COVID-19-Induced Myopathy and Diaphragmatic Weakness: A Case Report.

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that can induce myopathy, which can evolve into potentially life-threatening muscle weakness, including diaphragmatic paralysis. We present a case report of a 57-year-old female treated in the medical ICU for acute respiratory distress syndrome (ARDS) triggered by active COVID-19 infection, who subsequently developed worsening respiratory weakness from underlying COVID-19 myopathy manifesting as respiratory muscle weakness. Our patient's muscle biopsy highlights the development of muscle atrophy without evidence of inflammatory myopathy, making the presence of pre-existing autoimmune myopathy unlikely. While literature cites different biochemical etiologies for the development of myopathy, the exact mechanism behind this phenomenon is not yet defined.

SARS-CoV-2-induced myopathy: Clinical aspects, paraclinical changes, and therapeutic options

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a considerable global effect, posing notable challenges for clinicians, the pandemic becoming one of the most imperative international health emergencies lately. Among other more frequent manifestations, SARS-CoV-2 disease may also give rise to skeletal muscle involvement. Viral-induced skeletal muscle involvement is a potentially severe manifestation of COVID-19 (Coronavirus Disease 2019) and may be either acute, or in the context of "long-COVID”. The present review aimed to illustrate few aspects about pathomechanisms, clinical and paraclinical frames, and treatment options for SARS-CoV-2-induced muscle involvement. Notably, it has been stated that SARS-CoV-2 may have the ability to invade muscle myocytes directly, the disease having a variety of clinical manifestations, from myalgia and muscle weakness to rhabdomyolysis. Nevertheless, it is also important to take into account that most of patients with severe forms receiving mechanical ventilation for more than one week may have complications such as CIM (critical illness myopathy) and/or CIP (critical illness polyneuropathy) that may be clinically similar to SARS-CoV-2-induced myositis, yet may be differentiated paraclinically from it. Additionally, it was hypothesized that SARS-CoV-2 infection may constitute a trigger for autoimmune diseases such as polymyositis/ dermatomyositis. Presently, there are no diagnosis criteria and no specific therapeutic strategy for SARS-CoV-2-induced myositis. © 2022, Amaltea Medical Publishing House. All rights reserved.

Markedly prolonged compound muscle action potential duration in a patient with coronavirus disease 2019 related critical illness myopathy

A 56-year-old man admitted with coronavirus disease 2019 (COVID-19) became severely ill, required ventilator support and intensive care unit management. After ventilator weaning, he was found to have quadriparesis. Guillain-Barre syndrome (GBS) was suspected and administration of high-dose intravenous immunoglobulin (IVIg) was considered. However, markedly prolonged compound muscle action potential (CMAP) duration was observed, leading to a diagnosis of critical illness myopathy (CIM). Therefore, IVIg was not given at all, and supportive care was continued. A good functional recovery was obtained. Prolonged CMAP duration is a characteristic finding to CIM. CIM following severe COVID-19 infection is probably common, although the diagnostic value of prolonged CMAP duration is not widely recognized. This characteristic finding deserves more attention because it contributes to early differentiation between CIM and GBS and the use of IVIg in patients with COVID-19 may cause thrombotic complications and worsen the prognosis.Copyright © 2023 The Authors. Neurology and Clinical Neuroscience published by Japanese Society of Neurology and John Wiley & Sons Australia, Ltd.

TH-146. Neuromuscular involvement in severe Covid-19 patients. Our experience in EMG unit of terciary hospital

Introduction: Since the coronavirus disease 2019 (COVID-19) emerged in Wuhan, neurological complications affecting both the central and peripheral nervous systems have been reported. Multiple etiological mechanisms as immuno-mediation, direct nerve infection, prolonged intensive care units (ICU) hospitalization and prolonged positioning have been proposed as a cause of peripheral lesion. The aim of this study is to report an observational description of peripheral nervous system complications in patients with severe COVID-19. Method(s): We include patients with COVID-19 infections with weakness or sensory deficit, with one or more EMG tests carried out between April 2020 and December 2021. Standard neurophysiological techniques with motor and sensory nerve conductions, F responses and needle EMG exam in representative upper and lower limb muscles were performed. Result(s): A total of 89 patients were included, 66 males (74%) and 23 females (26%), with an average age of 55.7 years old (range from 11 to 90). Most of them (74%) were studied during hospitalization (16 of them during ICU admission). Nearly all patients (90%) had a prolonged ICU hospitalization (between 8 and 120 days). The reason for consultation was diffuse or focal weakness, difficulty in weaning, facial palsy or sensory deficits. The results of EMG tests showed myopathic findings in 61% of patients, focal peripheral nerve lesions in 64%, Guillain-Barre syndrome (GBS) in 5 (6%), and other types of peripheral polyneuropathy in 24%. From peripheral nerve injuries, peroneal neuropathy was the most frequent (58%), brachial plexopathy was found in 26%, median neuropathy in 25%, ulnar in 11%, lateral femoral cutaneous in 9%, axillary and spinal in 5%, radial and hypoglossal in 4% and musculocutaneous in 2%. Tapia's syndrome was diagnosed in two patients. Peripheral nerve injuries correlated with longer admissions in ICU and prone positioning. The follow-up studies showed a good recovery from myopathy but persistent motor sequelae in axonal GBS patients and in most peroneal nerve injuries. Neurophysiological findings are described. Conclusion(s): Peripheral nerve complications are frequent in patients affected by severe COVID-19 and prolonged hospitalization, mainly focal nerve injuries (61%), critical illness myopathy (64%) and peripheral polyneuropathy (30%) including GBS (5 patients). Prone and prolonged positioning in ICU may be associated with peripheral nerve injuries although other mechanisms cannot be excluded. Copyright © 2022

WE-163. Myopathy in Sars-CoV2-positive patients with Intensive Care Unit Acquired Weakness (ICUAW): correlations between neurophysiological anomalies and muscle biopsy findings

Introduction: A large number of patients with coronavirus disease 2019 (COVID-19) require intensive care unit (ICU) admission. Critically ill patients may develop neuromuscular complications such as critical illness myopathy (CIM) or neuropathy (CIP) or both (CIPM) although there could be other myopathic conditions, possibly caused by ICU stay, inflammatory response to the infection, or direct viral damage to the muscular fibers. Our aim is to detect the presence of myopathies in ICU patients affected by COVID-19 and characterize myopathic conditions, correlating neurophysiological anomalies to muscle biopsy findings. Method(s): We evaluated Sars-CoV2-positive patients, without a history of underlying neuromuscular disorders or risk factors, who developed generalized weakness during ICU stay. If patients presented a significant reduced force (Medical Research Council [MRC] score < 48/60) at least 5 days after ICU admission, they underwent neurophysiological evaluation and muscle biopsy. Electrodiagnosis included motor and sensory nerve conduction studies and F waves evaluation (also after 20 Hz repetitive nerve stimulation for 1 second). Qualitative electromyography (EMG) was performed in at least two muscles and quantitative EMG with multi-motor unit action potential (MUAP) analysis was obtained when possible. Vastus lateralis muscle biopsy samples underwent different histological and histochemical analysis. Based on histological findings, panels of antibodies/microbiological evaluation were chosen to characterize the underlying pathology. Result(s): Ten patients were included in the study. MRC sum score range was between 18 and 45. Nine patients underwent a neurophysiological diagnosis of CIM, while only one showed concomitant sensory involvement (CIPM). The most common neurophysiological abnormality was reduced compound muscle action potentials amplitude with concomitant increased duration. Spontaneous activity was seen in one patient. MUAP analysis showed myopathic changes in 8 out of 10 subjects (reduced mean MUAP duration and/or increased percentage of lower-limit duration outliers) with different severity degrees. One patient presented only increased amount of polyphasic potentials, while one subject had normal needle examination. Muscular histopathological features were consistent with primary myopathy (CIM) in all cases: in particular, all patient presented loss of myosin filaments, muscle fiber necrosis and fiber atrophy. These abnormalities were present in each patient and variably expressed. Conclusion(s): Our study highlights the importance of neurophysiological evaluations in ICU patients to better characterize ICUAW conditions and to identify different electromyographic patterns because different expression of CIM typical histopathological features explains variability in neurophysiological findings. Copyright © 2022

WE-159. Critical Illness Neuropathy in Severe COVID-19: a case series

Introduction: Neurological complications of SARS-CoV-2 disease have received growing attention, but only few studies have described to date clinical and neurophysiological findings in COVID patients during their stay in intensive care units (ICUs). Here, we assessed the presence of either critical illness neuropathy (CIP) or myopathy (CIM) in ICU patients. Method(s): Patients underwent a neurophysiological assessment, including bilateral examination of the median, ulnar, deep peroneal and tibial motor nerves and of the median, ulnar, radial, and sural sensory nerves. Needle electromyography (EMG) was performed for both distal and proximal muscles of the lower and upper limbs. The technique of Direct Muscle Stimulation (DMS) was applied either to the deltoid or tibialis anterior muscles. Peak to peak amplitudes and onset latencies of the responses evoked by DMS (DMSamp, DMSlat) or by motor nerve stimulation (MNSamp, MNSlat) were compared. The ratio MNSamp to DMSamp (NMR) and the MNSlat to DMSlat difference (NMD: MNSlat-DMSlat) were also evaluated. Result(s): Nerve conduction studies showed a sensory-motor polyneuropathy with axonal neurogenic pattern, as confirmed by needle EMG. Both MNSamp and NMR were significantly reduced when compared to controls (p < 0.0001), whereas MNSlat and NMD were markedly increased (p = 0.0049). Conclusion(s): We have described COVID patients in the ICU with critical illness neuropathy (CIP). The predominance of CIP as compared to critical illness myopathy (CIM) has implications for the functional recovery and rehabilitation strategies in severe COVID-19. Copyright © 2022

A prospective clinical study on the mechanisms underlying critical illness myopathy-A time-course approach.

BACKGROUND: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. METHODS: Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. RESULTS: (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma. CONCLUSIONS: The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

Critical Illness Myopathy in COVID-19 Patients: A Case Series

Aim and background: Management in COVID-19 includes the use of steroids, prolonged hospital stay, and long-term ventilatory care using muscle relaxants for lung-protective ventilation. These patients are subjected to fluctuating hemodynamics, blood sugar levels, secondary sepsis, systemic inflammatory response syndrome, and multi-organ dysfunction. This causes an increased risk for developing critical illness polyneuropathy and myopathy. Objectives: The literature assessing the effect of these risk factors on mortality in patients with COVID-19 is scarce. Hence, we assessed the effect of various risk factors and interventions on the long-term outcome in these patients. Materials and methods: We collected retrospective data of critically ill COVID-19 patients who developed from critical illness myopathy. The demographic details, clinical parameters, laboratory values, effect of protocol-based physiotherapy intervention, and long-term outcome of patients in term of residual weakness, dependency, and mortality was collected. Results: Out of the total 324 critically ill COVID-19 patients, 11 patients were diagnosed with critical illness myopathy and were included for data collection. Among the patients who developed critical illness myopathy, in-hospital mortality was around 36.4%. The use of protocol-based physiotherapy interventions like long sitting (P = 0.007) and, chair mobilization (p = 0.001) led to a significant reduction in mortality in COVID-19 patients. Conclusion: In patients with COVID-19 related critical illness myopathy, the use of protocol-based physiotherapy interventions leads to improved survival. Key messages: In patients with COVID-19 related critical illness myopathy, the use of protocol-based physiotherapy interventions has survival benefits.

MULTIFOCAL BONE INFARCT AS A LATE SIDE EFFECT OF STEROID IN A PATIENT WITH BILATERAL LUNG TRANSPLANTATION SECONDARY TO COVID-19 PNEUMONIA/ARDS

CASE: A 37-year-old Hispanic female was referred to a tertiary center nine months status-post lung transplant secondary to post-COVID ARDS for evaluation of constant, dull, aching, gradually progressive pain in her bilateral lower extremities that was insidious in onset. Lab work was notable for persistently elevated alkaline phosphatase. 12 months prior to this admission, the patient was admitted for COVID-19 pneumonia for a week of ongoing fever, shortness of breath, and chest discomfort. Her hospital course was complicated by PE, ARDS, pneumothorax, required chest tube placement, intubation and ECMO. She was treated with dexamethasone, remdesivir, ceftriaxone, azithromycin, and convalescent plasma. Unfortunately, the patient developed post-ARDS pulmonary fibrosis and she was unable to wean off ECMO. Three months later, she underwent lung transplantation for postCOVID ARDS. Post- operative course was significant for profound shock intraoperatively, acute blood loss with delayed chest closure, Grade 3 primary graft dysfunction (PGD), critical illness myopathy, AKI with a need for continuous renal replacement therapy (CRRT) / hemodialysis, and Aspergillus pneumonia. She received two doses of COVID-19 vaccination. The patient underwent a bone scan that showed asymmetrically increased uptake in the bilateral femoral metadiaphysis, metaphysis, and proximal tibial metaphysis. There was questionable increased uptake in the humeral heads. MRI of the tibia showed bilateral distal tibial metaphysis/epiphysis heterogeneous T1 and T2 signal intensity lesions compatible with intramedullary infarct. There was no evidence of acute fracture or dislocation. Overall, the findings were consistent with multifocal osteonecrosis secondary to corticosteroid treatment. She is currently managed with analgesics in view of a nonsurgical approach as advised by the orthopedic team. IMPACT/DISCUSSION: Coronavirus disease 2019 (COVID-19) pandemic continues to present critical challenges for public health and medical communities globally. Its manifestations are predominantly respiratory, with multiorgan dysfunction in severe cases. Skeletal involvement is uncommon. Systemic corticosteroids such as dexamethasone are frequently used as the standard of care for critically ill COVID-19 patients to alleviate the hyperinflammatory response and reduce the need for mechanical ventilation. However, long-term treatment with dexamethasone can increase the risk of the development of osteonecrosis. In this case report, to our knowledge, we describe the first case of multifocal bone infarction in a patient treated with corticosteroids status-post lung transplant secondary to COVID-19 pneumonia. CONCLUSION: Recognizing clinical features of multifocal bone infarct as a late effect of corticosteroid treatment may be challenging given a complicated history of transplant and COVID-19. However, it may be prudent to consider osteonecrosis when a patient with prior steroid treatment history presents with musculoskeletal complaints.

Metabolomic Profiling of Respiratory Muscles and Lung in Response to Long-Term Controlled Mechanical Ventilation.

Critical illness myopathy (CIM) and ventilator-induced diaphragm dysfunction (VIDD) are characterized by severe muscle wasting, muscle paresis, and extubation failure with subsequent increased medical costs and mortality/morbidity rates in intensive care unit (ICU) patients. These negative effects in response to modern critical care have received increasing attention, especially during the current COVID-19 pandemic. Based on experimental and clinical studies from our group, it has been hypothesized that the ventilator-induced lung injury (VILI) and the release of factors systemically play a significant role in the pathogenesis of CIM and VIDD. Our previous experimental/clinical studies have focused on gene/protein expression and the effects on muscle structure and regulation of muscle contraction at the cell and motor protein levels. In the present study, we have extended our interest to alterations at the metabolomic level. An untargeted metabolomics approach was undertaken to study two respiratory muscles (diaphragm and intercostal muscle) and lung tissue in rats exposed to five days controlled mechanical ventilation (CMV). Metabolomic profiles in diaphragm, intercostal muscles and lung tissue were dramatically altered in response to CMV, most metabolites of which belongs to lipids and amino acids. Some metabolites may possess important biofunctions and play essential roles in the metabolic alterations, such as pyruvate, citrate, S-adenosylhomocysteine, alpha-ketoglutarate, glycerol, and cysteine. Metabolic pathway enrichment analysis identified pathway signatures of each tissue, such as decreased metabolites of dipeptides in diaphragm, increased metabolites of branch-chain amino acid metabolism and purine metabolism in intercostals, and increased metabolites of fatty acid metabolism in lung tissue. These metabolite alterations may be associated with an accelerated myofibrillar protein degradation in the two respiratory muscles, an active inflammatory response in all tissues, an attenuated energy production in two respiratory muscles, and enhanced energy production in lung. These results will lay the basis for future clinical studies in ICU patients and hopefully the discovery of biomarkers in early diagnosis and monitoring, as well as the identification of future therapeutic targets.

Sex-Specific Aspects of Skeletal Muscle Metabolism in the Clinical Context of Intensive Care Unit-Acquired Weakness.

(1) Background: Female sex is considered a risk factor for Intensive Care Unit-Acquired Weakness (ICUAW). The aim is to investigate sex-specific aspects of skeletal muscle metabolism in the context of ICUAW. (2) Methods: This is a sex-specific sub-analysis from two prospectively conducted trials examining skeletal muscle metabolism and advanced muscle activating measures in critical illness. Muscle strength was assessed by Medical Research Council Score. The insulin sensitivity index was analyzed by hyperinsulinemic-euglycemic (HE) clamp. Muscular metabolites were studied by microdialysis. M. vastus lateralis biopsies were taken. The molecular analysis included protein degradation pathways. Morphology was assessed by myocyte cross-sectional area (MCSA). Multivariable linear regression models for the effect of sex on outcome parameters were performed. (3) Results: n = 83 (♂n = 57, 68.7%; ♀n = 26, 31.3%) ICU patients were included. ICUAW was present in 81.1%♂ and in 82.4%♀ at first awakening (p = 0.911) and in 59.5%♂ and in 70.6%♀ at ICU discharge (p = 0.432). Insulin sensitivity index was reduced more in women than in men (p = 0.026). Sex was significantly associated with insulin sensitivity index and MCSA of Type IIa fibers in the adjusted regression models. (4) Conclusion: This hypothesis-generating analysis suggests that more pronounced impairments in insulin sensitivity and lower MCSA of Type IIa fibers in critically ill women may be relevant for sex differences in ICUAW.

COVID-19 Neuromuscular Involvement in Post-Acute Rehabilitation.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with muscle and nerve injuries as a consequence of prolonged critical illness or the infection itself. In this study, we evaluated neuromuscular involvement in patients who underwent post-acute intensive rehabilitation after COVID-19. METHODS: Clinical and neurophysiological evaluations, including nerve conduction studies and electromyography, were performed on 21 consecutive patients admitted for rehabilitation after COVID-19. RESULTS: Clinical signs suggesting muscle or nerve involvement (weakness, reduced deep tendon reflexes, impaired sensitivity, abnormal gait) were found in 19 patients. Neurophysiological examinations confirmed neuromuscular involvement in 17 patients: a likely association of critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) was found in 5 patients; CIM alone was found in 4 patients; axonal sensory-motor polyneuropathy was found in 4 patients (CIP in 2 patients, metabolic polyneuropathy in 2 patients); Guillain-Barré syndrome was found in 2 patients (classical demyelinating sensory-motor polyneuropathy and acute motor axonal neuropathy, respectively); peroneal nerve injury was found in 1 patient; and pre-existing L4 radiculopathy was found in 1 patient. CONCLUSIONS: Neuromuscular involvement is a very common finding among patients admitted for rehabilitation after COVID-19, and proper investigation should be conducted when muscle or nerve injury is suspected for adequate rehabilitative strategy planning.

Electrophysiologic findings in patients with COVID-19 and quadriparesia in the northwest of Iran, A case series study and literature review.

BACKGROUND: As a global health pandemic, the novel severe acute respiratory syndrome-coronavirus 2 (SARS- CoV2) outbreak began in December 2019 which rapidly spread to more than 200 countries. Respiratory complications and fever are the most obvious symptoms. Sometimes the neurological features are superimposed on the main disease and complicate patient's status. CASE PRESENTATION: We describe 6 patients with COVID-19 and concomitant quadriparesia who underwent electrodiagnosis using EMG/NCS and results indicated 3 axonal variants of Guillain-Barré syndrome (GBS), including; 2 cases AMAN (acute motor axonal neuropathy), 1 case AMSAN (acute motor and sensory axonal neuropathy), three myopathies, including one combination of CIN/CIM (critical illness neuropathy/critical illness myopathy), one CIM and one acute polymyositis in these cases. CONCLUSION: Early diagnosis of the neuromuscular disorders of coronavirus could help for correct planning in the treatment of COVID-19 patients. Since GBS and inflammatory myopathies have an autoimmune basis, the immunotherapies such as IVIG, steroids, plasma exchange and other novel treatments as hemoperfusion can promise better and faster recovery in respiratory function and neuromuscular activity among COVID-19 patients who have musculature paralysis concomitantly. However, all these treatments are challenging and further clinical trials should be done to confirm the efficacy and safety of mentioned therapies.

Critical illness neuropathy in severe COVID-19: a case series.

INTRODUCTION: Neurological complications of SARS-CoV-2 disease have received growing attention, but only few studies have described to date clinical and neurophysiological findings in COVID patients during their stay in intensive care units (ICUs). Here, we neurophysiologically assessed the presence of either critical illness neuropathy (CIP) or myopathy (CIM) in ICU patients. MATERIALS AND METHODS: Patients underwent a neurophysiological assessment, including bilateral examination of the median, ulnar, deep peroneal and tibial motor nerves and of the median, ulnar, radial and sural sensory nerves. Needle electromyography (EMG) was performed for both distal and proximal muscles of the lower and upper limbs. In order to differentiate CIP from CIM, Direct Muscle Stimulation (DMS) was applied either to the deltoid or tibialis anterior muscles. Peak to peak amplitudes and onset latencies of the responses evoked by DMS (DMSamp, DMSlat) or by motor nerve stimulation (MNSamp, MNSlat) were compared. The ratio MNSamp to DMSamp (NMR) and the MNSlat to DMSlat difference (NMD: MNSlat - DMSlat) were also evaluated. RESULTS: Nerve conduction studies showed a sensory-motor polyneuropathy with axonal neurogenic pattern, as confirmed by needle EMG. Both MNSamp and NMR were significantly reduced when compared to controls (p < 0.0001), whereas MNSlat and NMD were markedly increased (p = 0.0049). CONCLUSIONS: We have described COVID patients in the ICU with critical illness neuropathy (CIP). COVID-related CIP could have implications for the functional recovery and rehabilitation strategies.

Intensive Care Unit-Acquired Weakness and Positioning-Related Peripheral Nerve Injuries in COVID-19: A Case Series of Three Patients and the Latest Literature Review.

A subgroup of COVID-19 patients requires intensive respiratory care. The prolonged immobilization and aggressive treatments predispose these patients to develop intensive care unit-acquired weakness (ICUAW). Furthermore, this condition could increase the chance of positioning-related peripheral nerve injuries. On the basis of the latest literature review, we describe a case series of three patients with COVID-19 who developed ICUAW complicated by positioning-related peripheral nerve injuries Every patient presented sensorimotor axonal polyneuropathy and concomitant myopathy in electrophysiological studies. Furthermore, muscle MRI helped the diagnosis of ICUAW, showing massive damage predominantly in the proximal muscles. Notably, nerve ultrasound detected positioning-related peripheral nerve injuries, even though the concomitant ICUAW substantially masked their clinical features. During the acute phase of severe COVID-19 infection, most medical attention tends to be assigned to critical care management, and neuromuscular complications such as ICUAW and positioning-related peripheral nerve injuries could be underestimated. Hence, when starting post-ICU care for COVID-19 cases, the combination of electrophysiological and imaging studies will aid appropriate evaluation on the patients with COVID-19-related ICUAW.

Clinical, Neurophysiological and Neuroimaging Findings of Critical Illness Myopathy After COVID-19.

Hypoxemic respiratory failure caused by coronavirus disease 2019 (COVID-19) may lead to prolonged intensive care unit stay and mechanical ventilation. Critically ill patients often develop intensive care unit acquired weakness (ICUAW), which is an umbrella term that encompasses critical illness polyneuropathy and critical illness myopathy. The aim of this paper is to report the clinical, neurophysiological, and radiological findings suggesting critical illness myopathy in three patients with critical COVID-19. Muscle magnetic resonance imaging may serve as a diagnostic tool for critical illness myopathy. Weaning failure and generalized muscle weakness with preserved sensation and cranial nerve function should alert physicians for ICUAW.

Clinical and neurophysiological characterization of muscular weakness in severe COVID-19.

OBJECTIVE: To report clinical and electroneuromyographic (ENMG) characteristics of patients affected by severe COVID-19 infection, evaluated for muscular weakness. MATERIALS AND METHODS: ENMGs performed for evaluation of diffuse weakness in patients who could not be discharged from semi-intensive care COVID unit because of difficulties in ventilation weaning were reviewed. Patients with severe COVID-19 infection who had undergone endotracheal intubation and able to co-operate were considered. ENMG protocol was focused on neurophysiological items that excluded or confirmed critical illness polyneuropathy (CIP), myopathy (CIM), or polyneuromyopathy (CIPM). Standardized clinical evaluation was performed using Medical Research Council (MRC) sum score. RESULTS: Eight patients were included in the study. All presented known risk factors for intensive care unit-acquired weakness (ICU-AW), and none of them had history of underlying neuromuscular disorders. ENMG findings were normal in two patients, while only two patients had an altered MRC sum score (< 48). Neuromuscular involvement was diagnosed in 6/8 patients (75%): 2 had CIP, 1 had possible CIM, 1 had CIPM, while 1 patient, with clinically evident weakness but equivocal ENMG findings, was classified as ICU-AW. Finally, 1 patient was diagnosed with acute demyelinating neuropathy. Patients with neuromuscular involvement were those with longer intubation duration and higher levels of IL-6 at admission. CONCLUSION: Neuromuscular complications are frequent in severe COVID-19 and cannot be excluded by MRC sum scores above 48. Standardized ENMG is helpful in guiding diagnosis when clinical evaluation is not reliable or possible. Elevated IL-6 at admission may be a predictor biomarker of ICU-AW in COVID-19.

Pathophysiology and management of critical illness polyneuropathy and myopathy.

Critical illness-associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into three major classifications based on the component of the neuromuscular system (i.e. peripheral nerves or skeletal muscle or both) that are affected. This includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and an overlap syndrome, critical illness polyneuromyopathy (CIPNM). It is a common complication observed in people with critical illness requiring intensive care unit (ICU) admission. Given CIAW is found in individuals experiencing grave illness, it can be challenging to study from a practical standpoint. However, over the past 2 decades, many insights into the pathophysiology of this condition have been made. Results from studies in both humans and animal models have found that a profound systemic inflammatory response and factors related to bioenergetic failure as well as microvascular, metabolic, and electrophysiological alterations underlie the development of CIAW. Current management strategies focus on early mobilization, achieving euglycemia, and nutritional optimization. Other interventions lack sufficient evidence, mainly due to a dearth of large trials. The goal of this Physiology in Medicine article is to highlight important aspects of the pathophysiology of these enigmatic conditions. It is hoped that improved understanding of the mechanisms underlying these disorders will lead to further study and new investigations for novel pharmacologic, nutritional, and exercise-based interventions to optimize patient outcomes.

Electrophysiological features of acute inflammatory demyelinating polyneuropathy associated with SARS-CoV-2 infection.

OBJECTIVE: To assess whether patients with acute inflammatory demyelinating polyneuropathy (AIDP) associated with SARS-CoV-2 show characteristic electrophysiological features. METHODS: Clinical and electrophysiological findings of 24 patients with SARS-CoV-2 infection and AIDP (S-AIDP) and of 48 control AIDP (C-AIDP) without SARS-CoV-2 infection were compared. RESULTS: S-AIDP patients more frequently developed respiratory failure (83.3% vs. 25%, P=0.000) and required intensive care unit (ICU) hospitalization (58.3% vs. 31.3%, P=0.000). In C-AIDP, distal motor latencies (DMLs) were more frequently prolonged (70.9% vs. 26.2%, P=0.000) whereas in S-AIDP distal compound muscle action potential (dCMAP) durations were more frequently increased (49.5% vs. 32.4%, P=0.002) and F waves were more often absent (45.6% vs. 31.8%, P=0.011). Presence of nerves with increased dCMAP duration and normal or slightly prolonged DML was elevenfold higher in S-AIDP (31.1% vs. 2.8%, P=0.000);11 S-AIDP patients showed this pattern in 2 nerves. CONCLUSION: Increased dCMAP duration, thought to be a marker of acquired demyelination, can also be oserved in critical illness myopathy. In S-AIDP patients, an increased dCMAP duration dissociated from prolonged DML, suggests additional muscle fiber conduction slowing, possibly due to a COVID-19-related hyperinflammatory state. Absent F waves, at least in some S-AIDP patients, may reflect α-motor neuron hypoexcitability because of immobilization during the ICU stay. These features should be considered in the electrodiagnosis of SARS-CoV-2 patients with weakness, to avoid misdiagnosis.

Case Report: Myopathy in Critically Ill COVID-19 Patients: A Consequence of Hyperinflammation?

Introduction: COVID-19-associated muscular complications may comprise myalgia, weakness, wasting, and rhabdomyolysis. Skeletal muscle damage in COVID-19 may be due to direct infection by the virus SARS-CoV-2 through interaction with the ACE2 receptor, systemic hyper-inflammatory state with cytokine release and homeostatic perturbation, an autoimmune process, or myotoxic drugs. Disclosing the cause of weakness in an individual patient is therefore difficult. Case Description: We report two patients, who survived typical COVID-19 pneumonia requiring intensive care treatment and who developed early on myalgia and severe proximal weakness in all four limbs. Laboratory exams revealed elevated serum creatine kinase and markedly increased C-reactive protein and interleukin 6, concurring with a systemic inflammatory response. On admission in neurorehabilitation (4 and 7 weeks after COVID-19 onset, respectively), the patients presented with proximal flaccid tetraparesis and limb-girdle muscle atrophy. Motor nerve conduction studies showed decreased amplitude and prolonged duration of compound muscle action potentials (CMAPs) with normal distal motor latencies and normal conduction velocities in median and ulnar nerves. Needle electromyography in proximal muscles revealed spontaneous activity in one and myopathic changes in both patients. Discussion: Clinical, laboratory, and electrodiagnostic findings in these patients were unequivocally consistent with myopathy. Interestingly, increased distal CMAP duration has been described in patients with critical illness myopathy (CIM) and reflects slow muscle fiber conduction velocity due to membrane hypo-excitability, possibly induced by inflammatory cytokines. By analogy with CIM, the pathogenesis of COVID-19-related myopathy might also depend on hyperinflammation and metabolic pathways that may affect muscles in a pathophysiological continuum from hypo-excitability to necrosis.