Neuromuscular disorders in critically ill patients: review and update

Neuromuscular disorders that are diagnosed in the intensive care unit (ICU) usually cause substantial limb weakness and contribute to ventilatory dysfunction. Although some lead to ICU admission, ICU-acquired disorders, mainly critical illness myopathy (CIM) and critical illness polyneuropathy (CIP), are more frequent and are associated with considerable morbidity. Approximately 25% to 45% of patients admitted to the ICU develop CIM, CIP, or both. Their clinical features often overlap; therefore, nerve conduction studies and electromyography are particularly helpful diagnostically, and more sophisticated electrodiagnostic studies and histopathologic evaluation are required in some circumstances. A number of prospective studies have identified risk factors for CIP and CIM, but their limitations often include the inability to separate CIM from CIP. Animal models reveal evidence of a channelopathy in both CIM and CIP, and human studies also identified axonal degeneration in CIP and myosin loss in CIM. Outcomes are variable. They tend to be better with CIM, and some patients have longstanding disabilities. Future studies of well-characterized patients with CIP and CIM should refine our understanding of risk factors, outcomes, and pathogenic mechanisms, leading to better interventions.     

Critical illness myopathy and polyneuropathy

Neuromuscular weakness commonly develops in the setting of critical illness. This weakness delays recovery and often causes prolonged ventilator dependence. An axonal sensory-motor polyneuropathy, critical illness polyneuropathy (CIP), is seen in up to one third of critically ill patients with the systemic inflammatory response syndrome (usually due to sepsis). An acute myopathy, critical illness myopathy (CIM), frequently develops in a similar setting, often in association with the use of corticosteroids and/or nondepolarizing neuromuscular blocking agents. These patients are often difficult to evaluate due to the limitations imposed by the critical care setting and may be further complicated by the presence of both CIP and CIM in varying degrees. This paper reviews the clinical and electrophysiologic features of these disorders, as well as the putative pathophysiology. In the case of CIM, an animal model has provided evidence that weakness in this disorder is caused by muscle membrane inexcitability due to altered membrane sodium currents and loss of myosin thick filaments.     

Critical illness myopathy: further evidence from muscle-fiber excitability studies of an acquired channelopathy

Recent studies have demonstrated acquired muscle inexcitability in critical illness myopathy (CIM) and have used direct muscle stimulation (DMS) techniques to distinguish neuropathy from myopathy as a cause of weakness in the critically ill. The mechanisms underlying weakness in CIM are incompletely understood and DMS is only semiquantitative. We report results from a series of 32 patients with CIM and demonstrate significant slowing of muscle-fiber conduction velocity (MFCV) and muscle-fiber conduction block during the acute phase of CIM, which correlates with prolonged compound muscle action potential (CMAP) duration, clinical severity, and course. We also used a paired stimulation technique to explore the excitability of individual muscle fibers in vivo. We demonstrate altered muscle-fiber excitability in CIM patients. Serial studies help define the course of these pathophysiological changes. Parallels are made between CIM and hypokalemic periodic paralysis. Our findings provide further evidence for muscle membrane dysfunction being the principal underlying abnormality in CIM.     

Neurological complications of sepsis: critical illness polyneuropathy and myopathy

Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles. It is now recognized that sepsis-mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients. CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control. The course is monophasic and self-limiting. Among the critical illness myopathies, three main types have been identified: a nonnecrotizing "cachectic" myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments ("thick filament myopathy") and an acute necrotizing myopathy of intensive care. Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase. The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved. In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers. Specific therapies have not been discovered. Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance. Steroids and muscle relaxants should be avoided or administered at the lowest dose possible.     

Neurological complications of sepsis: critical illness polyneuropathy and myopathy

Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles. It is now recognized that sepsis-mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients. CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control. The course is monophasic and self-limiting. Among the critical illness myopathies, three main types have been identified: a non-necrotizing “cachectic” myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments (“thick filament myopathy”) and an acute necrotizing myopathy of intensive care. Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase. The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved. In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers. Specific therapies have not been discovered. Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance. Steroids and muscle relaxants should be avoided or administered at the lowest dose possible. Received: 12 April 2001, Accepted: 23 April 2001     

危重病性多发性神经肌病电生理特点及对机械通气的影响

目的 浅析危重病性多发性神经肌病(CIPM)的电生理特点及对机械通气支持时间的影响.方法 应用丹麦Keypoint 4肌电图仪对重症监护病房中17例机械通气时间>1周仍未能脱机的肺部感染致呼吸衰竭患者进行神经电生理检测,观察其电生理特点并比较CIPM与非CIPM患者的机械通气时间.结果 17例患者中CIPM 9例,其中亚型危重病性多发性神经病(CIP)6例,危重病性肌病(CIM)3例.CIPM患者均表现四肢交感神经皮肤反应(SSR)异常和复合肌肉动作电位(CMAP)下降,CIP患者伴有感觉神经动作电位(SNAP)波幅减低而神经传导速度(NCV)正常.除2例CIP和2例CIM患者F波出现率减低外,全部CIPM患者重复神经电刺激、体感诱发电位及瞬目反射检测均正常.CIPM患者机械通气时间中位数(四分位数范围)为30.0 d(20.0～45.0 d),比非CIPM患者13.5 d(9.5～17.5 d)明显延长(U=7.500,P=0.006).结论 CIPM患者主要表现为CMAP和(或)SNAP波幅的减低,而NCV正常,全部患者SSR异常且脱机时间延长.     

Prolonged compound muscle action potential duration in critical illness myopathy

Critical illness myopathy (CIM) is a frequent cause of generalized weakness in the intensive care unit. Prolonged compound muscle action potential (CMAP) durations have been described in this patient population, and this study presents further data on CMAP duration in normal controls and patients with CIM. The findings highlight the importance of testing multiple nerve muscle combinations in weak, critically ill patients. Recognition of this pattern, which has not been widely described, can facilitate the diagnosis of CIM. Muscle Nerve, 2009     

Neuromuscular complications of severe COVID-19 in paediatric patients: Medium-term follow-up

Neuromuscular complications in paediatric patients with severe coronavirus disease 2019 (COVID-19) are poorly characterised. However, adult patients with severe COVID-19 reportedly present with frequent neuromuscular complications that mainly include critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and focal neuropathies. We examined the records of all paediatric patients with severe COVID-19 who were mechanically ventilated and experienced neuromuscular complications from our single tertiary centre between March 2020 and August 2021. During this period, 4/36 (11%) patients admitted to the paediatric ICU who were mechanically ventilated experienced neuromuscular complications (one CIM, two focal neuropathies, and one CIP associated with plexopathy). In three of them, the gamma genetic variant of SARS-CoV-2 was identified. At the 4–5 month follow-up, three of our patients exhibited slight clinical improvement. We conclude that paediatric patients with severe COVID-19 may present neuromuscular complications similar to adults (11%), and their medium-term prognosis seems unfavourable.     

Neuromuscular manifestations of critical illness

Critical illness, more precisely defined as the systemic inflammatory response syndrome (SIRS), occurs in 20%-50% of patients who have been on mechanical ventilation for more than 1 week in an intensive care unit. Critical illness polyneuropathy (CIP) and myopathy (CIM), singly or in combination, occur commonly in these patients and present as limb weakness and difficulty in weaning from the ventilator. Critical illness myopathy can be subdivided into thick-filament (myosin) loss, cachectic myopathy, acute rhabdomyolysis, and acute necrotizing myopathy of intensive care. SIRS is the predominant underlying factor in CIP and is likely a factor in CIM even though the effects of neuromuscular blocking agents and steroids predominate in CIM. Identification and characterization of the polyneuropathy and myopathy depend upon neurological examination, electrophysiological studies, measurement of serum creatine kinase, and, if features suggest a myopathy, muscle biopsy. The information is valuable in deciding treatment and prognosis.     

Critical illness polyneuropathy and myopathy]

Critical Illness Polyneuropathy (CIP) and Myopathy (CIM), either singly or in combination, are a common complication of critical illness. Both disorders may lead to severe weakness and require mechanical ventilation. CIP, as initially described by Bolton et al., in 1984, is a sensorimotor polyneuropathy that is often a complication of sepsis and multiorgan failure. In Japan, Horinouchi et al., first reported a case in 1994. CIM has been referred to by a number of different terms (acute quadriplegic myopathy, thick filament myopathy, acute necrotizing myopathy of intensive care, rapidly evolving myopathy with myosin-deficiency fibers) in the literature. A variety of serious problems (e.g., pneumonia, severe asthma, and lung or liver transplantation) and the concomitant use of high-dose intravenous corticosteroids and nondepolarizing neuromuscular blocking agents predispose to CIM. In Japan, Kawada et al., reported a first case as acute quadriplegic myopathy in 2000. There is no specific treatment for CIP and CIM. Minimizing the use of corticosteroids and nondepolarizing neuromuscular blocking agents in a critical illness setting may prove helpful in preventing the occurrence of these disorders. The prognosis is directly related to the age of the patient and the seriousness of the underlying illness.     

Long-term neuromuscular sequelae of critical illness

In this observational study, we analyzed the long-term neuromuscular deficits of survivors of critical illness. Intensive care unit-acquired muscular weakness (ICU-AW) is a very common complication of critical illness. Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are two main contributors to ICU-AW. ICU-AW is associated with an increased mortality and leads to rehabilitation problems. However, the long-term outcome of ICU-AW and factors influencing it are not well known. We analyzed the medical records of 490 survivors of critical illness, aged 18–75 years and located in the area of the study center. Intensive care unit (ICU) survivors with comorbidities that might influence neuromuscular follow-up examinations, muscle strength, or results of nerve conduction studies, such as renal or hepatic insufficiency, diabetes mellitus, or vitamin deficiency were excluded. A total of 51 patients were finally included in the study. Six to 24 months after discharge from the ICU, we measured the Medical Research Council (MRC) sum score, the Overall Disability Sum score (ODSS), and also performed nerve conduction studies and EMG. For all ICU survivors, the median MRC sum score was 60 (range 47–60) and the median ODSS score was 0 (range 0–8). CIP was diagnosed in 21 patients (41 %). No patient was diagnosed with CIM. Patients with diagnosis of CIP showed a higher median ODSS scores 1 (range 0–8) versus 0 (range 0–5); p < 0.001 and lower median MRC sum scores 56 (range 47–60) versus 60 (range 58–60); p < 0.001. The three main outcome variables MRC sum score, ODSS score and diagnosis of CIP were not related to age, gender, or diagnosis of sepsis. The MRC sum score (r = ?0.33; p = 0.02) and the ODSS score (r = 0.31; p = 0.029) were correlated with the APACHE score. There was a trend for an increased APACHE score in patients with diagnosis of CIP 19 (range 6–33) versus 16.5 (range 6–28); p = 0.065. Patients with the diagnosis of CIP had more days of ICU treatment 11 days (range 2–74) versus 4 days (range 1–61); p = 0.015, and had more days of ventilator support 8 days (range 1–59) versus 2 days (range 1–46); p = 0.006. The MRC sum score and the ODSS score were correlated with the days of ICU treatment and with the days of ventilator support. The neuromuscular long-term consequences of critical illness were not severe in our study population. As patients with concomitant diseases and old patients were excluded from this study the result of an overall favorable prognosis of ICU-acquired weakness may not be true for other patient’s case-mix. Risk factors for the development of long-term critical illness neuropathy are duration of ICU treatment, duration of ventilator support, and a high APACHE score, but not diagnosis of sepsis. Although ICU-AW can be serious complication of ICU treatment, this should not influence therapeutic decisions, given its favorable long-term prognosis, at least in relatively young patients with no concomitant diseases.     

Neuromuscular involvement in COVID-19 critically ill patients

ObjectiveCoronavirus disease 2019 (COVID-19) has a high incidence of intensive care admittance due to the severe acute respiratory syndrome (SARS). Intensive care unit (ICU)-acquired weakness (ICUAW) is a common complication of ICU patients consisting of symmetric and generalised weakness. The aim of this study was to determine the presence of myopathy, neuropathy or both in ICU patients affected by COVID-19 and whether ICUAW associated with COVID-19 differs from other aetiologies.MethodsTwelve SARS CoV-2 positive patients referred with the suspicion of critical illness myopathy (CIM) or polyneuropathy (CIP) were included between March and May 2020. Nerve conduction and concentric needle electromyography were performed in all patients while admitted to the hospital. Muscle biopsies were obtained in three patients.ResultsFour patients presented signs of a sensory-motor axonal polyneuropathy and seven patients showed signs of myopathy. One muscle biopsy showed scattered necrotic and regenerative fibres without inflammatory signs. The other two biopsies showed non-specific myopathic findings.ConclusionsWe have not found any distinctive features in the studies of the ICU patients affected by SARS-CoV-2 infection.SignificanceFurther studies are needed to determine whether COVID-19-related CIM/CIP has different features from other aetiologies. Neurophysiological studies are essential in the diagnosis of these patients.     

Critical illness polyneuropathy

Over the past three decades, there has been an increasing interest in cases of profound muscle weakness in critically ill, mechanically ventilated patients. Potential causes for these acute weakness syndromes are multiple and include disorders of the peripheral nerves, the neuromuscular junction, and muscle (Sliwa, 2000). This article will provide an overview of one potential cause of an acute weakness syndrome affecting peripheral nerves, critical illness polyneuropathy (CIP). A case study concerning a 32-year-old male who suffered multiple traumatic injuries, and who was treated for more than two years, is presented to illustrate the course of the syndrome. He required extensive interdisciplinary involvement to achieve independence in spite of ongoing neurological impairments.     

Early detection of evolving critical illness myopathy with muscle velocity recovery cycles

ObjectiveTo investigate the sensitivity of muscle velocity recovery cycles (MVRCs) for detecting altered membrane properties in critically ill patients, and to compare this to conventional nerve conduction studies (NCS) and quantitative electromyography (qEMG).MethodsTwenty-four patients with intensive care unit acquired weakness (ICUAW) and 34 healthy subjects were prospectively recruited. In addition to NCS (median, ulnar, peroneal, tibial and sural nerves) and qEMG (biceps brachii, vastus medialis and anterior tibial muscles), MVRCs with frequency ramp were recorded from anterior tibial muscle.ResultsMVRC and frequency ramp parameters showed abnormal muscle fiber membrane properties with up to 100% sensitivity and specificity. qEMG showed myopathy in 15 patients (63%) while polyneuropathy was seen in 3 (13%). Decreased compound muscle action potential (CMAP) amplitude (up to 58%) and absent F-waves (up to 75%) were frequent, but long duration CMAPs were only seen in one patient with severe myopathy.ConclusionsAltered muscle fiber membrane properties can be detected in patients with ICUAW not yet fulfilling diagnostic criteria for critical illness myopathy (CIM). MVRCs may therefore serve as a tool for early detection of evolving CIM.SignificanceCIM is often under-recognized by intensivists, and large-scale longitudinal studies are needed to determine its incidence and pathogenesis.     

Critical illness polyneuropathy: a case report

Critical illness polyneuropathy (CIP) is defined as a common complication of critically ilness patients who were admitted to the intensive care unit due to sepsis, multiple trauma and/or multi-organ failure. We aimed to present a patient who was diagnosed as CIP. He was admitted to our outpatient clinic due to weakness and pain in his lower extremities. He had been followed in an intensive care unit due to suicid five months ago. There were symmetrically and predominantly muscle weakness, sensory impairment, absence of deep tendon reflexes in his lower extremities. Electrophysiological evaluation demonstrated motor and sensory axonal distal polyneuropathy predominantly in lower extremities. At follow up, he had high fever, and elevated acute phase responses. Therefore source of infection was investigated and was suspected to a diagnosis of infective endocarditis. He was discharged to be hospitalized in cardiology clinic. With this case, we think that physiatrists should take into consideration a diagnosis of critical illness polyneuropathy in patients with symmetric motor weakness. In CIP, muscle weakness, sensory loss, neuropathic pain, and autonomic problems lengthened the rehabilitation period. Due to a diagnosis of infective endocarditis in our case, we point out that source of infection should be carefully investigated if there is acute phase responses in CIP patients even if during rehabilitation period.     

Possible role for nitric oxide dysregulation in critical illness myopathy

Muscle fiber inexcitability and myosin loss underlie weakness in critical illness myopathy (CIM). Nitric oxide (NO) takes part in the maintenance of muscle fiber resting potential and, in pathological conditions accompanied by oxidative stress, may damage proteins through peroxynitrite generation. Sepsis and other conditions associated with CIM may differentially affect expression of NO synthases (NOSs), so that both downregulation and upregulation with excessive peroxynitrite production can be hypothesized. In six patients with CIM we studied NOS1, NOS2, and NOS3 protein expression by immunohistochemistry and Western blot. To investigate peroxynitrite production, we performed immunohistochemistry for nitrotyrosine and measured nitrotyrosine levels by enzyme-linked immunosorbent assay. In three patients, sarcolemmal staining for NOS1 was selectively absent. In the others, it was absent in atrophic fibers and absent or reduced in non-atrophic fibers. Total NOS1 protein content was reduced by 41% in patients compared to controls, whereas no significant changes were found in levels and localization of NOS2, NOS3, and nitrotyrosine. Further studies are warranted to determine whether NOS1 loss plays a role in the pathophysiology of CIM, possibly reducing the release of NO at the sarcolemma and affecting muscle fiber excitability.     

Critical illness polyneuropathy,myopathy and neuronal biomarkers in COVID-19 patients: A prospective study

ObjectiveThe aim was to characterize the electrophysiological features and plasma biomarkers of critical illness polyneuropathy (CIN) and myopathy (CIM) in coronavirus disease 2019 (COVID-19) patients with intensive care unit acquired weakness (ICUAW).MethodsAn observational ICU cohort study including adult patients admitted to the ICU at Uppsala University Hospital, Uppsala, Sweden, from March 13th to June 8th 2020. We compared the clinical, electrophysiological and plasma biomarker data between COVID-19 patients who developed CIN/CIM and those who did not. Electrophysiological characteristics were also compared between COVID-19 and non-COVID-19 ICU patients.Results111 COVID-19 patients were included, 11 of whom developed CIN/CIM. Patients with CIN/CIM had more severe illness; longer ICU stay, more thromboembolic events and were more frequently treated with invasive ventilation for longer than 2 weeks. In particular CIN was more frequent among COVID-19 patients with ICUAW (50%) compared with a non-COVID-19 cohort (0%, p = 0.008). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp) levels were higher in the CIN/CIM group compared with those that did not develop CIN/CIM (both p = 0.001) and correlated with nerve amplitudes.ConclusionsCIN/CIM was more prevalent among COVID-19 ICU patients with severe illness.SignificanceCOVID-19 patients who later developed CIN/CIM had significantly higher NfL and GFAp in the early phase of ICU care, suggesting their potential as predictive biomarkers for CIN/CIM.     

Neuro-infections to be borne in mind]

We presented atypical manifestations in tuberculous meningitis (TbM) and herpes simplex encephalitis (HSE), lymphocytic dominant cerebrospinal fluid pleocytosis in bacterial meningitis, and a hitherto easily overlooked critical illness polyneuropathy (CIP) associated with sepsis. 1) We presented 2 TbM patients with atypical manifestations. One patient was a 25-year-old man who exhibited polymorphonuclear (PMN) dominant pleocytosis in CSF throughout his clinical course. He died the next day after a CSF culture yielded the growth of tuberculous bacilli, before receiving appropriate anti-TBM therapy. This was a rare TbM example of persistent PMN dominant CSF pleocytosis. The other patient was a 39-year-old woman whose CSF pleocytosis changed from lymphocytic dominant to PMN dominant about 1 month after the initiation of antituberculous chemotherapy. This CSF change was followed by multiple cerebral infarcts due to vauculitis caused by TbM. Administration of prednisolone caused marked improvement of the patient's symptomatology. Tuberculomas appeared transiently during anti-TbM therapy, consistent with paradoxical progression of tuberculoma. 2) A few patients with HSE may show atypical CSF findings such as PMN dominant pleocytosis, absence of pleocytosis, and low sugar value. Our national survey of HSE patients showed following percentages of these atypical findings: PMN dominant pleocytosis observed in 10% of the patients in the early stage and at the time of exacerbation, no pleocytosis in 0.9% (1 patient), and low sugar value in 4%. 3) Bacterial meningitis typically causes PMN dominant CSF pleocytosis. However, Listeria meningitis (LM) may cause lymphocytic dominant pleocytosis in 30% of the patients, particularly in elderly ones. We showed one such 69-year-old patient with persistent lymphocytic dominant CSF pleocytosis throughout the clinical course. 4) CIP, septic encephalopathy and critical illness myopathy are 3 major complications associated with sepsis. CIP is a frequent cause of neuromuscular weakness due to axonal dysfunction, which occurs to critically ill patients with sepsis, particularly when multiple organ dysfunctions are present. We showed our CIP patient associated with acute bacterial endocarditis and multiple organ failure. We should bear in mind these atypical manifestations, and frequent and important complications associated with sepsis such as CIP, to provide appropriate management to patients with neuro-infection and sepsis.     

Critical illness neuromuscular syndromes

Critical illness neuromyopathy (CINM) is suggested by bilateral diffuse weakness predominant in the proximal part of the limbs after improvement of the acute phase of critical illness. Although muscle and peripheral nerve are often involved in combination, muscle involvement alone is increasingly identified on electrophysiologic investigation, including direct muscle stimulation. CINM frequently involves the respiratory muscles and may result in delayed weaning and prolonged mechanical ventilation. Besides muscle immobilization and prolonged sepsis-induced multiorgan failure, which are risk factors for CINM, hyperglycemia and use of corticosteroids might have a deleterious effect on the neuromuscular system in critically ill patients, suggesting opportunities for preventive interventions.     

Neuromuscular disorders in critical illness

Neuromuscular disorders in the background of critical illness are under diagnosed. Standardized screening for weakness in the intensive care unit (ICU) setting is uncommon and persistent weakness as a sequel of critical illness is usually not recognized by physicians in the ICU for whom survival from acute illness is the primary outcome. The spectrum of illness ranges from isolated nerve entrapment with focal pain or weakness, to disuse muscle atrophy with mild weakness, and to severe myopathy or neuropathy with associated severe, prolonged weakness. This update focuses on neuromuscular disorders occurring in the critical care set up associated with diffuse and severe weakness.