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INVITED ARTICLE
COVID-19 and neuromuscular disorders
Amanda C. Guidon, MD, and Anthony A. Amato, MD
Neurology®2020;94:1-11. doi:10.1212/WNL.0000000000009566
Correspondence
Dr. Guidon
aguidon@partners.org
or Dr. Amato
aamato@bwh.harvard.edu
Abstract
The coronavirus 2019 (COVID-19) pandemic has potential to disproportionately and severely
affect patients with neuromuscular disorders. In a short period of time, it has already caused
reorganization of neuromuscular clinical care delivery and education, which will likely have
lasting effects on the field. This article reviews (1) potential neuromuscular complications of
COVID-19, (2) assessment and mitigation of COVID-19-related risk for patients with pre-
existing neuromuscular disease, (3) guidance for management of immunosuppressive and
immunomodulatory therapies, (4) practical guidance regarding neuromuscular care delivery,
telemedicine, and education, and (5) effect on neuromuscular research. We outline key
unanswered clinical questions and highlight the need for team-based and interspecialty col-
laboration. Primary goals of clinical research during this time are to develop evidence-based best
practices and to minimize morbidity and mortality related to COVID-19 for patients with
neuromuscular disorders.
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From the Division of Neuromuscular Medicine, Department of Neurol ogy, Massachusetts General Hospit al (A.C.G.), and Division of Neu romuscular Medicine, Department of
Neurology, Brigham and Woman’s Hospital (A.A.A.), Harvard Medical School, Bost on, MA.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Copyright © 2020 American Academy of Neurology 1
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Published Ahead of Print on May 5, 2020 as 10.1212/WNL.0000000000009566
Whereas several human coronaviruses, including hCoV-229E,
OC43, NL63, and HKU1, are associated with mild respiratory
symptoms, more severe coronavirus infections have appeared
over the last 2 decades. These newer coronavirus infections
can result in severe acute respiratory syndrome (SARS) and
include Middle East respiratory syndrome (MERS) and most
recently coronavirus disease 2019 (COVID-19). These severe
coronavirus infections have been associated with headache,
seizures, and stroke, but literature regarding neuromuscular
complications is scant. It is possible that associated neuro-
muscular disorders (NMDs) have occurred previously but
have been overshadowed by systemic manifestations.
During the current COVID-19 pandemic, we need to be vigi-
lant for neuromuscular complications that may be directly or
indirectly related to coronavirus infection (table 1). We should
also plan to adjust our clinical practices to prevent the spread of
COVID-19 and to care for patients with NMDs and the
complications they experience during this time. Finally, since
the effects of the pandemic are expected to persist for longer
than several weeks, we will want to adapt neuromuscular ed-
ucational training programs. This article reviews the current
state of knowledge and practice in these 3 areas, provides
guidance, and raises clinical questions for future investigation.
Assessment of overall risk from
COVID-19 in patients with NMD
Our current discussions with patients center upon risk and risk
mitigation. Risks will depend upon the specific NMD, other
comorbidities, age, and what immunotherapies the patients
may be receiving (table 2). We do not expect the majority of
patients, even in the higher risk categories, to have severe
complications of COVID-19. We also can reassure patients that
NMDs that spare swallowing and breathing muscles and where
treatment does not involve immunosuppression are not con-
sidered to be high risk in COVID-19. On the other hand,
patients may be in an overall higher-risk category due to other
demographic factors or health considerations. At this time, the
primary advice for all patients and their caregivers is to reduce
the risk of contracting the virus through social distancing,
handwashing, and stricter isolation in patients who are most at
risk. Internationally, neurologic (International MG/COVID
Working Group), rheumatologic (COVID-19 Global Rheu-
matology Alliance), and gastroenterologic (Surveillance Epi-
demiology of Coronavirus [COVID-19] Under Research
Exclusion [SECURE-IBD]) groups have begun to publish
consensus guidance statements to address clinical care and risk
mitigation during COVID-19 for specific patient populations,
with plans for updates as outcomes data become available.
Risk of infection causing a new NMD
There is a known risk of Guillain-Barr´e syndrome (GBS)
attributable to viral infections (e.g., influenza, H1N1, Zika,
Epstein-Barr virus). The rationale is that molecular mimicry
exists between specific viral proteins and proteins on pe-
ripheral nerves (e.g., gangliosides) leading to an innocent
bystander attack against the myelin or axon of peripheral
nerves. There is 1 reported case of GBS in association with
COVID-19; however, direct causality is uncertain.
1
GBS has
been reported rarely with other coronavirus infections.
2,3
There is no current evidence of direct viral invasion with in-
flammation and degeneration of motor neurons and peripheral
nerves as seen in some viral infections (e.g., poliovirus, entero-
virusD68,WestNile,herpeszoster, cytomegalovirus). In the
literature, there is 1 report of a 3-year-old child with acute flaccid
paralysiswhowascoinfectedwith 2 coronaviruses (HCoV 229E
and OC43).
4
However, the diagnosis was questionable; the child
had normal EMG and nerve conduction studies 1 and 3 weeks
after onset, normal CSF, and normal brain and spinal cord MRI.
Nevertheless, it is possible that the virus may be neurotropic and
directly infect and damage motor neurons and peripheral nerves.
Coronavirus infections may be associated with myopathies. In
recently published studies of COVID-19 in China, myalgia or
fatigue affected 44%–70% of hospitalized patients and in-
creased creatine kinase (CK) was present in up to 33% of
admitted patients.
5,6
No additional workup such as EMG,
muscle imaging, or histopathology was reported. Likewise, as
many as a third of patients infected with other coronavirus
infections manifested with myalgias and elevated CKs
7,8
and
rhabdomyolysis.
9,10
This suggests that coronavirus infections
may cause a viral myositis. Very sick patients with coronavirus
develop critical illness myopathy or polyneuropathy.
10–13
A
risk factor for developing critical illness myopathy is use of
nondepolarizing neuromuscular blocking agents. Neverthe-
less, this has not been reported in patients with other coro-
navirus receiving short courses of these medications.
14
Weakness related to type 2 muscle fiber atrophy from disuse
typically presents after 1 week in ill patients who are bedrid-
den and therefore will be a consideration in patients with
COVID-19.
Glossary
AANEM = American Academy of Neuromuscular and Electrodiagnostic Medicine; ALS = amyotrophic lateral sclerosis; CK =
creatine kinase; COVID-19 = coronavirus disease 2019; FcRn = neonatal Fc receptor; FDA = Food and Drug Administration;
GBS = Guillain-Barr´e syndrome; IST = immunosuppressive therapy; MERS = Middle East respiratory syndrome; MG =
myasthenia gravis; NMD = neuromuscular disorder; SARS = severe acute respiratory syndrome; SARS-CoV-2 = severe acute
respiratory syndrome coronavirus 2.
2Neurology | Volume 94, Number 22 | June 2, 2020 Neurology.org/N
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Risk of COVID-19 infection
exacerbating known or unmasking
previously unrecognized NMDs
There are no data regarding magnitude of risk of exacer-
bation due to COVID-19 or prior coronaviruses for rare
NMDs. Infection is a common trigger of exacerbation or
disease progression in many NMDs, both inherited and
immune-mediated. For example, infection has been the
leading cause of exacerbation of myasthenia gravis (MG) in
a retrospective study.
15
As such, we expect that we will
observe both increased rates of disease worsening and an
increased incidence of new presentations during the
COVID-19 pandemic.
Considerations for exacerbation in acquired and inherited
disorders are primarily related to degree of baseline cardiac
and respiratory dysfunction, bulbar weakness, underlying
pathophysiology of disease, and related comorbid con-
ditions. An updated review of consideration by disease has
been compiled.
16
Patients with motor neuron disease (e.g.,
amyotrophic lateral sclerosis [ALS], spinal muscular at-
rophy) and hereditary neuropathies with ventilatory
muscle involvement may be particularly susceptible to
infection. Those with metabolic myopathies (e.g., lipid
storage diseases and mitochondrial disorders) are at in-
creased risk of rhabdomyolysis with fever, infection, or
fasting (attributable to loss of appetite). In addition,
patients with various muscular dystrophies, including
myotonic dystrophy, and metabolic diseases (e.g., Pompe
disease) who have ventilatory muscle weakness or car-
diomyopathy are likely at increased risk for severe
COVID-19. Patients who develop COVID-19 may not
return to their prior baseline.
Risks of immunosuppressant and
immunomodulating therapies in
patients with autoimmune NMDs
Patients with NMDs who use immunosuppressive therapies
(ISTs) are likely at increased risk of contracting COVID-19 or
having a more severe course of the virus. This risk is variable
even among patients on ISTs and with the same disease (table
3). Published experience from Wuhan, China, to date has not
examined neuromuscular comorbidities or patients on
ISTs.
5,6
In looking to similar immunocompromised pop-
ulations where there has been work published, recent data
suggest a trend toward increased incidence rate of COVID-19
and increased rate of severe disease in patients with cancer
and cancer survivors in China.
17
As a result, the authors made
recommendations for this population that may be applicable
to immunocompromised patients with NMD at highest risk:
(1) intentional postponing of adjuvant chemotherapy or
elective surgery for stable cancer in endemic areas, (2)
stronger personal protection provisions for patients with
cancer or cancer survivors, and (3) consideration of more
intensive surveillance or treatment when patients with cancer
are infected with SARS coronavirus 2 (SARS-CoV-2), espe-
cially in older patients or those with other comorbidities.
17
In terms of managing ISTs,consensus statements are emerging
to guide patients and clinicians until we have data published on
outcomes.
18
Most outpatients without infection should con-
tinue to take their medications, with instructions to call their
neurologist and temporarily hold the medication if they de-
velop symptoms of infection. In some cases, after discussion
of risk and benefit between the patient and provider, some
patients may be able to continue ISTs or be treated with
adifferent, less immunosuppressive option. This involves
Table 1 Potential neuromuscular complications of coronavirus 2019 (COVID-19)
1. Risk of infection causing a new NMD
a. Guillain-Barr´
e syndrome
b. Myositis
c. Critical illness myopathy or polyneuropathy
2. Risk of infection exacerbating known or unmasking previously unrecognized NMD
a. Autoimmune disorders such as CIDP, MADSAM, MMN, MG, LEMS, myositis
b. Degenerative disorders such as ALS, SMA, hereditary neuropathies, muscular dystrophies, congenital myopathies, mitochondrial myopathies, metabolic
myopathies, and others
3. Risks of immunosuppressant/immunomodulating therapies in patients with autoimmune NMD
a. Increased risk of COVID-19 infection and more severe disease
b. Increased risks and severity of other infections in patients with COVID-19 in the setting of NMD treated with certain immunotherapies
c. Immunotherapies might make vaccines less effective
4. Risks of treatments for COVID-19
a. Hydroxychloroquine and chloroquine can cause a toxic neuropathy and myopathy
b. Antiviral treatments: lopinavir/ritonavir, remdesivir, others
5. Risks of vaccinations
a. Possible inflammatory neuropathy (e.g., Guillain-Barr´
e syndrome, plexitis, mononeuritis)
Abbreviations: ALS = amyotrophic lateral sclerosis; CIDP = chronic inflammatory demyelinating polyneuropathy; LEMS = Lambert-Eaton myasthenic syn-
drome; MADSAM = multifocal acquired demyelinating sensory and motor neuropathy; MG = myasthenia gravis; MMN = multifocal motor neuropathy; NMD =
neuromuscular disorder; SMA = spinal muscular atrophy.
Neurology.org/N Neurology | Volume 94, Number 22 | June 2, 2020 3
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
a discussion of potential risks and benefits related to COVID-
19 and underlying neuromuscular disease when adjusting doses
or stopping immunosuppressant or immunomodulatory ther-
apies. Examples of risk include age, comorbid medical prob-
lems, geographic location, household or occupational risk
factors, and underlying neuromuscular disease severity.
Avoiding abrupt cessation of a medication that may precipitate
aflare of the underlying condition, which could in turn ne-
cessitate higher doses of prednisone, IST, or hospital admis-
sion, is the goal. Holding or suspending prednisone is not
recommended.
Some therapies are not expected to increase the risk of
COVID-19 or severe disease, including immunoglobulin
therapy (intravenous or subcutaneous), complement in-
hibitor therapy (e.g., eculizumab), therapeutic plasma ex-
change, or neonatal Fc receptor (FcRn) antagonists (various
forms are now being assessed in clinical research trials). Re-
liance on infusion centers may increase the overall risks for
patients, so switching to home visits with or without visiting
nurses for these therapies (visiting nurses are not necessary
after training for subcutaneous infusions) may mitigate
but not eliminate the risks. Therefore, requirement for IV
administration needs to be taken into risk/benefit discussions.
Importantly, guidance statements are changing and risks and
benefits of IST may change over time. Check-ins from high-
risk patients with changes in circumstances are appropriate. At
this time, for most patients, we are working primarily on
education regarding risk reduction. Infrequently, we make
preemptive COVID-19–related medication adjustments in
dosing or drug. In the future, vaccination or knowledge that
a patient has developed immunity to COVID-19 could be
incorporated into risk stratification and treatment decisions
regarding further IST.
19
Additional specific guidance for patients with NMDs based on
drug regimen is outlined in table 4. For all patients, steps
towards efficient prescribing to promote social distancing by
minimizing trips to pharmacies is appropriate. This may in-
clude refilling prescriptions for 90 days and encouraging de-
livery through mail order pharmacies. Weighing benefits of
transitioning from infusion centers to home infusions will
depend on patients’overall COVID-19 risk, transportation
needs, geography/local resources, and insurance coverage.
The relative risk of COVID-19 at hospital-based centers
compared to home infusion is unknown.
Table 2 Coronavirus 2019 (COVID-19) risk by neuromuscular disease
Disorder
Level of risk for COVID-19 or having severe
COVID-19 disease course Comments
Motor neuron disease Moderate/high Higher risk related to more advanced disease, use of ventilator or noninvasive
ventilation, dysphagia, comorbid diseases
Neuropathies
Inherited All levels Low with uncomplicated neuropathy
High with autonomic involvement or cardiac involvement (e.g., amyloidosis),
scoliosis with respiratory involvement
Immune-mediated All levels Related to degree of immunosuppressive therapy and respiratory/bulbar
weakness
Idiopathic,
nutritional, toxic
Low No appreciable increased risks
NMJ
LEMS All levels Consider underlying malignancy/chemotherapy
gMG All levels Risk related to bulbar and respiratory weakness, immunosuppressive therapy
CMS All levels Adult-onset, stable for >10 years without bulbar or respiratory weakness likely
low risk
Actual or possible (based on mutation) bulbar or respiratory muscle weakness
higher risk
Muscle
Inherited All levels Risk related to bulbar and respiratory weakness
Related disease-specific comorbidities (i.e., diabetes, cardiac disease)
influences risk
Inflammatory/
immune-
mediated
All levels IST determines risk
Abbreviations: CMS = congenital myasthenic syndromes; gMG = generalized myasthenia gravis; IST = immunosuppressive therapy; LEMS = Lambert-Eaton
myasthenic syndrome; NMJ = neuromuscular junction.
4Neurology | Volume 94, Number 22 | June 2, 2020 Neurology.org/N
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COVID-19 vaccine efficacy and access
in NMDs
Robust COVID-19 vaccine development programs with
multiple candidates have launched.
19–21
Typically a years-
long process, the timeline has been accelerated. Multiple
types of vaccine candidates are in preclinical development.
Two that are currently in phase I clinical trials are RNA
and nonreplicating vector vaccines.
21
To our knowledge,
there are no live virus vaccines under consideration. This is
important for immunosuppressed patients as live vaccines
must be avoided. Whether immunosuppressive or immu-
nomodulatory therapy will make the COVID-19 vaccines
less effective is highly relevant for patients with NMDs and
will need study. Recommendations for timing of vaccine
administration with relation to dosing schedule of immu-
nosuppressive or immunomodulatory therapies, including
IV immunoglobulin, therapeutic plasma exchange, FcRn
antagonists, and B-cell-depleting therapies, will be needed
to maximize protective benefits. In addition, challenges
of adequate vaccine supply during a pandemic and fair al-
location based on risk are being addressed.
21,22
We antic-
ipate that data provided by disease-specific neuromuscular
groups during this time on risk for and outcomes of
COVID-19 in these groups will greatly inform risk strat-
ifications in the future. Pragmatically, we will also need to
consider how patients with NMD receiving telemedicine
or who are self-isolating will receive vaccination, when
available.
Management of patients with NMD
who develop COVID-19
At this time, there are no neuromuscular-specific recom-
mendations for patients who contract COVID-19 and addi-
tional outcome data are needed. Monitoring moderate to high
risk patients with NMDs closely for the possibility of more
rapid decline in respiratory function or for worsening of their
underlying neuromuscular disease is recommended. Tele-
health applications could be considered in the future for this
remote monitoring. Corticosteroids are not routinely given
for treatment of COVID-19 but are sometimes used in sepsis.
A discussion of the potential pros and cons of additional
corticosteroids is available.
23
Patients with NMD already on
corticosteroids may require stress doses. Typically, other
immunosuppression is held or continued based on the
patient’s clinical status from COVID-19 and the severity of
their underlying NMD. Discussion with the patient’s primary
neurologist and inpatient consult team if unavailable is
recommended.
Risks of treatments for COVID-19
Several antiviral drugs are in clinical trial for treatment of
COVID-19, including lopinavir/ritonavir, used for HIV in-
fection, and remdesivir, which inhibits viral RNA polymerases
and appears to show potent activity in vitro against members
of the filoviruses (e.g., Ebola virus) and coronaviruses (e.g.,
Table 3 Factors increasing risk of contracting coronavirus 2019 (COVID-19) or having more severe disease
Underlying immunotherapy
Immunosuppression with multiple agents
Additional factors
High doses of immunosuppressive therapy or cell/antibody-depleting therapies
Multiple immunosuppressive therapies, concurrently or sequentially
Highly active immune-mediated neuromuscular disease
Swallowing or respiratory muscle weakness
Other medical comorbidities
Pulmonary disease
Pulmonary hypertension
Renal impairments
Neutropenia or lymphopenia
Liver disease
Diabetes mellitus
Ischemic heart disease
Older age
Pregnancy (possible)
Neurology.org/N Neurology | Volume 94, Number 22 | June 2, 2020 5
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
SARS-CoV, MERS-CoV).
24
A recently published trial from
China found no efficacy of lopinavir/ritonavir in COVID-
19,
25
but other trials are ongoing and in preparation. With this
in mind, certain protease inhibitors may increase the risk of
peripheral neuropathy in patients with HIV,
26
but other
studies have found lopinavir/ritonavir does not increase the
risk and may actually reduce the risk of distal sensory
polyneuropathy in HIV-infected individuals.
27,28
Given the
duration of treatment in patients with COVID-19 infection,
we would suspect the likelihood of inducing or worsening
a preexisting polyneuropathy with lopinavir/ritonavir is likely
to be low. However, a toxic myopathy with rhabdomyolysis
has been reported in several cases of lopinavir/ritonavir
treatment in combination with a statin.
29–32
This is
Table 4 Patients with neuromuscular disease without coronavirus 2019 (COVID-19): treatment-specific guidance
Treatment type/medication
class Examples
Disorders
included Guidance
Symptomatic and other
therapies
Riluzole, botulinum toxins, antiepileptics,
benzodiazepines, pyridostigmine, diaminopyridine,
SSRIs, SNRIs, oral albuterol, mexiletine
ALS
ALS-related
sialorrhea
Neuropathic
pain
Muscle cramps
MG/LEMS
CMS
Myotonic
disorders
No specific dose change
Consider risk/benefit of routine monitoring
laboratory studies
Postpone nonurgent botulinum toxin
injections
Rx of controlled substances now typically
approved via virtual care with standard
safeguards
Nonimmunomodulatory
infusion and intrathecal
therapies, gene therapies
Edaravone, nusinersen/zolgensma, patisiran/
inotersen, lumizyme/myozyme
ALS
SMA
Hereditary
aTTR
amyloidosis
Pompe
Consider home infusions
Consider risk of exposures with infusions vs
risk of treatment interruption
Immunomodulatory
therapies
IVIg
SCIg
Plasma exchange
FcRn antagonists
GBS
CIDP/MADSAM
MMN
MG
LEMS
Myositis
Consider home infusions
Consider reducing frequency in stable
patients
Likely do not increase risk of virus
Complement inhibitors Eculizumab, clinical trials (zilucoplan, ravulizumab) MG
Immune-
mediated
necrotizing
myopathy
Consider home infusions
May encounter logistical challenges for
meningococcal immunizations: limited
availability of walk-in facilities, etc.
Likely does not increase COVID-19 risk
Corticosteroids Prednisone, methylprednisolone, deflazacort CIDP/MADSAM
MG
LEMS
Myositis
DMD
Consider lowest possible effective dose that
will prevent disease flare
Continue steroids unchanged in DMD
Consider stress dose as usual for illness
Avoid abrupt cessation for patients on
chronic steroids
Immunosuppressive
therapies
Azathioprine, mycophenolate mofetil,
methotrexate, tacrolimus, cyclosporine
CIDP/MADSAM
MG
LEMS
Myositis
Consider risk/benefit of routine monitoring
laboratories, consider spacing
Continuation of therapy typically
recommended, consider dose reduction if
otherwise medically indicated
Consider delaying initiation in stable patient
with mild disease until height of pandemic
has passed
Immunosuppressive/cell
depleting therapies
Rituximab, ocrelizumab, cyclophosphamide, clinical
trial drugs
CIDP/MADSAM
MMN
MG
LEMS
Myositis
Consider postponing infusions, spacing
dosing interval, or switching to a different
therapy
Avoid new starts unless no other good
alternative
Ancillary services/
evaluations
Physical therapy, occupational therapy, speech
therapy, clinical swallow evaluation, DME
All Indication is primarily urgent appointments
when ADL are limited and safety a concern
Consider telemedicine possibilities
Abbreviations: ADL = activities of daily living; ALS = amyotrophic lateral sclerosis; CIDP = chronic inflammatory demyelinating polyneuropathy; CMS =
congenital myasthenic syndromes; DMD = Duchenne muscular dystrophy; DME = durable medical equipment; FcRn = neonatal Fc receptor; GBS = Guillain-
Barr´
e syndrome; IVIg = IV immunoglobulin; LEMS = Lambert-Eaton myasthenic syndrome; MADSAM = multifocal acquired demyelinating sensory and motor
neuropathy; MG = myasthenia gravis; MMN = multifocal motor neuropathy; SCIg = subcutaneous immunoglobulin; SMA = spinal muscular atrophy; SNRI =
serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.
6Neurology | Volume 94, Number 22 | June 2, 2020 Neurology.org/N
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particularly important given early use of empiric high-dose
statins for COVID-19 and the independent association of
statins with rhabdomyolysis.
43
A small study suggested that
remdesivir and chloroquine may be effective in reducing
2019-nCoV infection in vitro
33
and clinical trials of these
agents are underway. Of note, no definite NMDs were asso-
ciated with remdesivir in a trial for Ebola, though pain in the
arms and legs was noted as a common complaint in healthy
controls.
34
Chloroquine and hydroxychloroquine have also been mentioned
as possible treatment for COVD-19. They are being used in
patients with infection and without proven benefitaspro-
phylaxis. Both drugs are associated with potential neuromuscular
side effects.
35,36
In vitro studies have demonstrated that chlo-
roquine blocked COVID-19 infection, as mentioned above.
36
A
short report of 100 patients in China noted that chloroquine
seemed to be beneficial, but without supportive data.
37
Rarely, patients taking chloroquine or hydroxychloroquine de-
velop slowly progressive, painless, proximal weakness and atro-
phy in the legs more than the arms.
38–43
In addition, length-
dependent sensory loss and reduced muscle stretch reflexes,
particularly at the ankle, may be related to a concomitant neu-
ropathy. Cardiac muscle can also be affected, leading to a car-
diomyopathy. Serum CK levels are usually slightly elevated.
Motor and sensory nerve conductions may show reduced
amplitudes with slightly slow conduction velocities. Needle EMG
can demonstrate positive sharp waves, fibrillation potentials, and
myotonic discharges, particularly in proximal muscles. Autopha-
gic vacuoles are often evident in skeletal and cardiac muscle fibers
on biopsy. Usually, but not invariably, this toxic neuromyopathy
does not develop unless patients are on high dosages for a year or
more. Given that patients would receive a much shorter course of
chloroquine and hydroxychloroquine, this toxic neuromyopathy
is unlikely to occur. Chloroquine and hydroxychloroquine have
also been associated with new-onset or worsening MG and are
typically used with caution in this patient group.
44,45
Azithromycin, a macrolide antibiotic, is also being used with
chloroquine or hydroxychloroquine for COVID-19. Macro-
lide therapy, however, the most common being azithromycin,
was not associated with reduced 90-day mortality or im-
provement in MERS-CoV RNA clearance in a study of
patients with MERS.
46
Importantly, macrolides also may
cause worsening of MG.
15
Risk of incident NMD with COVID-
19 vaccine
Another potential risk of vaccines is GBS and other acute in-
flammatory neuropathies (e.g., plexitis). This association is
strongest for swine flu. A slight increased risk of GBS has been
found in some studies of seasonal flu(influenza) vacci-
nation
47–49
but not all
50
and regardless, the risk of influenza in
most individuals outweighs the rare risk, if any, of GBS. Like-
wise, a small risk of GBS was reported in some
51–55
but not all
series
56,57
following H1N1 vaccination. These inflammatory
neuropathies are thought to arise due to molecular mimicry as
discussed previously between proteins on the virus and those on
peripheral nerves. Certainly, this will be important to measure in
future epidemiologic studies. There is no indication that a his-
tory of GBS or other immune-mediated neuromuscular disease
would preclude vaccination against COVID-19 at this time.
Changes in neuromuscular systems
of care
The COVID-19 pandemic has forced a rapid and un-
precedented reorganization of clinical care delivery worldwide.
In the United States, we are in the early stages of these mod-
ifications. Approach has been tailored by geographic location,
local COVID-19 prevalence, patient population, and practice
or institutional structures. Currently, the volume of elective or
nonurgent outpatient care has been significantly reduced. The
goal is to limit exposure to patients, communities, and medical
staff. No data regarding the scope of this effect have been
generated. The American Academy of Neuromuscular and
Electrodiagnostic Medicine (AANEM) published guidance
regarding clinical visits, electrodiagnostic testing, and tele-
medicine during COVID-19.
57
Currently, the AANEM
encourages physicians to “discuss issues related to patient care
with their hospitals and provide their recommendations re-
garding which patients need to be seen vs those that can be
delayed without impact on patient care or outcomes”and
“carefully consider when to cancel nonurgent procedures or
prioritize their more urgent patients in order to reduce po-
tential exposure and to ensure judicious use of potentially
limited supplies of personal protective equipment.”Like many
other institutions, we have adapted a triage system to allocate
scheduled outpatients to in-person encounters, telemedicine
encounters, or to delay the visit or procedure if medically
Table 5 Educational resources for patients
1. Centers for Disease Control and Prevention (cdc.gov/coronavirus/2019-nCoV/index.html)
2. General resources compiled by the Muscular Dystrophy Association (mda.org/covid19)
3. Guidance for the management of myasthenia gravis and Lambert-Eaton myasthenic syndrome during COVID-19 by the International MG/COVID Working
Group and a Webinar on myasthenia gravis and COVID by MGNET available on YouTube (myasthenia.org)
4. Recommendations for amyotrophic lateral sclerosis and specifically helpful suggestions for managing interactions with home health aides during COVID-
19 (als.ca/wp-content/uploads/2020/03/COVID-19-ALS-Clinician-Guidance-Document-2020-03-17-FINAL-EN.pdf)
Neurology.org/N Neurology | Volume 94, Number 22 | June 2, 2020 7
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appropriate. Most outpatient electrodiagnostic studies and
muscle and nerve biopsies may be postponed unless in case of
urgent need and the results would change management (e.g.,
new ALS, MG, immune-mediated neuropathy or myopathy).
Relevant patient-related and disease-specific outcomes and
systems-based measurements of care metrics should be evalu-
ated to assess the effect of these modifications.
Access to ancillary services and evaluation has been affected by
COVID-19. Outpatient pulmonary function tests may not be
performed due to increased risks. On a local level, our speech
therapy department had become credentialed to perform re-
mote video swallow assessment prior to COVID-19 and
therefore is able to continue this program. Fluoroscopic swal-
lowing studies are currently performed only for patients whose
dysphagia is unmanaged and may result in an unplanned hos-
pitalization. Overall, however, dysphagia is being evaluated and
treatedasmuchaspossiblewithvideosessions.Outpatient
physical therapists and occupational therapists have mainly been
communicating with patients by phone and patient portal ses-
sions, often sending photographs and videos of exercises or
equipment. Most outpatient and home therapists are seeing
only essential postoperative patients in our region. The Amer-
ican Physical Therapy Association and state-based physical
therapy organizations are organizing regarding telemedicine.
Some of our local occupational therapists can provide virtual
visits for follow-up for established patients. Medical equipment
(e.g., wheelchairs, Hoyer lifts) deliveries and custom bracing
have been significantly delayed in some regions. Virtual ancillary
services have been discussed in previous publications.
58,59
We have compiled a list of commonresources for patients who
have general inquiries about COVID-19 (table 5). Directing
patients to websites and other resources that are updated reg-
ularly is paramount, so that they have up-to-date information
when they choose to access the information. Disease-specific
links relating to ALS, MG, and recommendations for patients
who require home health aides are included. Family and
caregivers should be aware of their own ability to spread
COVID-19. In addition, high-flow noninvasive ventilation
aerosolizes infectious particles to the local environment and
requires appropriate measures to prevent spread.
Rapid integration of telemedicine
Before COVID-19, the rollout of telehealth in neurology and
particularly in neuromuscular medicine had been slow.
60
Now,
within a 2-week time period, many institutions in the United States
have transitioned heavily to telemedicine due to necessity and
relaxation of prior regulatory limitations.
61
Contributing factors to
slow adaptation before COVID-19 were reliance on a nuanced
strength,sensation,andreflex examination in neuromuscular
encounters. ALS clinics were early adapters prior to COVID-19.
62
Neuromuscular clinics and information about incorporation of
trainees are underrepresented in the limited data about outpatient
telemedicine in neurology.
63,64
Resources and telemedicine refer-
ences have been created by numerous professional societies in-
cluding the American Academy of Neurology and the American
Association for Neuromuscular and Electrodiagnostic Medicine.
With necessity to switch to telemedicine for most outpatient
encounters, neurologists are quickly discovering the strengths
and limitations of telemedicine, and new tools and skills re-
quired. It is important to keep in mind that these strengths and
limitations are not likely fully reflective of care in absence of the
pandemic.
65
For example, coordinating local laboratory or im-
aging evaluation and pulmonary function testing, which is typi-
cally straightforward, is now layered with additional challenge
and discussion of potential added COVID-19 exposure. We have
transformed most attending only and resident/fellows clinics
into telemedicine clinics to continue to provide both patient care
and clinical training. Limitations in the physical examination
preclude billing based on current complexity requirements in
most circumstances. Currently, for virtual/phone visits that re-
place outpatient visits, billing is based primarily on the attend-
ing’s synchronous video face-to-face time or time-based
synchronous phone interaction time with the patient. This bill-
ing structure has been reviewed in detail elsewhere and will likely
need modification if ongoing incorporation of residents and
fellows in outpatient neuromuscular telemedicine will con-
tinue.
66
In addition, best practices for performance of and billing
for virtual disease-specific neuromuscular examinations and
scales as well as incorporation of trainees into outpatient tele-
medicine settings is needed. To date, the visits that we perceive
have the highest and lowest benefit for telemedicine during the
Table 6 Telemedicine: Proposed utility/appropriateness by neuromuscular outpatient visit type during coronavirus 2019
(COVID-19)
High utility/
appropriateness Moderate utility/appropriateness Low utility/appropriateness
NMD follow-up
PN follow-up: stable or
management of
neuropathic pain
MG follow-up: stable
Myositis follow-up: stable
Inherited neuropathy or
myopathy follow-up: stable
New or unstable NMD
New or unstable PN
New MG: well-established diagnosis or unstable
new/follow-up
All patients with worsening symptoms to triage
need and timeframe for further or more urgent
care
All patients with discrepancy between reported symptoms and abnormal
examination findings
All disorders: second opinions for patients where nuances of physical
examination will highly influence medical decision-making and diagnostic
evaluation
Primary management of unstable patients
Abbreviations: MG = myasthenia gravis; NMD = neuromuscular disorder; PN = peripheral neuropathy.
8Neurology | Volume 94, Number 22 | June 2, 2020 Neurology.org/N
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
COVID-19 pandemic are outlined in table 6. Further studies on
outcomes and resource utilization as well as patient and provider
satisfaction with virtual visits will further inform what portions of
this emergency telemedicine will endure beyond COVID.
COVID-19’seffect on
neuromuscular training
In addition to professional and personal challenges for trainees
and teaching faculty and clinical reassignments, the COVID-19
pandemic has posed limitations on formal neuromuscular
training in residencies and fellowships. We see the immediate
effect for this year’s cohort, but anticipate that next year will also
be affected, either by ongoing reallocated clinical volume or the
need to catch up on differed routine outpatient care. To adapt
to these changes in real time and plan for the months ahead, we
have added new or modified fellowship activities, and involved
fellows in creating and testing these new structures (table 7).
We have found that new communication platforms (e.g.,
Microsoft Teams or other) have been essential for ongoing
formal and informal communications and to facilitate syn-
chronous supervision of fellows remotely in clinic. Readers of
Neurology®will have developed additional novel educational
strategies. We anticipate that there will be future collaboration
around these innovations to build and, after COVID-19, con-
tinuing those that have positively affected training.
COVID-19’seffect on
neuromuscular research
The effect of COVID-19 is of course not limited to neuro-
muscular research but will affect all medical specialties and
neurology subspecialties. We will focus on the effect in clinical
research, but certainly basic science and translation research
will be affected. For example, basic/translational researchers,
including graduate students and laboratory technicians, may
not be considered essential employees and will need to work
from home. Experimental studies on animals are being dis-
rupted. From our perspective of clinical researchers, there are
many challenges and we have selected some practical issues to
highlight.
1. There are challenges to new study start-up and close out
of recently completed trials. Site initiation visits and
routine monitoring by the sponsor of studies is being
prohibited in many academic hospitals. Those recently
completed studies may not be able to analyze data until
the monitor verifies source documents and what has been
entered into study databases. These difficulties may be
mitigated by allowing virtual study visits and monitoring.
2. Food and Drug Administration (FDA) guidance suggests
limiting on-site study visits to only those with conditions
in which available treatment options are limited and in
which the research drug has potential for benefit. The
clinical researcher weighs risks and benefits with each
individual participant in each clinical trial.
3. Research sites need to have the appropriate staffing to
maintain a clinical trial. Physician and nurse investigators
may be deployed from research duties to help manage
patients in the hospital. Likewise, research phlebotomists,
pharmacists, and other research staffmay be shifted to areas
of the hospital where they may be more needed. Study
coordinators may not be considered essential employees.
Backups are needed for research personnel in case they get
pulled away from research duties or become ill themselves.
4. It may be impossible for study participants to return to
the site for their research appointments because their
own illness puts them at increased risk in addition to what
was mentioned above. We need to convert as many study
visits as possible to virtual/phone visits, arrange for study
laboratories to be done locally close to where a participant
lives, and results to be sent back to the research site. We
will need regulators (e.g., FDA, European Union) to
understand that these laboratory studies that were
supposed to be sent and analyzed by a previously
approved central laboratory are going to be done locally
in many cases. Research needs to figure out how to
analyze the results coming from many laboratories.
Furthermore, we need to figure out how to handle
laboratory results in which the investigator was to be
blinded (e.g., such as CK levels in myositis trials). We
may need to add blinded coordinators assigned to handle
mail and faxes for these participants from their local
laboratories to be placed in research binders. We also
need to address how to handle missing data, particularly
Table 7 Early effect of coronavirus 2019 (COVID-19) on neuromuscular training activities
Increased Decreased Skill development
Virtual education (lecture series, waveform conference,
pathology conference, grand rounds)
Electrodiagnostic testing, neuromuscular medicine,
muscle and nerve histopathology self-study
Neuromuscular ultrasound self-study
Communication with patients by phone and patient portal
Bedside teaching
In-person and multidisciplinary clinics
Electrodiagnostic testing study volume,
inpatient and outpatient
Biopsy performance
Neuromuscular ultrasound
performance
Time spent on clinical notes
Work exclusively within the
neuromuscular division
Work in established systems of care
Telemedicine
Increased participation in hospital organization as
a whole
Developing new systems of care as a team, quality
improvement processes
New opportunities for formal teaching of medical
students and residents
Increased academic work, particularly that
immediately relevant to COVID-19
Training in formal and informal remote working
skills, individual and team-based
Neurology.org/N Neurology | Volume 94, Number 22 | June 2, 2020 9
Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
those involving primary outcome measures. Importantly,
we have to arrange for study drugs to be shipped to
participants and perform necessary oversight to ensure
participants are taking the study drug (e.g., collecting and
counting pills/syringes).
5. There is more administrative work for investigators and
coordinators. The above changes to an approved
protocol are considered protocol deviations (albeit minor
given the situation), but require submissions to in-
stitutional review boards as well as approval of new
amendments and informed consent forms.
6. Enrollment for clinical research is going to be slower and
studies take longer to complete than anticipated. This is
challenging to handle on a fixed budget on a grant.
Readers will think of more obstacles to research and how we
might mitigate these and others. We will all need to learn from
each other during these trying times.
Discussion
Data from the current COVID-19 pandemic regarding specific
risks and outcomes for patients with neuromuscular disease are
unknown. We will need new clinical structures including robust
telemedicine platforms and procedures to care for our patients
and to continue to educate trainees during this time. Expedited
publication of updated evidence-based guidance will be in-
formative. In the meantime, we can be vigilant in assessing
patients with neuromuscular disease for potential neuromus-
cular complications of COVID-19 and work towards mitigation
of COVID-19-related risk for patients with preexisting neuro-
muscular disease. Collaborative efforts among institutions will
help generate the data needed to inform management of rare
NMDs in the setting of COVID-19 and maintain clinical trials
and research despite current challenges.
Acknowledgment
The authors thank the Partners neuromuscular fellowship class
of 2020 (Joome Suh, MD; Leeann Burton, MD; Michael
Slama, MD, PhD; Sarah Madani, MD; Ariel Marks, MD; and
Salman Bhai, MD) and Chris Doughty, MD, associate
fellowship program director, for input on both telemedicine
and neuromuscular training during COVID-19; Virginia
Clarke, RN, and the MGH Medical Infusion Center stafffor
their work, dedication, and innovation; William S. David, MD,
PhD, for leadership; Amy Swartz, PT, Katherine Burke, PT,
and Stacey Sullivan, speech therapist, for input regarding PT/
OT and speech therapy during COVID; The Autoimmune
Neurology division at Massachusetts General Hospital and the
International MG/COVID workgroup for collaborative
approaches to shared new clinical challenges; research study
coordinators Louis Beers and Marie Guthrie and research
physical therapists Patricia Flynn, PT, and Emily Russo, PT,
for assisting in the evaluation of research participants; and
EMG/NCTs, including Peter McKeon, Catherine MacInnes,
Rosemary Difrancisco, and Abdusamad Essa, and administra-
tive assistants and practice managers, including Darlene Young
and Tamika Scott, for triaging hundreds of patient phone calls,
rescheduling neuromuscular clinics to virtual appointments,
and moving EMG and biopsy appointments to later dates.
Study funding
No targeted funding reported.
Disclosure
A.C. Guidonhas served as a consultant or on a medical advisory
board for Alexion, Momenta, and Ra Pharma; has received
royalties from Oakstone Publishing; and receives grant funding
from the Myasthenia Gravis Foundation of America. A.A.
Amato is Associate Editor for Neurology and received royalties
from Oakstone Publishing, Neuromuscular Disorders,Harrison’s
Principles of Internal Medicine,andUp-to-Date,andhasservedas
a consultant or on medical advisory board for Alexion and
Argenx. Go to Neurology.org/N for full disclosures.
Publication history
Received by Neurology April 5, 2020. Accepted in final form
April 9, 2020.
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Appendix Authors
Name Location Contribution
Amanda
C.
Guidon,
MD
Division of Neuromuscular
Medicine, Department of
Neurology, Massachusetts
General Hospital, Harvard
Medical School, Boston
Major role in departmental
actions contributing to
content, drafted and revised
the manuscript for
intellectual content
Anthony
A.
Amato,
MD
Division of Neuromuscular
Medicine, Department of
Neurology, Brigham and
Woman’s Hospital, Harvard
Medical School, Boston, MA
Major role in departmental
actions contributing to
content, drafted and revised
the manuscript for
intellectual content
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COVID-19 and neuromuscular disorders
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