Edited by: Jordi A. Matias-Guiu, Hospital Clínico San Carlos, Spain
Reviewed by: Fabiola De Marchi, AOU Maggiore della Carità, Italy; Raffaele Dubbioso, Federico II University Hospital, Italy; Juan Francisco Vázquez Costa, El Instituto de Investigación Médica del Hospital La Fe (HULAFE), Spain
This article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology
†ORCID: Bernat Bertran Recasens
Miguel Angel Rubio
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The COVID-19 pandemic has pushed health systems to their limit and forced readjustment of standards of care for different pathologies. Management of neuromuscular diseases becomes a challenge since most of them are chronic, disabling, progressive, and/or require immunosuppressive drugs. There are three main aspects of COVID-19 that affect neuromuscular diseases care. The first one relates to how SARS-CoV2 directly affects different neuromuscular pathologies. Respiratory weakness, as seen in myasthenia gravis, amyotrophic lateral sclerosis, and myopathies, and the use of immunomodulatory drugs (Myasthenia Gravis and Chronic Inflammatory Demyelinating Polyneuropathy) make this group of patients potentially more vulnerable. Secondly, safety measures also affect proper care, limiting care continuity, and physical rehabilitation (one of the essential aspects of myopathies treatment). Telemedicine can partially solve the problem allowing for a continuum of close care, avoiding unnecessary visits, and even guaranteeing the attention of professionals from tertiary care centers. However, one of the crucial steps in neuromuscular diseases is diagnosis, and in most scenarios, more than one face-to-face visit is needed. Lastly, the global COVID-19 situation will also have an economic impact on patients and their families. This situation is of particular concern given that neuromuscular diseases already present difficulties due to the scarcity of resources in terms of public healthcare and research.
The global pandemic situation due to COVID-19 has led to restructuring the management of different diseases. Beyond the transitory periods of total confinement that have occurred in most countries, the current situation entails a restriction of mobility due to the risk of infection of a disease for which, at the time, there is no curative treatment or vaccine. This threat has led to changes in healthcare paradigm: limited access to health centers, reconsideration of the gold standard of excellence in disease management, a thorough evaluation of the risk/benefit balance of specific interventions in the face of drug-disease interactions for a little-known infection and re-thinking of clinical trial procedures to ensure remote participation (from enrollment, dispensing of medication, and follow-up).
Neuromuscular diseases (from now on, NMD) are a heterogeneous group in terms of etiology, genetics, physiopathology, and treatments, that accounts from 2.8 to 18% of the referrals in the neurology department (
In this paper we will review different aspects where NMDs are affected by this scenario.
In many countries, cases of neurological disease, induced by the viral infection itself or by the secondary inflammatory reaction, have been reported. These include stroke, encephalopathy, myelitis, and peripheral nervous system diseases (
Regarding NMD, cases of isolated neuropathies of cranial nerves, acute paralysis similar to Guillain-Barré syndrome (GBS), Miller Fisher syndrome, and increased creatine kinase (CK) have been reported.
On a pathophysiological basis, GBS is considered an immune-mediated disease, but parainfectious cases have been seen during the COVID-19 pandemic. Thus, it is possible that the virus or the inflammation secondary to it damages the nerve (
CK elevation, in some cases, appears to be secondary to myositis of probable autoimmune etiology (autoimmune necrotizing myositis: NAM), although direct damage from the virus cannot be ruled out since skeletal muscle cells also express ACE2 (
Due to the large number of patients requiring admission to the ICU due to COVID-19 infection, several cases of critical illness myopathy (CIM) (
Finally, to date, only 3 possible cases of myasthenia gravis debut just after COVID-19 have been described (
Thus, since current data seem to indicate that COVID-19 infection can induce not only GBS but also other autoimmune diseases, it is essential to pay attention to different neurological symptoms in those patients.
In the literature and from our own experience, few patients with NMD have presented infection. This could be because they are aware of risks and took preventive measures, but also suggest that they are not at an increased risk of infection or severe illness. Even though certain patients with NMD who require immunosuppressive treatment or ventilatory support have a higher risk of infections, the risk of COVID-19 is not fully known and has been assumed by extrapolation. Thus, it seems logical to think that the poor prognostic factors are the same as the general population (age, obesity, cardiovascular risk factors, chronic high-dose corticosteroid treatment) (
There is little data regarding patients with NMD and COVID-19 infection. Cases of patients with myasthenia gravis who have had a SARS-CoV2 infection with a favorable evolution have been reported despite the fact that some have had to change their immunosuppressive treatment or have received treatment with hydroxychloroquine and/or antivirals (
There are not many reported cases of patients with other neuromuscular diseases such as immune-mediated neuropathies or ALS, and therefore, although always subject to a bias, could indicate that they do not seem to have a more severe infection or higher mortality.
Special caution must be focused in the use of certain therapies for the infection in NMD patients. During the pandemic, due to the need for urgent therapy, drugs that were believed to be effective (e.g., chloroquine or hydroxychloroquine, azithromycin, antivirals, dexamethasone and IL- inhibitors, etc.) have been administered. Actually in the first clinical studies conducted, only remdesivir and dexamethasone are effective (
Azithromycin and chloroquine should be avoided, specifically those with MG, as both have been associated with a worsening of the disease (
Regarding remdesivir, although some protease inhibitors had been associated with polyneuropathy, due to the short duration of treatment, only a few cases of toxic myopathy have been reported. In the case of MG, there is no evidence that remdesivir can induce clinical worsening (
Patients with COVID-19 have also an increased risk of thromboembolic events and therefore anticoagulant prophylaxis should be considered in patients that require also IVIG due to their underlying disease.
Finally, respiratory management has to be similar to the general population, taking into account the greater risk of respiratory muscles dysfunction.
One common problem of many NMD is the diagnosis delay and electrodiagnostic testing (EDX) plays an essential role. The restricted access to health centers has also limited the performance of EDX studies, as they require close contact with the patient over a prolonged period, and therefore could lead to further delay in diagnosis. Priority measures to ensure adequate safety in the studies are the use of personal protective equipment (PPE) and N95 masks, and the use of checklist of symptoms the day before the study. In cases of high-risk studies (i.e., facial studies, laryngeal electromyography), it is recommended to request polymerase chain reaction (PCR) studies on nasopharyngeal samples 24–48 h in advance (
Immunosuppressive treatment (including thymectomy in myasthenia gravis—MG) increases the risk of infections in patients with MG, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), or inflammatory myopathies. MG patients had an increased risk of infection of 39% (
In the particular case of COVID-19, as mentioned above, there is little data of real risk of infection in NMD patients. However, several cohorts of patients with autoimmune diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis, or optic neuromyelitis show that treatment with immunosuppressants does not increase the risk of suffering from COVID-19 and neither present a more severe form of infection (
However, since current data corresponds to a small number of patients, it seems reasonable to continue with the indications of the expert groups; individualize decisions regarding the patient's situation or comorbidities, modify the immunosuppressive drug to one with a better safety profile (i.e., intravenous immunoglobulins, plasmapheresis, or steroids), space out the doses or even postpone the initiation of the medication in cases of stable patients or those with mild symptoms (
Long term corticosteroids is the drug that increase most the risk of infections (20–50%) (
Plasmapheresis and intravenous immunoglobulins (IVIG) do not appear to increase the risk of infections, probably because they are often given in short courses, although long-term effect is unknown (
Prada et al., reported a cohort of 196 patients affected by immune-mediated neuromuscular diseases, with 0.6% laboratory-confirmed COVID-19 infection in those receiving IVIG or subcutaneous immunoglobulins, and 6.4% confirmed infection in those with other immunosuppressive treatment or no treatment. This could suggest a protective effect of chronic immunoglobulin therapy in the risk of COVID-19 infection. However, more studies are warranted to confirm this (
In patients with DMD/BMD, it is recommended to maintain the current treatment, including steroid therapy and oligonucleotide treatments (
Nowadays, several pharmacological treatments improve survival and motor skills of SMA patients. These treatments are nusinersen and gene therapy with Onasemnogene abeparvovec-xioi. Both have improved the quality of life, motor function and increased survival; and although these treatments are new, they should never be considered as elective or expendable. The delay of their administration should be avoided whenever possible, assessing the risks on an individual basis. In the case of nusinersen (intrathecal administration with a loading dose of 4 doses the first 2 months and then every 4 months), it has been reported that the delay of 1 month without medication leads to a 10% reduction of the drug in CSF. If there is a delay in administration, the schedule should not be readjusted, but rather follow initial proposed calendar to ensure optimal intrathecal medication levels (
Regarding other immunomodulatory treatments (mycophenolate mofetil, cyclophosphamide, azathioprine, etc.), the increased risk of infection is similar to corticosteroids (
Due to the fact that patients with NMD present frequent respiratory infections, it is important to do a close follow-up (by professionals of the multidisciplinary Unit as well as from primary care). As for household measures, ventilation devices, unless equipped with bacterial/viral filters (HEPA), as well as airway clearance devices (cough assist, nebulization), increase the risk of particle dispersion into the environment. Despite this, patients and caregivers should be warned not to modify the ventilation schedule to avoid errors. If possible, it is recommended to convert the tubing and mask circuitry to a closed system by using both a double-lumen tube with a viral/bacterial filter and a non-vented full-face mask to restrict viral spread (
During confinement and, currently, due to social distancing measures, the population is doing less physical activity (
A brief summary of the considerations to be taken into account in the management of the different NMDs is shown in
Neuromuscular disorders management in Covid-19 era.
- Encourage telematics assessments |
The status of clinical trials in NMD has been impaired during the pandemic situation with difficulties with new inclusions, treatment supplies and monitoring. Data reported from the NEALS (
Thus, in a situation in which the recruitment of patients with rare diseases is already complicated (
Telematic assessment of progression could evaluate more frequently and in daily environment for the patient and in turn could even reduce the duration and the number of subjects needed in clinical trials.
Finally, it is essential to prevent selection bias toward patients with ease in remote monitoring and more familiar with technology.
One of many faces of catastrophic COVID-19 situation is its social, occupational and economic impact in NMD patients and their families. For example, the estimation of the annual cost of an ALS patient is approximately 50,000 euros (
Other consequences are the increase in anxiety and feelings of loneliness that have been reported in NMD patients and their relatives/caregivers during confinement (
It is essential not to forget the psychological support for the patient, his family and the caregivers, even if it is remotely. As an example, DMD/BMD boys may have a spectrum of behavioral disorders, including some degree of intellectual disability and anxiety problems which will require close psychological follow-up.
Finally, because research is currently focused on finding therapeutic strategies for COVID-19, there is a redirection of interest (and thus funding) which may lead to a loss of already fragile research funding in NMD.
In situations with a high healthcare burden, it is important not to discriminate patients with chronic and rare diseases, from a therapeutic point of view. ICU doctors should discuss the case with the patient's permanent medical practitioner and/or expert center to understand the disease history and treatment plan of the patient (
Multiple clinical trials are currently underway to develop an effective vaccine against COVID-19. There are more than 120 vaccine candidates but neither uses live attenuated virus (
The current situation has pushed the limits of telehealth in NMDs, both in terms of implementation in medical centers and in terms of acceptability and skepticism by patients and health professionals. The gold standard of healthcare is multidisciplinary consultation, but this often involves drawbacks since patients and their families might spend many hours traveling and staying at the hospital with the fatigue and burden that this involves. Moreover, as the disease progresses and the problems of mobility and fatigue increase it becomes more challenging to travel and, conversely, contact with medical services becomes more necessary. Tele-health services must be conceived as an additional complimentary activity to face-to-face visits. Therefore, remote assistance is an essential opportunity for NMDs, even more so in this current pandemic situation. A survey of NEALS (North East ALS Consortium) to know the impact of the COVID-19 situation on ALS patient's healthcare and research (
In addition, the telehealth model allows the patients to hold the consultation in familiar environments, making it more comfortable to them, maintaining the link with multidisciplinary units even in more advanced stages (
Nowadays, we know that specific functional scales or aspects of physical examination can be performed telematically with strong correlation with their equivalents in face-to-face visits performed by health professionals (
Respiratory function monitoring is also essential since provide prognosis information, indicates proper timing of non-invasive ventilation, and are a crucial key of inclusion criteria of most clinical trials. However, there is a risk of producing aerosols during the examination. There is evidence of viability of home respiratory screening devices with a reasonable degree of correlation with in-hospital respiratory screening and hence its use must be encouraged. Several NMD finally will require the use of home mechanical ventilation. In many cases, it is possible to control the parameters from the hospital, avoiding unnecessary displacements.
Living with a NMD is a challenge not only for patients but for their caregivers and families, and COVID-19 pandemic situation represents even a greater stress test.
NMD patients are a group at risk, either because of respiratory affectation or their condition of immunosuppression. For this reason, it is important to individualize the management of NMD patients, considering the interventions and treatments individually and taking into account the risk of going to the hospital and the risk of not receiving proper attention.
On the other hand, telemedicine has suffered an accelerated expansion, representing an opportunity to improve clinical care management and research. Ideally, a combination of telematics and face-to-face visits would create a hybrid model that would be defined depending on the evolutionary moment of each patient.
The gold standard in the management of NMDs is the attention in multidisciplinary units, where holistic and global management of the patient's needs is given, as well as research and clinical trials are performed. Multidisciplinary units must continue to commit to excellence in care, but now in a remote scenario in which the wellness of the patient must still be the focus even in these uncertain times.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
All authors contributed to the study conception and design. The first draft of the manuscript was written by MR and BB commented on previous versions of the manuscript. All authors read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.