2023 Top Story in Neurology: Long-COVID Muscle Fatigue—A Common Multifactorial Symptom Without Muscle-Specific Pathophysiology
Long, or prolonged, COVID-19 (L-COVID), noted several months after even a mild COVID-19 infection, is characterized by a complexity of systemic, neuromuscular, musculoskeletal, and neuropsychiatric symptoms, including muscle fatigue, myalgias, painful tingling paresthesias, poor endurance, autonomic symptoms with elements of postural orthostatic tachycardia syndrome, brain fog, headaches, memory loss, and various neurocognitive disturbances, that collectively affect the patient's quality of life. The causes remain unclear; but, for the neuromuscular symptoms, several factors, including myopathic changes related to a direct viral infection, inflammatory muscle autoimmunity triggered by a viral infection, or a functional neurological disorder, have been implicated.
A new study by Agergaard et al1 focused on the muscle pathology and electrophysiology of the neuromuscular junction. The authors examined 84 patients with quantitative and single-fiber EMG and correlated the results with muscle histopathology results obtained from 8 patients. They found myopathic units in 50% of the patients, increased jitter in 17% to 25% of the tested muscles, and abnormalities in the nerve terminals and motor endplates in three muscle biopsy samples.1 They reported the presence of abnormal mitochondria, inflammation, and ischemia due to capillary injury in some biopsy samples from the same patients,2 collectively concluding that all these changes may explain the L-COVID muscle fatigue. These competently performed studies point to a buffet of neuromuscular abnormalities, ranging from endplate damage, reflecting a myasthenia-like process, to several myopathies related to inflammatory, mitochondrial, metabolic, or ischemic etiologies. However, the plethora of such mild and spotty findings noted in some muscles of some patients casts doubt on their specificity, raising fundamental concerns as to whether they are in any way connected to the patients’ complex symptomatology. Because COVID-19 does not infect the muscle,3 and none of the studied patients had clinical signs of myopathy other than fatigue and “give-way” weakness, such heterogenous and sporadically observed pathophysiological findings do not represent any specific neuromuscular entity, especially because the most common clinical problems experienced by the studied patients were headaches (86%) and memory disturbances (92%). Another recent study using muscle MRI imaging did not show any inflammatory or dystrophic processes but only minor microstructural abnormalities due to deconditioning.4 Indeed, deconditioning is not only common among patients with L-COVID but can also contribute to the patients’ reduced endurance and fatigue. If endplate dysfunction, as found by Agergaard et al, contributes to fatigue, a trial with pyridostigmine might have been considered.
Early in the pandemic, there was significant confusion and uncertainty due to over-interpretation of some nonspecific histological changes observed on some post–COVID-19 muscle biopsies.3 However, there has not been any convincing evidence supporting a direct effect of COVID-19 on the muscle tissue or specific post–COVID-19 persistent muscle inflammation, despite speculative statements in several publications; even last month, another study involving 250 patients with COVID-19, published in Muscle & Nerve, reported myopathic symptoms in 22.4% of the patients based only on some clinical symptoms.5 Apart from deconditioning and other still-unexplained etiologies, the main concluding message from all published reports is that muscle fatigue is a common and incapacitating symptom among patients with the L-COVID symptomatology spectrum that needs to be systematically investigated. However, it requires a multi-specialty assessment with a combination of neurophysiological, neurocognitive, neuropsychological, and genetic predisposition studies along with functional imaging of the central nervous system and careful patient selection with disease controls to exclude functional neurological disorders.
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Additional Info
- Agergaard J, Yamin Ali Khan B, Engell-Sørensen T, et al. Myopathy as a Cause of Long COVID Fatigue: Evidence From Quantitative and Single Fiber EMG and Muscle Histopathology. Clin Neurophysiol. 2023;148:65-75.
- Hejbøl EK, Harbo T, Agergaard J, et al. Myopathy as a Cause of Fatigue in Long-Term Post-COVID-19 Symptoms: Evidence of Skeletal Muscle Histopathology. Eur J Neurol. 2022;29:2832-2841.
- Dalakas MC. Unconvincing Evidence of SARS-CoV-2-Associated Myositis in Autopsied Muscles. JAMA Neurol. 2022;79(1):92.
- Enax-Krumova A, Forsting J, Rohm M, et al. Quantitative Muscle Magnetic Resonance Imaging Depicts Microstructural Abnormalities but no Signs of Inflammation or Dystrophy in Post-COVID-19 Condition. Eur J Neurol. 2023;30:970-981.
- Rajput SS, Aghoram R, Wadwekar V, et al. Skeletal Muscle Injury in COVID Infection: Frequency and Patterns. Muscle Nerve. 2023;68(6):873-878.
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