Neuromuscular Medicine & COVID-19

This article reviews the neuromuscular complications associated with COVID-19, outlining the implications of the SARS-CoV-2 pandemic for individuals with existing neuromuscular disorders. These implications may be related to a speculative increased risk of infection and more severe disease in this population or to exacerbation of underlying symptoms by COVID-19 or the therapies used to treat it. We also discuss some of the challenges faced by people with neuromuscular disorders during this pandemic, irrespective of the COVID-19 status (Table 1) and offer guidance for care of those with neuromuscular conditions with a focus on managing neuromuscular respiratory failure.

Neuromuscular Complications of SARS-CoV-2

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy characterized by rapidly progressive symmetric limb weakness and areflexia. Respiratory failure occurs in 20% to 30% of people with GBS. The main modalities of therapy are the administration of intravenous immunoglobulin (IVIG) and plasma exchange (PLEX).¹ GBS has been described in association with SARS-CoV-2^2-7 and other coronaviruses.^8,9 The pathophysiology of GBS is thought to occur through molecular mimicry between viral epitopes and peripheral nerves, which stimulates an autoimmune driven bystander attack against myelin or axons. There is no robust evidence of SARS-CoV-2 direct viral invasion of peripheral nerves.¹⁰

Although there are multiple case reports, the frequency of GBS in association with SARS-CoV-2 infection is unclear. GBS seems to affect men and people more than age 65 more frequently.¹¹ The latency between the onset of COVID-19 symptoms and time to onset of GBS ranges from 2 days to 4 weeks,¹² although cases in which weakness preceded typical COVID-19 symptoms have been described.^7,11 The frequency of respiratory failure is slightly higher in COVID-19-associated GBS compared with more commonly described GBS, likely a reflection of the concurrent pulmonary disease.¹¹ With COVID-19-associated GBS, cerebrospinal fluid (CSF) analysis findings frequently show a typical albumin-cytological dissociation. Sensorimotor axonal, mixed axonal and demyelinating and demyelinating findings have also been observed.^12,13 Miller-Fisher syndrome, a variant of GBS, has also been reported in association with SARS- CoV-2 infection.^3,5,14 Most individuals who developed COVID-19–associated GBS have been treated with IVIG with variable outcomes. Interestingly, IVIG has been proposed as a potential treatment of COVID-19.¹⁵ It is important to use caution with IVIG in those with COVID-19 because of the thromboembolic side effects of IVIG¹⁴ and the thrombotic complications of COVID-19.¹⁶ The hemodynamic status in critically ill patients can be a limiting factor to the use of PLEX and also poses a significantly higher risk of exposure to healthcare providers. IVIG therefore remains the first line therapy for GBS.^11,17

Muscle Complications

Muscle complications have been commonly associated with coronavirus infections^18,19 and in the setting of severe sepsis and critical illness.²⁰ Postmortem pathology from 8 people who died from SARS infections found myofiber necrosis (50%) or myofiber atrophy (50%). Immune-mediated myopathy and superimposed steroid myopathy were postulated as the causes, respectively.

Myalgia occurs in 36% to 70% of people with COVID-19.^18,21,22 A retrospective study from Wuhan, China reported 11% of individuals who had COVID-19 had skeletal muscle injury, defined by a creatinine kinase elevation >200 U/L associated with myalgia, with a higher incidence in those with severe infection.²³ In a group of 814 individuals with COVID-19 in Spain, 9% had elevated creatinine kinase and 3% had evidence of myopathy.²⁴ A case series from Italy reported 6 individuals with COVID-19 and flaccid quadriplegia, intact facial strength and ocular movements, normal to mildly elevated creatinine kinase, and evidence of myopathic abnormalities on electrophysiologic testing. Although the authors noted these are likely finding of critical illness myopathy, they also postulated a direct effect of SARS-CoV-2 on muscle fibers, supported by finding of angiotensin converting enzyme (ACE) 2 receptors on myofibers.²⁵ Myositis as a manifestation of COVID-19 has been documented with MRI in a person with interstitial pneumonitis, suggesting an autoimmune-mediated mechanism.²⁶ Rhabdomyolysis has also been described with COVID-19 coronavirus disease.^8,27 The frequency ranges from 0.2% to 1.1%,²⁸ and appears to be more prevalent in those patients with severe disease.²⁴

Mononeuropathies

In a cohort of 83 patients admitted to hospital with acute respiratory distress syndrome (ARDS) and COVID-19, 14.5% had mononeuropathies (sometimes multiple), most commonly in the ulnar, radial, and sciatic nerves. This could be related to the use of prone positioning for management of ARDS, considering as 11 of 12 individuals with mononeuropathies had been placed in prone positions.²⁹ However, whether this finding is directly associated with the prone position, the viral infection, or the multiple comorbidities seen in this patient group is unknown.

Neuromuscular Junction Disorders

In a series of 3 cases of new onset acetylcholine receptor antibody-positive (antiAChR⁺) myasthenia gravis (MG) after COVID-19, symptoms included diplopia, ptosis, dysphagia, and generalized weakness 5 to 7 days after the onset of febrile illness. A decrement in repetitive nerve stimulation and elevated titers of antiAChR were found in all 3 individuals. The authors concluded these are cases of new-onset MG and proposed a molecular mimicry mechanism.³⁰ The direct relationship between COVID-19 and the development of MG, however, is debatable. It is possible these patients had subclinical MG that was unmasked by viral illness or the use of antibiotics or antimalarials. To our knowledge, there are no other cases described in the literature and further studies are needed to determine if there is a true association between SARS-CoV-2 infection and the development of neuromuscular junction disorders.

Critical Illness Acquired Weakness

In those who are critically ill with COVID-19, determining if weakness is a manifestation of the critical illness itself or the complications associated with SARS-CoV-2 can be challenging. Severe respiratory distress, systemic inflammatory response, multiorgan failure, sepsis, hyperglycemia, steroid use, and neuromuscular blockade, all of which are commonly seen in people with COVID-19,³¹ are known to be associated with intensive care unit (ICU)-acquired weakness (ICUAW).^20,39 In a large case series, neurologic complications were more common in severe COVID-19, suggesting that neuromuscular manifestations could be related, at least in part, to the critical illness.^23,24

A single-center study reported that people with COVID-19 who required mechanical ventilation had ICUAW upon awakening (72%), at ICU discharge (52%), and at the time of hospital discharge (27%). Those who developed ICUAW had longer times on ventilation and in the ICU, higher morning glucose levels, and received more dialysis, corticosteroids, sedatives, analgesics, and neuromuscular blockade.³²

Neuromuscular Complications of COVID-19 Therapies

Lopinavir and ritonavir, 2 protease inhibitors, were studied as potential therapeutic agents for COVID-19 because use had improved clinical outcomes in patients with SARS. Both, however, failed to show clinical improvement for COVID-19 compared with standard of care alone.³³ Lopinavir and ritonavir, used in combination with a statin and particularly in patients with impaired renal function, have been associated with toxic myopathy and rhabdomyolysis.^34,35

Hydroxychloroquine and chloroquine were proposed as possible therapeutic agents for COVID-19, although no clinical evidence for this was found and emergency authorization was withdrawn in the US. It is widely known that these 2 drugs have neuromuscular side effects, including toxic myopathy and neuropathy and exacerbation of myasthenia gravis.^18,36-38 At the beginning of the pandemic, azithromycin was proposed as a treatment option for COVID-19. Although this drug is not currently used to treat COVID-19, it has also been identified as a trigger for myasthenia exacerbations.³⁹

COVID-19 and Underlying Neuromuscular Disease

Potential Increased Infection and Severe Disease Risks

There are no strong data suggesting people with neuro-muscular weakness are especially susceptible to infection by SARS-CoV-2 or a potentially more severe course of COVID-19,⁴⁰ particularly in people with bulbar or respiratory muscle weakness or treated with immunosuppressive medications.^18,41 Table 2 summarizes the factors thought to be associated with higher risk of acquiring COVID-19 and developing a more severe infection. People who have advanced motor neuron disease, particularly if associated with dysphagia and respiratory failure requiring use of invasive or noninvasive ventilation or other comorbidities, and those with inherited neuropathies with kyphoscoliosis and reduced lung volumes are considered to have high risk. Individuals with myopathies, particularly those with respiratory muscle involvement such as X-linked muscular dystrophies or myotonic dystrophy are at significant risk.⁴² Within this group, those with cardiomyopathy and certain metabolic or mitochondrial myopathies are also considered at higher risk of SARS-CoV-2 infection and development of severe COVID-19, but also are at risk of developing rhabdomyolysis in the setting of any infection, fasting, and fevers.¹⁸

Immunosuppression is considered a risk factor for infection and severe disease thus treatment decisions should be individualized. Steroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus in general should be continued after discussion with the patient of potential risks and benefits related to COVID-19 and underlying neuromuscular disease.

Several organizations, such as the association of British neurologists in association with subspecialist advisory groups⁴² and the World Muscle Society⁴³ have proposed guidance for people with specific neurologic diseases during the COVID-19 pandemic. In general, physicians caring for patients with neuromuscular disorders should reinforce public health recommendations including practicing social distancing, wearing facemasks, and handwashing.⁴⁴ Hospitalization should be avoided if possible but not be delayed when necessary.⁴³

COVID-19 in People With Neuromuscular Disease

In a series of 5 patients with antibody positive-MG who were hospitalized with COVID-19, 3 had severe respiratory distress secondary to COVID-19, 2 required intubation, and 1 required significant supplemental oxygen. Extubation was successful for 1 of these patients, others required tracheostomy for prolonged intubation. IVIG treatment was used to treat 2 individuals, 1 of whom had a myasthenia exacerbation. IVIG treatment was given to 2 individuals, 1 for signs of myasthenia exacerbation. Tocilizumab for COVID-19 and hydroxychloroquine/azithromycin were used for 1 and 2 patients respectively.⁴⁴ Individualized management of MG and Lambert Eaton myasthenic syndrome is recommended by the International MG/COVID-19 expert panel.⁴⁶ Physicians should be aware of which medications may trigger MG exacerbation, such antimalarial drugs (hydroxychloroquine and chloroquine) and aminoglycosides.^45,46 If these medications are used, patients should be carefully monitored.

Meta-analysis showed that the administration of systemic corticosteroids was associated with lower 28-day all-cause mortality in patients with COVID-19.⁴⁷ Although there are no clear recommendations for steroid use, specifically in the context of neuromuscular diseases, individuals already using chronic steroids may benefit from stress dose steroids, to avoid adrenal insufficiency and decrease overall mortality of COVID-19.^46,47 Treatment with other immunosuppressants may need to be delayed, particularly B-cell depleting agents (See also Neuroimmunomodulation and COVID-19 in this issue).^18,46

Living With Neuromuscular Disease In a Pandemic

The SARS-CoV-2 pandemic has greatly affected individuals with neuromuscular conditions, irrespective of their exposure risk or COVID-19 status and has led to an unprecedented change in neuromuscular medicine. Use of teleneurology, which despite allowing patients to continue safely receiving care while minimizing exposure risks and conserving personal protective equipment,⁴⁸ may be associated with delays in diagnosis and treatments. Al though some aspects of the neurologic examination can be performed virtually, assessment of the muscle tone and deep tendon reflexes cannot. This can lead to delays in the diagnosis of conditions such as amyotrophic lateral sclerosis, which relies on the presence of upper and lower motor neuron findings.⁴⁹ Use of electrodiagnostic testing poses an exposure risk for the healthcare provider owing to long duration of testing, the need for direct patient contact, and potential for contamination of the equipment.⁵⁰ The use of spirometry for monitoring disease progression and the availability of multidisciplinary care teams may be limited because of concern for increased risk of disease spread.⁴⁹

Patients with dysimmune neuropathies may also face additional challenges. Difficulties inherent to a virtual examination and limited access to electrodiagnostic studies may lead to delays in diagnosis and treatment, which can worsen prognosis and increase axonal loss in demyelinating neuropathies. Other considerations include the initiation of immunotherapy, which theoretically can increase the risk of infections, and the increased exposure risk of infusions or PLEX.⁵¹

Isolation requirements may also affect treatment regimens for those with neuromuscular diseases. The ability for patients to get their medications from the pharmacy and undergo therapies typically administered in hospital settings (eg, infusions or PLEX), may be difficult during these unprecedented times. We recommend writing for 90-day supply prescriptions to avoid frequent visits to the pharmacies, and if the patient is on an infusion therapy, switching to home infusion or subcutaneous IVIG if possible, to minimize exposure risks.

Neuromuscular Respiratory Failure

In COVID-19, secondary hypoxemic respiratory failure is common,⁵² but the course of the illness may also be magnified by neuromuscular respiratory failure, either as a result of exacerbation of underlying neuromuscular disease or a de novo neuromuscular complication. The diagnosis can be particularly challenging in critically ill patients; determining whether the respiratory failure is caused by the viral disease, represents respiratory muscle weakness from an underlying neuromuscular disorder, or is the development of a new neuromuscular disorder may be difficult. Certainly, neuromuscular weakness should be considered with prolonged mechanical ventilation and ventilator wean failure.

There are insufficient data to guide management of people with neuromuscular diseases who develop COVID-19 and those with moderate-to-severe neuromuscular disorders as potentially high risk for a severe course of COVID-19 is important, because these patients will require closer monitoring for development of respiratory muscle weakness.⁴⁰

Lung volumes and maximal inspiratory effort are the standard for evaluation of neuromuscular respiratory failure.⁵³ These are aerosolizing procedures, however, and therefore are not recommended to minimize the risk of transmission. In intubated patients, spontaneous tidal volumes <5 mL/kg can suggest neuromuscular respiratory weakness.⁴⁵ Hypercapnia, not typically associated with COVID-19, should raise concern for neuromuscular weakness.⁵⁴ The appearance of basal atelectasis can indicate diaphragmatic weakness and should prompt investigation of neuromuscular disorder as well.⁵⁵

Those with neuromuscular disorders are at high risk of mechanical ventilator dependence.⁴⁰ Noninvasive ventilation is typically the first-line intervention for patients with chronic neuromuscular disorders to delay intubation, improve symptoms, quality of life and survival.⁵³ The data on the use of high-flow nasal canula and non-invasive ventilation in patients with COVID-19 are limited. Early during the pandemic, some experts suggested avoidance of noninvasive ventilation modalities in COVID-19 because of the risk of transmission for the healthcare workers associated with aerosol-generating procedures.^56,57 A recently published meta-analysis suggests noninvasive techniques decrease the need for invasive mechanical ventilation and probably reduce mortality in patients with COVID-19, while still carrying potential for increased exposure risk to healthcare workers.⁵⁷ Some modified noninvasive ventilation interfaces have been proposed to minimize the risk by providing a more closed ventilation system,⁴⁰ however delaying intubation until the patient decompensates is potentially harmful and poses an additional risk for the healthcare workers.

Prone positioning has been used in patients with ARDS to improve oxygenation, and evidence suggests that it is helpful in patients with COVID-19.⁵⁸ However, this position can be challenging for patients with neuromuscular disorders, particularly in those with kyphoscoliosis and bulbar weakness.⁴⁰ The use of depolarizing muscle relaxants such as succinylcholine is discouraged owing to the risk of severe hyperkalemia and rhabdomyolysis.^54,59 Nondepolarizing agents should be used with caution in myotonic and neuromuscular junction disorders, spinal muscular atrophy, and immune-mediated neuropathies.⁵⁴

Conclusions

Neuromuscular complications have been associated with SARS-CoV-2 infection, including GBS, myopathy, rhabdomyolysis and ICUAW. Even though definitive evidence is lacking, neuromuscular manifestations may be related either to direct viral effect, or indirectly due to cytokine release syndrome, para- or post-infectious dysimmune mechanisms, critical illness, or as side effects of pharmacologic treatments.

Additionally, the COVID-19 pandemic has had multiple implications for patients with known neuromuscular diseases including the possibility of a higher risk of infection and higher severity of disease, and possible exacerbation of an underlying neuromuscular condition associated with the infection itself or its treatment. Neurologists need to remain vigilant and counsel patients on risk for infection and exacerbation of known disease. Other challenges among those with neuromuscular diseases include delay in diagnosis and difficulties accessing treatments caused by social distancing measures. In anyone with a neuromuscular disorder who develops COVID-19, close monitoring and early recognition and management of neuromuscular weakness is crucial in order to improve neurologic outcomes. Existing guidelines are based on expert consensus and more evidence is required.