Critical illness myopathy and neuropathy
Nicola Latronico, Elena Peli and Marco Botteri
Purpose of review
To present the major pathophysiological and diagnostic
features of critical illness myopathy (CIM) and
polyneuropathy (CIP), and to discuss problems concerning
the risk factors for CIM and CIP.
Recent findings
The pathophysiology of critical illness myopathy and
critical illness polyneuropathy is complex, involving
metabolic, inflammatory, and bioenergetic alterations. This
review cites new evidence supporting several
pathogenetic mechanisms. These include microvascular
changes in peripheral nerves (with increased endothelial
expression of E-selectin), the possible role for an altered
lipid serum profile in promoting organ dysfunction
(including nerve dysfunction), the damage or inhibition of
complex I of the respiratory chain as a cause of muscle
ATP depletion and bioenergetic failure, and the activation
of specific intracellular proteolytic systems causing
myofilament loss and apoptosis in CIM. The diagnostic
role of direct muscle stimulation and the rapid
quantification of myosin/actin ratio based on
electrophoresis are also presented.
Summary
Basic and clinical research is unraveling the
pathophysiological mechanisms of critical illness myopathy
and polyneuropathy, and methods for rapid diagnosis are
actively investigated. Future studies should better define
the population at risk of developing CIM and CIP. In fact,
although sepsis, multi-organ failure and steroids are often
cited as risk factors, uncertainty remains due to the poor
methodological quality of studies, or because of inferences
that are exclusively based on animal studies. New simplified
diagnostic techniques and machines for
electrophysiological investigations of peripheral nerves and
muscles in the intensive-care unit (ICU) patient would also
be welcome.
Keywords
mitochondrial dysfunction, multi-organ failure, myopathy,
neuropathy, polyneuropathy, sepsis
—132. ª 2005 Lippincott Williams & Wilkins.
Curr Opin Crit Care 11:126—
Institute of Anesthesiology-Intensive Care, University of Brescia, Spedali Civili
Brescia, Italy
Correspondence to Prof. Nicola Latronico, MD, Institute of Anesthesiology-
Intensive Care, University of Brescia Piazzale Ospedali Civili, 1 — 25125 Brescia,
Italy
Tel: +39 030 3995841/570; fax: +39 030 3995570;
e-mail: latronic@med.unibs.it
Current Opinion in Critical Care 2005, 11:126—
—132
126
Abbreviations
CIM critical illness myopathy
CIP critical illness polyneuropathy
DMS direct muscle stimulation
GBS Guillain— —Barré syndrome
ICU intensive-care unit
ª 2005 Lippincott Williams & Wilkins.
1070-5295
Introduction
‘Spontaneous weaknesses indicate disease.’ Hippocrates,
460–377 B.C.
The finding that critically ill patients may develop acute
polyneuropathy that leads to muscle weakness and paral-
ysis is fairly recent. The first systematic studies, conducted
in the early 1980s, suggested critical illness polyneuropathy
(CIP) was an uncommon syndrome [1], however clinical
research in the last two decades has shown that CIP is
an important, severe and persistent complication among
critically ill patients admitted to the intensive care unit
(ICU). Research has also demonstrated that CIP is often
associated with critical illness myopathy (CIM). In fact,
starting from the early 1990s, several studies based
on muscle biopsies [2–15••], muscle–nerve biopsies
[16] or specialized electrophysiological investigations
[13,15••,17,18] have shown that CIM is as common as
CIP. CIP and CIM often coexist, making their differential
diagnosis difficult or even impossible. Many terms have
been suggested to describe such an association, namely
polyneuromyopathy [4,15••] critical illness myopathy
and neuropathy (CRIMYNE) [16,19] and critical illness
polyneuropathy and myopathy [12].
In this review, we present the major clinical, pathogenetic
and diagnostic features of CIP and CIM, and discuss the
recent research suggesting that metabolic, inflammatory,
and bioenergetic alterations may play pivotal roles in caus-
ing peripheral nerve and muscle dysfunction in critically
ill patients.
Critical illness polyneuropathy
CIP is an acute axonal sensory-motor polyneuropathy
(Fig. 1), mainly affecting the lower limb nerves of critically
ill patients.
Pathogenesis
Microcirculatory damage has long been postulated as a pos-
sible mechanism causing impaired peripheral nerve [20]
and organ perfusion [21]. Bolton suggested a key role
 Critical illness myopathy and neuropathy Latronico et al. 127

Figure 1. Major electroneurographic features in axonal and demyelinating neuropathy

In axonal neuropathy, the total number of fibers is reduced; therefore, the nerve action potential amplitude is also reduced. Surviving fibers have
normal myelin sheath; therefore, the nerve conduction velocity remains within normal limits. In demyelinating neuropathy, the total number of fibers
is normal; however, the majority of them have lost their myelin sheath. Therefore, the electroneurographic findings mirror those of axonal forms
with normal amplitude and reduced velocity. Modified from [54].

for excessive vasodilatation and aggregation of cellular ele-
ments through activation of adhesion molecules [20].
Recently, increased expression of E-selectin has been dem-
onstrated in the endothelium of the epineurial and endo-
neurial vessels of peripheral nerves in critically ill septic
patients with CIP [22••]. E-selectin is not expressed on
the vascular endothelium of small vessels under basal
condition; its expression is considered a marker of endo-
thelial cell activation. Increased expression of E-selectin,
which is induced by proinflammatory cytokines such as
TNF-a and IL1, may in turn promote endothelial-cell leu-
kocyte adhesion and extravasation of activated leukocytes
within the endoneurial space, where they can induce tis-
sue injury with local cytokine production. Furthermore,
cytokines increase vascular permeability, thus favoring
the passage of neurotoxic factors into the endoneurium
[20,23].
Although the evidence supporting a microvascular pertur-
bation in sepsis and critical illness is robust, the direct in-
volvement of intracellular mechanisms is also evident
[24]. Sepsis and critical illness are complex conditions
in which inflammatory and metabolic events at a vascular
and cellular level contribute to organ failure. This is well
demonstrated by the substantial reduction of mortality
and morbidity (including CIP) in critically ill patients
treated with intensive insulin treatment [25].
Combined vascular and cellular events may cause a nerve
energy failure with reduced or absent nerve action poten-
tial, which in its early stages is a pure functional impair-
ment that can be documented by electrophysiological
investigations. With persisting critical illness, energy
supply and use are not restored and histologic alterations
ensue. Support for this theory comes from a previous
study, in which we found altered nerve function with pre-
served nerve structure in patients undergoing early nerve
biopsy, and altered function and structure in patients un-
dergoing late biopsy [16]. Hotchkiss et al. [26] also showed
a net divergence between in-vivo evidence of organ failure
and absence of histologic evidence of substantial organ
damage in patients dying of multi-organ failure, indicating
that cellular energy crisis with consequent functional im-
pairment can be a key process in critical illness.
Diagnosing critical illness polyneuropathy
The electroneurographic pattern in CIP is characterized
by an amplitude reduction of the nerve action potentials
(compound motor, sensory or both) with preserved normal
conduction velocity (Fig. 1). Conversely, in Guillain–Barré
syndrome (GBS), a demyelinating polyradiculoneuritis,
amplitude is normal and velocity is reduced (Fig. 1). Even
though such characteristic electroneurographic patterns
are useful to distinguishing the two syndromes, it is the
history and clinical findings that lead to the differential
diagnosis.
CIP is a relatively common complication conceivably aris-
ing during the ICU stay in the most severe critically ill
patients admitted to the ICU with a variety of medical,
128 Neuroscience
surgical and traumatic causes. No studies have prospec-
tively assessed the evolution of CIP starting at the time
of ICU admission in patients CIP-free. GBS is a rare
immune-mediated disease affecting 1–2 per 100000 pre-
viously healthy people. An infection, most frequently
a Campylobacter jejuni infection with diarrhea, precedes
by 2–3 weeks the onset of progressive weakness and sen-
sory disturbances (tingling, numbness, sometimes pain) in
two-thirds of cases. Importantly, inflammatory signs have
subsided by the time neurologic signs become evident. In
30% of cases the progression of disease causes the involve-
ment of the neuromuscular respiratory system with respi-
ratory failure needing ICU admission and mechanical
ventilation [27].
Clinical diagnosis is particularly important when dealing
with GBS cases with axonal pattern (5% of cases) [28]
or CIP cases with mixed axonal and demyelinating pattern
[29]. Before CIP was characterized, GBS was often
reported in critically ill patients after major surgery or
trauma. These may well have been CIP cases [30], but
this is still debated. Distinction between GBS and CIP
is important not only from a nosological perspective but
also for disease management, since specific treatments
are available for GBS [31,32], but not for CIP.
How many patients develop critical
illness polyneuropathy?
The real occurrence of CIP is enormously influenced by
a patient’s case-mix, diagnostic criteria and timing of ex-
amination. Although reported percentages are rather
impressive – 58% of patients with prolonged ICU stay
[33], 70 to 80% of patients with sepsis, septic shock or
multi-organ failure [34–37], 100% of patients with sepsis
and coma [16] – the number of patients with CIP dis-
charged from the ICU is small [19]. It is still unclear
whether this is due to the fact that CIP complicates the
clinical course of a subset of very severe critically ill patients
or is due to selection bias. For instance, in one study con-
ducted by De Jonghe et al. [38] inclusion criteria were me-
chanical ventilation lasting at least one week and recovery
of consciousness. The study involved 5 French ICUs,
lasted 15 months and enrolled 95 patients. Although the
authors defined this population as unselected, several
hundred patients had probably been admitted to their
ICUs during the study period. This is common to all
the series analyzed so far.
The method used to define diagnosis used can also influ-
ence the occurrence of CIP. Neurologic examination is less
sensitive than electrophysiological evaluation, and would
probably leave a substantial number of CIP patients
undiagnosed. On the other hand, electrophysiological
investigations would detect cases of CIP of little or no
clinical relevance. Finally, the timing of examination is
relevant, since CIP improves over time.
Critical illness myopathy
The term CIM describes an acute primary myopathy caus-
ing muscle weakness and paralysis in critically ill patients.
In 1997, Leijten [39] proposed that CIM should be
regarded as a correlate of CIP. In 1998, we [40] proposed
CIM as a comprehensive term to describe those myopa-
thies with pure functional impairment and normal histol-
ogy (acute quadriplegic myopathy), as well as those with
atrophy and necrosis. Necrosis can be subtle, requiring
electron microscopy for diagnosis (thick filament myopa-
thy), or it can be visible on optical microscopy, either as
sparse, diffuse or even massive lesions (acute necrotizing
myopathy). Recently, other authors have re-proposed this
definition, indicating a list of major and supporting elec-
trophysiological, histologic and biochemical criteria to
diagnose CIM [41]. Apart from leaving out a formal defi-
nition of critical illness, which should be preliminary, some
of the proposed criteria are questionable. For example,
major EMG criteria require the patient’s collaboration,
and cannot be used in unconscious patients; loss of myosin
at histology can be lacking in pure functional forms; serum
CK can be normal (as it commonly is) if muscle necrosis is
absent or scattered; sensory nerve action potential can be
abnormal since CIM and CIP may coexist. It is important
to emphasize that CIM is a primary myopathy, that is, not
secondary to muscle denervation. Histologic examination
often reveals signs of both primary (necrosis) and second-
ary (type grouping following nerve regeneration) myopa-
thy [16], indicating that CIM and CIP coexist.
Pathogenesis
In recent years, substantial progress has been made to
explain how muscle may become unexcitable while main-
taining a normal structure. Using an experimental model
with denervated rat muscle fibers and high-dose steroid,
Rich et al. demonstrated that the muscle may become com-
pletely unexcitable because of the combination of various
events: denervation-induced reduction in muscle resting
potential (from normal values of ÿ85 mV to ÿ60 mV), lack
of postdenervation down-regulation of membrane chloride
conduction [42], and shift in the voltage dependence of so-
dium channel fast inactivation to more negative potentials
(ÿ11 mV) [43,44••]. The hyperpolarizing shift of voltage-
dependence of sodium channel fast inactivation is of crucial
importance to reduce excitability in both denervated and
steroid-denervated fibers [44••], and is mainly, although
not exclusively, caused by steroids. Because a small per-
centage of denervated fibers also exhibit this same shift
in fast inactivation, it appears that corticosteroid treatment
simply increases the percentage of fibers that exhibit this
change [44••]. The density of embryonic sodium channel
isoform is increased in the model of steroid-denervated
fibers [42], however its level did not correlate closely with
the shift in fast inactivation [45••]. Rather, inactivation of
both embryonic (Nav1.5) and adult (Nav1.4) sodium

channel isoforms was shifted towards hyperpolarized
potentials. The limits of the steroid-denervation model is
the fact that high-dose steroids were used, an uncommon
clinical situation. In addition, cases with sudden onset of
paralysis and rapid recovery have been described in patients
not receiving steroids [46,47], indicating that other factors
can also be responsible for transmembrane resting potential
and sodium channel alteration.
Mitochondrial dysfunction is another piece of the puzzle,
which may be responsible for muscle function impairment.
Brealey et al. showed that the severity of sepsis correlated
with mitochondrial dysfunction, ATP depletion, intracellu-
lar glutathione depletion, and nitric oxide production in
skeletal muscle [14]. The low activity of the complex I
of the respiratory chain was probably caused by nitric ox-
ide, a reactive oxygen and nitrogen species, and was facil-
itated by depletion of the intracellular antioxidant reduced
glutathione. Damage or inhibition of complex I was in turn
responsible for decreasing the mitochondrial capability to
generate ATP. Bioenergetic failure is therefore an impor-
tant pathogenetic mechanism underlying sepsis-induced
muscle failure, similar to that described for peripheral
nerve failure (see above). Whether bioenergetic failure
correlates with muscle transmembrane resting potential
and sodium channel alteration remains unanswered.
The ultimate effectors of proteolysis are intracellular
proteolytic systems, namely the ubiquitin-proteasome,
calpains, lysosomal and non-lysosomal systems [48–50].
Activation of proteolytic systems, particularly ubiquitin-
proteasome and calpains, has long recognized to play
a role in CIM [4,40,51]. Pro-inflammatory cytokines, to-
gether with decreased levels of anabolic hormones (insu-
lin and insulin-like growth factor-1), and increased levels
of catabolic hormones (cortisol, catecholamines and glu-
cagon), generate a powerful catabolic effect, possibly to
make muscle amino acids available for key processes
[40]. Recently, Di Giovanni et al. [52••] studying patients
with CIM and muscle atrophy, showed that, while the ac-
tivation of the ubiquitine ligase pathway was common to
neurogenic and myogenic atrophy, only patients with
CIM activated the transforming growth factor (TGF)-
beta/MAPK pathway. TGF-beta/MAPK cascade is not
dysregulated in inflammatory myopathies associated with
necrotic features, including dermatomyositis, polymyositis
and inclusion body myopathy, and may represent a specific
feature of CIM leading to myofilament loss and apoptosis.
Diagnosing critical illness myopathy
Diagnosis of CIM and differential diagnosis between CIP
and CIM are often not possible in ICU patients for several
reasons. First, clinical differentiation is unreliable, because
patients cannot cooperate for accurate sensory and (in
some cases) motor testing. Second, needle electromyogra-
phy can help distinguish between the two entities only
Critical illness myopathy and neuropathy Latronico et al. 129
with fully cooperative patients [39]. In the usual ICU con-
dition, voluntary motor unit potential recruitment is often
absent or nonsustained because of severe weakness or poor
voluntary effort, therefore precluding a conclusive distinc-
tion between CIP and CIM based on recruitment patterns
and motor unit morphology. Third, routine studies provide
nonspecific data in both illnesses, including low-amplitude
compound muscle action potential, fibrillation potentials
and positive sharp waves. Preserved sensory nerve action
potential amplitude is not a unique feature of CIM, since
pure motor forms of CIP have been described [16,53]. Iso-
lated sensory nerve action potential amplitude reduction
rules out an ongoing myopathy, provided technical prob-
lems such as limb edema are excluded; however pure
sensory CIP is exceedingly rare [53]. Finally, as previously
cited, CIP and CIM often coexist.
Direct muscle stimulation (DMS) combined with stan-
dard investigation has been proposed to overcome some
of these problems [17,18]. In DMS both the stimulating
and the recording electrodes are placed in the muscle dis-
tal to the end-plate zone (Fig. 2) [54]. A patient with neu-
ropathy will have a reduced or absent action potential
when using conventional stimulation (i.e. through the
motor nerve), but normal action potential when using
DMS (Fig. 2b); in the case of myopathy, the action poten-
tial will be reduced or absent after both conventional stim-
ulation and DMS (Fig. 2c). Despite the apparent simplicity
of the technique, DMS is technically demanding and
requires thorough practice to obtain reliable results [15••].
Muscle biopsy is an invasive method, and results are not
immediately available. A percutaneous method using
a conchotome reduces invasiveness to a minimum. Rapid
methods (24 hours) to quantify the myosin/actin ratio
based on electrophoresis are also being studied [55••].
Stibler et al. showed that a mean value of the myosin/actin
ratio was 1.37 (SD 0.21) in controls and 0.37 (SD 0.17) in
CIM patients, without overlapping values [55••]. In cases
of persisting muscle weakness or paralysis of uncertain
cause, open muscle biopsy can rarely be indicated to ex-
clude infectious causes; inflammatory infiltrates are typi-
cally absent in CIM.
How many patients develop critical
illness myopathy?
The true occurrence of CIM is unknown. As for CIP, the
patient’s case-mix, the diagnostic criteria used, and the
timing of evaluation are factors influencing the occurrence
of CIM. The crude proportion of critically ill patients
reported to develop CIM varies substantially among cen-
ters and is useless, if population – the denominator of the
proportion – is not clearly defined. As an example, the oc-
currence of CIM was 0.09% of patients admitted when all
admissions in a 5-year period were considered (39 patients
130 Neuroscience
Figure 2. Direct muscle stimulation
With this technique, both the stimulating and the
recording electrodes are placed in the muscle so
that the action potential can be obtained even if the
nerve is damaged. In case of myopathy, the action
potential will be reduced or absent after
conventional stimulation through the nerve and
direct muscle stimulation. Modified from [54].
with CIM out of 44,000 patients admitted) [32], and 7%
when only 100 critically ill patients undergoing liver trans-
plantation in the same institution were considered [56].
We suggest using as a denominator the number of patients
with at least one organ failure defined according to the
Sequential Organ Failure Assessment (SOFA) score, which
has been validated for repeated daily evaluation [57,58].
Risk factors for critical illness myopathy
and polyneuropathy
Sepsis, multi-organ dysfunction syndrome, multi-organ
failure, female sex, use of corticosteroids, severe asthma,
ionic abnormalities, malnutrition and immobility are fre-
quently cited causes of CIP and CIM in humans [2,5–
7,14,16,18,33,35–38]. As already noted, many of these
studies selectively included patients with the risk factor
under evaluation, thus precluding a definite answer. In
De Jonghe et al.’s systematic review [33] the authors’ con-
clusion was that there was no strong evidence from clinical
studies to support unequivocally a causal relation between
sepsis and CIP or CIM. In the prospective, multicenter
cohort study from the same group [38], sepsis was not as-
sociated with ICU acquired paresis. Hyperglycemia is risk
factor for CIP [25]; however, normalization of the serum
lipid profile rather than glucose control independently
determines the beneficial effects of intensive insulin ther-
apy on morbidity and mortality [59••].
Conclusions
CIP and CIM complicate the clinical course of the most
severely ill patients admitted to ICUs. Future studies
should better define the clinical characteristics of such
patients to make different series comparable, and to de-
fine risk factors accurately. Defining a population at risk
of developing CIP, CIM or both would be of great interest
to patients, since these neuromuscular complications may
last for months or years after ICU discharge, causing
chronic disability [60–62]. The availability of simplified
diagnostic techniques and machines for electrophysiolog-
ical investigations of peripheral nerves and muscles in the
ICU patient would also be welcome.
Acknowledgement
We are indebted to Diego Manzoni, MD, who carefully reviewed this paper.
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