By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Prolonged fatigue after COVID-19 infection may be associated with evidence of myopathy, based on physical examination, electromyography, and muscle biopsy.
SOURCE: 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; Jun 6. doi: 10.1111/ene.15435. [Online ahead of print].
Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, coronavirus disease 2019 (COVID-19) patients may experience symptoms persisting beyond three months, referred to as “long COVID,” “post-COVID,” “chronic COVID,” and “post-acute sequelae of SARS-CoV-2 infection (PASC),” encompassing fatigue, dyspnea, and cough; psychological symptoms, such as anxiety or depression; and cognitive symptoms comprising poor memory and concentration. Less commonly, patients report persistent anosmia, headache, insomnia, dizziness, arthralgia, or myalgia. Several months following infection, fatigue continues in up to 50% to 70% of post-COVID-19 patients, and myopathy is documented frequently in these patients on electromyography (EMG). Do histological studies confirm myopathy in long-term fatigue seen post-COVID-19?
Between January and July 2021, 16 patients with post-COVID-19 fatigue, myalgia, or weakness, seen at the Aarhus University Hospital, Aarhus, Denmark, were included for study. Inclusion criteria required prior SARS-CoV-2 infection documented by a positive polymerase chain reaction (PCR) test or by the presence of antibodies in nonvaccinated patients, and at least three months of fatigue, myalgia, or weakness. All patients underwent detailed neurological examination, nerve conduction studies, quantitative EMG, and percutaneous conchotome biceps brachii muscle biopsy, analyzed with light and electron microscopy. Biopsy of the quadriceps femoris, using a Bergstrom 2 mm biopsy needle, was performed in the single child (age 15 years) in the group.
Quantitative motor unit potential (MUP) analysis was accomplished by sampling at least 20 MUPs during minimal contraction; measuring mean duration, amplitude, and percentage of polyphasic potentials; and comparing results to laboratory reference material. Blood studies included measurement of vitamin B12, A1c, thyroid-stimulating hormone (TSH), erythrocyte sedimentation rate (ESR), creatinine kinase (CK), myoglobin, lactic dehydrogenase (LDH), and myositis antibodies, including Mi-2 alpha, Mi-2 beta, TIF1 gamma, MDA5, NXP2, SAE1, Ku, PM-Scl100, PM-Scl75, Jo-1, SRP, PL-7, PL-12, EJ, OJ, and Ro-52.
Among the 16 patients, the mean age was 48 years, 13 (81%) were female, six required hospitalization for COVID-19, and one required supplemental oxygen acutely, but none had been critically ill or admitted to an intensive care unit, and none had comorbidity for neuromuscular disease. All complained of muscle fatigue during the acute infection as well as during long COVID, 13 had myalgias both during the acute infection and during long COVID, and 44% demonstrated Medical Research Council (MRC) grade 4 symmetrical shoulder abduction and hip flexion weakness.
Other symptoms present included dyspnea (88%), headache and cognitive complaints (81% each), and paresthesiae (69%). Only a single patient each had mildly elevated CK or expressed myositis TIF1 gamma autoantibody. Blood work otherwise was unremarkable. Nerve conduction studies were normal in all, and none had spontaneous activity on needle EMG. MUP analysis showed myopathic changes in 75%, with short duration MUPs, with or without decreased amplitude, an increased incidence of polyphasic potentials, and a myopathic interference pattern (full, with low amplitude). Histologically, all patients demonstrated muscle changes, including atrophy (38%), muscle regeneration (56%), mitochondrial changes (62%), inflammation (62%), and capillary findings (75%). Skeletal muscle is a major target of SARS-CoV-2, and post-COVID fatigue is associated with myopathy, which may be a consequence of a reduced energy supply resulting from mitochondrial changes documented on biopsy.
COMMENTARY
In addition to fatigue, cognitive and psychopathological disturbances occur in COVID-19 survivors, and these symptoms are associated with objective findings on brain magnetic resonance imaging (MRI) and electroencephalogram (EEG).1 Compared to healthy controls, two months following discharge from the hospital, patients with COVID-19 showed higher EEG regional current density and connectivity in the delta band using eLORETA (computer algorithm), and greater white matter hyperintensity load on MRI , which correlated with verbal memory deficit. Delta band connectivity and cognitive impairment improved over time, but patients with dysgeusia/hyposmia showed less memory improvement, and those with lower EEG delta band at baseline had worse cognitive function at follow-up. COVID-19 may leave a lasting pathology in both the central and peripheral nervous system.
REFERENCE
- Cecchetti G, Agosta F, Canu E, et al. Cognitive, EEG, and MRI features of COVID-19 survivors: A 10-month study. J Neurol 2022;269:3400-3412.
