Relationship between pulmonary, cough, and swallowing functions in individuals with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Evaluations of pulmonary, cough, and swallow function are frequently performed to assess disease progression in amyotrophic lateral sclerosis (ALS), yet the relationship between these functions remains unknown. We therefore aimed to determine relationships between these measures in individuals with ALS. METHODS: One hundred individuals with ALS underwent standardized tests: forced vital capacity (FVC), maximum expiratory/inspiratory pressure (MEP, MIP), voluntary cough peak expiratory flow (PEF), and videofluoroscopic swallow evaluation (VF). Duplicate raters completed independent, blinded ratings using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Descriptives, Spearman's Rho correlations, Kruskal-Wallis analyses, and Pearson's chi-squared tests were completed. RESULTS: Mean and standard deviation across pulmonary and cough measures were FVC: 74.2% predicted (± 22.6), MEP: 91.6 cmH2O (± 46.4), MIP cmH2O: 61.1 (± 28.9), voluntary PEF: 352.7 L/min (± 141.6). DIGEST grades included: 0 (normal swallowing): 31%, 1 (mild dysphagia): 48%, 2 (moderate dysphagia): 10%, 3 (severe dysphagia): 10%, and 4 (life-threatening dysphagia): 1%. Positive correlations were observed: MEP-MIP: r = .76, MIP-PEF: r = .68, MEP-PEF: r = .61, MIP-FVC: r = .60, PEF-FVC: r = .49, and MEP-FVC: r = .46, p < .0001. MEP (p = .009) and PEF (p = .04) differed across DIGEST safety grades. Post hoc analyses revealed significant between group differences in MEP and PEF across DIGEST safety grades 0 versus 1 and grades 0 versus 3, (p < .05). DISCUSSION: In this cohort of individuals with ALS, pulmonary function, and voluntary cough were associated. Expiratory metrics (MEP, PEF) were diminished in individuals with unsafe swallowing, increasing their risk for effectively defending the airway.

Profiling Number of Swallows per Bolus and Residue in Individuals With Amyotrophic Lateral Sclerosis.

PURPOSE: Swallowing efficiency impairments are the most prevalent and earliest manifestation of dysphagia in people with amyotrophic lateral sclerosis (pALS). We aimed to profile number of swallows elicited in pALS across thin liquid, moderately thick liquid, extremely thick liquid, and crackers compared to expected healthy reference data and to determine relationships between degree of pharyngeal residue, number of elicited swallows, and swallowing safety. METHOD: pALS underwent standardized videofluoroscopic swallowing studies of 10 bolus trials. Trained raters performed duplicate, independent, and blinded ratings to derive Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) efficiency and safety grades and Analysis of Swallowing Physiology: Events, Kinematics, and Timing (ASPEKT) percent total pharyngeal residue. Number of swallows per bolus was quantified (1 = typical, 2 = atypically high, 3 = extremely high). Kruskal-Wallis, Pearson chi-square, and odds ratio analyses were performed at bolus and participant levels. KEY RESULTS: At the bolus level (N = 2,523), number of swallows per bolus was observed to be, in rank order, as follows: atypically high (49.1%), extremely high (28.5%), and typical (22.4%). Mean number of swallows significantly differed by International Dysphagia Diet Standardisation Initiative level (p < .0001), with a higher number of swallows elicited in pALS for moderately thick versus thin liquids, extremely thick liquids, and crackers, p < .0001. Number of swallows per bolus increased with increasing DIGEST efficiency grades (p < .0001). Positive correlations were observed between ASPEKT percent residue and number of swallows for thin (r = .24) and moderately thick (r = .16) liquids, p < .05. DIGEST efficiency and safety grades were not significantly associated (p > .05). CONCLUSION AND INFERENCES: pALS demonstrated a higher number of swallows per bolus compared to healthy reference data that may represent a compensation for reductions in swallowing efficiency to clear pharyngeal residue.

Sensitivity and specificity of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised to detect dysarthria in individuals with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Given the widespread use of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) to measure disease progression in ALS and recent reports demonstrating its poor sensitivity, we aimed to determine the sensitivity and specificity of the ALSFRS-R bulbar subscale and speech item to detect validated clinical ratings of dysarthria in individuals with ALS. METHODS: Paired ALSFRS-R and validated Speech Intelligibility Test (SIT) data from individuals with ALS were analyzed. Trained raters completed duplicate, independent, and blinded ratings of audio recordings to obtain speech intelligibility (%) and speaking rate (words per minute, WPM). Binary dysarthria profiles were derived (dysarthria ≤96% intelligible and/or <150 WPM). Data were obtained using the Kruskal-Wallis test, receiver-operating characteristic (ROC) curve, area under the curve (AUC), sensitivity and specificity percentages, and positive/negative predictive values (PPV/NPV). RESULTS: A total of 250 paired SIT and ALSFRS-R data points were analyzed. Dysarthria was confirmed in 72.4% (n = 181). Dysarthric speakers demonstrated lower ALSFRS-R bulbar subscale (8.9 vs. 11.2) and speech item (2.7 vs. 3.7) scores (P < .0001). The ALSFRS-R bulbar subscale score had an AUC of 0.81 (95% confidence interval [CI] 0.75 to 0.86). A subscale score of ≤11 yielded a sensitivity of 86%, specificity of 57%, PPV of 84%, and NPV of 60% to correctly identify dysarthria status. The ALSFRS-R speech item score demonstrated an AUC of 0.81 to detect dysarthria (95% CI 0.76 to 0.85), with sensitivity of 79%, specificity of 75%, PPV of 89%, and NPV of 58% for a speech item cutpoint of ≤3. DISCUSSION: The ALSFRS-R bulbar and speech item subscale scores may be useful, inexpensive, and quick tools for monitoring dysarthria status in ALS.

Respiratory therapies for Amyotrophic Lateral Sclerosis: A state of the art review.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition noteworthy for upper and lower motor neuron death. Involvement of respiratory motor neuron pools leads to progressive pathology. These impairments include decreases in neural activation and muscle coordination, progressive airway obstruction, weakened airway defenses, restrictive lung disease, increased risk of pulmonary infections, and weakness and atrophy of respiratory muscles. These neural, airway, pulmonary, and neuromuscular changes deteriorate integrated respiratory-related functions including sleep, cough, swallowing, and breathing. Ultimately, respiratory complications account for a large portion of morbidity and mortality in ALS. This state-of-the-art review highlights applications of respiratory therapies for ALS, including lung volume recruitment, mechanical insufflation-exsufflation, non-invasive ventilation, and respiratory strength training. Therapeutic acute intermittent hypoxia, an emerging therapeutic tool for inducing respiratory plasticity will also be introduced. A focus on emerging evidence and future work underscores the common goal to continue to improve survival for patients living with ALS.

Maximum Phonation Time as a Surrogate Marker for Airway Clearance Physiologic Capacity and Pulmonary Function in Individuals With Amyotrophic Lateral Sclerosis.

PURPOSE: The increased use of telehealth practices has created a critical need for home-based surrogate markers for prognostic respiratory indicators of disease progression in persons with amyotrophic lateral sclerosis (pALS). Given that phonation relies on the respiratory subsystem of speech production, we aimed to examine the relationships between maximum phonation time (MPT), forced vital capacity, and peak cough flow and to determine the discriminant ability of MPT to detect forced vital capacity and peak cough flow impairments in pALS. METHOD: MPT, peak cough flow, forced vital capacity, and ALS Functional Rating Scale scores were obtained from 62 pALS (El-Escorial Revised) every 3 months as part of a longitudinal natural history study. Pearson's correlations, linear regressions, and receiver operator characteristic curve analyses with the area under the curve (AUC), sensitivity, specificity, and likelihood ratios were calculated. RESULTS: The mean age of pALS was 63.14 ± 10.95 years, 49% were female, and 43% had bulbar onset. MPT predicted forced vital capacity, F(1, 225) = 117.96, p < .0001, and peak cough flow, F(1, 217) = 98.79, p < .0001. A significant interaction was noted between MPT and ALS Functional Rating Scale-Revised respiratory subscore for forced vital capacity, F(1, 222) = 6.7, p = .010, and peak cough flow, F(1, 215) = 4.37, p = .034. The discriminant ability of MPT was excellent for peak cough flow (AUC = 0.88) and acceptable for forced vital capacity (AUC = 0.78). CONCLUSIONS: MPT is a simple clinical test that can be measured via telehealth and represents a potential surrogate marker for important respiratory and airway clearance indices. Further larger studies are required to validate these findings with remote data collection. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22186408.

Respiratory Strength Training in Amyotrophic Lateral Sclerosis: A Double-Blind, Randomized, Multicenter, Sham-Controlled Trial.

BACKGROUND AND OBJECTIVE: The objective of this study was to evaluate the short-term physiologic effect and one-year functional effect of a 12-week inspiratory and expiratory respiratory strength training (RST) program in individuals with amyotrophic lateral sclerosis (ALS). METHODS: A double-blinded, randomized, sham-controlled trial was conducted in 45 individuals with early-stage ALS. Participants were randomized into 12 weeks of active RST (30% load, n = 23) or sham RST (0% load, n = 22). An intent-to-treat analysis was conducted. Linear regression of pre-post change with group status and pretest scores as predictors was conducted. Primary outcomes included maximum expiratory and inspiratory pressure (MEP, MIP), and secondary outcomes were cough spirometry and forced vital capacity. Exploratory follow-up outcomes included one-year global and bulbar decline (ALS Functional Rating Scale-Revised [ALSFRS-R] total and bulbar subscale slope), oral intake status, and time to noninvasive ventilation (NIV). RESULTS: TheRST completion rate was 91% with no RST-related adverse events. A 12-week RST program led to increases in MEP (p = 0.004), but not MIP (p = 0.33). On average, MEP increased by 20.8 cm H2O after active RST (95% CI +7.6 to +33.9) and decreased by 1.0 cm H2O (95% CI -9.1 to +7.2) after sham RST. Mean MIP increased by 8.9 cm H2O (95% CI +1.5 to +16.3) and 4.8 cm H2O (95% CI -0.6 to +10.2) for the active and sham groups, respectively. Regarding secondary outcomes, RST led to significant increases in cough peak inspiratory flow (p = 0.02); however, it did not affect cough expiratory flow (p = 0.06) or FVC (p = 0.60). Regarding 12-month outcomes, a significant difference in the ALSFRS-R bulbar subscale slope was observed across treatment groups, with a more than two-fold faster rate of bulbar decline in the sham vs active RST groups observed (-0.29 vs -0.12 points/month, p = 0.02). Total ALSFRS-R slope, feeding status, and time to NIV did not differ across treatment groups (p > 0.05). DISCUSSION: RST was well tolerated and led to improvements in some, but not all, short and long-term outcomes. RST represents a proactive rehabilitative intervention that could increase physiologic capacity of specific breathing and airway clearance functions during the early stages of ALS. Further work is needed to determine optimal training intensity, resistance load specifications, and potential long-term functional outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a mild-intensity respiratory strength training program improves maximum expiratory pressure, but not maximum inspiratory pressure, in patients with early-stage ALS.

Profiles of Dysarthria and Dysphagia in Individuals With Amyotrophic Lateral Sclerosis.

PURPOSE: While dysarthria and dysphagia are known bulbar manifestations of amyotrophic lateral sclerosis (ALS), the relative prevalence of speech and swallowing impairments and whether these bulbar symptoms emerge at the same time point or progress at similar rates is not yet clear. We, therefore, sought to determine the relative prevalence of speech and swallowing impairments in a cohort of individuals with ALS and to determine the impact of disease duration, severity, and onset type on bulbar impairments. METHOD: Eighty-eight individuals with a confirmed diagnosis of ALS completed the ALS Functional Rating Scale-Revised (ALSFRS-R), underwent videofluoroscopy (VF), and completed the Sentence Intelligibility Test (SIT) during a single visit. Demographic variables including disease duration and onset type were also obtained from participants. Duplicate, independent, and blinded ratings were completed using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale and SIT to index dysphagia (DIGEST ≥ 1) and dysarthria (< 96% intelligible and/or < 150 words per minute) status. Descriptive statistics, Pearson chi-squared tests, independent-samples t tests, and odds ratios were performed. RESULTS: Dysphagia and dysarthria were instrumentally confirmed in 68% and 78% of individuals with ALS, respectively. Dysarthria and dysphagia were associated (p = .01), and bulbar impairment profile distributions in rank order included (a) dysphagia - dysarthria (59%, n = 52), (b) no dysphagia - dysarthria (19%, n = 17), (c) no dysphagia - no dysarthria (13%, n = 11), and (d) dysphagia - no dysarthria (9%, n = 8). Participants with dysphagia or dysarthria demonstrated 4.2 higher odds of exhibiting a bulbar impairment in the other domain than participants with normal speech and swallowing (95% CI [1.5, 12.2]). There were no differences in ALSFRS-R total scores or disease duration across bulbar impairment profiles (p > .05). ALSFRS-R bulbar subscale scores were significantly lower in individuals with dysphagia versus no dysphagia (8.4 vs. 10.4, p < .0001) and dysarthria versus no dysarthria (8.5 vs. 10.9, p < .0001). Dysphagia and onset type (p = .003) and dysarthria and onset type were associated (p < .0001). CONCLUSIONS: Over half of the individuals with ALS in this study demonstrated both dysphagia and dysarthria. Of those with only one bulbar impairment, speech was twice as likely to be the first bulbar symptom to degrade. Future studies are needed to confirm these findings and determine the longitudinal progression of bulbar impairments in this patient population.

Maximum lingual pressure impacts both swallowing safety and efficiency in individuals with amyotrophic lateral sclerosis.

BACKGROUND: Although reduced lingual strength is a confirmed early manifestation of amyotrophic lateral sclerosis (ALS), its functional impact on swallowing remains unclear. We therefore sought to examine relationships between maximum anterior isometric lingual pressure (MAIP) with swallowing safety, swallowing efficiency, and swallowing timing metrics in a large cohort of individuals with ALS. METHODS: Ninety-seven participants with ALS completed a standardized videofluoroscopic swallowing examination (VF) and lingual pressure testing (Iowa Oral Performance Instrument). Duplicate and blinded ratings of the Penetration-Aspiration Scale (PAS) and Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) percent efficiency (%C2-C42 ) and timing (laryngeal vestibule closure (LVC) duration: amount of time (milliseconds, msec) between LVC onset and laryngeal vestibule opening; time-to-LVC: hyoid burst to onset of LVC (msec); and swallow reaction time: interval between bolus passing ramus of mandible and onset of LVC (msec)) were performed across bolus trials. Swallowing safety (safe PAS: 1, 2, 4; unsafe PAS: 3, 5, 6, 7, and 8) and efficiency (inefficient: ≥3% worst total residue) were derived. Statistical analyses including descriptives, binary logistic regressions, and Spearman's rho correlations were performed (α = 0.05). KEY RESULTS: Mean MAIP was 36.3 kPa (SD: 18.7). Mean MAIP was higher in those with safe swallowing as compared to those who penetrated (mean difference: 12 kPa) or aspirated (mean difference: 18 kPa). Individuals with efficient swallowing demonstrated higher MAIP than those with inefficient swallowing (mean difference: 11 kPa). Binary logistic regression analyses revealed increasing MAIP was significantly associated with a 1.06 (95% CI: 1.03-1.09) and 1.04 (95% CI: 1.01-1.06) greater odds of safe and efficient swallowing, respectively. No relationships were observed between MAIP and swallow reaction time across all bolus trials. Longer time-to-LVC (5 ml thin liquid: rs  = -0.35, p = 0.002; cup sip thin liquid: rs  = -0.26, p = 0.02; moderately thick liquid: rs  = -0.28, p = 0.01) and prolonged LVC duration (cup sip thin liquid, rs  = -0.34, p = 0.003) were associated with lower MAIP. CONCLUSIONS AND INFERENCES: Reduced lingual strength was confirmed in this group of 97 individuals with ALS that was associated with a diminished ability to effectively transport boluses and aide in laryngeal vestibule closure to prevent entry of material into the airway.

Functional Lingual Pressure Thresholds for Swallowing Safety and Efficiency Impairments in Amyotrophic Lateral Sclerosis.

Although reductions in lingual strength are reported in individuals with amyotrophic lateral sclerosis (ALS) that are associated with dysphagia; determination of a functional lingual pressure threshold (FLPT) has not yet been established. The present study therefore sought to identify an FLPT for impaired swallowing safety and efficiency in individuals with ALS.Thirty individuals with ALS completed a standardized videofluoroscopic swallowing examination and maximum anterior isometric lingual pressure testing using the Iowa Oral Performance Instrument. Duplicate, blinded ratings of the validated Penetration-Aspiration Scale (PAS) scores and Analysis of Swallowing Physiology: Events, Kinematics and Timing (ASPEKT) were performed. Binary classifications of safety (unsafe: PAS: ≥ 3) and efficiency (inefficient: ≥ 3% worst total pharyngeal residue) were derived. Descriptives and receiver operating characteristic curve analyses (AUC, sensitivity, specificity) were performed.Unsafe and inefficient swallowing were instrumentally confirmed in 57% and 70% of ALS patients, respectively. Across the entire cohort, the mean maximum lingual physiologic capacity was 32.1 kilopascals ('kPa'; SD: 18.1 kPa). The identified FLPT for radiographically confirmed unsafe swallowing was 43 kPa (sensitivity: 94%, specificity: 62%, AUC 0.82, p = 0.003). FLPT for inefficient swallowing was 46 kPa (sensitivity: 86%, specificity: 56%, AUC = 0.77, p = 0.02).These data provide preliminary FLPT data in a small cohort of individuals with ALS that need to be further investigated in larger cohorts to inform clinical screening practices.

Discriminant Ability of the Eating Assessment Tool-10 to Detect Swallowing Safety and Efficiency Impairments.

OBJECTIVES/HYPOTHESIS: Quick, sensitive dysphagia screening tools are necessary to identify high-risk patients for further evaluation in busy multidisciplinary amyotrophic lateral sclerosis (ALS) clinics. We examined the relationship between self-perceived dysphagia using the validated Eating Assessment Tool-10 (EAT-10) and videofluoroscopic analysis of swallowing safety and efficiency. STUDY DESIGN: Prospective, observational, longitudinal study. METHODS: Individuals with ALS completed the EAT-10 and a videofluoroscopic swallowing study. Duplicate, independent, blinded analyses of the validated Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale were performed to index swallowing safety and efficiency (mild dysphagia: DIGEST ≥ 1, moderate dysphagia: DIGEST ≥ 2). A between-groups analysis of variance with Games-Howell test for post-hoc pairwise comparisons was performed to examine EAT-10 scores across dysphagia severity levels. Receiver operator characteristic curve analysis, area under the curve (AUC), sensitivity, specificity, positive-negative predictive values (PPV, NPV), and odds ratios (OR) were derived. RESULTS: Four hundred and thirty five paired EAT-10 and DIGEST scores were analyzed. Mean EAT-10 score was 8.48 (95% confidence interval [CI]: 7.63-9.33). Individuals with dysphagia demonstrated higher EAT-10 scores (mild: 4.1 vs. 11.3, moderate: 6.0 vs. 17.5, P < .001). Mean EAT-10 scores increased across DIGEST levels (D0: 4.1, D1: 7.9, D2: 15.1, D3: 20.4, D4: 39.0). For mild dysphagia, an EAT-10 cut score of 3 was optimal: AUC 0.74 (95% CI: 0.69-0.78; sensitivity: 77%; specificity: 53%; PPV: 71%; NPV: 60%; OR: 3.5). An EAT-10 cut score of 7 optimized detection of moderate dysphagia: AUC 0.83 (95% CI: 0.78-0.87; sensitivity: 81%; specificity: 66%; PPV: 39%; NPV: 93%; OR: 8.1). CONCLUSION: The EAT-10 is an easy-to-administer dysphagia screening tool with good discriminant ability for use in ALS clinics. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:2319-2326, 2022.

Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: A preliminary study.

Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O2, 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted.

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

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. We further sought to examine the impact of global and bulbar disease progression (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised "ALSFRS-R" total and bulbar scores, respectively), disease duration, and onset type on swallowing impairment profiles. 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. The ALSFRS-R was completed to derive ALSFRS-R total and bulbar subscale scores. Demographic data (disease duration and onset type) for each participant was also recorded.  Descriptives, 2 × 2 contingency tables with Fishers exact test, and independent samples t-tests were performed (α = 0.05). 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%). There were no differences in global disease progression or disease duration across swallowing impairment profiles. ALSFRS-R bulbar subscale scores were significantly lower in unsafe versus safe swallowers, p < 0.05. Spinal onset patients had a greater proportion of safe swallowers as compared to bulbar onset patients (p = 0.000, Fisher's exact test). Both spinal and bulbar onset patients demonstrated a higher prevalence of inefficient swallowers as compared to efficient swallowers (p = 0.04, Fisher's exact test). 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.

Discriminant ability of the 3-ounce water swallow test to detect aspiration in amyotrophic lateral sclerosis.

BACKGROUND: Given the need for quick and accurate dysphagia screening tools to optimize referral workflows and resource utilization in fast-paced multidisciplinary amyotrophic lateral sclerosis (ALS) clinics, we evaluated the discriminant ability of the 3 oz. water swallow test (WST) to detect aspiration in individuals with ALS. METHODS: A total of 212 paired 3 oz. WST (index test) and standardized videofluoroscopic swallow studies (reference test) were completed in individuals with a confirmed diagnosis of ALS. Blinded raters analyzed swallowing safety using the validated penetration-aspiration scale (PAS; non-aspirator: PAS < 6; aspirator: PAS ≥ 6). Receiver operating characteristic curve analysis, area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated. KEY RESULTS: Index test: 78 (36.8%) WSTs were scored as a fail and 134 (63.2%) as a pass. REFERENCE TEST: Aspiration was confirmed in 67 (31.6%) reference tests with 145 (68.4%) reference tests verified as having no aspiration. Sensitivity and specificity of the 3 oz. WST to detect radiographically confirmed aspiration was 55.2% and 71.7%, respectively (AUC: 0.635, PPV: 47.4%, NPV: 77.6%). CONCLUSIONS & INFERENCES: In this dataset, the 3 oz. WST did not demonstrate adequate sensitivity or specificity to detect aspiration in people with ALS as a stand-alone dysphagia screening tool.

Keratinocyte Biomarkers Distinguish Painful Diabetic Peripheral Neuropathy Patients and Correlate With Topical Lidocaine Responsiveness.

This study investigated quantifiable measures of cutaneous innervation and algesic keratinocyte biomarkers to determine correlations with clinical measures of patient pain perception, with the intent to better discriminate between diabetic patients with painful diabetic peripheral neuropathy (PDPN) compared to patients with low-pain diabetic peripheral neuropathy (lpDPN) or healthy control subjects. A secondary objective was to determine if topical treatment with a 5% lidocaine patch resulted in correlative changes among the quantifiable biomarkers and clinical measures of pain perception, indicative of potential PDPN pain relief. This open-label proof-of-principle clinical research study consisted of a pre-treatment skin biopsy, a 4-week topical 5% lidocaine patch treatment regimen for all patients and controls, and a post-treatment skin biopsy. Clinical measures of pain and functional interference were used to monitor patient symptoms and response for correlation with quantitative skin biopsy biomarkers of innervation (PGP9.5 and CGRP), and epidermal keratinocyte biomarkers (Nav1.6, Nav1.7, CGRP). Importantly, comparable significant losses of epidermal neural innervation (intraepidermal nerve fibers; IENF) and dermal innervation were observed among PDPN and lpDPN patients compared with control subjects, indicating that innervation loss alone may not be the driver of pain in diabetic neuropathy. In pre-treatment biopsies, keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling were all significantly increased among PDPN patients compared with control subjects. Importantly, no keratinocyte biomarkers were significantly increased among the lpDPN group compared with control. In post-treatment biopsies, the keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling intensities were no longer different between control, lpDPN, or PDPN cohorts, indicating that lidocaine treatment modified the PDPN-related keratinocyte increases. Analysis of the PDPN responder population demonstrated that increased pretreatment keratinocyte biomarker immunolabeling for Nav1.6, Nav1.7, and CGRP correlated with positive outcomes to topical lidocaine treatment. Epidermal keratinocytes modulate the signaling of IENF, and several analgesic and algesic signaling systems have been identified. These results further implicate epidermal signaling mechanisms as modulators of neuropathic pain conditions, highlight a novel potential mode of action for topical treatments, and demonstrate the utility of comprehensive skin biopsy evaluation to identify novel biomarkers in clinical pain studies.

Sleep disorders in myotonic dystrophies.

Myotonic dystrophies (DM), the most common muscular dystrophies, are known to have significant sleep disturbances. We analyzed the literature on sleep and excessive daytime sleepiness (EDS) in DM over the past 30 years. In this review we provide a brief overview of sleep, sleep disorders, and methods of assessment. We also analyze data regarding major sleep disorders in DM patients, including: sleep-disordered breathing (SDB), with both central and obstructive sleep apneas (CSA,OSA); EDS; sleep-related movement disorders; and poor sleep quality. We review the possible pathogenesis of these disorders and outline management strategies. We also consider possible future avenues for research. The findings highlight the complex set of sleep-related problems, including the primary abnormality of sleep control in myotonic dystrophies. In individual patients the roles of poor sleep hygiene, SDB, primary hypersomnia, and excess fatigue require careful assessment for appropriate management.

The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin.

In addition to large plexiform neurofibromas (pNF), NF1 patients are frequently disfigured by cutaneous neurofibromas (cNF) and are often afflicted with chronic pain and itch even from seemingly normal skin areas. Both pNFs and cNF consist primarily of benign hyperproliferating nonmyelinating Schwann cells (nSC). While pNF clearly arise within deep nerves and plexuses, the role of cutaneous innervation in the origin of cNF and in chronic itch and pain is unknown. First, we conducted a comprehensive, multi-molecular, immunofluorescence (IF) analyses on 3mm punch biopsies from three separate locations in normal appearing, cNF-free skin in 19 NF1 patients and skin of 16 normal subjects. At least one biopsy in 17 NF1 patients had previously undescribed micro-lesions consisting of a small, dense cluster of nonpeptidergic C-fiber endings and the affiliated nSC consistently adjoining adnexal structures-dermal papillae, hair follicles, sweat glands, sweat ducts, and arterioles-where C-fiber endings normally terminate. Similar micro-lesions were detected in hind paw skin of mice with conditionally-induced SC Nf1-/- mutations. Hypothesizing that these microlesions were pre-cNF origins of cNF, we subsequently analyzed numerous overt, small cNF (s-cNF, 3-6 mm) and discovered that each had an adnexal structure at the epicenter of vastly increased nonpeptidergic C-fiber terminals, accompanied by excessive nSC. The IF and functional genomics assays indicated that neurturin (NTRN) and artemin (ARTN) signaling through cRET kinase and GFRα2 and GFRα3 co-receptors on the aberrant C-fiber endings and nSC may mutually promote the onset of pre-cNF and their evolution to s-cNF. Moreover, TrpA1 and TrpV1 receptors may, respectively, mediate symptoms of chronic itch and pain. These newly discovered molecular characteristics might be targeted to suppress the development of cNF and to treat chronic itch and pain symptoms in NF1 patients.

Combined respiratory training in an individual with C9orf72 amyotrophic lateral sclerosis.

This case study examined the impact of a respiratory strength training program targeting inspiratory and expiratory musculature in an individual with C9orf72 amyotrophic lateral sclerosis (ALS). The individual tolerated 24 months of respiratory training completed at home, 50 repetitions per day, and 5 days per week. Significant increases in maximum inspiratory pressure (from 71 to 134 centimeters of water), maximum expiratory pressure (from 108 to 197 centimeters of water) and peak cough flow (from 331 to 655 Liters per minute) were noted and forced vital capacity remained unchanged. A moderate intensity respiratory strength training program applied early in the disease progression improved function in this C9orf72 ALS individual.

Paraneoplastic Lambert-Eaton Myasthenic Syndrome With Limbic Encephalitis: Clinical Correlation With the Coexistence of Anti-VGCC and Anti-GABAB Receptor Antibodies.

OBJECTIVE: To characterize Lambert-Eaton myasthenic syndrome and limbic encephalitis with coexistent voltage-gated calcium channel (VGCC) antibody and γ-aminobutyric acid (GABA) B receptor antibody. METHODS: Case study. RESULTS: A 57-year-old man presented with 6 months of weakness, unsteadiness, and vision difficulties. Examination revealed proximal weakness and diminished reflexes. Electrodiagnostic study revealed low-amplitude motor potentials and facilitation on high-frequency stimulation. Laboratory evaluation identified P/Q-type VGCC antibody. Positron emission tomography identified a mediastinal lesion, confirmed as small-cell lung carcinoma. The patient developed confusion and seizures. Cerebrospinal fluid analysis identified antibodies to GABAB receptor. CONCLUSIONS: This case describes a patient with Lambert-Eaton myasthenic syndrome, limbic encephalitis, and autoantibodies to VGCC and GABAB receptor. Atypical presentation of paraneoplastic neurological syndromes could indicate the presence of a second antibody that may have significant impact on therapy.

Defining SOD1 ALS natural history to guide therapeutic clinical trial design.

IMPORTANCE: Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. OBJECTIVE: To establish an updated natural history of ALSSOD1. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. MAIN OUTCOMES AND MEASURES: Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. RESULTS: Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). CONCLUSIONS AND RELEVANCE: SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.

Increased levels of hyper-stable protein aggregates in plasma of older adults.

Proteins that misfold into hyper-stable/degradation-resistant species during aging may accumulate and disrupt protein homeostasis (i.e., proteostasis), thereby posing a survival risk to any organism. Using the method diagonal two-dimensional (D2D) SDS-PAGE, which separates hyper-stable SDS-resistant proteins at a proteomics level, we analyzed the plasma of healthy young (<30 years) and older (60-80 years) adults. We discovered the presence of soluble SDS-resistant protein aggregates in the plasma of older adults, but found significantly lower levels in the plasma of young adults. We identified the inflammation-related chaperone protein haptoglobin as the main component of the hyper-stable aggregates. This observation is consistent with the growing link between accumulations of protein aggregates and aging across many organisms. It is plausible higher amounts of SDS-resistant protein aggregates in the plasma of older adults may reflect a compromise in proteostasis that may potentially indicate cellular aging and/or disease risk. The results of this study have implications for further understanding the link between aging and the accumulation of protein aggregates, as well as potential for the development of aging-related biomarkers. More broadly, this novel application of D2D SDS-PAGE may be used to identify, quantify, and characterize the degradation-resistant protein aggregates in human plasma or any biological system.