International Journal of Speech-Language Pathology
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Pharyngeal transit in patients with chronic progressive external ophthalmoplegia Danielle Ramos Domenis, Raphaela B. Granzotti, Claudia Ferreira Sobreira & Roberto Oliveira Dantas To cite this article: Danielle Ramos Domenis, Raphaela B. Granzotti, Claudia Ferreira Sobreira & Roberto Oliveira Dantas (2015) Pharyngeal transit in patients with chronic progressive external ophthalmoplegia, International Journal of Speech-Language Pathology, 17:4, 384-389, DOI: 10.3109/17549507.2014.941935 To link to this article: http://dx.doi.org/10.3109/17549507.2014.941935
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Date: 06 November 2015, At: 06:03
International Journal of Speech-Language Pathology, 2015; 17(4): 384–389
Pharyngeal transit in patients with chronic progressive external ophthalmoplegia
DANIELLE RAMOS DOMENIS1, RAPHAELA B. GRANZOTTI1, CLAUDIA FERREIRA SOBREIRA2 & ROBERTO OLIVEIRA DANTAS3
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1Federal
and
University of Sergipe, Lagarto, Brazil, 2Medical School of Ribeirão Preto USP, Neurosciences, RibeirãoPreto, Brazil, School of Ribeirão Preto USP, Internal Medicine, Ribeirão Preto, Brazil
3Medical
Abstract Purpose: A common presentation of mitochondrial myopathies is chronic progressive external ophthalmoplegia (CPEO). Dysphagia is a complaint in about 50% of cases. Method: This investigation evaluated pharyngeal transit in patients with CPEO. Videofluoroscopic swallowing evaluation was performed with paste, liquid and solid boluses in 14 patients with CPEO and in 16 normal volunteers. Result: There was no difference between patients and volunteers in the duration of pharyngeal swallowing events with the liquid bolus. Compared to control participants, patients with CPEO had significantly shorter duration of pharyngeal transit for paste and solid boluses, of pharyngeal clearance for paste bolus, and of upper oesophageal sphincter transit for paste and solid boluses. Spontaneous multiple swallows and effortful swallows were performed by patients but not by the volunteers. Conclusion: It was concluded that patients with CPEO have shorter pharyngeal transit duration of paste and solid boluses than normal volunteers, which may be a consequence of a spontaneous smaller bolus volume in each swallow and/or effortful swallows.
Keywords: Dysphagia, neurodegenerative diseases, swallowing
Introduction Mitochondrial myopathies are a clinically heterogeneous group of disorders that can affect multiple systems in addition to skeletal muscles (DiMauro, Bonilla, Zeviani, Nakagawa, & DeVivo, 1985; Nardin & Johns, 2001). Fatigue may be the main complaint and most often disproportionate to the degree of muscle weakness and atrophy detected. It may be stationary, progressive or episodic, may affect both sexes at any age and may be sporadic or familial (Dias-Tosta, 1994). The more frequent syndromes consequent to mitochondrial DNA rearrangements are: Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalopathy with lactic acidosis (MELAS) (Marie, 1994). There is heterogeneous clinical presentation of these diseases, with the need of histochemical and genetic analysis for accurate diagnosis and classification. A common presentation of mitochondrial myopathies is chronic progressive external ophthalmoplegia (CPEO), which can appear alone or associated with
the involvement of other systems (Franceschina, Salani, Bordoni, Sciacco, Napoli, Comi, et al., 1998). CPEO may be associated with the presence of a large, single or multiple deletion of mitochondrial DNA and a point mutation (Carod-Artal, Solano-Palacios, Playan-Ariso,Viana-Brandi, Lopez-Gallardo, Andreu, et al., 2003; Nardin & Johns, 2001). The population prevalence of single and large scale mitochondrial DNA deletion is 1.2/100,000 to 2.9/100,000 (Aure, Baulmy, Laforet, Jardel, Eymard, & Lombes, 2007). Prevalence of clinically manifest mitochondrial myopathies is described as 9.2/100,000 and at risk for the disease are 16.5/100,000 children and adults younger than retirement age (Schaefer, McFarland, Blakely, He, Whittakes, Taylor, et al., 2008). The disease is characterized by a progressive evolution which causes ptosis of the eyelids, alterations of eye movements with normal pupils and in some cases involvement of the facial musculature. It may be often associated with multi-systemic alterations, affecting the retina, cerebellum, cochlea and facial and laryngeal muscles (Garciduenas, Loria, Sagastegui, & Garcia, 2000; Smits, Heijdra, Cuppen, & Van Engelen, 2011).
Correspondence: Dr. Roberto Oliveira Dantas, Sao Paulo University, Ribeirao Preto, Brazil. E-mail: [email protected] ISSN 1754-9507 print/ISSN 1754-9515 online © 2014 The Speech Pathology Association of Australia Limited Published by Informa UK, Ltd. DOI: 10.3109/17549507.2014.941935
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Pharyngeal transit in CPEO
Swallowing problems are a manifestation of the disease (Garciduenas et al., 2000; Jimenez-Caballero, Serviá, Cabeza, Marsal-Alonso, & Alvarez-Tejerina, 2006; Smits, Heijdra, Cuppen & Van Engelen, 2011; Vu, Sciacco, Tanji, Nichter, Bonilla, Chatkupt, et al., 1998), with dysphagia being a complaint in ∼ 50% of cases (Aure et al., 2007). Respiratory problems, such as pneumonia, are presently a major cause of death in CPEO and the weakness of laryngeal musculature with increased risk of aspiration of liquid or solid food and reduction of glottic closure during coughing is one of the hypotheses for the presence of respiratory infections. Moreover, opening impairment of the upper oesophageal sphincter (UES) and increase in UES pressure have been described as situations that may affect pharyngeal transit. There is also impairment of oesophageal contractions, mainly in the proximal oesophageal body (Domenis, Okubo, Sobreira, & Dantas, 2011; Kornblum, Broicher, Waltherm, et al., 2001; Smits, Heijdra, Cuppen & Van Engelen, 2011). Our aim in this study was to evaluate by videofluoroscopy the pharyngeal transit of liquid, paste and solid boluses in patients with mitochondrial myopathy-type CPEO. Our hypothesis was that this disease causes alterations of the pharyngeal phase of swallowing.
Method Participants Videofluoroscopic evaluation of pharyngeal transit was performed in 14 patients with CPEO and in 16 normal volunteers. All patients were submitted to clinical evaluation before videofluoroscopy. Swallowing clinical evaluation was performed by the first author (speechlanguage pathologist) and consisted of the evaluation
of facial movements, tongue mobility (lateralization, elevation), tongue strength (assessed by a spatula against the movement of the tongue), lip mobility, strength of the lips, soft palate mobility and presence of spontaneous cough. Functional evaluation was performed with swallowing 5 mL and free volumes of liquid, paste and solid boluses and evaluated labial closure, chewing, duration of oral phase, bolus control, oral cavity residue after swallowing, cervical auscultation, presence of coughing, choking, hoarseness, multiple swallows, manoeuvres during swallowing and the presence of a wet voice. Alteration in clinical evaluation was considered mild, moderate or severe, depending of the number and intensity of alterations observed. The diagnosis of CPEO was made by histochemical analysis of a skeletal muscle biopsy and by mitochondrial DNA analysis. They were five men and nine women, aged 15–62 years, mean ⫽ 35.3 years. By clinical judgement, none of them had cerebral dysfunction, cognitive decline or neuropsychiatric abnormalities. Ten patients had a single mitochondrial DNA deletion, two had multiple deletions and two had a point mutation (Table I). Nine (64.3%) had the sensation that the food was stuck in their throat, five (35.7%) had difficulty swallowing hard foods, five had choking during swallows (35.7%), and three (21.4%) had weakness in swallowing. Five patients had no swallowing symptoms. The group of normal volunteers consisted of six men and 10 women without symptoms, swallowing problems or neurologic diseases, aged 21–44 years, mean ⫽ 27.5 years. The mean age of the normal volunteers was not different of the mean age of the patients (p ⬎ 0.05). The study was approved by the Human Research Committee of the University Hospital of Ribeirão Preto and all patients and volunteers gave written informed consent to participate in the investigation.
Table I. Characteristics of the patients with chronic progressive external ophthalmoplegia (CPEO) included in the investigation.
Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14
385
Gender
Age (years)
Disease duration (years)
Mitochondrial DNA analysis
Swallowing complaint
Reduction of perioral and tongue force
F M F F M F M F M M F F F F
56 44 62 27 59 44 37 31 21 15 30 15 23 31
11 31 34 23 26 20 17 10 12 12 25 10 09 11
SD SD MD PM 3243 SD SD SD MD SD SD PM 3243 SD SD SD
⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺
⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺
F, Female; M, Male; SD, Single mitochondrial DNA deletion; MD, Multiple mitochondrial DNA deletion; PM 3243, Point mutation 3243; ⫺, no; ⫹, mild.
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Procedure The videofluoroscopic examination was done using the radiologic instrument Arcomax Phillips model BV 300 (Veenpluis, The Netherlands) and the digital image processing system Ever Focus model EDSR 100 VI.2 (Taipei, Taiwan) with a DVR (Ever Focus) monitor run at 60 frames/second and a clock time that indicates digital time in seconds and hundredths of a second on each video frame. During the videofluoroscopic evaluation, all participants swallowed in triplicate the sequence of paste, liquid and solid boluses. The results for each measurement for each participant were the mean of the three swallows performed. In patients with multiple swallows the first of them was measured. The paste bolus was prepared with 50 mL of water, 15 mL of 100% liquid barium sulphate (Bariogel 100%, Laboratory Cristalia, Itapira SP, Brazil) and 15 mL of instant food thickener (Thick & Easy, Hormel Health Labs, Austin, MN) and was given to the patients and volunteers with a spoon. The liquid bolus was 50 mL of water with 15 mL of 100% liquid barium sulphate, given to the subjects with a cup, and the solid bolus was a Brazilian cookie coated with liquid barium. The volume of liquid and paste bolus swallowed was 5 mL and the cookie weighed 2.2 g.
Measures The beginning of the pharyngeal phase of swallowing was considered to be the moment when the bolus head reached the posterior part of the nasal spine, located at the end of the hard palate, at the beginning of the soft palate. It was taken as the zero reference for the timing of pharyngeal swallowing events. The end of the pharyngeal phase was the moment when the bolus tail crossed the upper oesophageal sphincter. The following features were timed: (1) onset and end of hyoid movement, (2) the moment when the bolus head reached the posterior part of the nasal spine, (3) the moment when the bolus tail reached the posterior part of the nasal spine, which was also the end of oral phase, and (4) the onset and offset of upper oesophageal sphincter (UES) opening. From these timings we calculated the duration of the pharyngeal transit (bolus tail at the posterior part of the nasal spine until the offset of UES opening), duration of pharyngeal clearance (bolus head at the posterior part of the nasal spine until the offset of UES opening), UES opening duration (time between onset and end of UES opening) and duration of hyoid movement (time between onset and end of hyoid movement). Oral transit was not included in the measurement of pharyngeal transit time. An effortful swallow consists of squeezing all the muscles involved in swallowing. It was perceived by corporal, facial and head movements. Multiple swallows were considered to be present when the participants performed two or more swallows to ingest the bolus
volume. Multiple and effortful swallows were performed voluntarily by the patients, without orientation of the researchers. Laryngeal penetration occurred when the bolus residues went inside the airways but did not cross the vocal folds and laryngeal aspiration occurred when the bolus residues went below the vocal folds. Statistical analysis Statistical analysis was done by the Center of Quantitative Analysis of the Medical School of Ribeirão Preto, University of São Paulo, using a linear model with mixed effects (Schall, 1991). The model was adjusted using the Proc Mixed feature of the SAS software version 9 (Littell, Milliken, Stroup, & Woffinger, 1996). We also used the Fisher test to compare the proportion of patients with alterations of swallowing. The results are reported as mean and standard deviation, unless stated otherwise. A p-value of 0.05 or less was considered significant.
Results Ten of the 14 patients demonstrated abnormalities on videofluoroscopic evaluation; among these 10, six (60%) had tongue and lip muscle weakness and six (60%) had swallowing alterations during the clinical evaluation of swallowing (Table II). In the videofluoroscopic examination, oral residues for solid bolus in control was seen in five (31%), in two also for paste bolus and in one for liquid bolus and oral residues for solid bolus in patients was seen in 10 (71.4%), in four also for paste bolus and in one for liquid bolus. Oral residue was estimated at about one third of the total bolus volume in all cases. Pharyngeal residues were observed in one (6.3%) of the controls and in four (28.6%) of the patients with CPEO with swallows Table II. Results of the clinical and videofluoroscopic evaluations.
Swallowing alteration Patients Gender in clinical evaluation 1 2 3 4 5 6 7 8 9 10 11 12 13 14
F M F F M F M F M M F F F F
⫹S ⫹S ⫹ P, ⫹⫹ S ⫹ P, ⫹⫹ S ⫺ ⫹⫹ S ⫹ P, ⫹⫹ S ⫺ ⫺ ⫺ ⫹⫹ P, ⫹⫹ L, ⫹⫹⫹ S ⫺ ⫺ ⫺
Videofluoroscopic alterations of swallowing ⫺ ⫹S ⫹ P, ⫹⫹ S ⫹ P, ⫹⫹ S ⫹⫹ S ⫹S ⫹ P, ⫹⫹ S ⫹S ⫺ ⫹S ⫹⫹ P, ⫹⫹ L, ⫹⫹⫹ S ⫺ ⫺ ⫹S
⫺, no; ⫹, mild; ⫹⫹, moderate; ⫹⫹⫹, severe; S, Solid; P, Paste; L, Liquid.
Pharyngeal transit in CPEO
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Pharyngeal transit duration was shorter in CPEO patients than in controls (p ⬍ 0.04), with swallows of paste and solid boluses (Figure 1). With the paste bolus the pharyngeal clearance and the UES transit were shorter in CPEO patients than in controls (p ⱕ 0.05, Table III) and with the solid bolus, the UES transit duration was shorter in CPEO patients than in controls (p ⬍ 0.01). There was no difference between patients and controls in the duration of hyoid movement (p ⬎ 0.05). Also, all patients had UES opening.
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Figure 1. Pharyngeal transit duration, in seconds, in patients with chronic progressive external ophthalmoplegia (CPEO) and controls, after swallows of liquid, paste and solid boluses. The horizontal bars represent the mean. * p ⬍ 0.04 vs controls.
of the liquid bolus (p ⫽ 0.16), in none of the controls and in five (35.7%) of the patients with the paste bolus (p ⫽ 0.01) and in four (25.0%) of the controls and seven (50.0%) of the patients with the solid bolus (p ⫽ 0.14). Laryngeal penetration was observed in three (50.0%) patients with CPEO when swallowing a liquid bolus (p ⫽ 0.09) and in one (7.1%) when swallowing a paste bolus (p ⫽ 0.47). None of the patients had laryngeal penetration with the solid bolus and none of the participants of the control group had penetration with liquid, paste or solid boluses. None of the patients or control participants had laryngeal aspiration. During the examination, two compensatory manoeuvres were carried out voluntarily by some patients with CPEO. These manoeuvres were effortful swallowing and multiple swallows. Effortful swallowing was observed in 7.1% of the patients after swallows of a liquid bolus (p ⫽ 0.47, compared to controls), in 28.6% with a paste bolus (p ⫽ 0.04) and in 46.1% with a solid bolus (p ⬍ 0.01). Multiple swallows were observed in 21.4% of patients for the paste bolus (p ⫽ 0.09, compared to controls) and in 30.8% for the solid (p ⫽ 0.03) bolus. When asked about performing such manoeuvres, participants reported reduction in symptoms when using it. Normal volunteers did not perform multiple or effortful swallows. Compared with the normal volunteers a significantly higher number of patients performed effortful swallowing for paste and solid boluses and more multiple swallows for solid bolus (p ⬍ 0.05).
Discussion Videofluoroscopy has been increasingly used for investigation of swallowing changes in myopathies (Aloysius, Born, Kinali, Davis, Pane, & Mercuri, 2008; Cox, Verschuuren, Verbist, Niks, Wintzen, & Badrising, 2009; Kim, Han, Jeong, & Beom, 2010; Kornblum et al., 2001; Langdon, Mulcahy, Shepherd, Low, & Mastaglia, 2012; Leonard, Kendall, Johnson, & McKenzie, 2001; Manjaly, Vaughan-Shaw, Dale, Tyler, Corlett, & Frost, 2012; Wohlgemuth, Swart, Kalf, Joosten, Van de Vliet, & Padberg, 2006). In mitochondrial myopathy, studies are mostly focused on the diagnosis of cricopharyngeal dysfunctions, with little emphasis on oropharyngeal alterations (Aure et al., 2007). The complaints of the patients were mainly related to solid and dry foods, with food stuck in the pharynx (64.3%) as the most common sensation. This finding is consistent with the literature in different myopathies (Aloysius et al., 2008; Jimenez-Caballero et al., 2006; Langdon et al., 2012; Leonard et al., 2001). The pharyngeal phase of swallowing in healthy subjects lasts ∼ 1 second or less (Dantas, Kern, Massey, Dodds, Kahrilas, Brasseur, et al., 1990; Kendall, McKenzie, Leonard, Gonçalves, & Walker, 2000). In some studies of patients with different types of neurological diseases, there is an increase of this time (Cola, Gatto, Silva, Spadotto, Schelp, & Henry, 2010; Johnson, McKenzie, Rosenquist, Lieberman, & Sievers, 1992; Leonard et al., 2001; Santos, Cassiani, & Dantas, 2011). The pharyngeal transit duration in the present study was shorter than in healthy individuals for all consistencies, and statistically significant for paste and solid boluses. One justification for this result may be the fact that, for these consistencies, the final volume swallowed was
Table III. Duration of swallowing events, in seconds, during videofluoroscopic examination with swallows of liquid, paste and solid boluses, in patients with CPEO (n ⫽ 14) and controls (n ⫽ 16). The results are shown as mean (SD). Liquid Controls Pharyngeal transit Pharyngeal clearance UOS transit Hyoid movement
0.50 0.72 0.61 0.90
(0.14) (0.20) (0.17) (0.24)
CPEO 0.44 0.66 0.58 0.87
(0.16) (0.17) (0.24) (0.21)
Paste p 0.10 0.44 0.25 0.58
Controls 0.52 0.92 0.60 0.87
(0.16) (0.60) (0.16) (0.15)
Solid
CPEO 0.43 0.68 0.50 0.95
(0.12) (0.26) (0.13) (0.23)
p 0.03 0.05 0.01 0.19
UOS, Upper Oesophageal Sphincter; CPEO, Chronic Progressive External Ophthalmoplegia.
Controls 0.54 0.95 0.57 1.07
(0.14) (0.79) (0.14) (0.22)
CPEO 0.39 0.74 0.42 0.97
(0.11) (0.49) (0.09) (0.17)
p 0.01 0.07 0.01 0.13
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lower, since many of these patients had residues in the oral cavity (71.4% of the patients) and pharynx (53.8% of the patients) with swallows of a solid bolus. To test this hypothesis, a scintigraphic study of swallowing in stroke patients also found reduced pharyngeal transit duration in patients with residues in the oral cavity (Silva, Fabio, & Dantas, 2008). In the pharyngeal phase, the food moves through the pharynx to the oesophagus by a flow pressure generated by the oral ejection. Many studies have pointed out that increased viscosity of the bolus requires a greater oral and pharyngeal muscle activity (Dantas et al., 1990; Reimers-Neils, Logemann, & Larson, 1994), which justifies the tendency of patients with myopathy to have residues when ingesting food of solid and paste consistency. This observation is confirmed in our study, since the majority of patients with oral muscle weakness in clinical evaluation showed a large amount of oropharyngeal residue. The presence of residues in the pharynx increases the risk of laryngotracheal aspiration (Leonard et al., 2001; Noll, Rommel, Davidson, & Omar, 2011). There is a frequent observation of compensatory manoeuvres during swallowing in patients with myopathies (Leonard et al., 2001; Oh, Brumfield, Hoskin, Stolp, Murray, & Basford, 2007; Wohlgemuth et al., 2006). The spontaneous manoeuvre of multiple swallows occurs frequently in patients with residue in the oral cavity and pharynx and may signal difficulty in oral propulsion and changes in pharyngeal contraction (Padovani, Moraes, Mangili, & Andrade, 2007). In healthy young individuals, swallowing with effort influences not only the magnitude of the events but also the biomechanical events during the pharyngeal phase of swallowing, turning the bolus into the pharynx at a high speed (Hiss & Huckabee, 2005; Steele & Huckabee, 2007). In our study, the presence of spontaneous manoeuvres performed by some patients as a strategy for reducing complaints likely contributed to the absence of aspiration as well as reduced pharyngeal transit duration. In another study of patients with inflammatory myopathy, the use of compensatory manoeuvres showed positive results in the reduction of risk for aspiration and improvement in swallowing dynamics (Oh et al., 2007). Many studies have linked measures of pharyngeal transit as a factor predictive of laryngotracheal aspiration in neurological diseases (Bingjie, Tong, Xinting, Jianmin, & Guijun, 2010; Power, Hamdy, Goulermans, Tyrrell, Turnbull, & Thompson, 2009). In a study with a large number of stroke patients the duration of food passage through the pharynx was predictive of laryngotracheal aspiration (Power et al., 2009). In our study, the fact that no patient showed aspiration during the examination could be justified by the shorter pharyngeal transit duration compared to healthy participants; however, some patients had laryngeal penetration which indicates the possibility
of aspiration. Although no patient presented laryngotracheal aspiration during videofluoroscopy, it is not possible to rule out such a risk. The number of patients enrolled may have not been sufficient to demonstrate such an event, considering that aspiration pneumonia may be the major cause of death in mitochondrial myopathies (Klopstock, Jaksch, & Gasser, 1999). In the present study, only one type of the previously cited diseases was studied in order to make the group more homogeneous. The clinical criteria used for this choice were frequency of disease onset and complaints related to swallowing reviewed in the literature. Changes in the biomechanics of swallowing found in the pharyngeal phase reinforce the importance of speech therapy through guidance about the adequacy of food consistency, use of compensatory postural manoeuvres as well as the performance of exercises, when indicated, to improve muscle strength, seeking reduction of complaints and symptoms and consequently improving the quality-of-life of the patients. Aerobic exercise and strength training appears to be safe and may be effective in the treatment of mitochondrial myopathies (Voet, Van der Kooi, Riphagen, Lindrman, Van Engelen, & Geurts, 2013). The improvement of swallow with exercises in these patients needs evidences about safety and efficacy. The main limitation of this investigation was the number of patients included. This is the same seen in previous publications, which had a smaller number of patients, a fact consequent of the disease prevalence. However, we were able to demonstrate that our hypothesis was correct, there is alteration in the pharyngeal phase of swallow in patients with CPEO. In conclusion, patients with mitochondrial myopathy-type CPEO have shorter pharyngeal transit duration than asymptomatic volunteers, which may be a consequence of the smaller bolus volume in each swallow and/or effortful swallows. Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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ISSN: 1754-9507 (Print) 1754-9515 (Online) Journal homepage: http://www.tandfonline.com/loi/iasl20
Pharyngeal transit in patients with chronic progressive external ophthalmoplegia Danielle Ramos Domenis, Raphaela B. Granzotti, Claudia Ferreira Sobreira & Roberto Oliveira Dantas To cite this article: Danielle Ramos Domenis, Raphaela B. Granzotti, Claudia Ferreira Sobreira & Roberto Oliveira Dantas (2015) Pharyngeal transit in patients with chronic progressive external ophthalmoplegia, International Journal of Speech-Language Pathology, 17:4, 384-389, DOI: 10.3109/17549507.2014.941935 To link to this article: http://dx.doi.org/10.3109/17549507.2014.941935
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Date: 06 November 2015, At: 06:03
International Journal of Speech-Language Pathology, 2015; 17(4): 384–389
Pharyngeal transit in patients with chronic progressive external ophthalmoplegia
DANIELLE RAMOS DOMENIS1, RAPHAELA B. GRANZOTTI1, CLAUDIA FERREIRA SOBREIRA2 & ROBERTO OLIVEIRA DANTAS3
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1Federal
and
University of Sergipe, Lagarto, Brazil, 2Medical School of Ribeirão Preto USP, Neurosciences, RibeirãoPreto, Brazil, School of Ribeirão Preto USP, Internal Medicine, Ribeirão Preto, Brazil
3Medical
Abstract Purpose: A common presentation of mitochondrial myopathies is chronic progressive external ophthalmoplegia (CPEO). Dysphagia is a complaint in about 50% of cases. Method: This investigation evaluated pharyngeal transit in patients with CPEO. Videofluoroscopic swallowing evaluation was performed with paste, liquid and solid boluses in 14 patients with CPEO and in 16 normal volunteers. Result: There was no difference between patients and volunteers in the duration of pharyngeal swallowing events with the liquid bolus. Compared to control participants, patients with CPEO had significantly shorter duration of pharyngeal transit for paste and solid boluses, of pharyngeal clearance for paste bolus, and of upper oesophageal sphincter transit for paste and solid boluses. Spontaneous multiple swallows and effortful swallows were performed by patients but not by the volunteers. Conclusion: It was concluded that patients with CPEO have shorter pharyngeal transit duration of paste and solid boluses than normal volunteers, which may be a consequence of a spontaneous smaller bolus volume in each swallow and/or effortful swallows.
Keywords: Dysphagia, neurodegenerative diseases, swallowing
Introduction Mitochondrial myopathies are a clinically heterogeneous group of disorders that can affect multiple systems in addition to skeletal muscles (DiMauro, Bonilla, Zeviani, Nakagawa, & DeVivo, 1985; Nardin & Johns, 2001). Fatigue may be the main complaint and most often disproportionate to the degree of muscle weakness and atrophy detected. It may be stationary, progressive or episodic, may affect both sexes at any age and may be sporadic or familial (Dias-Tosta, 1994). The more frequent syndromes consequent to mitochondrial DNA rearrangements are: Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalopathy with lactic acidosis (MELAS) (Marie, 1994). There is heterogeneous clinical presentation of these diseases, with the need of histochemical and genetic analysis for accurate diagnosis and classification. A common presentation of mitochondrial myopathies is chronic progressive external ophthalmoplegia (CPEO), which can appear alone or associated with
the involvement of other systems (Franceschina, Salani, Bordoni, Sciacco, Napoli, Comi, et al., 1998). CPEO may be associated with the presence of a large, single or multiple deletion of mitochondrial DNA and a point mutation (Carod-Artal, Solano-Palacios, Playan-Ariso,Viana-Brandi, Lopez-Gallardo, Andreu, et al., 2003; Nardin & Johns, 2001). The population prevalence of single and large scale mitochondrial DNA deletion is 1.2/100,000 to 2.9/100,000 (Aure, Baulmy, Laforet, Jardel, Eymard, & Lombes, 2007). Prevalence of clinically manifest mitochondrial myopathies is described as 9.2/100,000 and at risk for the disease are 16.5/100,000 children and adults younger than retirement age (Schaefer, McFarland, Blakely, He, Whittakes, Taylor, et al., 2008). The disease is characterized by a progressive evolution which causes ptosis of the eyelids, alterations of eye movements with normal pupils and in some cases involvement of the facial musculature. It may be often associated with multi-systemic alterations, affecting the retina, cerebellum, cochlea and facial and laryngeal muscles (Garciduenas, Loria, Sagastegui, & Garcia, 2000; Smits, Heijdra, Cuppen, & Van Engelen, 2011).
Correspondence: Dr. Roberto Oliveira Dantas, Sao Paulo University, Ribeirao Preto, Brazil. E-mail: [email protected] ISSN 1754-9507 print/ISSN 1754-9515 online © 2014 The Speech Pathology Association of Australia Limited Published by Informa UK, Ltd. DOI: 10.3109/17549507.2014.941935
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Pharyngeal transit in CPEO
Swallowing problems are a manifestation of the disease (Garciduenas et al., 2000; Jimenez-Caballero, Serviá, Cabeza, Marsal-Alonso, & Alvarez-Tejerina, 2006; Smits, Heijdra, Cuppen & Van Engelen, 2011; Vu, Sciacco, Tanji, Nichter, Bonilla, Chatkupt, et al., 1998), with dysphagia being a complaint in ∼ 50% of cases (Aure et al., 2007). Respiratory problems, such as pneumonia, are presently a major cause of death in CPEO and the weakness of laryngeal musculature with increased risk of aspiration of liquid or solid food and reduction of glottic closure during coughing is one of the hypotheses for the presence of respiratory infections. Moreover, opening impairment of the upper oesophageal sphincter (UES) and increase in UES pressure have been described as situations that may affect pharyngeal transit. There is also impairment of oesophageal contractions, mainly in the proximal oesophageal body (Domenis, Okubo, Sobreira, & Dantas, 2011; Kornblum, Broicher, Waltherm, et al., 2001; Smits, Heijdra, Cuppen & Van Engelen, 2011). Our aim in this study was to evaluate by videofluoroscopy the pharyngeal transit of liquid, paste and solid boluses in patients with mitochondrial myopathy-type CPEO. Our hypothesis was that this disease causes alterations of the pharyngeal phase of swallowing.
Method Participants Videofluoroscopic evaluation of pharyngeal transit was performed in 14 patients with CPEO and in 16 normal volunteers. All patients were submitted to clinical evaluation before videofluoroscopy. Swallowing clinical evaluation was performed by the first author (speechlanguage pathologist) and consisted of the evaluation
of facial movements, tongue mobility (lateralization, elevation), tongue strength (assessed by a spatula against the movement of the tongue), lip mobility, strength of the lips, soft palate mobility and presence of spontaneous cough. Functional evaluation was performed with swallowing 5 mL and free volumes of liquid, paste and solid boluses and evaluated labial closure, chewing, duration of oral phase, bolus control, oral cavity residue after swallowing, cervical auscultation, presence of coughing, choking, hoarseness, multiple swallows, manoeuvres during swallowing and the presence of a wet voice. Alteration in clinical evaluation was considered mild, moderate or severe, depending of the number and intensity of alterations observed. The diagnosis of CPEO was made by histochemical analysis of a skeletal muscle biopsy and by mitochondrial DNA analysis. They were five men and nine women, aged 15–62 years, mean ⫽ 35.3 years. By clinical judgement, none of them had cerebral dysfunction, cognitive decline or neuropsychiatric abnormalities. Ten patients had a single mitochondrial DNA deletion, two had multiple deletions and two had a point mutation (Table I). Nine (64.3%) had the sensation that the food was stuck in their throat, five (35.7%) had difficulty swallowing hard foods, five had choking during swallows (35.7%), and three (21.4%) had weakness in swallowing. Five patients had no swallowing symptoms. The group of normal volunteers consisted of six men and 10 women without symptoms, swallowing problems or neurologic diseases, aged 21–44 years, mean ⫽ 27.5 years. The mean age of the normal volunteers was not different of the mean age of the patients (p ⬎ 0.05). The study was approved by the Human Research Committee of the University Hospital of Ribeirão Preto and all patients and volunteers gave written informed consent to participate in the investigation.
Table I. Characteristics of the patients with chronic progressive external ophthalmoplegia (CPEO) included in the investigation.
Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14
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Gender
Age (years)
Disease duration (years)
Mitochondrial DNA analysis
Swallowing complaint
Reduction of perioral and tongue force
F M F F M F M F M M F F F F
56 44 62 27 59 44 37 31 21 15 30 15 23 31
11 31 34 23 26 20 17 10 12 12 25 10 09 11
SD SD MD PM 3243 SD SD SD MD SD SD PM 3243 SD SD SD
⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺
⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺
F, Female; M, Male; SD, Single mitochondrial DNA deletion; MD, Multiple mitochondrial DNA deletion; PM 3243, Point mutation 3243; ⫺, no; ⫹, mild.
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Procedure The videofluoroscopic examination was done using the radiologic instrument Arcomax Phillips model BV 300 (Veenpluis, The Netherlands) and the digital image processing system Ever Focus model EDSR 100 VI.2 (Taipei, Taiwan) with a DVR (Ever Focus) monitor run at 60 frames/second and a clock time that indicates digital time in seconds and hundredths of a second on each video frame. During the videofluoroscopic evaluation, all participants swallowed in triplicate the sequence of paste, liquid and solid boluses. The results for each measurement for each participant were the mean of the three swallows performed. In patients with multiple swallows the first of them was measured. The paste bolus was prepared with 50 mL of water, 15 mL of 100% liquid barium sulphate (Bariogel 100%, Laboratory Cristalia, Itapira SP, Brazil) and 15 mL of instant food thickener (Thick & Easy, Hormel Health Labs, Austin, MN) and was given to the patients and volunteers with a spoon. The liquid bolus was 50 mL of water with 15 mL of 100% liquid barium sulphate, given to the subjects with a cup, and the solid bolus was a Brazilian cookie coated with liquid barium. The volume of liquid and paste bolus swallowed was 5 mL and the cookie weighed 2.2 g.
Measures The beginning of the pharyngeal phase of swallowing was considered to be the moment when the bolus head reached the posterior part of the nasal spine, located at the end of the hard palate, at the beginning of the soft palate. It was taken as the zero reference for the timing of pharyngeal swallowing events. The end of the pharyngeal phase was the moment when the bolus tail crossed the upper oesophageal sphincter. The following features were timed: (1) onset and end of hyoid movement, (2) the moment when the bolus head reached the posterior part of the nasal spine, (3) the moment when the bolus tail reached the posterior part of the nasal spine, which was also the end of oral phase, and (4) the onset and offset of upper oesophageal sphincter (UES) opening. From these timings we calculated the duration of the pharyngeal transit (bolus tail at the posterior part of the nasal spine until the offset of UES opening), duration of pharyngeal clearance (bolus head at the posterior part of the nasal spine until the offset of UES opening), UES opening duration (time between onset and end of UES opening) and duration of hyoid movement (time between onset and end of hyoid movement). Oral transit was not included in the measurement of pharyngeal transit time. An effortful swallow consists of squeezing all the muscles involved in swallowing. It was perceived by corporal, facial and head movements. Multiple swallows were considered to be present when the participants performed two or more swallows to ingest the bolus
volume. Multiple and effortful swallows were performed voluntarily by the patients, without orientation of the researchers. Laryngeal penetration occurred when the bolus residues went inside the airways but did not cross the vocal folds and laryngeal aspiration occurred when the bolus residues went below the vocal folds. Statistical analysis Statistical analysis was done by the Center of Quantitative Analysis of the Medical School of Ribeirão Preto, University of São Paulo, using a linear model with mixed effects (Schall, 1991). The model was adjusted using the Proc Mixed feature of the SAS software version 9 (Littell, Milliken, Stroup, & Woffinger, 1996). We also used the Fisher test to compare the proportion of patients with alterations of swallowing. The results are reported as mean and standard deviation, unless stated otherwise. A p-value of 0.05 or less was considered significant.
Results Ten of the 14 patients demonstrated abnormalities on videofluoroscopic evaluation; among these 10, six (60%) had tongue and lip muscle weakness and six (60%) had swallowing alterations during the clinical evaluation of swallowing (Table II). In the videofluoroscopic examination, oral residues for solid bolus in control was seen in five (31%), in two also for paste bolus and in one for liquid bolus and oral residues for solid bolus in patients was seen in 10 (71.4%), in four also for paste bolus and in one for liquid bolus. Oral residue was estimated at about one third of the total bolus volume in all cases. Pharyngeal residues were observed in one (6.3%) of the controls and in four (28.6%) of the patients with CPEO with swallows Table II. Results of the clinical and videofluoroscopic evaluations.
Swallowing alteration Patients Gender in clinical evaluation 1 2 3 4 5 6 7 8 9 10 11 12 13 14
F M F F M F M F M M F F F F
⫹S ⫹S ⫹ P, ⫹⫹ S ⫹ P, ⫹⫹ S ⫺ ⫹⫹ S ⫹ P, ⫹⫹ S ⫺ ⫺ ⫺ ⫹⫹ P, ⫹⫹ L, ⫹⫹⫹ S ⫺ ⫺ ⫺
Videofluoroscopic alterations of swallowing ⫺ ⫹S ⫹ P, ⫹⫹ S ⫹ P, ⫹⫹ S ⫹⫹ S ⫹S ⫹ P, ⫹⫹ S ⫹S ⫺ ⫹S ⫹⫹ P, ⫹⫹ L, ⫹⫹⫹ S ⫺ ⫺ ⫹S
⫺, no; ⫹, mild; ⫹⫹, moderate; ⫹⫹⫹, severe; S, Solid; P, Paste; L, Liquid.
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Pharyngeal transit duration was shorter in CPEO patients than in controls (p ⬍ 0.04), with swallows of paste and solid boluses (Figure 1). With the paste bolus the pharyngeal clearance and the UES transit were shorter in CPEO patients than in controls (p ⱕ 0.05, Table III) and with the solid bolus, the UES transit duration was shorter in CPEO patients than in controls (p ⬍ 0.01). There was no difference between patients and controls in the duration of hyoid movement (p ⬎ 0.05). Also, all patients had UES opening.
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Figure 1. Pharyngeal transit duration, in seconds, in patients with chronic progressive external ophthalmoplegia (CPEO) and controls, after swallows of liquid, paste and solid boluses. The horizontal bars represent the mean. * p ⬍ 0.04 vs controls.
of the liquid bolus (p ⫽ 0.16), in none of the controls and in five (35.7%) of the patients with the paste bolus (p ⫽ 0.01) and in four (25.0%) of the controls and seven (50.0%) of the patients with the solid bolus (p ⫽ 0.14). Laryngeal penetration was observed in three (50.0%) patients with CPEO when swallowing a liquid bolus (p ⫽ 0.09) and in one (7.1%) when swallowing a paste bolus (p ⫽ 0.47). None of the patients had laryngeal penetration with the solid bolus and none of the participants of the control group had penetration with liquid, paste or solid boluses. None of the patients or control participants had laryngeal aspiration. During the examination, two compensatory manoeuvres were carried out voluntarily by some patients with CPEO. These manoeuvres were effortful swallowing and multiple swallows. Effortful swallowing was observed in 7.1% of the patients after swallows of a liquid bolus (p ⫽ 0.47, compared to controls), in 28.6% with a paste bolus (p ⫽ 0.04) and in 46.1% with a solid bolus (p ⬍ 0.01). Multiple swallows were observed in 21.4% of patients for the paste bolus (p ⫽ 0.09, compared to controls) and in 30.8% for the solid (p ⫽ 0.03) bolus. When asked about performing such manoeuvres, participants reported reduction in symptoms when using it. Normal volunteers did not perform multiple or effortful swallows. Compared with the normal volunteers a significantly higher number of patients performed effortful swallowing for paste and solid boluses and more multiple swallows for solid bolus (p ⬍ 0.05).
Discussion Videofluoroscopy has been increasingly used for investigation of swallowing changes in myopathies (Aloysius, Born, Kinali, Davis, Pane, & Mercuri, 2008; Cox, Verschuuren, Verbist, Niks, Wintzen, & Badrising, 2009; Kim, Han, Jeong, & Beom, 2010; Kornblum et al., 2001; Langdon, Mulcahy, Shepherd, Low, & Mastaglia, 2012; Leonard, Kendall, Johnson, & McKenzie, 2001; Manjaly, Vaughan-Shaw, Dale, Tyler, Corlett, & Frost, 2012; Wohlgemuth, Swart, Kalf, Joosten, Van de Vliet, & Padberg, 2006). In mitochondrial myopathy, studies are mostly focused on the diagnosis of cricopharyngeal dysfunctions, with little emphasis on oropharyngeal alterations (Aure et al., 2007). The complaints of the patients were mainly related to solid and dry foods, with food stuck in the pharynx (64.3%) as the most common sensation. This finding is consistent with the literature in different myopathies (Aloysius et al., 2008; Jimenez-Caballero et al., 2006; Langdon et al., 2012; Leonard et al., 2001). The pharyngeal phase of swallowing in healthy subjects lasts ∼ 1 second or less (Dantas, Kern, Massey, Dodds, Kahrilas, Brasseur, et al., 1990; Kendall, McKenzie, Leonard, Gonçalves, & Walker, 2000). In some studies of patients with different types of neurological diseases, there is an increase of this time (Cola, Gatto, Silva, Spadotto, Schelp, & Henry, 2010; Johnson, McKenzie, Rosenquist, Lieberman, & Sievers, 1992; Leonard et al., 2001; Santos, Cassiani, & Dantas, 2011). The pharyngeal transit duration in the present study was shorter than in healthy individuals for all consistencies, and statistically significant for paste and solid boluses. One justification for this result may be the fact that, for these consistencies, the final volume swallowed was
Table III. Duration of swallowing events, in seconds, during videofluoroscopic examination with swallows of liquid, paste and solid boluses, in patients with CPEO (n ⫽ 14) and controls (n ⫽ 16). The results are shown as mean (SD). Liquid Controls Pharyngeal transit Pharyngeal clearance UOS transit Hyoid movement
0.50 0.72 0.61 0.90
(0.14) (0.20) (0.17) (0.24)
CPEO 0.44 0.66 0.58 0.87
(0.16) (0.17) (0.24) (0.21)
Paste p 0.10 0.44 0.25 0.58
Controls 0.52 0.92 0.60 0.87
(0.16) (0.60) (0.16) (0.15)
Solid
CPEO 0.43 0.68 0.50 0.95
(0.12) (0.26) (0.13) (0.23)
p 0.03 0.05 0.01 0.19
UOS, Upper Oesophageal Sphincter; CPEO, Chronic Progressive External Ophthalmoplegia.
Controls 0.54 0.95 0.57 1.07
(0.14) (0.79) (0.14) (0.22)
CPEO 0.39 0.74 0.42 0.97
(0.11) (0.49) (0.09) (0.17)
p 0.01 0.07 0.01 0.13
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lower, since many of these patients had residues in the oral cavity (71.4% of the patients) and pharynx (53.8% of the patients) with swallows of a solid bolus. To test this hypothesis, a scintigraphic study of swallowing in stroke patients also found reduced pharyngeal transit duration in patients with residues in the oral cavity (Silva, Fabio, & Dantas, 2008). In the pharyngeal phase, the food moves through the pharynx to the oesophagus by a flow pressure generated by the oral ejection. Many studies have pointed out that increased viscosity of the bolus requires a greater oral and pharyngeal muscle activity (Dantas et al., 1990; Reimers-Neils, Logemann, & Larson, 1994), which justifies the tendency of patients with myopathy to have residues when ingesting food of solid and paste consistency. This observation is confirmed in our study, since the majority of patients with oral muscle weakness in clinical evaluation showed a large amount of oropharyngeal residue. The presence of residues in the pharynx increases the risk of laryngotracheal aspiration (Leonard et al., 2001; Noll, Rommel, Davidson, & Omar, 2011). There is a frequent observation of compensatory manoeuvres during swallowing in patients with myopathies (Leonard et al., 2001; Oh, Brumfield, Hoskin, Stolp, Murray, & Basford, 2007; Wohlgemuth et al., 2006). The spontaneous manoeuvre of multiple swallows occurs frequently in patients with residue in the oral cavity and pharynx and may signal difficulty in oral propulsion and changes in pharyngeal contraction (Padovani, Moraes, Mangili, & Andrade, 2007). In healthy young individuals, swallowing with effort influences not only the magnitude of the events but also the biomechanical events during the pharyngeal phase of swallowing, turning the bolus into the pharynx at a high speed (Hiss & Huckabee, 2005; Steele & Huckabee, 2007). In our study, the presence of spontaneous manoeuvres performed by some patients as a strategy for reducing complaints likely contributed to the absence of aspiration as well as reduced pharyngeal transit duration. In another study of patients with inflammatory myopathy, the use of compensatory manoeuvres showed positive results in the reduction of risk for aspiration and improvement in swallowing dynamics (Oh et al., 2007). Many studies have linked measures of pharyngeal transit as a factor predictive of laryngotracheal aspiration in neurological diseases (Bingjie, Tong, Xinting, Jianmin, & Guijun, 2010; Power, Hamdy, Goulermans, Tyrrell, Turnbull, & Thompson, 2009). In a study with a large number of stroke patients the duration of food passage through the pharynx was predictive of laryngotracheal aspiration (Power et al., 2009). In our study, the fact that no patient showed aspiration during the examination could be justified by the shorter pharyngeal transit duration compared to healthy participants; however, some patients had laryngeal penetration which indicates the possibility
of aspiration. Although no patient presented laryngotracheal aspiration during videofluoroscopy, it is not possible to rule out such a risk. The number of patients enrolled may have not been sufficient to demonstrate such an event, considering that aspiration pneumonia may be the major cause of death in mitochondrial myopathies (Klopstock, Jaksch, & Gasser, 1999). In the present study, only one type of the previously cited diseases was studied in order to make the group more homogeneous. The clinical criteria used for this choice were frequency of disease onset and complaints related to swallowing reviewed in the literature. Changes in the biomechanics of swallowing found in the pharyngeal phase reinforce the importance of speech therapy through guidance about the adequacy of food consistency, use of compensatory postural manoeuvres as well as the performance of exercises, when indicated, to improve muscle strength, seeking reduction of complaints and symptoms and consequently improving the quality-of-life of the patients. Aerobic exercise and strength training appears to be safe and may be effective in the treatment of mitochondrial myopathies (Voet, Van der Kooi, Riphagen, Lindrman, Van Engelen, & Geurts, 2013). The improvement of swallow with exercises in these patients needs evidences about safety and efficacy. The main limitation of this investigation was the number of patients included. This is the same seen in previous publications, which had a smaller number of patients, a fact consequent of the disease prevalence. However, we were able to demonstrate that our hypothesis was correct, there is alteration in the pharyngeal phase of swallow in patients with CPEO. In conclusion, patients with mitochondrial myopathy-type CPEO have shorter pharyngeal transit duration than asymptomatic volunteers, which may be a consequence of the smaller bolus volume in each swallow and/or effortful swallows. Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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