115

Acute Manifestations of Neuromuscular Disease

Christyn Edmundson, MD1 Shawn J. Bird, MD1

1 Department of Neurology, Hospital of the University of Address for correspondence Shawn J. Bird, MD, Department of
Pennsylvania, Philadelphia, Pennsylvania Neurology, Hospital of the University of Pennsylvania, 3400 Spruce
Street, 3 West Gates, Philadelphia, PA
Semin Neurol 2019;39:115–124. (e-mail: Shawn.bird@uphs.upenn.edu).

Abstract Neuromuscular emergencies may be defined as disorders or exacerbation of diseases of

the peripheral nervous system that are rapidly progressive and potentially life-
threatening. Such disorders can affect any level of the peripheral nervous system,
Keywords from the muscle to the anterior horn cell. While their clinical manifestations may vary,
► neuromuscular severe morbidity and mortality is most frequently the result of neuromuscular
emergencies respiratory failure. Some disorders, such as Guillain–Barré syndrome, provide the

Downloaded by: University of Massachusetts - Amherst. Copyrighted material.

► myasthenia gravis additional threat of severe, and potentially irreversible, nerve loss. Others, such as
► Guillain–Barré rhabdomyolysis and malignant hyperthermia, may produce serious medical complica-
syndrome tions. This article reviews neuromuscular emergencies by localization in the peripheral
► tetanus nervous system of the underlying disorder, as well as the identification and manage-
► botulism ment of neuromuscular respiratory failure.

General Approach to Neuromuscular Assessment of Respiratory Function

Emergencies
Neuromuscular disorders causing acute, generalized weak-
ness may be life-threatening, primarily through their effects
on respiratory and bulbar muscles. Acute, generalized weak-
ness may result from multiple localizations within the
peripheral nervous system. Features such as the presence
or absence of sensory symptoms, reflex changes, distribution
of muscle weakness, extraocular muscle involvement, and
involvement of other organ systems can aid the clinician in
localizing the patient’s disorder. ►Table 1 describes classic
findings by localization within the peripheral nervous sys-
tem. Additional studies, including electromyography (EMG)
and nerve conduction studies (NCSs), various blood tests,
and cerebrospinal fluid (CSF) sampling, can also help estab-
lish a diagnosis (see ►Table 2).
Evaluation and Management of Respiratory Failure
Acute neuromuscular disorders can result in life-threaten-
ing respiratory failure. Regardless of the cause of neuro-
muscular weakness, the signs and symptoms of respiratory
failure are similar and measures of respiratory function and
decisions regarding intubation follow common principles
(see ►Table 3).
Symptoms and signs suggestive of neuromuscular respira-
tory failure include dyspnea and orthopnea, tachypnea,
hypophonia, staccato speech, weak cough, use of accessory
respiratory muscles, and paradoxical breathing.1 Patients
with neuromuscular weakness threatening respiratory func-
tion often also have weakness of neck flexion and extension
and weakness of pharyngeal muscles, manifesting as dys-
phagia and difficulty clearing secretions. All patients with
acute or progressive signs of neuromuscular respiratory
failure should be admitted to an intensive care for close
monitoring and respiratory support, if needed.
While oxygenation should be monitored continuously,
hypoxemia and hypercarbia are insensitive measures of
muscle weakness, as they often develop only after the onset
of severe respiratory failure. Vital capacity (VC), maximal
inspiratory pressure (MIP; also known as negative inspira-
tory force [NIF]), and maximal expiratory pressure (MEP) are
the most useful measures of respiratory muscle function in
neuromuscular weakness. In practical terms, the VC and MIP
(NIF) are the most commonly used bedside parameters in the
hospital setting. VC is the maximum volume exhaled after
maximum inspiration, and reflects both inspiratory and
expiratory muscle strength. Normal values for VC vary by
age, gender, and height, though VC less than 30 mL/kg of ideal

Issue Theme Emergency Neurology; Copyright © 2019 by Thieme Medical DOI https://doi.org/
Guest Editors, Joshua N. Goldstein, MD, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0038-1676838.
PhD, and Jeffrey M. Ellenbogen, MMSc, New York, NY 10001, USA. ISSN 0271-8235.
MD Tel: +1(212) 584-4662.
116 Acute Manifestations of Neuromuscular Disease Edmundson, Bird

Table 1 Physical findings by localization in neuromuscular emergencies

Motor Respiratory Reflexes Sensory

Localization
Muscle Proximal limb and neck muscle weakness Possible involvement Usually unchanged Unchanged
Neuromuscular Proximal limb and neck muscle weakness Frequent involvement Usually unchanged Unchanged
junction or descending weakness. Frequent ocular
and bulbar involvement
Nerve Typically ascending weakness. Possible Possible involvement Reduced Frequent
bulbar involvement. Rare ocular involvement
involvement
Anterior horn cell Variable patterns of weakness Possible involvement Usually reduced Unchanged

Table 2 Essential diagnostics and disease-specific treatments in neuromuscular emergencies

Essential diagnostic tests Disease-specific treatment

Downloaded by: University of Massachusetts - Amherst. Copyrighted material.

Disorder
Rhabdomyolysis Serum CK IV fluids
Urinalysis Sodium bicarbonate if acidemia present
Mannitol if low urine output
Malignant hyperthermia Serum CK Dantrolene
ABG Ventilation with 100% O2
Urinalysis Cooling measures
Myasthenic crisis AChR and MuSK antibodies PLEX or IVIG
Nerve conduction studies
with repetitive stimulation
CT chest
Botulism Culture or isolation of toxin Botulism antitoxin
Guillain–Barré syndrome Lumbar puncture for CSF studies PLEX or IVIG
Nerve conduction studies
Viral motor neuronopathies Lumbar puncture for CSF studies None
Tetanus Wound culture, if possible Wound debridement
Antibiotics
Human tetanus immunoglobulin
or equine antitoxin
IV magnesium

Abbreviations: ABG, arterial blood gas; AChR, acetylcholine receptor; CK, creatinine kinase; CSF, cerebrospinal fluid; IVIG, intravenous immunoglobulin;
MuSK, muscle specific kinase; PLEX, plasmapheresis.

Table 3 Triggers for intubation in neuromuscular respiratory

measuring the negative pressure generated at the mouth.
failure
While normal values for MIP vary by age and gender,2 an MIP
of 0 to 30 cm H2O is suggestive of severe respiratory muscle
Triggers for elective Triggers for emergent
intubation intubation weakness. MEP is a measure of expiratory force, which is
most important for cough and secretion clearance. Measure-
SBC < 20 Somnolence
ments of VC, MIP, and MEP may be complicated by technical
FVC < 20 mL/kg Hypoxemia factors, such as facial weakness resulting in a poor seal with
MIP < 30 cm H2O Hypercapnia the spirometer, and such values should be considered in the
MEP < 40 cm H2O broader clinical context. In that circumstance, more reliance
is placed on the clinical symptoms and signs of respiratory
Abbreviations: FVC, forced vital capacity; MEP, maximal expiratory failure (see previously).
pressure; MIP, maximum inspiratory pressure; SBC, single breath count.
The single breath count (SBC) is a useful surrogate for VC in
situations where equipment for formal testing of respiratory
body weight may suggest respiratory muscle weakness in muscle strength is not available, such as during prehospital
patients with neuromuscular disorders. The MIP reflects care. To obtain an SBC, the patient is asked to maximally inhale
inspiratory muscle strength and is obtained by asking a and then count up from one on a single breath. We find this
patient to maximally inhale against a closed valve while maneuver to be more reliable if this is demonstrated by the

Seminars in Neurology Vol. 39 No. 1/2019

 Acute Manifestations of Neuromuscular Disease
examiner first. The SBC has been shown to correlate with VC
and MIP in patients with myasthenia gravis (MG).3 Each
number counted on the SBC corresponds with roughly
100 mL of VC. For example, an SBC of 10 roughly correlates
to a VC of 1 L and an SBC of 40 roughly correlates to a VC of 4 L.
Respiratory Support in Neuromuscular Respiratory
Failure
Endotracheal intubation with positive pressure ventilation
(PPV) is the preferred method of respiratory support in
patients with neuromuscular respiratory failure, as it has
the advantage of providing the capacity for both ventilation
and secretion clearance. There are no data comparing PPV to
noninvasive positive pressure ventilation (NPPV) in patients
with neuromuscular weakness.4 NPPV may be considered in
some select cases, but should be reserved for patients whose
weakness is expected to quickly resolve, who are able to
adequately manage secretions, and whose pulmonary para-
meters can be closely followed up in an ICU setting.
It is preferable to perform endotracheal intubation as an
elective procedure in patients who show signs of impending
neuromuscular respiratory failure, rather than as an emer-
gent response to respiratory collapse producing hypercapnia
and hypoxemia.1 The decision to intubate a patient with
neuromuscular weakness is made based on a combination of
clinical findings and objective measures of respiratory func-
tion. Serial VC and MIP can help establish a trend in respira-
tory function and should be performed frequently in patients
at risk for neuromuscular respiratory failure.
The timing of elective intubation has been most thor-
oughly studied in patients with Guillain–Barré syndrome
(GBS) and MG. In GBS patients, progression to respiratory
failure was associated with VC less than 20 mL/kg, MIP less
than 30 cm H2O, and MEP less than 40 cm H2O, sometimes
known as the “20/30/40 rule,” or a reduction of more than
30% in any of these measures.5 We advocate these thresholds
as a guide for elective intubation in patients with acute
neuromuscular weakness. Clinical features that should
prompt strong consideration of intubation include signs of
respiratory distress, such as drowsiness, inability to lie flat
due to increased dyspnea, use of accessory muscles, or
inadequate secretion clearance. Failure to rapidly improve
with NPPV should also prompt intubation.
Principles of weaning mechanical ventilation in patients
with neuromuscular respiratory failure are similar to the
general population. There are multiple methods for weaning
mechanical ventilation, with no single agreed-upon best
approach. In broad terms, the most successful weaning
strategies emphasize a daily assessment of breathing func-
tion and judicious use of sedative medications.6,7 Once the
underlying cause of neuromuscular respiratory failure has
been identified and addressed, we prefer daily spontaneous
breathing trials (SBTs) with low levels of inspiratory pressure
support to assess a patient’s progress toward readiness for
extubation.8,9 When a patient successfully passes an SBT, the
endotracheal tube is typically removed. Patients should be
closely monitored following extubation using MIP and VC to
detect individuals who may require reintubation. Aggressive
Edmundson, Bird 117
airway clearance may help prevent reintubation. If patients
require prolonged ventilation, or if the underlying cause of
neuromuscular respiratory failure cannot be reversed, tra-
cheostomy should be considered.
Disorders by Localization
Neuromuscular Junction
Myasthenia Gravis
Myasthenia gravis is an autoimmune disorder caused by
antibodies directed at proteins on the postsynaptic neuro-
muscular junction of skeletal muscle. MG is characterized as
ocular or generalized, depending on the pattern of muscle
involvement. In patients with generalized MG, acetylcholine
receptor (AChR) antibodies are present in approximately
85%. Muscle-specific kinase (MuSK) antibodies are found in
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
38 to 50% of patients who lack detectable AChR antibodies.
Six percent to 12% of patients with MG will lack these
antibodies, and are termed seronegative.10 Thymic tumors,
primarily thymoma, are present in up to 15% of patients with
AChR antibody-positive MG.11
Clinical Features
Myasthenia gravis is characterized by fluctuating weakness
that worsens with activity and improves with rest. In ocular
MG, weakness is limited to periocular muscles, resulting in
fluctuating ptosis and diplopia. In generalized MG, weakness
may also involve oropharyngeal, respiratory, and limb muscles.
Myasthenic crisis is defined as worsening of myasthenic
symptoms requiring intubation or noninvasive ventilation.
Ventilatory support may be required due to respiratory
muscle weakness or severe bulbar muscle weakness causing
upper airway obstruction or aspiration. Impending myasthe-
nic crisis is defined as rapid clinical worsening of myasthenic
weakness that could rapidly lead to myasthenic crisis.12 As
many as 10 to 20% of patients with MG experience at least
one myasthenic crisis.13 Myasthenic crisis may be precipi-
tated by a variety of factors including infection, medications,
a surgical procedure, or pregnancy and childbirth. Mortality
in patients with myasthenic crisis has declined over the past
decades to approximately 5%,14 and often results from
systemic complications such as infection or cardiac disease.
Cholinergic crisis, or paradoxical worsening of myasthe-
nic symptoms with exposure to excessively high doses of
anticholinesterase medication, potentially could be mista-
ken for myasthenic crisis. However, cholinergic crisis is
rarely, if ever, seen. Cholinergic crisis does not occur in
patients taking standard pharmacologic doses for MG
(<120 mg pyridostigmine every 3 hours).
Diagnosis
In patients presenting with impending or manifest myasthenic
crisis, the cause of respiratory and bulbar symptoms may be
readily apparent if they carry a preexisting diagnosis of MG.
However, myasthenic crisis is the first manifestation of MG in
13 to 20% of patients.15–17 Testing for MG in this setting should
focus on confirming the presence of this disease with serum
Seminars in Neurology Vol. 39 No. 1/2019
118 Acute Manifestations of Neuromuscular Disease Edmundson, Bird
antibodies, or demonstrating a disorder of neuromuscular
transmission through electrodiagnostic testing.
Serum tests for AChR and MuSK antibodies, if not known,
should be performed. Slow repetitive nerve stimulation
(RNS) at a rate of 2 to 3 Hz shows a significant decrement
of motor response amplitudes in roughly 80% of patients
with generalized MG. While the sensitivity of slow RNS is
much lower in patients with ocular MG, patients with
myasthenic crisis by definition have generalized MG, making
slow RNS a useful confirmatory test in the acute setting.
Patients treated for myasthenic crisis may require central
venous access. While proximal nerve stimulation, and RNS,
has traditionally been avoided in patients with central
venous access, it appears that both may be safe, though
this has not been assessed in critically ill individuals.18
Single-fiber EMG is the most sensitive test available for
MG, but is technically challenging and generally unfeasible
in the ICU setting. Chest CT or MRI imaging should also be
performed to assess for the presence of thymoma in patients
with a new diagnosis of MG.
In the setting of strong clinical suspicion for impending or
manifest myasthenic crisis, definitive treatment should not
be delayed by these diagnostic tests, which may be pursued
concurrently with the treatment measures discussed later.
Treatment
In addition to identifying and addressing possible precipi-
tants of MG exacerbation (e.g., infection), the mainstays of
treatment for myasthenic crisis are respiratory management
and treatment with rapid acting therapies, such as intrave-
nous immunoglobulin (IVIG) or plasmapheresis (PLEX).
Patients with myasthenic crisis require care in an ICU
setting, while those with impending crisis may be cared for
either in an ICU or stepdown unit, depending on the severity of
symptoms and rate of progression.12 In patients who are not
yet intubated, respiratory function should be monitored clo-
sely, as described in section “Assessment of Respiratory Func-
tion,” including MIP and VC assessment every 2 to 4 hours. In
patients who meet the criteria described in ►Table 3, intuba-
tion should be considered, preferably on an elective basis prior
to frank respiratory collapse. Pyridostigmine is usually held in
MG patients after intubation, as this medication can increase
respiratory secretions, complicating pulmonary management.
In addition to the general principles of weaning mechanical
ventilation discussed earlier, particular attention should be
given to preventing respiratory muscle fatigue in patients with
MG. Both extubation failure and reintubation are common in
myasthenic patients,19 and predictors of prolonged ventilation
include age greater than 50, elevated baseline serum bicarbo-
nate, and a low peak FVC in the first week of mechanical
ventilation.20
In addition to respiratory monitoring and support, patients
with impending or manifest myasthenic crisis should be
treated with rapid therapy, either IVIG 2 g/kg over 5 days or
PLEX with three to five exchanges over 1 to 2 weeks. Although
clinical trials suggest that IVIG and PLEX are equally effective in
the treatment of MG, expert consensus suggests that PLEX
works more quickly.12 Ultimately, the choice between the two
Seminars in Neurology Vol. 39 No. 1/2019
therapies depends on patient comorbidities and the institu-
tional availability of each therapy.
Additionally, during impending or manifest myasthenic
crisis, high-dose corticosteroids (i.e., prednisone 60–80 mg
daily) may be started in an attempt to better control the MG
in the weeks after the beneficial effects of PLEX or IVIG have
worn off. However, high-dose corticosteroids may precipi-
tate exacerbation in myasthenic symptoms or even myasthe-
nic crisis 5 to 10 days after initiating therapy. High-dose
corticosteroids may be started several days after starting
IVIG or PLEX because the quick onset of action of PLEX and
IVIG prevents the transient worsening that would otherwise
occur due to the initiation of high-dose corticosteroids.
Corticosteroid-sparing immunosuppressive therapies
commonly used for long-term treatment, such as azathiopr-
ine, mycophenolate mofetil, cyclosporine, and tacrolimus,
take months to produce a therapeutic effect. While initiation
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
of such therapies may be considered to optimize long-term
disease control, they do not play a role in urgent care of
myasthenic crisis. Similarly, thymectomy, which may
improve outcomes in patients with generalized AChR anti-
body-positive MG, even in those without thymoma,21 takes
months to years to be beneficial and should be deferred until
the disease has been stabilized.
Botulism
Botulism is a disorder of presynaptic neuromuscular trans-
mission caused by exposure to botulinum toxin, a potent
neurotoxin produced by the anaerobic bacillus, Clostridium
botulinum (C. botulinum). Cases of botulism are rare, with
roughly 200 reported per year in the United States.22 Multi-
ple serotypes of botulinum toxin have been identified (A-
H),23 all of which diminish the release of acetylcholine-
containing vesicles from the presynaptic nerve terminal
and thus prevent postsynaptic membrane depolarization.
Serotypes A, C, and E target SNAP-25, while serotypes B, D, F,
and G target the AMP/synaptobrevin complex.24 While its
effects on the neuromuscular junction of both skeletal and
smooth produce many of its characteristic findings, botuli-
num toxin can target multiple tissues, including motor and
sensory neurons as well as the cholinergic innervation of the
sweat, tear, and salivary glands.25
Infant botulism occurs when spores are ingested from
honey or environmental dust/soil containing C. botulinum
spores. Adult botulinum is most commonly foodborne,
resulting from ingestion of foods containing preformed
toxin, typically home-canned foods. Adult botulism may
also result from in vivo toxin production from wounds
infected with C. botulinum, particularly in the setting of
parenteral drug abuse. Iatrogenic disease from cosmetic
Botox injections, adult intestinal colonization, and bioterror-
ism-related botulism are much less common.26
Clinical Features
Botulism classically presents with acute onset of bilateral
cranial neuropathies causing ptosis, ophthalmoplegia, facial
weakness, and bulbar weakness, followed by progressive,
symmetric descending, flaccid paralysis affecting the limbs
 Acute Manifestations of Neuromuscular Disease
and respiratory muscles.26 Sensory symptoms or signs are
not present. Symptoms of dysautonomia, such as blurred
vision, mydriasis with nonreactive pupils, postural hypoten-
sion, xerostomia, and anhidrosis, may also be present. These
autonomic symptoms can help differentiate botulism from
myasthenic crisis. Most forms of GBS evolve as an ascending
paralysis (although there are frequent exceptions to this) and
have sensory symptoms and/or signs.
Patients affected by foodborne botulism often experience
a prodrome of gastrointestinal (GI) illness and an incubation
period as short as 2 hours and as long as 12 days from
ingestion of toxin to illness.27 Those with wound-associated
botulism may not experience symptoms for days to weeks
after wound infection. Symptoms typically progress over
days to weeks, with a slow recovery over weeks to months.
Diagnosis
Botulism may be presumptively diagnosed based on clinical
findings and a history of possible toxin exposure. According to
the U.S. Centers for Disease Control and Prevention (CDC), the
core elements of botulism are absence of fever, preserved state
of consciousness, absence of sensory deficits except for blurred
vision, symmetrical motor deficit, normal heart rate, or bra-
dycardia and normal blood pressure, which help distinguish
botulism from other causes of acute flaccid paralysis (AFP).
Three features, when all present, have a sensitivity identifying
botulism in 78 to 89% of patients. These are the absence of
fever, at least one symptom of cranial neuropathy, and at least
one sign of cranial neuropathy.28
The diagnosis of botulism may be confirmed by identify-
ing toxin or isolating C. botulinum in a variety of samples,
including serum, stool, wound specimens, or food sources.
However, such confirmatory testing may not yield positive
results early in the disease course and should not delay
prompt treatment. EMG is not necessary for diagnosis, but
may prove supportive in uncertain cases. Characteristic
electrodiagnostic findings in botulism include small motor
response amplitudes on NCS that augment after exercise or
an incremental response with fast RNS (20–50 Hz).
Treatment
In addition to close monitoring of respiratory function in an
intensive care setting and considering mechanical ventilation
when indicated, botulism antitoxin is the main therapeutic
intervention. The antibodies contained in antitoxin neutralize
botulinum toxin that has not already been internalized to
presynaptic nerve terminals. The use of antitoxin has been
shown to reduce mortality in botulism, and early administra-
tion of antitoxin may have better effect than later administra-
tion.29 Thus, if clinical suspicion for botulism is high, antitoxin
administration should not be delayed while awaiting the
results of diagnostic studies. In the United States, heptavalent
botulism antitoxin containing antibodies to botulism toxin
types A to G is available through state health departments and
the CDC. Additionally, human-derived botulism immune glo-
bulin is available to treat cases of infant botulism.
In foodborne and infant botulism, the use of antibiotics is
not recommended as they may cause lysis of C. botulinum and
Edmundson, Bird 119
increase intraluminal GI toxin concentrations. In wound botu-
lism, treatment with penicillin G is typically initiated after
wound debridement and antitoxin administration. In food-
borne botulism, gastric lavage, cathartics, and enemas may
also be used to remove unabsorbed toxin from the GI tract.
Peripheral Nerves and Nerve Roots
Guillain–Barré Syndrome
Guillain–Barré syndrome is an eponym used to describe a
group of acute immune-mediated disorders of the peripheral
nerves and/or nerve roots. With an annual incidence in North
America and Europe of 1 to 2 cases per 100,000, GBS is one of
the most common neuromuscular emergencies.30,31 The
most common (90%) GBS variant in North America is acute
inflammatory demyelinating polyneuropathy (AIDP).32
Other variants include Miller–Fisher syndrome (MFS), Bick-
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
erstaff encephalitis, acute motor and sensory axonal neuro-
pathy (AMSAN), and acute motor axonal neuropathy
(AMAN). GBS is often triggered by infection caused by
viruses, including Campylobacter jejuni, cytomegalovirus,
Epstein–Barr virus, Mycoplasma pneumoniae, varicella-zos-
ter virus, and Zika virus,33,34 and neurologic deficits gener-
ally begin 10 to 14 days later. It is thought that these
infections induce an aberrant immune response to the
nerves and spinal roots through molecular mimicry.
Clinical Features
While clinical symptoms may vary, GBS typically presents as a
rapidly progressive, ascending, symmetric weakness asso-
ciated with numbness, paresthesias, or pain of the limbs and
areflexia on examination. Additionally, facial nerve palsies are
common in patients with GBS, as are signs of dysautonomia,
such as GI dysmotility, bradycardia, or tachycardia, and fluc-
tuations in blood pressure.35 Respiratory muscle weakness
frequently develops, and 10 to 40% of patients ultimately
require endotracheal intubation.31,36 In patients with the
MFS variant of GBS, the triad of areflexia, ophthalmoplegia,
and ataxia may be present. Patients with the AMAN variant,
which is more common in parts of Asia,37,38 present with
progressive weakness with preservation of sensation.
GBS is a monophasic illness that reaches its nadir within
4 weeks in the vast majority of patients.39 Some patients
experience treatment-related fluctuations in disease severity,
but clinical deterioration beyond roughly 1 month of symptom
onset should prompt consideration of alternative diagnoses,
such as chronic inflammatory demyelinating polyneuropathy.
Diagnosis
The initial diagnosis of GBS is based on clinical presentation,
but evaluation of cerebral spinal fluid (CSF), NCS, serum
antibodies, and neuroimaging may help support the diag-
nosis and exclude disease mimics. Although the CSF and NCS
may be normal in some patients in the first week or two of
symptoms, treatment and these diagnostic studies should
not be delayed in a patient with a clinical diagnosis of GBS.
CSF in GBS patients classically shows cytoalbuminological
dissociation (an increased protein with a normal cell count).
Seminars in Neurology Vol. 39 No. 1/2019
120 Acute Manifestations of Neuromuscular Disease Edmundson, Bird
CSF protein is normal in roughly half of patients in the first
week of the disease, but is elevated in 70 to 90% of patients if
collected 2 weeks after symptom onset.39,40 A CSF pleocy-
tosis should prompt consideration of GBS mimics, such as
Lyme disease, HIV, and sarcoidosis, though 15% of GBS have a
mild CSF pleocytosis of 5 to 50 cells.39 NCS usually allow
confirmation of an acute neuropathy and are useful in
discriminating between demyelinating (AIDP) and axonal
(AMAN and AMSAN) GBS subtypes. NCS also provides a
measure of motor axonal loss, which may influence the
physician’s assessment of disease prognosis. NCS can be
normal early in the course of the disease and electrodiag-
nostic findings develop over weeks.32 Serial NCS during the
hospital course are frequently helpful in definitively estab-
lishing the subtype and severity of GBS. Serum antibodies to
GQ1b are often positive in the MFS and Bickerstaff encepha-
litis variants of GBS.41–43 MRI of the lumbar spine can help
exclude disorders such as cauda equina syndrome, and may
show thickening or enhancement of the spinal nerve roots.44
Treatment
In addition to respiratory monitoring and support (see section
“Evaluation and Management of Respiratory Failure”), treat-
ment with IVIG or PLEX is indicated for most patients with
GBS. Treatment should be initiated as soon as there is a clinical
diagnosis of GBS and should not wait for confirmation by
lumbar puncture or NCS. IVIG and PLEX have been found to be
similarly effective in the treatment of GBS, though patients are
more likely to complete a course of treatment with IVIG.45,46
The choice between the two agents depends on the patient’s
comorbidities and institutional availability. IVIG dosing is
typically 2 mg/kg spread over 5 days, and PLEX is typically
with four to six exchanges over 8 to 10 days. Additionally,
supportive care for autonomic dysfunction should be pro-
vided, including cardiac monitoring, management of blood
pressure fluctuations and arrhythmias, and management of GI
dysmotility and urinary retention.
Muscle
Rhabdomyolysis
Rhabdomyolysis is a disorder in which an insult to the muscle
causes myocyte necrosis and release of their intracellular
contents, resulting in markedly elevated serum creatinine
kinase (CK) levels.47 Rhabdomyolysis may be caused by a
wide variety of precipitants, including drugs, toxins, infec-
tions, seizures, trauma, or muscle overexertion in individuals
with underlying muscle disorders or those who are poorly
trained.48
Clinical Features
Rhabdomyolysis is classically characterized by the triad of
muscle pain, muscle weakness, and myoglobinuria, often
manifest as dark urine, though all three of these are present
in only a minority of cases.49 The relative degree and distribu-
tion of muscle pain and weakness varies with the underlying
cause and the patient. Patients may also experience general-
ized symptoms including fever, malaise, nausea, and vomiting.
Seminars in Neurology Vol. 39 No. 1/2019
In its mildest form, rhabdomyolysis may present with asymp-
tomatic elevation in CK, but in more severe forms this disorder,
complications such as acute kidney injury (AKI) may prove life-
threatening.
Diagnosis
A diagnosis of rhabdomyolysis is primarily based on the
identification of a marked elevation in serum CK levels or
myoglobin in the urine. A serum CK value greater than five
times the upper limit of normal is used by some in the
definition of this condition.48,49 Urine myoglobin is often
elevated within hours after the inciting insult, but rapidly
normalizes. A urinalysis may also provide evidence of myo-
globinuria when the urine tests positive for heme by dipstick
even after centrifugation, which would remove red blood cells
from the fluid.
It is essential to assess for hypovolemia, AKI, electrolyte
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
abnormalities, and disseminated intravascular coagulation
(DIC), as these complications may be life-threatening. When
myoglobin is degraded it releases heme pigments which
may injure the kidneys by a variety of mechanisms,50,51 and
AKI occurs in one-third to one-half of patients with rhab-
domyolysis.48,49 Hyperkalemia and hypophosphatemia may
occur due to release from damaged myocytes. Hypocalce-
mia may be present in early rhabdomyolysis as calcium
enters damaged myocytes, with rebound hypercalcemia
during recovery as calcium is released.52,53 DIC is an
infrequent complication of severe rhabdomyolysis, but
should be suspected in patients who develop thrombosis
or hemorrhage. Occasionally, a compartment syndrome
may develop due to muscle swelling, especially after fluid
resuscitation.
EMG and muscle biopsy are not necessary for the diagnosis
of rhabdomyolysis, but may be helpful in diagnosing underlying
inflammatory of metabolic myopathies. These tests should be
considered in cases where these myopathies are suspected,
such as recurrent rhabdomyolysis, or the failure of the serum
CK to return to normal after rhabdomyolysis has been treated.
Treatment
In addition to the recognition and prompt management of
DIC, electrolyte abnormalities, and compartment syndrome,
the mainstay of treatment of rhabdomyolysis is early and
aggressive hydration with IV fluids, with the primary goal of
preventing AKI. The mechanism by which volume repletion
protects renal function is unknown, though theories include
the prevention of renal vasoconstriction and promoting
removal of myoglobin casts from renal tubules.54 Higher
CK level correlates with a greater risk for AKI,55,56 but even
patients with a relatively low CK on admission can go on to
develop AKI and should be monitored closely.55 Limited
prospective data exist comparing IV fluid types and rates
of administration. The most comprehensive review of litera-
ture recommends fluid administration as soon as possible,
preferably within the first 6 hours after muscle injury, at a
rate that maintains a urine output of at least 300 mL/hour or
more for at least the first 24 hours.54 During volume resus-
citation, patients should be monitored closely for signs of
 Acute Manifestations of Neuromuscular Disease
fluid overload, particularly in those who have already sus-
tained kidney injury or have preexisting liver or cardiac
disease.
Additional agents, such as sodium bicarbonate and man-
nitol, have been advocated to promote diuresis and prevent
myoglobin cast formation. However, there are no prospective
data to support their effectiveness over IV fluid alone. It has
been suggested that sodium bicarbonate be used only when
necessary to correct systemic acidosis, and mannitol be used
only if needed to maintain a urine output of greater than 300
mL/hour despite adequate fluid administration.54
Malignant Hyperthermia
Malignant hyperthermia (MH) is a rare but life-threatening
complication of exposure to volatile anesthetics, such as
halothane and isoflurane, and/or succinylcholine.57,58 Sus-
ceptibility to MH appears to be due to genetic mutations in
certain genetic skeletal muscle receptors, most frequently the
ryanodine receptor (RYR1).59 In these susceptible patients,
exposure to triggering agents can lead to unregulated calcium
efflux from the sarcoplasmic reticulum to the intracellular
space, causing sustained muscle contraction. This sustained
contraction generates more heat than the body can dissipate,
resulting in severe hyperthermia, increased oxygen consump-
tion, and widespread organ dysfunction.
Clinical Features
Early signs of MH include hypercarbia, sinus tachycardia,
isolated rigidity of the masseter muscle, or generalized muscle
rigidity. Particularly during a surgical procedure, the first sign
of MH may be an unexplained rise in end-tidal CO2. Findings
that may develop as MH progresses include hyperthermia,
metabolic and respiratory acidosis, rhabdomyolysis, bleeding
related to DIC, and ventricular arrhythmias. MH can also lead
to renal failure, heart failure, and pulmonary edema.58,60
Diagnosis
Diagnosis of MH during the acute event is based on clinical
presentation in patients exposed to potentially triggering
agents. Muscle rigidity, hypercarbia, hyperkalemia, tachy-
cardia, tachypnea, myoglobinuria, and hyperthermia in iso-
lation or combination, without another clear explanation,
should prompt concern for MH. Laboratory studies are not
required for presumptive diagnosis, but abnormalities on
arterial blood gas (acidemia), basic metabolic panel (hyper-
kalemia), and serum CK may support the diagnosis.
Muscle biopsy, EMG and genetic testing for mutations,
may establish the underlying cause of susceptibility to MH,
but these studies are of secondary concern during the acute
presentation.
Treatment
Treatment of MH necessitates management in an intensive
care unit. The triggering agent should be identified and dis-
continued. If a surgical procedure is in process, it should be
halted, if possible, and if the patient is not already intubated, an
endotracheal tube should be placed. The patient should be
hyperventilated with 100% O2 until end tidal CO2 has normal-
Edmundson, Bird 121
ized.61 Dantrolene should initially be administered in an IV
bolus of 2 mg/kg, which should be repeated as needed until the
cardiac and respiratory systems are stabilized.61 Dantrolene,
the only known antidote for MH, inhibits RYR1 receptor–
mediated efflux of calcium from the sarcoplasmic reticulum.62
Patients with elevated core temperatures should be cooled
using cold IV saline and external cooling devices. Additionally,
it is essential to monitor for and address hypotension, acid-
emia, hyperkalemia, DIC, and rhabdomyolysis.
Anterior Horn Cell
Acute Flaccid Paralysis: Infectious Motor
Neuronopathies
Acute flaccid paralysis is caused by viral infection of the
lower motor neurons. Historically, polio virus was the most
common cause of AFP, but is now rare thanks to widespread
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
immunization. West Nile virus (WNV) and a variety of non-
polio enterovirus are also known to cause AFP.63–66
Clinical Features
Viral AFP is characterized by asymmetric flaccid weakness
involving the limbs, bulbar muscles, or respiratory muscles.
Viral AFP may be associated with encephalopathy, and is
almost always seen in concert with systemic symptoms such
as fever, lymphadenopathy, rash, diarrhea, and vomiting,
which precede the onset of neurologic symptoms by hours
to days.64,67,68
Diagnosis
Evaluation of CSF is essential in the evaluation of viral AFP.
Regardless of the underlying infectious agent, there is typically
elevated protein and a lymphocytic pleocytosis, though early
in the disease course the pleocytosis is frequently neutrophi-
lic.66,69 The causative virus may be identified through a variety
of testing methods. For WNV, the gold standard for confirming
the diagnosis is by identification of immunoglobulin M anti-
body in the CSF.64 For polio, diagnosis may be established by
polymerase chain reaction amplification of RNA from the CSF
or by isolation of the virus from the nasopharynx or stool.67
Electrodiagnostic findings in AFP depend largely on the timing
of testing.
Treatment
Treatment for all forms of viral AFP is largely supportive,
including respiratory management and early mobilization
and therapy to help mitigate long-term disability. IVIG has
been suggested as a possible therapeutic agent in the treat-
ment of WNV, though no prospective studies support its use.
A single randomized, placebo-controlled trial of IVIG treat-
ment in WNV has been conducted, though only limited
results have been published to date.70
Tetanus
Tetanus is caused by toxin produced by the anaerobic
bacterium Clostridium tetani, which is found in soil and is
typically introduced to the body through wound inoculation.
Tetanus toxin enters peripheral nerves and is carried to the
Seminars in Neurology Vol. 39 No. 1/2019
122 Acute Manifestations of Neuromuscular Disease Edmundson, Bird
α-motor neurons via retrograde axonal transport. The toxin
prevents release of inhibitory neurotransmitters, resulting in
sustained discharge of motor neurons. This manifests clini-
cally as the characteristic motor spasm of tetanus.71,72
Thanks to high rates of vaccination with tetanus toxoid,
tetanus is rare in developed countries such as the United
States,73 though it is endemic in resource-limited settings
and remains a major public health challenge.74
Clinical Features
The incubation period from wound inoculation to symptom
onset of tetanus ranges from a few days to several weeks.73,75
Tetanus typically presents with painful tonic contractions
and intermittent spasms of the skeletal muscles, resulting in
the classic findings of masseter spams, opisthotonus (spas-
modic hyperextension of the neck and back), and risus
sardonicus (spasm of the facial muscles mimicking a grin).
Pharyngeal or thoracic muscle spasm may lead to respiratory
compromise, frequently requiring endotracheal intuba-
tion.76 Urine catecholamine excretion in patients with teta-
nus exceeds that of other critically ill patients,77 and
autonomic dysfunction is common in severe tetanus.78
Diagnosis
The diagnosis of tetanus is based on clinical findings. C. tetani
can be cultured from wounds in roughly 50% of patients,79
but the capacity for such cultures may not be present in
resource-limited settings.
Treatment
Airway management and respiratory support is essential in
the treatment of tetanus. Unlike many other neuromuscular
emergencies, respiratory compromise in tetanus occurs pri-
marily due to spasm of thoracic and pharyngeal muscles.
Because tetanus toxin cannot be displaced from neural tissues
and recovery takes weeks to months, patients often require
prolonged ventilation and early tracheostomy should be con-
sidered.76 Removal of the source of tetanus toxin is essential,
including wound debridement and antibiotic treatment with
metronidazole or penicillin.80,81 Unbound tetanus toxin can be
neutralized with the administration of human tetanus immu-
noglobulin or equine antitoxin, depending on availability.
Spasms should be treated with benzodiazepines, propofol, or
neuromuscular blockade if needed. Antihypertensive and
morphine may be considered in the management of auto-
nomic dysfunction. Magnesium sulfate infusion has been
shown to reduce the requirement for other drugs to control
muscle spasms and cardiovascular instability.82
Conclusions
Neuromuscular emergencies represent a diverse collection
of disorders with a wide range of clinical manifestations.
These disorders frequently present with sudden onset or
rapid progression of motor dysfunction that can result in
respiratory failure, irreversible loss of peripheral nerve, or
threaten damage to other organ systems. Prompt identifica-
tion and appropriate management of these disorders in an
Seminars in Neurology Vol. 39 No. 1/2019
acute care setting is essential to minimizing both mortality
and long-term morbidity in affected patients.
Conflict of Interest
None.
References
1 Rabinstein AA, Wijdicks EF. Warning signs of imminent respira-
tory failure in neurological patients. Semin Neurol 2003;23(01):
97–104
2 Harik-Khan RI, Wise RA, Fozard JL; The Baltimore Longitudinal
Study of Aging. Determinants of maximal inspiratory pressure.
Am J Respir Crit Care Med 1998;158(5, Pt 1):1459–1464
3 Elsheikh B, Arnold WD, Gharibshahi S, Reynolds J, Freimer M,
Kissel JT. Correlation of single-breath count test and neck flexor
muscle strength with spirometry in myasthenia gravis. Muscle
Nerve 2016;53(01):134–136
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
4 Luo F, Annane D, Orlikowski D, et al. Invasive versus non-invasive
ventilation for acute respiratory failure in neuromuscular disease and
chest wall disorders. Cochrane Database Syst Rev 2017;12:CD008380
5 Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF.
Anticipating mechanical ventilation in Guillain-Barré syndrome.
Arch Neurol 2001;58(06):893–898
6 Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired
sedation and ventilator weaning protocol for mechanically ven-
tilated patients in intensive care (Awakening and Breathing
Controlled trial): a randomised controlled trial. Lancet 2008;
371(9607):126–134
7 Ely EW, Baker AM, Dunagan DP, et al. Effect on the duration of
mechanical ventilation of identifying patients capable of breath-
ing spontaneously. N Engl J Med 1996;335(25):1864–1869
8 Ouellette DR, Patel S, Girard TD, et al. Liberation from mechanical
ventilation in critically ill adults: an official American College of
Chest Physicians/American Thoracic Society Clinical Practice
Guideline: inspiratory pressure augmentation during sponta-
neous breathing trials, protocols minimizing sedation, and non-
invasive ventilation immediately after extubation. Chest 2017;
151(01):166–180
9 Schmidt GA, Girard TD, Kress JP, et al; ATS/CHEST Ad Hoc
Committee on Liberation from Mechanical Ventilation in Adults.
Official executive summary of an American Thoracic Society/
American College of Chest Physicians Clinical Practice Guideline:
liberation from mechanical ventilation in critically ill adults. Am J
Respir Crit Care Med 2017;195(01):115–119
10 Bird SJ. Diagnosis of myasthenia gravis. Post TW, ed. UpToDate.
2018. Available at: https://www.uptodate.com/contents/diagno-
sis-of-myasthenia-gravis. Accessed July 30, 2018
11 Castleman B. The pathology of the thymus gland in myasthenia
gravis. Ann N Y Acad Sci 1966;135(01):496–505
12 Sanders DB, Wolfe GI, Benatar M, et al. International consensus
guidance for management of myasthenia gravis: executive sum-
mary. Neurology 2016;87(04):419–425
13 Wendell LC, Levine JM. Myasthenic crisis. Neurohospitalist 2011;
1(01):16–22
14 Alshekhlee A, Miles JD, Katirji B, Preston DC, Kaminski HJ.
Incidence and mortality rates of myasthenia gravis and myasthe-
nic crisis in US hospitals. Neurology 2009;72(18):1548–1554
15 Berrouschot J, Baumann I, Kalischewski P, Sterker M, Schneider D.
Therapy of myasthenic crisis. Crit Care Med 1997;25(07):1228–1235
16 Rabinstein AA, Mueller-Kronast N. Risk of extubation failure in
patients with myasthenic crisis. Neurocrit Care 2005;3(03):213–215
17 O’Riordan JI, Miller DH, Mottershead JP, Hirsch NP, Howard RS. The
management and outcome of patients with myasthenia gravis
treated acutely in a neurological intensive care unit. Eur J Neurol
1998;5(02):137–142
 Acute Manifestations of Neuromuscular Disease
18 London ZN, Mundwiler A, Oral H, Gallagher GW. Nerve conduc-
tion studies are safe in patients with central venous catheters.
Muscle Nerve 2017;56(02):321–323
19 Seneviratne J, Mandrekar J, Wijdicks EF, Rabinstein AA. Predictors
of extubation failure in myasthenic crisis. Arch Neurol 2008;65
(07):929–933
20 Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical
features, mortality, complications, and risk factors for prolonged
intubation. Neurology 1997;48(05):1253–1260
21 Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group.
Randomized trial of thymectomy in myasthenia gravis. N Engl J
Med 2016;375(06):511–522
22 Centers for Disease Control and Prevention (CDC). National
Botulism Surveillance Summary. 2016. Available at: https://
www.cdc.gov/botulism/pdf/Botulism-2016-SUMMARY-508.pdf.
Accessed on July 25, 2018
23 Barash JR, Arnon SS. A novel strain of Clostridium botulinum that
produces type B and type H botulinum toxins. J Infect Dis 2014;
209(02):183–191
24 Rossetto O, Megighian A, Scorzeto M, Montecucco C. Botulinum
neurotoxins. Toxicon 2013;67:31–36
25 Kumar R, Dhaliwal HP, Kukreja RV, Singh BR. The botulinum toxin as
a therapeutic agent: molecular structure and mechanism of action
in motor and sensory systems. Semin Neurol 2016;36(01):10–19
26 Sobel J. Botulism. Clin Infect Dis 2005;41(08):1167–1173
27 Chatham-Stephens K, Fleck-Derderian S, Johnson SD, Sobel J, Rao
AK, Meaney-Delman D. Clinical features of foodborne and wound
botulism: a systematic review of the literature, 1932-2015. Clin
Infect Dis 2017;66(Suppl 1):S11–S16
28 Rao AK, Lin NH, Griese SE, Chatham-Stephens K, Badell ML, Sobel J.
Clinical criteria to trigger suspicion for botulism: an evidence-based
tool to facilitate timely recognition of suspected cases during spora-
dic events and outbreaks. Clin Infect Dis 2017;66(Suppl 1):S38–S42
29 O’Horo JC, Harper EP, El Rafei A, et al. Efficacy of antitoxin therapy
in treating patients with foodborne botulism: a systematic review
and meta-analysis of cases, 1923-2016. Clin Infect Dis 2017;66
(Suppl 1):S43–S56
30 Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population inci-
dence of Guillain-Barré syndrome: a systematic review and meta-
analysis. Neuroepidemiology 2011;36(02):123–133
31 Alshekhlee A, Hussain Z, Sultan B, Katirji B. Guillain-Barré syn-
drome: incidence and mortality rates in US hospitals. Neurology
2008;70(18):1608–1613
32 Hadden RD, Cornblath DR, Hughes RA, et al; Plasma Exchange/
Sandoglobulin Guillain-Barré Syndrome Trial Group. Electrophy-
siological classification of Guillain-Barré syndrome: clinical asso-
ciations and outcome. Ann Neurol 1998;44(05):780–788
33 Yuki N, Hartung HP. Guillain-Barré syndrome. N Engl J Med 2012;
366(24):2294–2304
34 Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome.
Lancet 2016;388(10045):717–727
35 Anandan C, Khuder SA, Koffman BM. Prevalence of autonomic
dysfunction in hospitalized patients with Guillain-Barré syn-
drome. Muscle Nerve 2017;56(02):331–333
36 Sharshar T, Chevret S, Bourdain F, Raphaël JC; French Cooperative
Group on Plasma Exchange in Guillain-Barré Syndrome. Early
predictors of mechanical ventilation in Guillain-Barré syndrome.
Crit Care Med 2003;31(01):278–283
37 Ogawara K, Kuwabara S, Mori M, Hattori T, Koga M, Yuki N. Axonal
Guillain-Barré syndrome: relation to anti-ganglioside antibodies
and Campylobacter jejuni infection in Japan. Ann Neurol 2000;48
(04):624–631
38 Ye Y, Wang K, Deng F, Xing Y. Electrophysiological subtypes and
prognosis of Guillain-Barré syndrome in northeastern China.
Muscle Nerve 2013;47(01):68–71
39 Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA,
Jacobs BC. Diagnosis of Guillain-Barré syndrome and validation of
Brighton criteria. Brain 2014;137(Pt 1):33–43
Edmundson, Bird 123
40 Wong AH, Umapathi T, Nishimoto Y, Wang YZ, Chan YC, Yuki N.
Cytoalbuminologic dissociation in Asian patients with Guillain-
Barré and Miller Fisher syndromes. J Peripher Nerv Syst 2015;20
(01):47–51
41 Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome:
clinical and immunological range. J Neurol Neurosurg Psychiatry
2001;70(01):50–55
42 Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum anti-
GQ1b IgG antibody is associated with ophthalmoplegia in Miller
Fisher syndrome and Guillain-Barré syndrome: clinical and immu-
nohistochemical studies. Neurology 1993;43(10):1911–1917
43 Willison HJ, Veitch J, Paterson G, Kennedy PG. Miller Fisher
syndrome is associated with serum antibodies to GQ1b ganglio-
side. J Neurol Neurosurg Psychiatry 1993;56(02):204–206
44 Bertorini T, Halford H, Lawrence J, Vo D, Wassef M. Contrast-
enhanced magnetic resonance imaging of the lumbosacral roots
in the dysimmune inflammatory polyneuropathies. J Neuroima-
ging 1995;5(01):9–15
45 Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-
Barré syndrome. Cochrane Database Syst Rev 2017;2:CD001798
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
46 Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin
for Guillain-Barré syndrome. Cochrane Database Syst Rev 2014;
(09):CD002063
47 Nance JR, Mammen AL. Diagnostic evaluation of rhabdomyolysis.
Muscle Nerve 2015;51(06):793–810
48 Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evalua-
tion of 475 hospitalized patients. Medicine (Baltimore) 2005;84
(06):377–385
49 Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyo-
lysis. Medicine (Baltimore) 1982;61(03):141–152
50 Zager RA. Combined mannitol and deferoxamine therapy for
myohemoglobinuric renal injury and oxidant tubular stress.
Mechanistic and therapeutic implications. J Clin Invest 1992;90
(03):711–719
51 Liu ZZ, Mathia S, Pahlitzsch T, et al. Myoglobin facilitates angio-
tensin II-induced constriction of renal afferent arterioles. Am J
Physiol Renal Physiol 2017;312(05):F908–F916
52 Llach F, Felsenfeld AJ, Haussler MR. The pathophysiology of altered
calcium metabolism in rhabdomyolysis-induced acute renal fail-
ure. Interactions of parathyroid hormone, 25-hydroxycholecalci-
ferol, and 1,25-dihydroxycholecalciferol. N Engl J Med 1981;305
(03):117–123
53 Akmal M, Bishop JE, Telfer N, Norman AW, Massry SG. Hypocal-
cemia and hypercalcemia in patients with rhabdomyolysis with
and without acute renal failure. J Clin Endocrinol Metab 1986;63
(01):137–142
54 Scharman EJ, Troutman WG. Prevention of kidney injury follow-
ing rhabdomyolysis: a systematic review. Ann Pharmacother
2013;47(01):90–105
55 de Meijer AR, Fikkers BG, de Keijzer MH, van Engelen BG, Drenth
JP. Serum creatine kinase as predictor of clinical course in
rhabdomyolysis: a 5-year intensive care survey. Intensive Care
Med 2003;29(07):1121–1125
56 Mikkelsen TS, Toft P. Prognostic value, kinetics and effect of
CVVHDF on serum of the myoglobin and creatine kinase in
critically ill patients with rhabdomyolysis. Acta Anaesthesiol
Scand 2005;49(06):859–864
57 Wappler F. Malignant hyperthermia. Eur J Anaesthesiol 2001;18
(10):632–652
58 Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB.
Clinical presentation, treatment, and complications of malignant
hyperthermia in North America from 1987 to 2006. Anesth Analg
2010;110(02):498–507
59 Litman RS, Griggs SM, Dowling JJ, Riazi S. Malignant hyperthermia
susceptibility and related diseases. Anesthesiology 2018;128
(01):159–167
60 Riazi S, Larach MG, Hu C, Wijeysundera D, Massey C, Kraeva N.
Malignant hyperthermia in Canada: characteristics of index
Seminars in Neurology Vol. 39 No. 1/2019
124 Acute Manifestations of Neuromuscular Disease Edmundson, Bird
anesthetics in 129 malignant hyperthermia susceptible probands.
Anesth Analg 2014;118(02):381–387
61 Schneiderbanger D, Johannsen S, Roewer N, Schuster F. Manage-
ment of malignant hyperthermia: diagnosis and treatment. Ther
Clin Risk Manag 2014;10:355–362
62 Paul-Pletzer K, Yamamoto T, Bhat MB, et al. Identification of a
dantrolene-binding sequence on the skeletal muscle ryanodine
receptor. J Biol Chem 2002;277(38):34918–34923
63 Suresh S, Forgie S, Robinson J. Non-polio enterovirus detection
with acute flaccid paralysis: A systematic review. J Med Virol
2018;90(01):3–7
64 Petersen LR, Brault AC, Nasci RS. West Nile virus: review of the
literature. JAMA 2013;310(03):308–315
65 Greninger AL, Naccache SN, Messacar K, et al. A novel outbreak
enterovirus D68 strain associated with acute flaccid myelitis
cases in the USA (2012-14): a retrospective cohort study. Lancet
Infect Dis 2015;15(06):671–682
66 Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical
features, diagnosis, and management of enterovirus 71. Lancet
Neurol 2010;9(11):1097–1105
67 Howard RS. Poliomyelitis and the postpolio syndrome. BMJ 2005;
330(7503):1314–1318
68 Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive
disease. Ann Neurol 2006;60(03):286–300
69 Tyler KL, Pape J, Goody RJ, Corkill M, Kleinschmidt-DeMasters BK.
CSF findings in 250 patients with serologically confirmed West Nile
virus meningitis and encephalitis. Neurology 2006;66(03):361–365
70 Hart J Jr, Tillman G, Kraut MA, et al; NIAID Collaborative Antiviral
Study Group West Nile Virus 210 Protocol Team. West Nile virus
neuroinvasive disease: neurological manifestations and prospec-
tive longitudinal outcomes. BMC Infect Dis 2014;14:248
71 Farrar JJ, Yen LM, Cook T, et al. Tetanus. J Neurol Neurosurg
Psychiatry 2000;69(03):292–301
Seminars in Neurology Vol. 39 No. 1/2019
72 Lalli G, Bohnert S, Deinhardt K, Verastegui C, Schiavo G. The
journey of tetanus and botulinum neurotoxins in neurons. Trends
Microbiol 2003;11(09):431–437
73 Centers for Disease Control and Prevention (CDC). Tetanus sur-
veillance — United States, 2001-2008. MMWR Morb Mortal Wkly
Rep 2011;60(12):365–369
74 Afshar M, Raju M, Ansell D, Bleck TP. Narrative review: tetanus-a
health threat after natural disasters in developing countries. Ann
Intern Med 2011;154(05):329–335
75 Saltoglu N, Tasova Y, Midikli D, Burgut R, Dündar IH. Prognostic
factors affecting deaths from adult tetanus. Clin Microbiol Infect
2004;10(03):229–233
76 Bunch TJ, Thalji MK, Pellikka PA, Aksamit TR. Respiratory failure in
tetanus: case report and review of a 25-year experience. Chest
2002;122(04):1488–1492
77 Thwaites CL, Yen LM, Cordon SM, et al. Urinary catecholamine
excretion in tetanus. Anaesthesia 2006;61(04):355–359
78 Thwaites CL, Beeching NJ, Newton CR. Maternal and neonatal
tetanus. Lancet 2015;385(9965):362–370
79 Campbell JI, Lam TM, Huynh TL, et al. Microbiologic characteriza-
Downloaded by: University of Massachusetts - Amherst. Copyrighted material.
tion and antimicrobial susceptibility of Clostridium tetani isolated
from wounds of patients with clinically diagnosed tetanus. Am J
Trop Med Hyg 2009;80(05):827–831
80 Ganesh Kumar AV, Kothari VM, Krishnan A, Karnad DR. Ben-
zathine penicillin, metronidazole and benzyl penicillin in the
treatment of tetanus: a randomized, controlled trial. Ann Trop
Med Parasitol 2004;98(01):59–63
81 Ahmadsyah I, Salim A. Treatment of tetanus: an open study to
compare the efficacy of procaine penicillin and metronidazole. Br
Med J (Clin Res Ed) 1985;291(6496):648–650
82 Thwaites CL, Yen LM, Loan HT, et al. Magnesium sulphate for
treatment of severe tetanus: a randomised controlled trial. Lancet
2006;368(9545):1436–1443