Neuromuscular & Autonomic Complications of COVID-19
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NEUROMUSCULAR
DISORDERS
Neuromuscular &
Autonomic Complications
of COVID-19
Potential causal relationships can be assessed by criteria of strength, consistency,
temporality, biologic gradient, plausibility, coherence, and analogy.
By Helmar C. Lehmann, MD
COVID-19, first reported in December 2019
and declared a “Public Health Emergency
of International Concern” in March 2020,
has caused a recorded 3,857,563 deaths. The
still-ongoing pandemic of COVID‑19 caused
by SARS‑CoV‑2 infection has also spawned
an unprecedentedly large body of literature describing
new onset or aggravation of extrapulmonary conditions,
particularly neurologic disease, in temporal association
with COVID‑19. An analysis of publication trends in the
last 15 months reveals an ever-growing number of papers
describing, analyzing, and summarizing multiple aspects of
COVID‑19 and neuromuscular conditions (Figure).
At a glance, this number may suggest a causal relation-
ship between COVID‑19 and neuromuscular disease, but
biases could overestimate the significance and erroneously
indicate causality. Bibliometric analysis demonstrates that
this “tsunami” of COVID‑19 publications contains a high
number of poor-quality studies and a low number of stud-
ies of higher evidence (eg, clinical trials, large-cohort data
registries, or meta-analysis).1,2 Most published articles related
to COVID‑19 and neuromuscular disorders are case series
or reports. Only 25% of more than 2,000 papers published Figure. The number of new articles and preprints indexed in the US
on COVID‑19 in the first quarter of 2020 contained origi- National Library of Medicine (pubmed.gov) related to COVID‑19
nal data.3 Although case reports are important to raise overall (green line) increased rapidly in the first 3 quarters of 2020,
awareness of rare and novel associations, they are, in most plateaued in the 4th quarter and then began to decline in the first
instances, insufficient to establish causality. To assess evi- quarter of 2021. In contrast, papers related to neurologic disease
dence of neuromuscular and autonomic complications of and COVID‑19 (blue line) or neuromuscular disease and COVID‑19
COVID‑19, objective criteria are required. Criteria for assess- (red line) continue to expand rapidly.
ing causality proposed by Bradford Hill in 1965 consist of
9 characteristics: strength, consistency, specificity, temporal- experimental evidence and specificity are lacking for all con-
ity, biologic gradient, plausibility, coherence, experiment, and ditions. For coherence, it has been argued that data from
analogy.4,5 Not all can be applied in this setting; for example, severe acute respiratory syndrome (SARS) and Middle East
32 PRACTICAL NEUROLOGY JULY/AUGUST 2021
NEUROMUSCULAR
DISORDERS
respiratory syndrome (MERS) epidemics could be consulted, in which molecular mimicry is essential. This mechanism,
because these coronaviruses share a 50% to 80% homology however, requires viral epitopes (ie, peptide or protein) with
with SARS‑CoV‑2.5 The extent to which neuromuscular con- similarity to molecules expressed in the peripheral nervous
ditions discussed in this review meet these criteria is sum- system, allowing antibodies to the virus to cross-react with
marized in the Table. endogenous proteins. Data suggesting such cross-reaction
could occur, are mixed. A genomic and proteomic analysis
Guillain-Barré and Miller Fisher Syndromes showed no significant similarity between SARS‑CoV‑2 and
Guillain-Barré syndrome (GBS) and Miller-Fisher syn- human proteins.7 Other analyses demonstrated shared oli-
drome (MFS) were among the earliest neurologic complica- gopeptides between SARS‑CoV‑2 and 2 human heat-shock
tions reported in people with SARS‑CoV‑2 infection and proteins11 and up to 34 proteins that have an oligopeptide
COVID‑19. Evidence for the criteria strength and consistency sequence shared by the SARS‑CoV‑2 spike glycoprotein.12
is weak, however. Although the incidence of GBS was report- Whether heat-shock proteins or any of the other proteins
ed to be 2.6 higher in the first wave of the pandemic in Italy,6 with homology to SARS‑CoV‑2 are relevant targets of aber-
studies from the United Kingdom7 and Singapore8 reported rant immune responses in GBS is unknown, however. The
a lower incidence of GBS during the pandemic. The occur- analogy criterion might be strong for GBS because numer-
rence of GBS within 2 to 4 weeks after SARS‑CoV‑2 infection ous viruses are commonly accepted as triggers for GBS
does meet the criteria of temporality.9 The time interval including human herpes viruses, cytomegalovirus, varicella
between SARS‑CoV‑2 infection and onset of GBS varies and zoster and influenza.13,14 Whether existing evidence is coher-
is sometimes impossible to determine because GBS has been ent is debatable. Using the suggestion that coherent data
observed after asymptomatic SARS‑CoV‑2 infection. In more could be derived from experience with SARS and MERS, no
than 80% of those affected, GBS symptoms co-occurred with case of GBS after either has been reported and only 1 case
COVID‑19 symptoms, including the need for artificial ventila- was reported after MERS. On a cautionary note, the overall
tion, which may mask a clear delineation of the conditions.10 number of infected individuals for SARS and MERS is low,
Regarding the criteria of a biologic gradient, data are lacking thus these epidemics may not serve as good models to study
in that it is not known whether increased exposure, more rare complications. Experimental evidence for a relationship
severe disease course, or higher virus load predispose people between SARS‑CoV‑2 and GBS or MFS is lacking. In contrast,
infected with SARS‑CoV‑2 to GBS. this has been shown for other postinfectious molecular
GBS after SARS‑CoV‑2 infection is biologically plausible, mimicry in GBS (eg, gangliosides targeted by autoantibodies
based on the conception of GBS as a postinfectious disorder that are generated by infection with Campylobacter jejuni).15
TABLE. EVALUATING POTENTIAL CAUSAL Chronic Inflammatory Demyelinating
RELATIONSHIP OF SARS-COV-2 INFECTION Polyradiculoneuropathy
AND NEUROMUSCULAR DISORDERs Chronic inflammatory demyelinating polyradiculoneuro-
pathy (CIDP) is a chronic progressive or relapsing inflam-
Biologic gradient
matory autoimmune neuropathy. It typically presents as
subacute evolving symmetric neurologic deficits, distrib-
Temporality
Consistency
Plausibility
Coherence
uted distally and proximally. CIDP variants include distal
Strength
Analogy
acquired demyelinating symmetric (DADS), multifocal
acquired demyelinating sensory and motor neuropathy
(MADSAM, or Lewis‑Sumner syndrome), and pure motor or
Rhabdomyolysis x x x x x x x sensory variants (see Chronic Inflammatory Demyelinating
ICU-acquired weakness x x x x Polyradiculoneuropathy in this issue).16 Although post-
Neuralgic amyotrophy x x x COVID‑19 CIDP is plausible, the frequency of reports is
Guillain Barré syndrome x x x
low such that strength, consistency, and biologic gradient
is lacking. The general plausibility of COVID‑19 causing
Autonomic dysfunction x x x CIDP derives from the pathogenic concept of CIDP as an
Myositis x x autoimmune condition triggered by bacterial or viral infec-
CIDP x x tions. In contrast to GBS, however, the spectrum of infec-
Myasthenia gravis x
tions preceding CIDP is much less known. In a cohort study
of 92 people with CIDP, approximately one-third could
Abbreviations: CIDP, chronic inflammatory demyelinating identify an infection within 6 weeks before CIDP onset, and
polyradiculo-neuropathy; ICU, intensive care unit. of those individuals, 60% remembered a nonspecific upper
JULY/AUGUST 2021 PRACTICAL NEUROLOGY 33NEUROMUSCULAR
DISORDERS
respiratory tract infection.19 Thus, neither evidence from Whether dexamethasone improves this risk is unclear
analogy, nor coherence can be invoked. In summary it is because data from trials has not reported changes in CK lev-
very unlikely that CIDP is triggered or exacerbated by infec- els during treatment.
tion with SARS‑CoV‑2 or COVID‑19. Viruses are known to trigger myositis, making myositis
after COVID‑19 plausible.30 Although direct infection of
Myasthenia Gravis muscles by viruses is rare, because muscle fibers express the
Several case reports from Italy, Germany, and the US angiotensin-converting enzyme 2 (ACE2) receptor through
describe onset of ocular or generalized myasthenia gravis which SARS‑COV‑2 enters cells, COVID‑19 may be an excep-
(MG) 5 to 10 days after COVID‑19, which may lay within tion. This hypothesis, however, needs confirmation and
the range of a temporally plausible timeframe. The con- therefore Hill’s criterion of analogy does not apply. Only a
cept of postinfectious MG, however, is not well developed. few cases of myositis have been reported after COVID‑19,
Considering there is a background incidence for MG of 2 to and these diagnoses were predominantly based only on non-
3 per 100,000 per year,20 a much higher number of post- specific MRI changes.31 A small case series reported 5 people
COVID‑19 cases of MG than have been reported would be who had dermatomyositis with COVID‑19 and responded
expected to fulfill the causality criteria of strength, consis- to corticosteroids or intravenous immunoglobulin (IVIG).32
tency, and biologic gradient. Fatigue and muscle weakness, but not myalgia, are common-
ly present in patients 6 months after COVID‑19.26,33 From
Neuralgic Amyotrophy the 9 Bradford Hill criteria, only plausibility and temporality
Neuralgic amyotrophy (ie, Parsonage Turner syndrome) are supported, whereas strength, consistency, specificity,
is an idiopathic inflammatory neuropathy of the upper biologic gradient, coherence, and analogy are not.
limbs that usually affects the upper part of the brachial Rhabdomyolysis is a clinical and biochemical syndrome
plexus.21 Therefore, a brachial plexus neuritis preceded caused by acute skeletal muscle necrosis. With rhabdomyoly-
by SARS‑CoV‑2 infection appears principally plausible. sis, clinically significant myoglobinuria may occur and leads
Infections with DNA and RNA viruses, including hepatitis E, to renal failure in 15% to 33% of cases.34 Rhabdomyolysis has
parvovirus B19, HIV, herpes viruses, and West Nile virus can many causes, including substance abuse, trauma, extreme
precede neuralgic amyotrophy supporting an analogous overexertion, epileptic seizures, and less frequently, viral
autoimmune pathophysiologic mechanism. A few reported infections. Rhabdomyolysis has been described in MERS and
cases of neuralgic amyotrophy occurred approximately SARS, fulfilling criteria for analogy, and coherence may apply.
2 weeks after people had COVID‑19, suggesting temporal- Virally mediated rhabdomyolysis is thought to be caused
ity.22 Like MG, however, the incidence of neuralgic amyot- by direct viral invasion of muscle, and as noted, muscle cells
rophy is estimated as 1 to 3 per 100,000 per year,23 making do express the ACE2 receptor through which SARS‑CoV‑2
the reported cases within the error margin of any statistical infects the host, making SARS‑COV‑2-induced rhabdomy-
evidence. Hence, the causality criteria strength, consistency, olysis plausible. Strength and consistency are supported
and biologic gradient are absent. by numerous case reports of rhabdomyolysis during or after
COVID‑19 infection as well as 2 retrospective studies that
Myalgia, Myositis, and Rhabdomyolysis reported an incidence ranging from 2.2% to 17% in persons
Myalgias are considered among the most common and hospitalized with COVID‑19.35,36 This incidence increases to
early neurologic symptoms of COVID‑19, affecting up to up to 50% of those in the intensive care unit (ICU),37 sup-
50% of all patients.24 In approximately half of these individu- porting a biologic gradient. Male sex, obesity, hypertension,
als, myalgias improve within a few days, similar to symptoms diabetes mellitus, and chronic kidney disease are risk factors
of fever and cough. The proportion of individuals who had for rhabdomyolysis.
COVID‑19 (hospitalized or not) who complain about myal-
gia decreases by 6 months after illness to 2% to 4%.25,26 ICU-acquired weakness (ICUAW)
Approximately one-third of people with COVID-19 have The term ICU-acquired weakness (ICUAW) is used to
an elevated serum CK level,24 and these individuals had describe polyneuropathy and/or myopathy that occurs in
a higher likelihood of death from COVID‑19 (odds ratio persons who are critically ill during admission to the ICU.
[OR], 2.1 when CK>185 U/l),27 but this association was not ICUAW after COVID‑19 is biologically plausible, considering
found in a comparable study.28 Additionally, much higher the high rates of intensive care, sepsis, and prolonged venti-
likelihood of COVID‑19-related mortality is seen with other lation with COVID‑19, which are all risk factors for ICUAW.
prognostically relevant laboratory parameters (eg, OR, 45.43 People who have recovered from COVID‑19 frequently
with elevated lactate dehydrogenase).27 Elevated CK also is complain about muscle weakness, as long as 6 months after
not specific for COVID‑19 and occurs in severe influenza.29 the disease,26 which may point to a relevant proportion of
34 PRACTICAL NEUROLOGY JULY/AUGUST 2021NEUROMUSCULAR
DISORDERS
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COVID‑19 are unavailable. A prospective study from Finland 15. Yuki N, Susuki K, Koga M, et al. Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligo-
saccharide causes Guillain-Barre syndrome. Proc Natl Acad Sci U S A. 2004;101(31):11404-11409.
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