Diaphragmatic Weakness Research Articles

Mitochondrial oxidative stress induces leaky ryanodine receptor during mechanical ventilation

RationaleVentilator-induced diaphragm dysfunction (VIDD) increases morbidity and mortality in critical care patients. Although VIDD has been associated with mitochondrial oxidative stress and calcium homeostasis impairment, the underling mechanisms are still unknown. We hypothesized that diaphragmatic mitochondrial oxidative stress causes remodeling of the ryanodine receptor (RyR1)/calcium release channel, contributing to sarcoplasmic reticulum (SR) Ca2+ leak, proteolysis and VIDD. MethodIn mice diaphragms mechanically ventilated for short (6 h) and long (12 h) period, we assessed mitochondrial ROS production, mitochondrial aconitase activity as a marker of mitochondrial oxidative stress, RyR1 remodeling and function, Ca2+ dependent proteolysis, TGFβ1 and STAT3 pathway, muscle fibers cross-sectional area, and diaphragm specific force production, with or without the mitochondrial targeted anti-oxidant peptide d-Arg-2′, 6′-dimethyltyrosine-Lys-Phe-NH2 (SS31). Measurements and main results6 h of mechanical ventilation (MV) resulted in increased mitochondrial ROS production, reduction of mitochondrial aconitase activity, increased oxidation, S-nitrosylation, S-glutathionylation and Ser-2844 phosphorylation of RyR1, depletion of stabilizing subunit calstabin1 from RyR1, increased SR Ca2+ leak. Preventing mROS production by SS31 treatment does not affect the TGFβ1 and STAT3 activation, which suggests that mitochondrial oxidative stress is a downstream pathway to TGFβ1 and STAT3, early involved in VIDD. This is further supported by the fact that SS-31 rescue all the other described cellular events and diaphragm contractile dysfunction induced by MV, while SS20, an analog of SS31 lacking antioxidant properties, failed to prevent these cellular events and the contractile dysfunction.Similar results were found in ventilated for 12 h. Moreover, SS31 treatment prevented calpain1 activity and diaphragm atrophy observed after 12 h of MV.This study emphasizes that mitochondrial oxidative stress during 6 h-MV contributes to SR Ca2+ leak via RyR1 remodeling, and diaphragm weakness, while longer periods of MV (12 h) were also associated with increased Ca2+-dependent proteolysis and diaphragm atrophy.

Hemorrhagic Shock Sensitized the Diaphragm to Ventilator-Induced Dysfunction through the Activation of IL-6/JAK/STAT Signaling-Mediated Autophagy in Rats.

Mechanical ventilation (MV) is a major life support technique for the management of trauma-associated hemorrhagic shock (HS). Ventilator-induced diaphragm dysfunction (VIDD), one of the most common complications of MV, has been well demonstrated in animal and human studies. However, few data are available concerning the effects of MV on diaphragm function in HS victims. In the present study, we found diaphragm muscle atrophy and weakness in HS but not in healthy animals after 4 hours of MV. The inhibition of autophagy resulted in reduced muscle fiber atrophy and improved forces. In addition, we observed diaphragmatic interleukin- (IL-) 6 overexpression and activation of its downstream signaling JAK/STAT in HS animals after MV, and either the neutralization of IL-6 or the inhibition of the JAK/STAT pathway attenuated autophagy, diaphragm atrophy, and weakness. Importantly, treatment with nonselective antioxidant exerted no protective effects against VIDD in HS animals. In addition, in vitro study showed that exogenous IL-6 was able to induce activation of JAK/STAT signaling and to increase autophagy in C2C12 cells. Moreover, the inhibition of JAK/STAT signaling abolished IL-6-induced cell autophagy. Together, our results suggested that HS sensitized the diaphragm to ventilator-induced atrophy and weakness through the activation of IL-6/JAK/STAT signaling-mediated autophagy in rats.

NIVOLUMAB-INDUCED MYOCARDITIS, MYOSITIS, AND RESPIRATORY FAILURE

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Nivolumab is a checkpoint inhibitor first approved for the treatment of metastatic melanoma. Several autoimmune side effects have been reported secondary to nivolumab, including autoimmune pneumonitis, hepatitis, colitis, myocarditis and myositis. We describe a case of myocarditis and myositis with diaphragmatic muscle weakness leading to hypercarbic respiratory failure after treatment with nivolumab, a previously unreported constellation of adverse events CASE PRESENTATION: A 61 years old male with metastatic melanoma underwent resection melanoma and thereafter received his first dose of nivolumab. He presented 7 days later with atrial fibrillation and moderately reduced EF (41-49%) on Echocardiogram. His initial troponin was 2.95 NG/ML. He underwent a left heart catherization showing clean coronaries without any culprit lesions. His CPK was noted to be 4000 IU/L on admission with Aldolase of 84U/L. Patient was obtunded and a CT head showed multiple cerebral embolic strokes. He was intubated and mechanically ventilated. Patient failed multiple extubation trials and underwent tracheostomy insertion for respiratory support and PEG tube insertion for functional dysphagia. Patient underwent CT chest scan showing small lung volumes and elevated diaphragm without any evidence of pulmonary embolism. Patient was gradually weaned off mechanical ventilation to tracheal mask. His muscle strength also improved as his CPK trended down to 90 IU/L and his Aldolase also trended down to 17 U/L. His troponin trended down gradually to 0.08 NG/ML. His ANA titer was also noted to be elevated at 1:160. Patient refused EMG testing and refused to be started on corticosteroids. He was diagnosed with Nivolumab induced myocarditis, myositis, diaphragmatic weakness and was discharged to rehab after a 36 day hospital stay. DISCUSSION: Nivolumab has been recently reported to cause myositis, myocarditis and myasthenia like syndromes. Patients in those case series had elevated CPK, ANA titer and LDH. Onset of side effects is highly variable, ranging from 1 day post infusion to several months. Usually autoimmune side effects of nivolumab are treated with corticosteroids. Depending on the grade severity of the side effect, the decision to discontinue nivolumab is made. It is important to recognize autoimmune side effects of Nivolumab early as we could have spared the patient a tracheostomy placement had he been treated with corticosteroids early upon onset of side effects. CONCLUSIONS: Recognize diaphragmatic muscle weakness as a side effect of Nivolumab. Early treatment with corticosteroids can be life saving and helps shorten hospital stay. Discontinuing nivolumab use is appropriate, though it is unclear whether switching to other immune checkpoint inhibitor is a safer strategy. Further research is required as the use of immune checkpoint point increases in Oncology. Reference #1: Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al.Fulminant myocarditis withncombination immune checkpoint blockade. N Engl J Med 2016; 375:1749–1755. Reference #2: Nora Möhn et al. Acute progressive neuropathy–myositis–myasthenia-like syndrome associated with immune-checkpoint inhibitor therapy in patients with metastatic melanoma. Melanoma Research 6 March 2019. Reference #3: Syed S Mahmood et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. Journal of the American College of Cardiology Apr 2018, 71 (16) 1755-1764; https://doi.org/10.1016/j.jacc.2018.02.037 DISCLOSURES: No relevant relationships by Amit Chopra, source=Web Response No relevant relationships by Wafic Itani, source=Web Response No relevant relationships by Boris Medarov, source=Web Response No relevant relationships by Ali Wazir, source=Web Response

STATIN-INDUCED DIAPHRAGMATIC MUSCLE WEAKNESS CAUSING HYPERCAPNIA AND SHORTNESS OF BREATH

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Statins are commonly used medications in medicine. One of their side effects is muscle injury. We present a case of a patient (PT) who presented with chronic shortness of breath (SOB) and hypercapnia secondary to statin therapy. CASE PRESENTATION: A 77 y/o male with history of DM, HTN, HLD and Asthma; no smoking or toxic exposures presented to the hospital due to SOB on exertion for the last 5-6 months. His SOB was relieved by rest, but noted hoarseness and weakness with discomfort of his legs. Upon admission PT had stable VS, physical exam was unremarkable with no muscle tenderness and clear lungs. Chest X-ray and CT scan (Fig. 1) showed only bibasilar atelectasis and small lung volumes. Cardiovascular work up was negative. Laboratory evaluation was significant for an elevated Creatinine Kinase of 470 U/L. He had been on Atorvastatin with increased dosage by his PCP a few months prior. Serum HCO3 level was elevated at 35 mmol/L without diuretic use. An arterial blood gas confirmed hypercapnia(pH 7.37, PCO2 58, PO2 67, O2 saturation at 92% at room air). Thyroid function test were normal and myositis work up was sent for ESR, Anti-Jo, Anti-Ro, Anti-La antibody, Lactate levels, ANA and were found to negative. BMI was calculated to 28. Aldolase was elevated at 21 U/L. Pulmonary Function testing (PFT) were performed showing a restrictive lung pattern with FEV1/FVC ratio of 89% with FVC 41% predicted, TLC was 3.39 L (68% predicted) (Fig.2), DLCO was 49% predicted with a normal DLCO/VA. Tidal-flow volume loop was almost completely shifted to the left suggesting that the PT couldn’t take a deeper breath as there was no airway obstructive pattern. After workup was completed, the statin was discontinued and the PT's SOB slowly improved over the course of a few days. He was successfully discharged without additional intervention. DISCUSSION: Statin induced myopathy is the most common side effect associated to statin therapy(1). Hypercapnia secondary to statin therapy causing diaphragmatic muscle weakness is uncommon in the literature.(2) Most people associate statin myopathies with skeletal muscle and diaphragmatic involvement is not routinely considered. In our PT any underlying lung pathology was ruled out by imaging studies along with central causes for hypoventilation. Autoimmune myositis work up was negative, thyroid function was normal and PFT were consistent with a restrictive lung defect suggesting muscle weakness given negative CT findings for interstitial lung disease or other extra-thoracic causes of restriction. Cognitive biases can frequently limit consideration of rarer causes of dyspnea. CONCLUSIONS: Hypercapnia in the hospital setting is mistakenly attributed to COPD without other causes being considered. We suggest statin induced myopathy causing diaphragmatic weakness to be considered as a differential on PTs on statin and unexplained SOB especially due to the frequency of their use. Reference #1: Upreti, Sunita, Beenish Fayyaz, and Ramchandran P. Bongu. "Anti-HMG-CoA reductase myopathy, an undesirable evolution of statin induced myopathy: a case report.” Journal of Community Hospital Internal Medicine Perspectives 9.1 (2019): 33-35 Reference #2: Biagioni, Bradly, et al. "Diaphragmatic Weakness Due to Statin Myopathy.” Chest 150.4 (2016): 1085A. DISCLOSURES: No relevant relationships by Walter Chua, source=Web Response No relevant relationships by Christian Lopez-Padilla, source=Web Response

A RARE CASE OF CHEMOTHERAPY-INDUCED PHRENIC NEUROPATHY

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Chemotherapy induced peripheral neuropathy is a well described sequela of several chemotherapeutic agents, which can lead to permanent symptoms and disability in up to 40% of cancer survivors1. Large sensory nerve fibers are most commonly affected; however, motor neuropathy can also develop. Up to 20 to 40% of patients receiving platinum compounds have been reported to experience sensory neurotoxicity, however motor neuropathy is uncommon. Furthermore, motor impairment of the phrenic nerve has rarely been encountered with only four prior case reports being found in the literature2,3,4,5. Only one possible case of platinum associated phrenic neuropathy has been described4. CASE PRESENTATION: A 34 year old male with a metastatic right testicular cancer presented with a three month history of progressive dyspnea on exertion. He had undergone right orchiectomy & had received 4 cycles of chemotherapy with bleomycin, cisplatin and etoposide. Symptoms were first noted during the final cycle of chemotherapy, which continued to progress over the next two months. Physical exam was notable for clear lungs on auscultation with no evidence of diaphragmatic paradox. Pulmonary function tests showed a restrictive pattern, with low maximal inspiratory and expiratory pressures (Figure 1). Repeat CT showed bibasilar atelectasis with low lung volumes on scout film when compared to prior chest x-ray (Figure 2). Fluoroscopic sniff evaluation demonstrated evidence of right greater than left diaphragmatic weakness, and phrenic nerve EMG, while within normal limits, was notable for asymmetric right side predominant nerve conduction discrepancies consistent with possible fascicular phrenic neuropathy. Constellation of findings was most concerning for drug induced phrenic neuropathy leading to diaphragmatic weakness. DISCUSSION: Chemotherapy induced phrenic motor neuropathy leading to diaphragmatic weakness or paralysis is a rarely described phenomenon. Of the four prior case reports, two were associated with vincristine, which is more associated with motor neuropathies2,3. Only one these case reports described a phrenic neuropathy associated with a regimen that included a platinum based agent4. However, this case also involved radiation therapy, which has been associated with phrenic neuropathy in prior case reports. Here we describe a clear case of platinum associated phrenic neuropathy leading to symptomatic diaphragmatic weakness. CONCLUSIONS: Platinum based chemotherapy is a possible cause of phrenic neuropathy leading to diaphragmatic impairment. Reference #1: Park SB, Goldstein D, Krishnan AV, Lin CSY, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC. Chemotherapy-induced peripheral neurotoxicity: A critical analysis. Ca Cancer J Clin. 2013;63: 419-437 Reference #2: Stevens WW, Sporn PHS. Bilateral diaphragm weakness after chemotherapy for lymphoma. Am J Respir Crit Care Med. 2014;189(7):12 Reference #3: Gilliland P, Holguin M. Phrenic nerve paralysis due to vincristine. Leuk Lymphoma. 2007;48(12): 2452-2453 DISCLOSURES: No relevant relationships by Vivek Iyer, source=Web Response No relevant relationships by Mark Norton, source=Web Response

P2625Pathophysiology of diaphragm involvement in systolic heart failure: insights from diaphragm ultrasound and phrenic nerve stimulation studies

Abstract Background Diaphragm ultrasound allows for assessment of both diaphragm excursion and thickness. Cervical and cortical magnetic stimulation (CEMS and COMS) with recording of the diaphragmatic compound motor action potential (CMAP) is diagnostically useful to evaluate the conductive properties of the inspiratory pathway. Systolic heart failure (HF) is characterized by a loss of systolic pump function. Diaphragm weakness in HF has been reported to potentially contribute to exercise intolerance Methods 14 patients with systolic HF (11 men, 3 women; 64±12 years, NYHA 2±0.9, LVEF 36.1±5.6%) and 12 healthy controls matched for age and gender (4 men, 8 women; 56±8 years) underwent spirometric lung function testing and assessment of diaphragm excursion (during tidal breathing, TB, voluntary sniff, VS and deep breathing, DB) and thickness of the right hemidiaphragm by ultrasound. COMS and CEMS of the phrenic nerves with simultaneous bilateral recording of the diaphragm CMAP using surface electrodes was performed in 9 patients. Results Compared to controls, HF patients showed reduced forced vital capacity (75.46±18.05% vs. 107.62±17.13%, p<0.05). Diaphragm excursion amplitude was significantly reduced in HF patients (4.29±1.35 cm vs. 7.34±2.10 cm, p<0.05). Diaphragm contractility was impaired too, as reflected by the diaphragm thickening ratio (DTR; 2.01±0.46 vs. 2.53±0.74, p<0.05). Diaphragm CMAP following COMS and CEMS of the phrenic nerves revealed normal latencies in HF patients compared to controls (COMS Latency; 19.05±2.37 msec vs. 18.97±3.59 msec, p= n. s.). Conclusions Diaphragm involvement in systolic HF is reflected by reduced FVC and impaired ultrasound parameters of diaphragm function. Diaphragmatic pathology is likely to be myopathic because magnetic phrenic nerve conduction studies show no abnormalities. Diaphragm ultrasound may be useful as a diagnostic tool for assessment of diaphragm function in systolic HF. Acknowledgement/Funding This study was supported by Sanofi-Genzyme, Neu-Isenburg, Germany. The funders had no role in study design, data collection and analysis, preparation.

O.15MRI as a tool to indicate early diaphragmatic weakness in adult patients with Pompe disease

Muscle weakness causing respiratory insufficiency, is one of the typical characteristics in patients with Pompe disease. Early recognition of respiratory muscle weakness is important to allow an early start of treatment. The sensitivity of standard pulmonary function tests to detect diaphragmatic weakness at an early stage is questionable. MRI enables visualization of diaphragmatic motion in detail. The aim of this study was to find early signs of diaphragmatic weakness in Pompe patients.

EP.122Recurrent pneumothorax in an adult case of Ullrich congenital muscular dystrophy – case report and review of literature

Collagen VI related muscular dystrophy is caused by dominant or recessive mutations in the COL6A1, COL6A2 or COL6A3 genes and comprises of a spectrum of rare neuromuscular disorders including the early-onset and more severe Ulrich congenital muscular dystrophy, the milder adult form of Bethlem myopathy and an intermediate phenotype. They are characterised clinically by progressive muscle weakness, distal hyperlaxity, joint contractures and respiratory insufficiency. Respiratory failure develops with progression of the condition and is caused by respiratory muscle (diaphragm and intercostal) weakness as well as spinal and thoracic deformities. Intrinsic lung disease is not common, but pneumothorax, occurring as a single event or as recurrent episodes is being increasingly recognised in these patients. Our patient is a 22 year old female with Ulrich congenital muscular dystrophy caused by heterozygous mutation in exon 9 of COL6A1 gene. She was known to have a restrictive lung defect with scoliosis since childhood. Nocturnal ventilatory support was initiated at the age of 18 following a sleep study showing evidence of hypoventilation. She developed a spontaneous left sided pneumothorax at 21 years old, requiring intercostal drain (ICD) insertion followed by chemical pleurodesis via ICD. A contralateral spontaneous pneumothorax occurred 8 months later, which was complicated by PEA arrest requiring intubation and ventilation; followed by a protracted recovery period. This case is being presented to increase the awareness of a potentially life threatening complication associated with this condition. A first presentation of spontaneous pneumothorax in these patients should lead to careful assessment of lung parenchymal changes and consideration of definitive pre-emptive contralateral intervention.

Taurine administration ablates sepsis induced diaphragm weakness

Infection induced diaphragm weakness is a major contributor to death and prolonged mechanical ventilation in critically ill patients. Infection induced muscle dysfunction is associated with activation of muscle proteolytic enzymes, and taurine is known to suppress proteolysis. We therefore postulated that taurine administration may prevent infection induced diaphragm dysfunction. The purpose of this study was to test this hypothesis using a clinically relevant animal model of infection, i.e. cecal ligation puncture induced sepsis (CLP). Studies were performed on (n = 5–7 mice/group): (a) sham operated controls, (b) animals with sepsis induced by CLP, (c) sham operated animals given taurine (75 mg/kg/d, intraperitoneally), and (d) CLP animals given taurine. At intervals after surgery animals were euthanized, diaphragm force generation measured in vitro, and diaphragm calpain, caspase and proteasomal activity determined. CLP elicited a large reduction in diaphragm specific force generation at 24 h (1–150 Hz, p < 0.001) and taurine significantly attenuated CLP induced diaphragm weakness at all stimulation frequencies (p < 0.001). CLP induced significant increases in diaphragm calpain, caspase and proteasomal activity; taurine administration prevented increases in the activity of all three pathways. In additional time course experiments, diaphragm force generation remained at control levels over 72 h in CLP animals treated with daily taurine administration, while CLP animals demonstrated severe, sustained reductions in diaphragm strength (p < 0.01 for all time points). Our results indicate that taurine administration prevents infection induced diaphragm weakness and reduces activation of three major proteolytic pathways. Because this agent is has been shown to be safe, non-toxic when administered to humans, taurine may have a role in treating infection induced diaphragm weakness. Future clinical studies will be needed to assess this possibility.

Skeletal myofiber VEGF deficiency leads to mitochondrial, structural, and contractile alterations in mouse diaphragm.

Diaphragm dysfunction accompanies cardiopulmonary disease and impaired oxygen delivery. Vascular endothelial growth factor (VEGF) regulates oxygen delivery through angiogenesis, capillary maintenance, and contraction-induced perfusion. We hypothesized that myofiber-specific VEGF deficiency contributes to diaphragm weakness and fatigability. Diaphragm protein expression, capillarity and fiber morphology, mitochondrial respiration and hydrogen peroxide (H2O2) generation, and contractile function were compared between adult mice with conditional gene ablation of skeletal myofiber VEGF (SkmVEGF-/-; n = 12) and littermate controls (n = 13). Diaphragm VEGF protein was ~50% lower in SkmVEGF-/- than littermate controls (1.45 ± 0.65 vs. 3.04 ± 1.41 pg/total protein; P = 0.001). This was accompanied by an ~15% impairment in maximal isometric specific force (F[1,23] = 15.01, P = 0.001) and a trend for improved fatigue resistance (P = 0.053). Mean fiber cross-sectional area and type I fiber cross-sectional area were lower in SkmVEGF-/- by ~40% and ~25% (P < 0.05). Capillary-to-fiber ratio was also lower in SkmVEGF-/- by ~40% (P < 0.05), and thus capillary density was not different. Sarcomeric actin expression was ~30% lower in SkmVEGF-/- (P < 0.05), whereas myosin heavy chain and MAFbx were similar (measured via immunoblot). Mitochondrial respiration, citrate synthase activity, PGC-1α, and hypoxia-inducible factor 1α were not different in SkmVEGF-/- (P > 0.05). However, mitochondrial-derived reactive oxygen species (ROS) flux was lower in SkmVEGF-/- (P = 0.0003). In conclusion, myofiber-specific VEGF gene deletion resulted in a lower capillary-to-fiber ratio, type I fiber atrophy, actin loss, and contractile dysfunction in the diaphragm. In contrast, mitochondrial respiratory function was preserved alongside lower ROS generation, which may play a compensatory role to preserve fatigue resistance in the diaphragm.NEW & NOTEWORTHY Diaphragm weakness is a hallmark of diseases in which oxygen delivery is compromised. Vascular endothelial growth factor (VEGF) modulates muscle perfusion; however, it remains unclear whether VEGF deficiency contributes to the onset of diaphragm dysfunction. Conditional skeletal myofiber VEGF gene ablation impaired diaphragm contractile function and resulted in type I fiber atrophy, a lower number of capillaries per fiber, and contractile protein content. Mitochondrial function was similar and reactive oxygen species flux was lower. Diaphragm VEGF deficiency may contribute to the onset of respiratory muscle weakness.

Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot-Marie-Tooth disease 1A.

Diaphragm weakness in Charcot-Marie-Tooth disease 1A (CMT1A) is usually associated with severe disease manifestation. This study comprehensively investigated phrenic nerve conductivity, inspiratory and expiratory muscle function in ambulatory CMT1A patients. Nineteen adults with CMT1A (13 females, 47 ± 12 years) underwent spiromanometry, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, with recording of diaphragm compound muscle action potentials (dCMAP, n = 15), transdiaphragmatic and gastric pressures (twPdi and twPgas, n = 12). Diaphragm motor evoked potentials (dMEP, n = 15) were recorded following cortical magnetic stimulation. Patients had not been selected for respiratory complaints. Disease severity was assessed using the CMT Neuropathy Scale version 2 (CMT-NSv2). Healthy control subjects were matched for age, sex, and body mass index. The following parameters were significantly lower in CMT1A patients than in controls (all P < .05): forced vital capacity (91 ± 16 vs 110 ± 15% predicted), maximum inspiratory pressure (68 ± 22 vs 88 ± 29 cmH2 O), maximum expiratory pressure (91 ± 23 vs 123 ± 24 cmH2 O), and peak cough flow (377 ± 135 vs 492 ± 130 L/min). In CMT1A patients, dMEP and dCMAP were delayed. Patients vs controls showed lower diaphragm excursion (5 ± 2 vs 8 ± 2 cm), diaphragm thickening ratio (DTR, 1.9 [1.6-2.2] vs 2.5 [2.1-3.1]), and twPdi (8 ± 6 vs 19 ± 7 cmH2 O; all P < .05). DTR inversely correlated with the CMT-NSv2 score (r = -.59, P = .02). There was no group difference in twPgas following abdominal muscle stimulation. Ambulatory CMT1A patients may show phrenic nerve involvement and reduced respiratory muscle strength. Respiratory muscle weakness can be attributed to diaphragm dysfunction alone. It relates to neurological impairment and likely reflects a disease continuum.

Association Between Antinuclear Antibodies and interstitial lung Diseases in patients with Systemic Lupus Erythematosus

AbstractIntroduction: Systemic Lupus Erythematosus (SLE) is adisease primarily affecting women in their child-bearing years. SLE can affect any component of the respiratory system and manifest with pleuritis (with or without effusion), interstitial lung disease (ILD), alveolar hemorrhage, diaphragmatic weakness, pulmonary hypertension, airways disease, or pulmonary embolism. ILD occurs with a lower frequency in SLE compared with other connective tissue disease (CTD) subtypes. It is not known whether SLE-ILD differs from ILD in other CTD subtypes. Aim of the work: estimate the possible relationship between interstitial lung diseases and different antinuclear antibodies among patients with systemic lupus erythematosus.Patients and Methods: Cross sectional clinical study. A total of 100 SLE patients attending to Sohag University Hospitals will be included in the study. Patients included in this study will be classified as SLE patients according to either the 2012 SLICC criteria or the new 2017 ACR/EULAR SLE classification criteria. Results: ANA (antinuclear antibody) positivity, chest manifestations like (cough, dyspnea, expectoration, fever&hemoptysis) are predictive variates for SLE-ILD. Conclusion: We observed a population of SLE-ILD and concluded that ANA (antinuclear antibody) positivity, chest manifestations like (cough, dyspnea, expectoration, fever&hemoptysis) are predictive variates for SLE-ILD. Also ANAIF speckled pattern has specificity to SLE-ILD and AntiSS-A/Ro52KD antibody is more specific to SLE-ILD. We recom‌mend HRCT and PFT scan in these SLE patients.

Diagnostic tools in late onset Pompe disease (LOPD).

Pompe disease is a rare metabolic disorder due to deficiency of the lysosomal acid alpha-glucosidase (GAA) that causes glycogen accumulation in all tissues with a predominant involvement of skeletal muscle. The late onset form of Pompe disease (LOPD) is characterized by a progressive weakness of proximal and axial muscles, often mimicking limb-girdle muscular dystrophies or inflammatory myopathies, with respiratory distress mainly due to a diaphragmatic weakness. Diagnostic delay is still common, and clinicians need a high index of suspicion to recognize this condition because the disorder is quite rare, the clinical spectrum is wide, and signs and symptoms are not distinguishable from those in other neuromuscular disorders that present in a similar fashion. Diagnostic laboratory tests are quite fast and reliable to detect the enzymatic deficiency. Enzyme replacement therapy has been available for several years, and other new therapeutic strategies such as gene therapy are underway. Here, we discuss the main diagnostic tools currently used for the evaluation of patients with suspected LOPD.

The nature of respiratory muscle weakness in patients with late-onset Pompe disease

Late-onset Pompe disease (LOPD) causes myopathy of skeletal and respiratory muscles, and phrenic nerve pathology putatively contributes to diaphragm weakness. The aim of this study was to investigate neural contributions to diaphragm dysfunction, usefulness of diaphragm ultrasound, and involvement of expiratory abdominal muscles in LOPD. Thirteen patients with LOPD (7 male, 51±17 years) and 13 age- and gender-matched controls underwent respiratory muscle strength testing, ultrasound evaluation of diaphragm excursion and thickness, cortical and cervical magnetic stimulation (MS) of the diaphragm with simultaneous recording of surface electromyogram and twitch transdiaphragmatic pressure (twPdi; n = 6), and MS of the abdominal muscles with recording of twitch gastric pressure (twPgas; n = 6). The following parameters were significantly reduced in LOPD patients versus controls: forced vital capacity (p<0.01), maximum inspiratory and expiratory pressure (both p<0.001), diaphragm excursion velocity (p<0.05), diaphragm thickening ratio (1.8 ± 0.4 vs. 2.6 ± 0.6, p<0.01), twPdi following cervical MS (12.0 ± 6.2 vs. 19.4 ± 4.8 cmH2O, p<0.05), and twPgas following abdominal muscle stimulation (8.8 ± 8.1 vs. 34.6 ± 17.1 cmH2O, p<0.01). Diaphragm motor evoked potentials and compound muscle action potentials showed no between-group differences. In conclusion, phrenic nerve involvement in LOPD could not be electrophysiologically confirmed. Ultrasound supports assessment of diaphragm function. Abdominal expiratory muscles are functionally involved in LOPD.

TGF-β Pathway Inhibition Protects the Diaphragm From Sepsis-Induced Wasting and Weakness in Rat.

Sepsis is a frequent complication in patients in intensive care units (ICU). Diaphragm weakness, one of the most common symptoms observed, can lead to weaning problems during mechanical ventilation. Over the last couple of years, members of the transforming growth factor (TGF) β family, such as myostatin, activin A, and TGF-β1, have been reported to strongly trigger the activation of protein breakdown involved in muscle wasting. The aim of this study was to investigate the effect of TGF-β inhibitor LY364947 on the diaphragm during chronic sepsis.Rats were separated into four groups exposed to different experimental conditions: Control group, Septic group, Septic group with inhibitor from day 0 (LY D0), and Septic group with inhibitor from day 1 (LY D1). Sepsis was induced in rats by cecal ligation and puncture, and carried out for 7 days.Chronic sepsis was responsible for a decrease in body weight, food intake and diaphragm's mass. The inhibitor was able to abolish diaphragm wasting only in the LY D1 group. Similarly, LY364947 had a beneficial effect on the diaphragm contraction only for the LY D1 group. SMAD3 was over-expressed and phosphorylated within rats in the Septic group; however, this effect was reversed by LY364947. Calpain-1 and -2 as well as MAFbx were over-expressed within individuals in the Septic group. Yet, calpain-1 and MAFbx expressions were decreased by LY364947.With this work, we demonstrate for the first time that the inhibition of TGF-β pathway during chronic sepsis protects the diaphragm from wasting and weakness as early as one day post infection. This could lead to more efficient treatment and care for septic patients in ICU.

Respiratory capacity is maintained despite Duchenne muscular dystrophy-related diaphragm weakness.

Respiratory capacity is maintained despite Duchenne muscular dystrophy-related diaphragm weakness.

Diaphragm contractile weakness due to reduced mechanical loading: role of titin.

The diaphragm, the main muscle of inspiration, is constantly subjected to mechanical loading. Only during controlled mechanical ventilation, as occurs during thoracic surgery and in the intensive care unit, is mechanical loading of the diaphragm arrested. Animal studies indicate that the diaphragm is highly sensitive to unloading, causing rapid muscle fiber atrophy and contractile weakness; unloading-induced diaphragm atrophy and contractile weakness have been suggested to contribute to the difficulties in weaning patients from ventilator support. The molecular triggers that initiate the rapid unloading atrophy of the diaphragm are not well understood, although proteolytic pathways and oxidative signaling have been shown to be involved. Mechanical stress is known to play an important role in the maintenance of muscle mass. Within the muscle's sarcomere, titin is considered to play an important role in the stress-response machinery. Titin is a giant protein that acts as a mechanosensor regulating muscle protein expression in a sarcomere strain-dependent fashion. Thus titin is an attractive candidate for sensing the sudden mechanical arrest of the diaphragm when patients are mechanically ventilated, leading to changes in muscle protein expression. Here, we provide a novel perspective on how titin and its biomechanical sensing and signaling might be involved in the development of mechanical unloading-induced diaphragm weakness.

Intensive care unit–acquired weakness: unanswered questions and targets for future research

Intensive care unit–acquired weakness (ICU-AW) is the most common neuromuscular impairment in critically ill patients. We discuss critical aspects of ICU-AW that have not been completely defined or that are still under discussion. Critical illness polyneuropathy, myopathy, and muscle atrophy contribute in various proportions to ICU-AW. Diagnosis of ICU-AW is clinical and is based on Medical Research Council sum score and handgrip dynamometry for limb weakness and recognition of a patient’s ventilator dependency or difficult weaning from artificial ventilation for diaphragmatic weakness (DW). ICU-AW can be caused by a critical illness polyneuropathy, a critical illness myopathy, or muscle disuse atrophy, alone or in combination. Its diagnosis requires both clinical assessment of muscle strength and complete electrophysiological evaluation of peripheral nerves and muscles. The peroneal nerve test (PENT) is a quick simplified electrophysiological test with high sensitivity and good specificity that can be used instead of complete electrophysiological evaluation as a screening test in non-cooperative patients. DW, assessed by bilateral phrenic nerve magnetic stimulation or diaphragm ultrasound, can be an isolated event without concurrent limb muscle involvement. Therefore, it remains uncertain whether DW and limb weakness are different manifestations of the same syndrome or are two distinct entities. Delirium is often associated with ICU-AW but a clear correlation between these two entities requires further studies. Artificial nutrition may have an impact on ICU-AW, but no study has assessed the impact of nutrition on ICU-AW as the primary outcome. Early mobilization improves activity limitation at hospital discharge if it is started early in the ICU, but beneficial long-term effects are not established. Determinants of ICU-AW can be many and can interact with each other. Therefore, future studies assessing early mobilization should consider a holistic patient approach with consideration of all components that may lead to muscle weakness.

Mechanical ventilation causes diaphragm dysfunction in newborn lambs

BackgroundDiaphragm weakness occurs rapidly in adult animals treated with mechanical ventilation (MV), but the effects of MV on the neonatal diaphragm have not been determined. Furthermore, it is unknown whether co-existent lung disease exacerbates ventilator-induced diaphragmatic dysfunction (VIDD). We investigated the impact of MV (mean duration = 7.65 h), either with or without co-existent respiratory failure caused by surfactant deficiency, on the development of VIDD in newborn lambs.MethodsNewborn lambs (1–4 days) were assigned to control (CTL, non-ventilated), mechanically ventilated (MV), and MV + experimentally induced surfactant deficiency (MV+SD) groups. Immunoblotting and quantitative PCR assessed inflammatory signaling, the ubiquitin-proteasome system, autophagy, and oxidative stress. Immunostaining for myosin heavy chain (MyHC) isoforms and quantitative morphometry evaluated diaphragm atrophy. Contractile function of the diaphragm was determined in isolated myofibrils ex vivo.ResultsEqual decreases (25–30%) in myofibrillar force generation were found in MV and MV+SD diaphragms compared to CTL. In comparison to CTL, both MV and MV+SD diaphragms also demonstrated increased STAT3 transcription factor phosphorylation. Ubiquitin-proteasome system (Atrogin1 and MuRF1) transcripts and autophagy indices (Gabarapl1 transcripts and the ratio of LC3B-II/LC3B-I protein) were greater in MV+SD relative to MV alone, but fiber type atrophy was not observed in any group. Protein carbonylation and 4-hydroxynonenal levels (indices of oxidative stress) also did not differ among groups.ConclusionsIn newborn lambs undergoing controlled MV, there is a rapid onset of diaphragm dysfunction consistent with VIDD. Superimposed lung injury caused by surfactant deficiency did not influence the severity of early diaphragm weakness.

Sleep Disturbances in Patients with Disorders of the Nerve and Muscle Diseases

Recognize sleep disorders associated with neuromuscular diseases. Neuromuscular diseases can be associated with various sleep disorders. Diaphragmatic weakness, bulbar dysfunction, pharyngeal neuropathy, and central neurodegeneration cause sleep-disordered breathing. Spinal cord hyperexcitability, loss of inhibitory descending pathways, and neuropathy promote restless legs syndrome. Reduced cerebrospinal fluid (CSF) hypocretin, central dysfunction of sleep regulation, and degeneration of GABAergic intracortical circuits may contribute to central hypersomnia. Dysfunction of the nigrostriatal dopaminergic system, associated with neurodegenerative diseases and certain neuromuscular disorders, may be a common pathophysiologic mechanism responsible for the loss of rapid eye movement (REM) sleep muscle atonia and REM sleep behavior disorder (RBD). Different neuromuscular disorder may be more susceptible to specific sleep disturbances. A low threshold needs to be maintained for the diagnosis and treatment of sleep disorders in neuromuscular diseases, due to their high prevalence, lack of symptom specificity, and presence even in minimally symptomatic patients. However, loss of REM atonia may be protective against sleep-disordered breathing. There are reasonable pathophysiologic mechanisms such as respiratory muscle weakness, upper airway obstruction, and central dysfunction that explain the link between sleep disorders and neuromuscular diseases