69 | M | 23 | 4 | + | − | + | ‐ | + | Tablet | 2 | 1156 |
| 18 | 59 | M | 11 | 3 | − | − | + | + | + | Tablet | 3 | 1055 |
| 19 | 61 | M | 5 | 2 | − | − | − | − | − | Tablet | 1 | 1306 |
| 20 | 82 | M | 5 | 5 | + | − | + | + | + | Tablet | 1 | 600 |
| Mean (SD) | 68.8 (12.2) | 12.3 (6.4) | 3.9 (1.0) | 9:0 | 1:8 | 2:7 | 3:6 | 3.0 (2.3) | 701.9 (358.4) | |||
PD, Parkinson's disease; PAS, Penetration Aspiration Scale; LED, levodopa‐equivalent dose; SD, standard deviation; M, male; F, female.
No significant differences in frequency of awareness of dysphagia (P = 0.61), structural abnormalities in the pharynx (P = 1.00), or PAS (1.5 ± 1.5 vs. 3.0 ± 2.4; P = 0.12) were identified between the groups. The frequencies of pooling of saliva (P = 0.02), delayed swallowing reflex (P = 0.01), and residual drug in the pharynx (P = 0.002) were significantly higher in the DOP group than in the group without the DOP.
The OR for residual drug in the pharynx for the DOP was 42.7 (95% confidence interval [CI], 1.89–962.9). ORs for awareness of dysphagia, pooling of saliva, and delayed swallowing reflex were 2.25 (95% CI, 0.29–17.8), 14.00 (95% CI, 1.25–156.6), and 15.8 (95% CI, 1.75–141.4), respectively.
Discussion
In general, levodopa is rapidly absorbed from the small intestine. Most PD patients who take levodopa experience improvement in their symptoms about 30 minutes after taking the drug. The benefit lasts for about 3 to 5 hours in patients with early‐stage PD. The duration of action of levodopa decreases gradually as the disease progresses. Most patients with advanced PD thus need to take medications many times a day. A disturbance during swallowing may thus have consequences in terms of the effectiveness of medical treatment.7 In the present study, FEES demonstrated that awareness of dysphagia, pooling of saliva, and a delayed swallowing reflex were not associated with the DOP. Only a disturbance during swallowing for tablets, such as residual tablet in the pharynx, was associated with the occurrence of the DOP (Figure 1). Furthermore, no relationship was identified between PAS and the DOP. PAS is designed to quantify airway invasion of material and response to airway invasion of material; therefore, PAS may be not adequate to evaluate drug swallowing function.
Figure 1.
Videoendoscopic findings. Cases 1 and 2 are patients without the delayed‐on phenomenon. The drug vanishes after the swallowing reflex. Cases 12 to 18 are patients with the delayed‐on phenomenon. In cases with the delayed‐on phenomenon, the drug remains after the swallowing reflex (arrow).
The exact mechanisms underlying the DOP remain unclear. Various putative factors are considered to be associated with the occurrence of the DOP, such as impaired gastric motility and deformity of the gastrointestinal tract. One of the most accepted theories is that impaired gastric motility is associated with the occurrence of the DOP. Several previous reports have demonstrated that gastric emptying is prolonged in PD patients with response fluctuations,15 and peak plasma levodopa has also been associated with delayed gastric emptying in patients with PD.16, 17 However, Tanaka and colleagues12 examined gastric emptying in PD patients with the DOP and no on, those without the DOP and no on, and control participants. That study demonstrated that gastric emptying time did not differ significantly between patients with the DOP and no on and those without the DOP and no on, suggesting that impaired gastric motility might not be associated with the DOP in PD patients. Another theory is that deformity of the gastrointestinal tract may induce the DOP or no on. Indeed, Japanese PD patients with a cascade stomach showed inhibited absorption of levodopa and no increases in plasma levodopa concentrations.18 Because the frequency of deformity of the gastrointestinal tract including cascade stomach is not high, deformity of the gastrointestinal tract may be associated with the DOP in only a small proportion of PD patients.12 The present study suggested a new insight, that swallowing dysfunction may induce residual drug in the pharynx, and swallowing dysfunction of these drugs may be associated with the DOP. A meta‐analysis of PD showed that oropharyngeal dysphagia is prevalent in at least a third of PD patients.3 Furthermore, most PD patients must take medicine many times a day, particularly in the off phase. A disturbance during tablet swallowing may thus occur in many patients with PD. Residual tablet in the pharynx is thus thought to be incidentally swallowed more than 30 minutes after taking the drug, explaining the delays in the appearance of drug effects. Actually, in a previous case report, videofluorographic swallowing studies of a PD patient with the DOP and no on phenomenon showed the retention of tablets in the pharynx.19 Taking all these results into account, we considered that the occurrence of the DOP may be associated with multiple factors, such as impaired gastric motility, deformity of the gastrointestinal tract, and a disturbance during drug swallowing.
Determining the best dosage form for the administration of drugs is crucial to avoid the DOP in PD patients. Nonoral therapy in PD is considered to be useful for patients with a drug‐swallowing disturbance. A patch of rotigotine, a dopamine agonist with activity against both D1 and D2 families, is a commonly used nonoral drug for PD patients with a swallowing disturbance. A previous report demonstrated that the rotigotine patch improved swallowing function during both the oral and pharyngeal phases.19, 20 Furthermore, pharyngeal transit time was decreased by the rotigotine patch. Indeed, residual drug in the pharynx in case 9 was improved after starting the rotigotine patch (data not shown). Moreover, subcutaneous injection of apomorphine, a dopamine agonist with activity against both D1 and D2 families, improved swallowing function, mainly in the early stages of PD.21 Subcutaneous injection of apomorphine has been shown to significantly reduce off time in PD patients. Although no reports have shown that continuous apomorphine infusion therapy improves swallowing function as evaluated by videofluorographic swallowing studies or FEES, it can improve swallowing function because continuous apomorphine infusion therapy improves the pooling of saliva and swallowing on the nonmotor symptoms scale.22
The limitations of this study were, first, its retrospective nature and the small number of enrolled patients. However, given the retrospective manner of this study, all of the patients were not aware of the purpose of this study. Awareness of the purpose could potentially influence the way that they swallowed the medications. Second, this study does not necessarily reflect the actual state of drug‐swallowing disturbance in PD patients because inserting the scope through the nose may make it difficult for patients to swallow a drug. However, few previous studies have showed evidence of swallowing dysfunction by FEES. Third, the sizes and shapes of drugs vary, but the effects of size and shape of drugs on swallowing in patients with PD could not be evaluated. Fourth, the frequency of awareness of dysphagia by patients could vary depending on the questions asked. For example, when asking patients “if they were aware of dysphagia,” they often answer “no” to this question, but when asking about specific symptoms such as drooling, coughing with eating and drinking, or food “sticking” in the throat, they change their answer to “yes.” Thus, the style of questions can also present bias. Further study of drug swallowing in patients with PD is needed. Fifth, we measured pharyngeal residue before any spontaneous swallows; therefore, we might not capture typical performance. It may be difficult to judge residue after a single swallow if patients typically perform 2 swallows to clear a bolus. Providing patients with a liquid wash could help to clear residue and could be a useful compensatory strategy for people at risk for the DOP. Sixth, given that FEES ratings are subjective, there is potentially an interrater variability.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
J.F.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
S.F: 1B, 1C, 2B, 2C, 3B
G.U.: 1B, 1C, 2B, 3B
H.A.: 1B, 1C, 2C, 3B
S.Y.: 1B, 1C, 2C, 3B
T.M.: 1B, 1C, 2C, 3B
Y.T.: 1A, 1B, 1C, 2C, 3B
Disclosures
Ethical Compliance Statement
The study was approved by the institutional review board of the Fukuoka University Hospital and the institutional review board of the Omuta Hospital for medical research ethics and followed the principles outlined in the Declaration of Helsinki. Informed consent for the fiberoptic endoscopic evaluation of swallowing was obtained from each patient prior to participation. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
This study was funded by JSPS KAKENHI Grants 15K19501 and 17K12069. The authors have no conflict of interest to declare.
Financial Disclosures for the Previous 12 Months
S.F. receives research support from JSPS KAKENHI Grant 15K19501. G.U. receives research support from JSPS KAKENHI Grant 17K12069. J.F., H.A., S.Y., T.M., and Y.T. have nothing to disclose.
Jiro Fukae and Shinsuke Fujioka contributed equally.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Kalia LV, Lang AE. Parkinson's disease. Lancet 2015;386:896–912. [DOI] [PubMed] [Google Scholar]
- 2. Melamed E, Ziv I, Djaldetti R. Management of motor complications in advanced Parkinson's disease. Mov Disord 2007;22:S379–S384. [DOI] [PubMed] [Google Scholar]
- 3. Kalf JG, de Swart BJ, Bloem BR, Munneke M. Prevalence of oropharyngeal dysphagia in Parkinson's disease: a meta‐analysis. Parkinsonism Relat Disord 2012;18:311–315. [DOI] [PubMed] [Google Scholar]
- 4. Mehanna R, Jankovic J. Respiratory problems in neurologic movement disorders. Parkinsonism Relat Disord 2010;16:628–638. [DOI] [PubMed] [Google Scholar]
- 5. Leow LP, Huckabee ML, Anderson T, Beckert L. The impact of dysphagia on quality of life in ageing and Parkinson's disease as measured by the Swallowing Quality of Life (SWAL‐QOL) questionnaire. Dysphagia 2010;25:216–220. [DOI] [PubMed] [Google Scholar]
- 6. Nagaya M, Kachi T, Yamada T, Igata A. Videofluorographic study of swallowing in Parkinson's disease. Dysphagia 1998;13:95–100. [DOI] [PubMed] [Google Scholar]
- 7. Umemoto G, Tsuboi Y, Kitashima A, Furuya H, Kikuta T. Impaired food transportation in Parkinson's disease related to lingual bradykinesia. Dysphagia 2011;26:250–255. [DOI] [PubMed] [Google Scholar]
- 8. Kalf JG, de Swart BJ, Bloem BR. Difficulty with pill swallowing in Parkinson's disease. Mov Disord 2011;26:S191. [Google Scholar]
- 9. Umemoto G, Fujioka S, Yanamoto S, Fukae J, Tsuboi Y. A case of sudden deterioration in Parkinson disease. Neurology 2016;87:1422. [DOI] [PubMed] [Google Scholar]
- 10. Nacci A, Ursino F, La Vela R, Matteucci F, Mallardi V, Fattori B. Fiberoptic endoscopic evaluation of swallowing (FEES): proposal for informed consent. Acta Otorhinolaryngol Ital 2008;28:206–211. [PMC free article] [PubMed] [Google Scholar]
- 11. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico‐pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Tanaka Y, Kato T, Nishida H, et al. Is there a difference in gastric emptying between Parkinson's disease patients under long‐term L‐dopa therapy with and without motor fluctuations? An analysis using the 13C‐acetate breath test. J Neurol 2009;256:1972–1976. [DOI] [PubMed] [Google Scholar]
- 13. Butler SG, Markley L, Sanders B, Stuart A. Reliability of the penetration aspiration scale with flexible endoscopic evaluation of swallowing. Ann Otol Rhinol Laryngol 2015;124:480–483. [DOI] [PubMed] [Google Scholar]
- 14. Baijens LW, Pilz W, Kremer B, Passos VL. Identifying patterns of FEES‐derived swallowing trajectories using group‐based trajectory model. Dysphagia 2015;30:529–539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Djaldetti R, Baron J, Ziv I, Melamed E. Gastric emptying in Parkinson's disease: patients with and without response fluctuations. Neurology 1996;46:1051–1054. [DOI] [PubMed] [Google Scholar]
- 16. Dizdar N, Granérus AK, Hannestad U, et al. L‐dopa pharmacokinetics studied with microdialysis in patients with Parkinson's disease and a history of malignant melanoma. Acta Neurol Scand 1999;100:231–237. [DOI] [PubMed] [Google Scholar]
- 17. Doi H, Sakakibara R, Sato M, et al. Plasma levodopa peak delay and impaired gastric emptying in Parkinson's disease. J Neurol Sci 2012;319:86–88. [DOI] [PubMed] [Google Scholar]
- 18. Miyaue N, Tada S, Ando R, et al. Cascade stomach associated with delayed‐on or no‐on phenomenon in a patient with Parkinson's disease. Mov Disord 2017;32:1492–1493. [DOI] [PubMed] [Google Scholar]
- 19. Tomita S, Oeda T, Umemura A, et al. Video‐fluoroscopic swallowing study scale for predicting aspiration pneumonia in Parkinson's disease. PLoS One 2018;13:e0197608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Hirano M, Isono C, Sakamoto H, Ueno S, Kusunoki S, Nakamura Y. Rotigotine transdermal patch improves swallowing in dysphagic patients with Parkinson's disease. Dysphagia 2015;30:452–456. [DOI] [PubMed] [Google Scholar]
- 21. Tison F, Wiart L, Guatterie M, et al. Effects of central dopaminergic stimulation by apomorphine on swallowing disorders in Parkinson's disease. Mov Disord 1996;11:729–732. [DOI] [PubMed] [Google Scholar]
- 22. Martinez‐Martin P, Reddy P, Antonini A, et al. Chronic subcutaneous infusion therapy with apomorphine in advanced Parkinson's disease compared to conventional therapy: a real life study of non motor effect. J Parkinsons Dis 2011;1:197–203. [DOI] [PubMed] [Google Scholar]