Swallowing Safety and Efficiency Impairment Profiles in Individuals with Amyotrophic Lateral Sclerosis.

Abstract

Background:

Dysphagia is common in individuals with amyotrophic lateral sclerosis (ALS) and associated with reductions in quality of life and health-related outcomes. Despite the high prevalence of dysphagia in ALS, functional impairment profiles of swallowing safety and efficiency have not been comprehensively examined. We therefore aimed to determine the relative prevalence of unsafe and inefficient swallowing in a large cohort of individuals with ALS.

Methods:

One hundred individuals with ALS completed a standardized videofluoroscopic swallowing examination. Two independent and blinded raters performed validated ratings of safety (Penetration-Aspiration Scale, PAS) and efficiency (Analysis of Swallowing Physiology: Events, Kinematics, and Timing, ASPEKT % residue). Binary classifications of safety (unsafe: PAS ≥ 3), efficiency (inefficient: total residue ≥3% of C2-4²) and global swallowing status were derived. Descriptives and a 2x2 contingency table with Fishers exact test were performed (α =0.05).

Results:

Prevalence of unsafe and inefficient swallowing was 48% and 73%, respectively. Global swallowing profiles were, in rank order: unsafe and inefficient (39%), inefficient but safe (34%), safe and efficient (18%), and unsafe but efficient (9%).

Conclusions:

Dysphagia was prevalent in this group of individuals with ALS. Approximately half demonstrated safety impairments and two-thirds had impairments in swallowing efficiency. Inefficient swallowing was approximately four times more likely to be the initial functional impairment in patients with one pathophysiologic functional impairment. A longitudinal study is needed to examine the temporal evolution of dysphagia in ALS.

Introduction

Difficulty swallowing (dysphagia) is reported in up to 85% of individuals with ALS [1] with progressive weakness and spasticity of bulbar and aerodigestive tract musculature impacting swallowing function [2]. Execution of safe swallowing necessitates that individuals can adequately protect the airway from entry of ingested material [3]. The primary line of defense against airway invasion during swallowing is laryngeal vestibule closure (LVC), a highly integrated sequence of events that rapidly occur to seal off the airway [4]. LVC is noted to involve several physiological components including arytenoid adduction and approximation of the arytenoids to the epiglottis, epiglottic inversion, tongue base retraction, hyolaryngeal excursion, and pharyngeal constriction [4]. Successful LVC relies upon complete and timely movement of structures and closure that lasts for an adequate duration [5]. In individuals with ALS, reduced swallowing safety has been associated with reduced hyolaryngeal movement (a component of LVC) [6-8], delayed duration to LVC [9], and incomplete closure of the laryngeal vestibule [9-11]. Airway defense mechanisms during swallowing are also noted to be impaired with a high prevalence of ‘silent’ aspiration [12] and reduced cough expiratory flow rates or sheering forces noted to effectively remove tracheal aspirate from the airway [13,14].

Swallowing efficiency refers to the ability to transport food and liquids from the oral cavity and through to the esophagus without post-swallow residue [15]. The ability to effectively move material through the alimentary tract (without accumulation of residue) is thought to relate to adequate pressure generation behind the bolus to allow adequate propulsive forces [16,17]. Indeed, swallowing is noted to be a largely pressure-based phenomenon [18] wherein there is a pressure differential created between muscles of the swallowing musculature in a rostral caudal manner relative to the bolus [19]. The closure and contraction of muscles such as the lip and tongue behind the bolus create a high pressure zone, whereas relaxation of muscles at the junction of the pharynx and esophagus in front of the bolus results in a low pressure zone [20]. The difference between these two pressure zones permit movement of the bolus through the oropharynx [19].

Although both efficiency and safety are important functional aspects of swallowing, to date, published reports in ALS have focused predominantly on profiling swallowing safety [21]. Only one recent report exists that has examined swallowing efficiency using validated metrics in a small sample of 19 patients with ALS [22]. Thus, the relative occurrence and the relative functional impairment profiles for individuals with ALS remain unclear and no group has examined global functional profiles of both swallowing safety and efficiency in a comprehensive group of ALS patients. The lack of understanding regarding the relative occurrence of swallowing safety and efficiency impairments presents a potential barrier to clinical practice and management of bulbar dysfunction in ALS. Specifically, ALS is a fast progressing disease that is noted to be fatal within ~2 years from symptom onset [23]. Given this rapid trajectory, it is imperative that clinicians are aware of the manifestation and evolution of swallowing impairments so appropriate therapeutic goals can be chosen and implemented early to help maximize function longer into the disease course. Further, since the literature has overwhelmingly focused on swallowing safety impairments in ALS [21], there has been a limited opportunity to understand whether swallowing efficiency is a meaningful therapeutic target in this patient population. Thus, broadening our understanding of both safety and efficiency profiles by examining this theme in a large sample with direct imaging of swallowing will potentially increase therapeutic options available to target swallowing impairments in ALS.

Therefore, the purpose of the present study was to examine functional global profiles of deglutition in a large cohort of individuals with ALS. Specifically, we wished to first delineate and compare the prevalence of impairment in both swallowing safety and efficiency and then to determine global functional swallowing profiles. We further sought to examine the impact of disease duration, disease severity, and ALS onset type on swallowing safety and efficiency profiles. Given that the lips and tongue are documented to demonstrate the earliest deterioration of bulbar musculature during ALS disease progression [24] and their relative role in bolus propulsion and swallowing efficiency [25,26]; we hypothesized that impairments in swallowing efficiency would be more prevalent than those in swallowing safety. We further hypothesized that longer disease duration, greater disease severity, and a bulbar onset type would be associated with unsafe and inefficient swallowing.

Methods

Participants

100 individuals were recruited from an academic neurology clinic thus representing a convenience single site sample. Inclusion criteria were: 1) confirmed diagnosis of probable or definite ALS (El-Escorial criteria revisited) [27] by a neuromuscular neurology specialist; 2) participant was still consuming some form of oral intake; 3) no allergies to barium; 4) no history of stroke, head and neck cancer, or other conditions such as gastrointestinal disorders impacting swallowing; and 5) not pregnant. Given that pulmonary and respiratory involvement invariably develop in patients with ALS [28] and up to 50% [29] of these patients experience frontotemporal dementia; these individuals were not excluded from the cohort as we wanted to include a fairly representative sample. The present study was part of a longitudinal natural history study wherein participants attended serial research evaluations every three months. This report includes data collected and analyzed from the baseline evaluation only. This study was approved by the university Institutional Review Board and conducted in accordance with the Declaration of Helsinki and each participant provided written informed consent.

Procedures:

Demographic Data:

Demographic data including participant age, disease onset type (bulbar or spinal onset), and disease duration in months were recorded for each participant at the beginning of the research evaluation.

Global Disease Severity:

Global disease severity was indexed using the validated Amyotrophic Lateral Rating Scale-Revised (ALSFRS-R) [27]. The ALSFRS-R consists of 12 questions regarding bulbar, limb, and respiratory function. Each question is rated on a scale ranging from 0 (total loss of function) to 4 (total loss of function). Scores from each individual question are then added together to generate a total score ranging from 0 to 48 with higher scores representing milder stages of disease progression and lower scores indicating advanced disease. The ALSFRS-R bulbar subscale score was also calculated for each participant. The ALSFRS-R bulbar subscale includes three questions regarding 1) speech, 2) swallowing and 3) salivation. Bulbar subscale scores range from 0 (total loss of bulbar function) to 12 (intact bulbar function) with lower scores reflecting a greater degree of bulbar involvement.

Videofluoroscopic Swallowing Examination:

Assessment of swallowing function was undertaken using the gold standard videofluoroscopic swallowing evaluation (VFSE). Participants were seated at 90 degrees in a TransMotion Medical TMM3 Videofluroscopy Swallow Study Treatment Chair (Ocala, FL) and imaged in a lateral plane of view using a properly collimated Phillips BV Endura System fluoroscopic C-arm unit (GE OEC 8800 Digital Mobile C-Arm System). High-resolution images which were recorded continuously at a rate of 30 frames per second using a TIMS Dicom system (Version 3.2, TIMS Medical, TM, Chelmsford, MA) that automatically spliced each bolus trial for subsequent analysis. A standardized bolus presentation was utilized that included the following Varibar® barium sulfate trials (Bracco Imaging, Monroe Township, NJ): three 5-mL thin liquid trials from a 30-mL medicine cup (40% w/v ratio); comfortable cup sip of 90-mL of thin liquid from a cup (Solo Clear Graduated Medicine Cups, Lake Forest, IL); consecutive cup sip challenge of remaining thin liquid; three 5-mL thin honey liquid from a tablespoon; two tablespoons of pudding; ¼ graham cracker (Honey Maid, Mondelez Global LLC, East Hanover, NJ) with pudding; and a 13mm E-Z-Disk™ barium tablet. Except for the sequential swallow challenge trials, patients were cued to hold the bolus then swallow with the patient self-administering each bolus trial (unless unable to, in which case the examiner assisted). To ensure patient safety, following the second instance of aspiration on the same bolus type, the third trial would not be administered, and the participant would move to the next thickest consistency.The VFSE was terminated in the instance of a third aspiration event or if the patient accumulated residue greater than 75% in the valleculae or pyriform sinuses that was unable to be cleared.

Analyses and Outcomes of Interest:

All videofluoroscopic analyses were performed post-hoc by two independent raters. Raters completed a standardized training program that included completing reliability training and testing to obtain competencies (≥90% accuracy) of a dataset previously double-rated films in the same patient population. Bolus trials were blinded and presented in a randomized fashion (one bolus per clip). Raters first performed a visual inspection for presence of residue before completing ratings on a given swallowing trial. Only new airway invasion and residue material/events were rated. Further, to reduce potential for this issue, research clinicians performing the VFSE implemented a liquid wash (water) in between bolus trials if they visualized residue. One hundred percent agreement was required for duplicate ratings and a discrepancy meeting that included four expert raters held to finalize ratings for any discrepanices. To establish intrarater reliability, 10% of safety and effiency ratings, respectively, were selected randomly and re-rated by the first author.

Swallowing Safety:

Swallowing safety was determined utilizing the validated Penetration-Aspiration Scale (PAS) [30]. The PAS is an eight-point ordinal scale that denotes the depth of airway invasion during a swallow and the patient’s response to any penetrated or aspirated material. The scale ranges from a score of 1 (no airway invasion) to a score of 8 (silent aspiration). Two independent blinded raters performed PAS ratings on every elicited swallow for each bolus trial. Following previous methods [31-33], the worst PAS score obtained across all trials and consistencies excluding the consecutive cup sips was used for statistical analyses. Binary swallowing safety classifications were also derived and were defined as Safe (PAS: ≤ 2) and Unsafe (PAS: ≥ 3).

Swallowing Efficiency:

Post-swallow residue in the valleculae, pyriform sinuses, and extra pharyngeal spaces were analyzed utilizing the Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) [34] method. Residue ratings were performed for the first trial of the 5-mL thin liquid, 5-mL thin honey liquid and comfortable cup sip of thin liquid for a total of three bolus trials analyzed. Given the time required to perform ratings, we chose the most meaningful trials as preliminary work from our lab has shown that the thin-liquid and honey trials elicit greater amounts of residue than pudding trials. Two independent and blinded raters used ImageJ software (National Institutes of Health, Bethesda, MD) following the published ASPEKT methods [34]. Briefly, raters carefully traced the distance between vertebrae C2 and C4 using the ImageJ line tool on the swallow rest frame (the terminal frame of the swallow) [34]. The area of residue in pixels in the valleculae, pyriform sinuses, and extra pharyngeal spaces were then traced using the selection brush and freehand tools on the frame of swallow rest as illustrated in Figure 1. The percent residue at each anatomical site, relative to the squared length of an individualized C2–C4 anatomical scalar, was determined for the initial swallow of each bolus trial. Percent residue across the three pharyngeal sites were then summed to produce a total percent pharyngeal residue for each bolus trial. Similar to methods utilized for safety and PAS scores, binary efficiency classifications were derived using the worst total residue across the three bolus trials analyzed. Efficient swallowing was defined as: total pharyngeal residue <3%. Inefficient swallowing was defined as: total pharyngeal residue ≥ 3%. A 3% threshold was selected given that this represents the established upper limit (2 standard deviations) of residue in normative healthy reference data [35].

Fig 1.

Visual depiction of the Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT [34]) methodology for residue in a lateral videofluoroscopic still image. Residue was indexed across three anatomical sites including the valleculae (“V”, red outlined space), pyriform sinuses (“PS”, yellow outlined space), and extra pharyngeal spaces (“EX”, black outlined space) depicted in 1A. The residue area in pixels was then expressed as a percentage relative to the individualized C2-C4 vertebrae distance (blue line) squared. Figure 1B illustrates an example of a valleculae residue tracing with the C2-4² anatomical scalar that serves as the denominator of the equation

Global Swallowing Status:

Global swallowing status was derived for each particpant that was operationally defined as:

1. Safe and efficient: PAS: ≤2 and total phryngeal residue: <3%

2. Safe and inefficient: PAS: ≤2 and total phryngeal residue: ≥3%

3. Unsafe and efficient: PAS: ≥3 and total phryngeal residue: <3%

4. Unsafe and inefficient: PAS: ≥3 and total phryngeal residue: ≥3%

Statistical Analysis

Descriptive statistics were generated to characterize cohort demographics and swallowing profiles (Aim 1). A 2x2 contingency table with Fisher’s exact test was utilized to determine global swallowing impairment profiles (Aim 2). Independent samples t-tests were used to compare disease duration and disease severity across swallowing impairment profiles. 2x2 contingency tables with Fisher’s exact test were utilized to examine swallowing impairment profiles across disease onset types (Aim 3). Cohen’s kappa was used to determine interrater and intrarater reliability for safety ratings. Two-way mixed intraclass correlation coefficients (ICCs) were generated to examine interrater and intrarater reliability for efficiency ratings. SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, NY) was used for all statistical analyses with alpha set at 0.05.

Results

Participant demographics are presented in Table 1. There was substantial agreement [36] between the two raters for safety ratings, κ = 0.734 (95% CI: 0.62-0.85), p <0.05. Almost perfect agreement was achieved for intrarater safety ratings κ = 0.846 (95% CI: 0.56-1.13), p <0.05. “Good” to “excellent” [37] interrater (ICC: 0.89; 95% CI: 0.86-0.92) and intrarater (ICC: 0.94; 95% CI: 0.87-0.97) reliability were noted for efficiency ratings. Swallowing safety data and profiles are presented in Figure 2 and denote that 52% demonstrated safe swallowing, 23% penetration, and 25% tracheal aspiration (Fig 2B). Within the aspirator sub-group, silent aspiration (i.e., no cough response to tracheal aspirate) represented the most common profile occurring in 72% (n=18) (Fig 2C). Swallowing efficiency profiles are summarized in Table 2 and indicate that 73% of patients demonstrated inefficient swallowing and 27% efficient swallowing. Mean worst residue occurred in the valleculae and extra pharyngeal spaces on the thin honey trials and pyriform sinus residue was most prominent on the cup sip trials.

Table 1.

Demographic data for this cohort of patients with ALS.

Demographics	Mean	Minimum	Maximum	Standard Deviation
Age (years)	63	28	85	10.8
Gender	48% Male (N=48)	N/A	N/A	N/A
Onset Type	45.8% Spinal (N=44)	N/A	N/A	N/A
Ethnicity	89% Caucasian (N=89)	N/A	N/A	N/A
Disease Duration (months)	24.8	5	109	20.5
ALSFRS-R Total Score	34.9	16	48	7.6
ALSFRS-R Bulbar Score	8.9	3	12	2.5

Note: Onset type was unknown for four participants; ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [27].

Fig 2.

Summary of swallowing safety profiles in this group of 100 individuals with amyotrophic lateral sclerosis. A) Bar chart depicting relative frequency of Penetration-Aspiration Scale (PAS [30]) scores. B) Overall safety classification profiles which indicated that 52% were safe (PAS < 2), 23% were penetrators (PAS: 3-5), and 25% demonstrated tracheal aspiration (PAS ≥ 6). C) In those who aspirated (n=25), ‘silent aspiration’ was the most common response profile occurring in 72% (n=18) and with 80% (n=20) unable to clear tracheal aspirate. Representative videofluoroscopy images depicting safe swallowing (D), penetration (E) and aspiration (F)

Table 2.

Mean pharyngeal residue expressed as percentage relative to the individualized C2-4² vertebrae scalar (95% confidence interval) across bolus types and anatomical zones.

	Valleculae %C2-42	Pyriforms %C2-42	Extra %C2-42	Norms*
5ml Thin	1.1 (0.3, 1.5)	0.7 (0.4, 1.0)	0.8 (0.5, 1.2)	0.68 (0.38, 0.99)
Cup Sip Thin	1.8 (1.4, 2.2)	1.6 (1.0, 2.3)	1.9 (1.3, 2.4)	0.68 (0.38, 0.99)
Tbspn Thin Honey	2.5 (2.0, 2.9)	1.3 (0.9, 1.7)	2.1 (1.5, 2.6)	0.57 (0.38, 0.76)
Site Average	1.8 (1.6, 2.1)	1.2 (0.9, 1.5)	1.6 (1.3, 1.8)

^*Normative data derived from Steele and colleagues [34].

Global swallowing profile data are presented in Table 3. Inefficient and unsafe swallowing represented the most common profile that was noted in 39% (n=39) of patients, while efficient and unsafe swallowing represented the least common profile occurring in only 9% (n=9) of individuals with ALS. Distribution of global swallowing impairment profiles did not significantly differ (p=0.11, Fisher’s exact test).

Table 3.

Functional global profiles.^*

	Efficient	Inefficient
Safe	18 (18%)	34 (34%)	n=52
Unsafe	9 (9%)	39 (39%)	n=48
	n=27	n=73

^*Efficient: worst total residue <3% C2-4²; Inefficient: worst total residue ≥3% C2-4²

Safe: worst Penetration Aspiration Scale (PAS [30]) score 1-2; Unsafe: worst PAS score ≥3

There were no significant differences in global disease severity (i.e. ALSFRS-R total scores) or disease duration between safe versus unsafe swallowers or efficient versus inefficient swallowers, p>0.05. Bulbar disease severity (i.e. ALSFRS-R bulbar subscale scores) was significantly lower in unsafe (M: 7.7) versus safe (M: 10.1) swallowers, t(95)=5.5, p<0.05. ALSFRS-R bulbar subscale scores did not significantly differ between individuals classified as efficient versus inefficient, p>0.05. Contingency table analyses revealed swallowing safety (p=0.000, Fisher’s exact test) and swallowing efficiency profiles (p=0.04, Fisher’s exact test) significantly differed across onset types. Specifically, there was a greater proportion of spinal onset patients demonstrating safe swallowing as compared to bulbar onset patients (Figure 3A). Both spinal and bulbar onset patients demonstrated a higher prevalence of inefficient versus efficient swallowers (Figure 3B).

Fig 3.

Pie charts denoting swallowing safety and efficiency profiles across amyotrophic lateral sclerosis (ALS) onset types in this cohort of 100 individuals with ALS. A) A 2x2 contingency table with Fisher’s exact test revealed the relative distribution of safety profiles across spinal and bulbar onset patients significantly differed (p=0.000, Fisher’s exact test). Specifically, 73% of spinal onset patients were classified as safe (Penetration-Aspiration Scale [30] ‘PAS’ ≤ 2) and 27% were unsafe (PAS ≥ 3). Conversely, only 37% of bulbar onset ALS patients were classified as safe whereas 63% were unsafe. B) The relative distribution of efficiency profiles significantly differed across ALS onset types (p=0.04, Fisher’s exact test). Both spinal (64%) and bulbar onset (81%) patients had a greater prevalence of inefficient swallowers (inefficient: %C2-C4² ≥3%) than efficient swallowers.

Discussion

The present study sought to determine the relative prevalence of unsafe and inefficient swallowing in a large group of individuals with ALS. Results confirmed our hypothesis and denoted impairments in approximately half and three-quarters of patients in our cohort in safety and efficiency, respectively. Although global swallowing profiles were not noted to significantly differ, a striking finding was that only 9 participants demonstrated impairments in safety with preserved efficiency, compared to 34 participants who demonstrated impairments in efficiency with preserved safety. Thus, inefficient swallowing was approximately four times more likely to be the initial functional impairment in patients with one pathophysiologic functional impairment.

In this cohort of 100 individuals with ALS, 23% demonstrated mild or early safety impairment as indicated by penetration into the airway at or above the level of the true vocal folds while 25% demonstrated more advanced safety impairment with confirmed tracheal aspiration below the level of the true vocal folds. Similar to our previous findings [12], the majority of aspirating ALS patients (80%) could not, or did not, expel aspirate material from the airway, with silent aspiration representing the most common response profile occurring in approximately three-quarters of aspirators. The latter finding is of interest considering the fact that ALS is historically considered to be a motor disorder [38]. Our current and previous findings however highlight potential disruption to upper airway sensory receptors that regulate a reflexive cough motor response to tracheal aspirate. Alternatively, given the degenerative nature of ALS, it is also possible that these patients may gradually become desensitized to, or habituate to, repeated aspiration events as has been noted in other patient populations [39,40]. These observations and potential implications regarding the underlying mechanisms of unsafe swallowing and aberrant airway defense mechanisms in ALS warrant further investigation. Such future work could utilize more sophisticated methods capable of assessing the integrity of both the afferent and efferent pathways regulating reflexive cough behaviors of the upper airway to better understand the pathologic mechanisms governing these aberrant safety profiles.

Only one in every five ALS patients who aspirated demonstrated an effective defensive cough response to effectively expel tracheal aspirate which lend support to our earlier findings [12]. Collectively, these data highlight the need for prophylactic interventions to improve airway defense physiologic capacity prior to impending decline. Given the unfortunate knowledge that these functions have impending decline, there exists a critical ‘window of opportunity’ during the very early stages of the disease where function could be targeted [41]. Such prophylactic and proactive interventions have been recommended for use in ALS and other neurodegenerative patient populations to increase physiologic reserve and the ability to retain function over the course of the inevitable disease decline [41,42].

In this group of individuals with ALS, inefficient swallowing was more frequent than unsafe swallowing (73% versus 48% respectively). Only one other study has examined efficiency impairment profiles in ALS [22] and reported inefficient swallowing in 53% of their small cohort of 19 patients. Our prevalence of inefficient swallowers was higher and is likely due to differences in sample size and disease severity between the two study cohorts.

As hypothesized, impairments in swallowing efficiency were more prevalent than those in safety. We originally hypothesized this profile given the published reports of observed early degradation of the lips and the tongue that are noted to become impaired prior to other bulbar structures [24,43-46]. Indeed, it has been suggested that a ‘temporal progression’ of bulbar musculature impairment occurs in ALS wherein the lips and tongue are affected earlier in the ALS disease course than the palatal and pharyngeal muscles [46]. Given their role in bolus propulsion and oral containment during swallowing, early impairment to the lips and tongue likely contribute to early reductions to bolus control, force generation, and bolus transport which, in turn, could result in post-swallow residue. Considering findings in other neurogenic patient populations that residue increases aspiration risk on subsequent swallows [47], ineffective bolus clearance in patients with ALS is concerning.Global swallowing profiles revealed a relatively similar frequency of safe/inefficient swallowers and unsafe/inefficient swallowers. However, our finding that impairments in efficiency with preserved safety occurred in 34% of ALS patients compared to only 9% of those with impairments in safety with preserved efficiency was notable. These data indicate that the frequency of efficiency being the first impairment in ALS patients noted to have one impairment was approximately four times higher. These findings and the overall findings of a higher prevalence of impairments in efficiency, suggest that efficiency impairments may arise earlier in the ALS disease progression whereas safety impairments typically progress later in the disease course. Given the cross-sectional nature of data collection, however, a longitudinal study is needed to validly confirm our preliminary observations that suggest a temporal pattern or evolution of swallowing impairments in individuals with ALS. Preserved swallowing safety may reflect the importance of airway protection for survival and also the ability for individuals with ALS to implement compensations impacting safety for a longer duration of time. Specifically, it could be that penetrators demonstrate deficits such as impaired base of tongue retraction which contributes to material entering the airway, but they still have other intact mechanisms of LVC to compensate and prevent deeper airway invasion. Meanwhile, aspirators may have overall decompensation of the oropharynx wherein there is insufficient base of tongue retraction, impaired mechanisms of LVC, and a loss of the continuum of airway protective behaviors. In other words, the presence of aspiration in unsafe swallowers may also relate to and reflect decompensation and the loss of other pharyngeal muscles and airway protective mechanisms. Future research investigating mechanisms of airway safety in ALS will help improve our knowledge regarding the evolution of unsafe swallowing in these patients.

Neither disease duration nor global disease severity (ALSFRS-R total score) significantly differed across swallowing safety and efficiency profiles. Given that ALS disease duration does not always reflect extent of bulbar disease involvement or overall severity of impairment given the different symptom onset sites and relative rates of progression across onset type [48], this finding is not entirely surprising. Similarly, as the total ALSFRS-R score is a global estimate of disease severity across the limb, axial, and bulbar systems; this measure may not be sensitive enough to reflect nuanced changes in swallowing function. Interestingly, the ALSFRS-R bulbar subscale score was significantly lower in unsafe swallowers as compared to safe swallowers. This finding may relate to sentiments expressed earlier where unsafe swallowing in ALS may reflect overall decompensation of the bulbar musculature which would be indicated by lower (worse) bulbar subscale scores. This study also revealed that onset type had an impact on the swallowing safety and efficiency impairment profiles. Individuals with a spinal onset were noted to have a greater prevalence of safe swallowers as compared to bulbar onset patients. Since spinal onset patients have their initial manifestations in the limb musculature and develop swallowing difficulties later in the disease course [49], this finding was expected. However, examining differences in swallowing efficiency profiles across ALS onset types revealed that both spinal and bulbar onset patients had a significantly greater percentage of inefficient versus efficient swallowers. These data further lend to the notion of a potential temporal evolution of swallowing impairment in ALS where efficiency may be impacted earlier in the disease course. In the ongoing natural history study in our laboratory, we are planning to conduct more robust analyses to better understand the impact of disease duration, disease severity, and onset type on the manifestation and trajectory of dysphagia in ALS.

Collectively, these data have important clinical implications for healthcare professionals working within this patient population. Our data denote that there is a need for improved therapeutics for swallowing efficiency in ALS as impairments in this aspect of swallowing appear to occur early and frequently. This need is perhaps more critical given data from a recent review [21] which notes the limited interventions available to directly target swallowing function in ALS, and of those available, they are primarily focused improving swallowing safety versus efficiency. Given the rapid and terminal nature of ALS; it is imperative that clinicians optimize dysphagia management to focus on the most salient aspects of bulbar decline to maximize function. These data suggest that earlier in the disease course, efforts in therapy should focus on methods to improve swallowing efficiency whereas later interventions should target declines in swallowing safety. As prior research has noted, however, it is best to use an instrumental assessment such as VFSE to understand each patient’s swallowing function and guide clinical decision-making accordingly [11,21]. Ultimately, given that both swallowing efficiency and safety are likely to be affected during disease progression, future research should investigate the efficacy of combinatorial interventions that target both aspects of swallowing function in patients with ALS.

There are a few important limitations of this study to acknowledge. First, data were collected from a single patient visit and thus cannot provide detailed information regarding the temporal progression of functional impairment profiles. Given the cross sectional nature of this study, the only patients we can comment on for the relative emergence and timing of swallowing impairments are those with only one impairment in either swallowing safety or efficiency. Of these (n=43), efficiency was the first impairment in 79% and safety in 21% of these individuals. To better explore this trend, a longitudinal study wherein these themes are examined over time is needed to understand the manifestation and progression swallowing impairments in ALS. An ongoing natural history study in our laboratory will afford the opportunity to further explore a potential temporal evolution of swallowing impairment in ALS. Second, methods utilized in this investigation focused on examination of functional swallowing safety and efficiency profiles utilizing validated metrics of the PAS and percentage pharyngeal residue. It must be noted that these outcomes while providing an overview of functional profiles, cannot detail underlying mechanisms that govern, or contribute to, unsafe or inefficient swallowing. Other metrics of the ASPEKT methods such as timing and kinematics related to LVC, upper esophageal sphincter opening and pharyngeal constriction, and participant sip size could be looked at in future studies to further inform mechanisms contributing to the observed functional profiles. Future work will focus on characterizing the multifaceted aspects of swallowing safety and efficiency to better understand how these impairments manifest and evolve in individuals with ALS. We also acknowledge that residue ratings in the present study were not performed on all bolus trials. Future research should incorporate residue ratings on a greater array of bolus volumes and consistencies to better detail swallowing efficiency profiles in this patient population. Finally, it is important to recognize that this study was conducted in a cohort of individuals with moderate disease progression as indicated by their mean ALSFRS-R total score (35). Therefore, it is unclear how these results would generalize to other ALS patients at differing disease severities. Future research comparing patients at the mild, moderate, and severe stages of the disease is necessary to better understand how these swallowing impairment profiles might change based on level of disease severity.

In conclusion, findings from the current cross-sectional investigation indicate that swallowing efficiency impairments were more prevalent than safety impairments and more likely to be the first presenting functional impairment. These data suggest a potential temporal evolution of dysphagia in ALS to be further explored in an ongoing longitudinal study.