Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 1: Physiology and anatomy.

BACKGROUND AND PURPOSE: When optimising radiotherapy treatments today, the pharyngeal constrictor muscles and the larynx are usually regarded as the swallowing organs at risk (SWOARs). The purpose of this study was to identify and describe additional, previously undefined groups of muscles (functional units) involved in crucial components of swallowing (hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion), and to emphasise their relevance in radiation-induced dysphagia. MATERIAL AND METHODS: Based on available literature on human anatomy and swallowing physiology, the functional units of muscles involved in HLE, TBR and tongue motion have been identified and described. RESULTS AND CONCLUSION: Functional swallowing units (FSUs) were defined as groups of swallowing muscles sharing their function, that are in close proximity to each other. Seven FSUs involved in HLE, TBR and tongue motion were identified: floor of mouth, thyrohyoid muscles, posterior digastric/stylohyoid muscles complex, longitudinal pharyngeal muscles, hyoglossus/styloglossus muscles complex, genioglossus muscles, intrinsic tongue muscles. The swallowing physiology and anatomy of the FSUs described in this paper will lead to a greater understanding of radiation-induced dysphagia mechanisms and, consequently, to an improvement in the development of swallowing sparing strategies. This article (PART 1) serves as the theoretical foundation for a subsequent article (PART 2), which provides detailed delineation guidelines for FSUs.

Increased Expression of MuRF1 Is Associated with Radiation-induced Laryngeal Muscle Atrophy.

BACKGROUND: Laryngeal muscles play an important role in breathing, sound production and trachea protection against food. Laryngeal dysfunctions during radiotherapy for head and neck cancers are common. In the present study, we aimed to investigate the early effect of radiation on the laryngeal muscles in vivo and possible mechanisms involved in this process. MATERIALS AND METHODS: Eight-week-old female C57bl/ mice received neck irradiation with a single dose of 25 Gy and bilateral thyroarytenoid (TA) muscles of mice were collected at day 3, 7 and 10 post-irradiation for evaluating muscle size, myosins, myosin heavy chain (MyHC) composition and MuRF1 protein levels. RESULTS: A significant reduction in the size of muscle fibers and myosins in the TA muscles were observed at days 3, 7, 10 after radiation (p<0.05). The loss of IIB myosin was more severe than that of IIA/X myosins at day 7 post-irradiation (75% vs. 64%). MuRF1 protein level was markedly increased at day 7 and 10 after radiation (p<0.05). CONCLUSION: Radiation induced an acute muscle fiber atrophy and myosin loss in the intrinsic laryngeal muscles. MuRF1 may play an important role in the radiation-induced protein degradation in the laryngeal muscles and warrants further investigation.

Rehabilitación de músculos orofaríngeos con ejercicios y electroterapia para el síndrome de apnea-hipoapnea obstructiva del sueño / Rehabilitation of oropharyngeal muscles with muscle reeducation and electrostimulation in obstructive sleep apnea syndrome

Introducción. El síndrome de apnea obstructiva del sueño (SAOS) tiene repercusiones importantes en la morbimortalidad de los pacientes. Los tratamientos alternos a la presión positiva continua en la vía aérea (CPAP) han resultado poco eficaces, poco seguros o de alta complejidad. Objetivo. Describir los efectos de un programa ambulatorio de reeducación de la musculatura orofacial y extralaríngea y aplicación de electroestimulación (TENS) aplicado a pacientes con SAOS en un hospital universitario de nivel III. Diseño. Estudio de serie de casos incidentes, prospectivo, con pacientes seleccionados consecutivamente. Material y métodos. Diecisiete pacientes con SAOS leve, moderado o severo que asistieron a 24 sesiones (3 semanales) de 30 minutos, de ejercicios orofaríngeos y electroestimulación. Los pacientes fueron evaluados al inicio y al final de la intervención mediante antropometría, polisomnografía, escala de somnolencia de Epworth, SAQLI y tolerancia al CPAP. La tolerancia al CPAP fue evaluada por una escala visual calificada de 1 a 10 (10 correspondía a tolerancia máxima). Las variables cualitativas se describieron en frecuencias y las variables cuantitativas en promedios o medianas dependiendo del tipo de distribución. Resultados. El índice de apnea-hipoapnea mejoró de 22 a 13 por hora, el SAQLI mejoró de 4,65 a 5,33 y Epworth pasó de 7 a 5 después de la intervención. La tolerancia al CPAP mejoró de 3 a 9. Las sesiones fueron bien toleradas, no se presentaron eventos adversos importantes. Cuatro pacientes presentaron dolor muscular facial. Conclusiones. Los ejercicios de reeducación con electroterapia son fáciles, reproducibles, seguros y potencialmente beneficiosos para el SAOS, con mínimos efectos secundarios (AU)

Introduction. Obstructive sleep apnea syndrome (OSA) is associated with increased morbidity and mortality. Alternative interventions to continuous positive airway pressure (CPAP) lack efficacy and safety or are highly complex. Objective. To describe the effects of an outpatient program of orofacial and extralaryngeal muscle re-education combined with electro-stimulation (TENS) of the same muscle groups in patients with OSA attending a tertiary level university hospital. Design. Prospective, incident case series, with consecutively selected patients. Methods. Participants consisted of 17 patients with mild, moderate or severe OSA who attended 24 thirty-minute sessions (three per week) of oropharyngeal exercises and electro-stimulation. The patients were evaluated at the beginning and end of the intervention by anthropometry, polysomnography, the Epworth sleepiness scale, and the Calgary Sleep Apnea Quality of Life (SAQLI) index. CPAP tolerance was evaluated by a visual scale rated from 1 to 10 (10 indicating maximum tolerance). Qualitative variables were described by frequencies, and quantitative variables by means and medians, depending on the type of distribution. Results. After the intervention, the apnea - hypopnea index improved from 22 to 13 per hour, the SAQLI index improved from 4.65 to 5.33, and the Epworth scale from 7 to 5. CPAP tolerance increased from 3 to 9. The sessions were well tolerated with no adverse events of importance. Four patients reported facial muscular pain. Conclusions. Electrotherapy plus active exercises of the oropharyngeal muscles are easy, feasible, safe, and potentially beneficial for OSA, with minimal side effects (AU)

Dose-volume-related dysphagia after constrictor muscles definition in head and neck cancer intensity-modulated radiation treatment.

OBJECTIVE: Dysphagia remains a side effect influencing the quality of life of patients with head and neck cancer (HNC) after radiotherapy. We evaluated the relationship between planned dose involvement and acute and late dysphagia in patients with HNC treated with intensity-modulated radiation therapy (IMRT), after a recontouring of constrictor muscles (PCs) and the cricopharyngeal muscle (CM). METHODS: Between December 2011 and December 2013, 56 patients with histologically proven HNC were treated with IMRT or volumetric-modulated arc therapy. The PCs and CM were recontoured. Correlations between acute and late toxicity and dosimetric parameters were evaluated. End points were analysed using univariate logistic regression. RESULTS: An increasing risk to develop acute dysphagia was observed when constraints to the middle PCs were not respected [mean dose (Dmean) ≥50 Gy, maximum dose (Dmax) >60 Gy, V50 >70% with a p = 0.05]. The superior PC was not correlated with acute toxicity but only with late dysphagia. The inferior PC was not correlated with dysphagia; for the CM only, Dmax >60 Gy was correlated with acute dysphagia ≥ grade 2. CONCLUSION: According to our analysis, the superior PC has a major role, being correlated with dysphagia at 3 and 6 months after treatments; the middle PC maintains this correlation only at 3 months from the beginning of radiotherapy, but it does not have influence on late dysphagia. The inferior PC and CM have a minimum impact on swallowing symptoms. ADVANCES IN KNOWLEDGE: We used recent guidelines to define dose constraints of the PCs and CM. Two results emerge in the present analysis: the superior PC influences late dysphagia, while the middle PC influences acute dysphagia.

Impact of radiotherapy on laryngeal intrinsic muscles.

Ionizing radiation as a cancer therapy is associated with a variety of undesirable side effects. Consequently, radiotherapy can negatively affect neuromuscular function. Clinical observations have identified problems with swallowing and voice function. Our study aims to evaluate the impact of radiotherapy on laryngeal soft tissues using image analysis to quantify its effect on the structure of the vocalis and thyroarytenoid muscles. Case control study, retrospective analysis. We collected total laryngectomy specimens from six patients with persistent or recurrent cancer who had received preoperative radiotherapy (60-66 Gy). The control group consisted of total laryngectomy specimens from six patients who underwent surgery as primary treatment. Sampling of the specimens only included non-cancerous laryngeal tissue. Laryngeal histological slices were evaluated using digital morphometric analysis system. Percentage of fibrosis and density of muscle fibers within the thyroarytenoid muscle were evaluated in both groups. We found no significant quantitative differences in muscle fibrosis (7.92% vs. 7.52%, P > 0.1). Changes were rather qualitative and included changes in the organization of the muscular fibers. A significant reduction in muscle fibers, however, was observed in the samples from irradiated larynges (66.45% vs. 42.03%, P < 0.01). Our analysis suggests that radiotherapy is responsible for a significant reduction in muscle fibers in the thyroarytenoid muscle and that these changes occur during treatment or relatively early after its completion. Loss of muscle mass after irradiation correlates with clinical observations of muscle weakness and decreased function in patients who undergo radiotherapy.

Weekly dose-volume parameters of mucosa and constrictor muscles predict the use of percutaneous endoscopic gastrostomy during exclusive intensity-modulated radiotherapy for oropharyngeal cancer.

PURPOSE: To define predictors of percutaneous endoscopic gastrostomy (PEG) use during intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer. METHODS AND MATERIALS: Data for 59 consecutive patients treated with exclusive IMRT at a single institution were recovered. Of 59 patients, 25 were treated with hyperfractionation (78 Gy, 1.3 Gy per fraction, twice daily; "HYPER"); and 34 of 59 were treated with a once-daily fractionation schedule (66 Gy, 2.2 Gy per fraction, or 70 Gy, 2 Gy per fraction; "no-HYPER"). On the basis of symptoms during treatment, a PEG tube could have been placed as appropriate. A number of clinical/dosimetric factors, including the weekly dose-volume histogram of oral mucosa (OM DVHw) and weekly mean dose to constrictors and larynx, were considered. The OM DVHw of patients with and without PEG were compared to assess the most predictive dose-volume combinations. RESULTS: Of 59 patients, 22 needed a PEG tube during treatment (for 15 of 22, ≥3 months). The best cutoff values for OM DVHw were V9.5 Gy/week <64 cm(3) and V10 Gy/week <54 cm(3). At univariate analysis, fractionation, mean weekly dose to OM and superior and middle constrictors, and OM DVHw were strongly correlated with the risk of PEG use. In a stepwise multivariate logistic analysis, OM V9.5 Gy/week (≥64 vs. <64 cm(3)) was the most predictive parameter (odds ratio 30.8, 95% confidence interval 3.7-254.2, p = 0.0015), confirmed even in the no-HYPER subgroup (odds ratio 21, 95% CI 2.1 confidence interval 210.1, p = 0.01). CONCLUSIONS: The risk of PEG use is drastically reduced when OM V9.5-V10 Gy/week is <50-60 cm(3). These data warrant prospective validation.

Quantitative analysis of myosin heavy chain expression change in laryngeal muscle after irradiation in rats.

PURPOSE: Radiotherapy for head and neck cancer does not impair the voice quality as much as laser treatment or surgery, but it can induce muscle wasting and fibrosis and symptoms of dry mouth. We investigated the effect of irradiation on the myosin heavy chain (MyHC) expression in laryngeal muscles. MATERIALS AND METHODS: Rats were irradiated with one dose of 10, 15, 20, 25, 30, or 35 Gy and other rats were irradiated with 20 Gy. The thyroarytenoid (TA), posterior cricoarytenoid (PCA), and cricothyroid (CT) muscles were subjected to reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Two weeks after irradiation with 10, 15, or 20 Gy, all the MyHC type expressions had decreased in a dose-dependent manner in the TA, PCA, and CT muscles, and especially the expression of MyHC IIa decreased much more than the expressions of the other MyHC isoforms in all muscles. In the 20 Gy-irradiated rats, almost all the MyHC isoform expressions declined over 12 weeks in the TA, PCA, and CT muscles, except for the MyHC I expression in the PCA and CT muscle. The MyHC IIa expression was markedly decreased in all the muscles. CONCLUSION: The laryngeal muscles responded differently to radiation, but they showed a time-dependent and long-lasting decrease in the expressions of all the MyHC isoforms in the TA, PCA, and CT muscles. In particular, the expression of the MyHC IIa isoform in all the muscles may be more sensitive to irradiation than the expressions of the other MyHC isoforms.

Candidate dosimetric predictors of long-term swallowing dysfunction after oropharyngeal intensity-modulated radiotherapy.

PURPOSE: To investigate long-term swallowing function in oropharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT), and to identify novel dose-limiting criteria predictive for dysphagia. METHODS AND MATERIALS: Thirty-one patients with Stage IV oropharyngeal squamous carcinoma enrolled on a Phase II trial were prospectively evaluated by modified barium swallow studies at baseline, and 6, 12, and 24 months post-IMRT treatment. Candidate dysphagia-associated organs at risk were retrospectively contoured into original treatment plans. Twenty-one (68%) cases were base of tongue and 10 (32%) were tonsil. Stage distribution was T1 (12 patients), T2 (10), T3 (4), T4 (2), and TX (3), and N2 (24), N3 (5), and NX (2). Median age was 52.8 years (range, 42-78 years). Thirteen patients (42%) received concurrent chemotherapy during IMRT. Thirteen (42%) were former smokers. Mean dose to glottic larynx for the cohort was limited to 18 Gy (range, 6-39 Gy) by matching IMRT to conventional low-neck fields. RESULTS: Dose-volume constraints (V30 < 65% and V35 < 35% for anterior oral cavity and V55 < 80% and V65 < 30% for high superior pharyngeal constrictors) predictive for objective swallowing dysfunction were identified by univariate and multivariate analyses. Aspiration and feeding tube dependence were observed in only 1 patient at 24 months. CONCLUSIONS: In the context of glottic laryngeal shielding, we describe candidate oral cavity and superior pharyngeal constrictor organs at risk and dose-volume constraints associated with preserved long-term swallowing function; these constraints are currently undergoing prospective validation. Strict protection of the glottic larynx via beam-split IMRT techniques promises to make chronic aspiration an uncommon outcome.

Self-triggered functional electrical stimulation during swallowing.

Hyolaryngeal elevation is essential for airway protection during swallowing and is mainly a reflexive response to oropharyngeal sensory stimulation. Targeted intramuscular electrical stimulation can elevate the resting larynx and, if applied during swallowing, may improve airway protection in dysphagic patients with inadequate hyolaryngeal motion. To be beneficial, patients must synchronize functional electrical stimulation (FES) with their reflexive swallowing and not adapt to FES by reducing the amplitude or duration of their own muscle activity. We evaluated the ability of nine healthy adults to manually synchronize FES with hyolaryngeal muscle activity during discrete swallows, and tested for motor adaptation. Hooked-wire electrodes were placed into the mylo- and thyrohyoid muscles to record electromyographic activity from one side of the neck and deliver monopolar FES for hyolaryngeal elevation to the other side. After performing baseline swallows, volunteers were instructed to trigger FES with a thumb switch in synchrony with their swallows for a series of trials. An experimenter surreptitiously disabled the thumb switch during the final attempt, creating a foil. From the outset, volunteers synchronized FES with the onset of swallow-related thyrohyoid activity (approximately 225 ms after mylohyoid activity onset), preserving the normal sequence of muscle activation. A comparison between average baseline and foil swallows failed to show significant adaptive changes in the amplitude, duration, or relative timing of activity for either muscle, indicating that the central pattern generator for hyolaryngeal elevation is immutable with short term stimulation that augments laryngeal elevation during the reflexive, pharyngeal phase of swallowing.