ABSTRACT: Recent studies have demonstrated acquired muscle inexcit-

ability in critical illness myopathy (CIM) and have used direct muscle stim-
ulation (DMS) techniques to distinguish neuropathy from myopathy as a
cause of weakness in the critically ill. The mechanisms underlying weakness
in CIM are incompletely understood and DMS is only semiquantitative. We
report results from a series of 32 patients with CIM and demonstrate signif-
icant slowing of muscle-fiber conduction velocity (MFCV) and muscle-fiber
conduction block during the acute phase of CIM, which correlates with
prolonged compound muscle action potential (CMAP) duration, clinical se-
verity, and course. We also used a paired stimulation technique to explore
the excitability of individual muscle fibers in vivo. We demonstrate altered
muscle-fiber excitability in CIM patients. Serial studies help define the
course of these pathophysiological changes. Parallels are made between
CIM and hypokalemic periodic paralysis. Our findings provide further evi-
dence for muscle membrane dysfunction being the principal underlying
abnormality in CIM.
Muscle Nerve 37: 14 –22, 2008

CRITICAL ILLNESS MYOPATHY: FURTHER EVIDENCE

FROM MUSCLE-FIBER EXCITABILITY
STUDIES OF AN ACQUIRED CHANNELOPATHY
DAVID C. ALLEN, MB, BS, RAMAMURTHY ARUNACHALAM, MD, and KERRY R. MILLS, PhD

Academic Unit of Clinical Neurophysiology, Guy’s, King’s & St. Thomas’ School of Medicine,
King’s College Hospital, London SE5 9RS, UK

Accepted 19 July 2007

Muscle weakness is common in the intensive care
unit (ICU). The differential diagnosis includes crit-
ical illness myopathy (CIM) or polyneuropathy
(CIP), demyelinating or axonal forms of Guillain–
Barré syndrome, neuromuscular junction disorders,
and central causes. The acquired neuromuscular dis-
orders frequently present as difficulty in weaning
from a ventilator and diffuse flaccid weakness. Clin-
ical examination in the ICU is often a poor differ-
entiator between myopathic and neurogenic causes,
and both can be associated with spontaneous activity
on needle electromyography (EMG) and reduced
Abbreviations: APB, abductor pollicis brevis; AH, abductor hallucis; CIM,
critical illness myopathy; CIP, critical illness polyneuropathy; CK, creatine
kinase; CMAP, compound muscle action potential; DMS, direct muscle stim-
ulation; EMG, electromyography; HPP, hypokalemic periodic paralysis; ICU,
intensive care unit; ISI, interstimulus interval; MFCV, muscle-fiber conduction
velocity; MNS, motor nerve stimulation; MRC, Medical Research Council;
SNAP, sensory nerve action potential; TA, tibialis anterior
Key words: compound muscle action potential; critical illness myopathy;
direct muscle stimulation; hypokalemic periodic paralysis; muscle-fiber con-
duction velocity
Correspondence to: R. Arunachalam, Southampton University Hospitals
NHS Trust, Tremona Road, Southampton SO16 6YD, UK; e-mail:
r.arunachalam@soton.ac.uk
© 2007 Wiley Periodicals, Inc.
Published online 30 August 2007 in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/mus.20884
amplitude of the compound muscle action potential
(CMAP) on motor nerve stimulation. Careful sen-
sory examination is also often not possible and sen-
sory nerve action potentials (SNAPs) may be difficult
to obtain due to edema and other factors in the
critically ill. Voluntary recruitment is often absent or
limited, making motor unit potential analysis diffi-
cult or impossible. Furthermore, low-amplitude
polyphasic motor unit potentials may be seen in
both myopathy and early reinnervation.
Debate has continued with respect to the primary
process in critical illness quadriplegia. Muscle-fiber
inexcitability in CIM has been demonstrated in ani-
mal models and by means of direct muscle stimula-
tion (DMS) in humans.32,33 Although only semiquan-
titative, this technique has subsequently been used to
distinguish between neuropathy and myopathy in
the ICU in several studies.2,25,33,43 It relies upon mea-
suring the ratio of the CMAP amplitude obtained
from nerve-mediated stimulation of a muscle and
direct stimulation of the same muscle. However, this
approach has potential pitfalls, one of them being
that the ratio will diagnose a myopathy in normal
muscle.
Bolton and others have noted a decline in am-
plitude and increase in duration of CMAPs in early

14 Critical Illness Myopathy MUSCLE & NERVE January 2008

CIM, suggesting primary dysfunction of the muscle-
fiber membrane.5,9,31 Although not the main empha-
sis of the investigation, one previous study has re-
ported evidence of slow muscle-fiber conduction
velocity (MFCV) in CIM.43 The investigators did not
draw particular attention to this finding, considering
it secondary to fiber diameter reduction; however,
they did demonstrate concurrent muscle inexcitabil-
ity, by means of reduced DMS CMAP amplitudes.
The interrelationships between CMAP parameters,
particularly duration, MFCV, and individual muscle-
fiber excitability in vivo, have not been studied pre-
viously.
The prime objective of this study was to deter-
mine whether there is dysfunction at the level of the
muscle membrane in human CIM. We aimed to
study the excitability characteristics of single muscle
fibers in vivo as well as to correlate these with CMAP
parameters and clinical findings.
PATIENTS AND METHODS
We studied 32 patients with CIM, with an average age
of 49 years. Patients were assessed clinically and un-
derwent neurophysiological examination including
nerve conduction studies, routine EMG, and repeti-
tive nerve stimulation at ICU bedside.
Patients diagnosed with CIM fulfilled the follow-
ing criteria: acute severe illness; acute quadriplegia
or quadriparesis; and no evidence of alternative di-
agnosis. Electrophysiologically, patients had normal
SNAPs and motor conduction velocities, small
CMAP amplitudes, and EMG findings consistent
with a myopathy or electrically inactive muscle. Pa-
tients with electrophysiological findings consistent
with other disorders were excluded.
We had no histological data, so accordingly,
where the clinical and electrophysiological findings
were consistent with a probable diagnosis of CIM in
line with the proposed criteria,22 we extended the
examination, when possible, to study MFCV and
muscle-fiber excitability. Lacomis et al. suggested
that evidence of muscle inexcitability might replace
histological evidence.22 Patients were classified
broadly into two categories according to their overall
muscle power, taken as an average. Patients who
were able to move limbs against gravity at grade 3 or
better on the Medical Research Council (MRC) scale
were classified as having mild–moderate weakness.
Those who had no movement of limbs or who could
only move with gravity eliminated (MRC grade 2)
were classified as having severe–very severe weak-
ness.
Critical Illness Myopathy
We used the technique for calculation of muscle-
fiber conduction velocity as described by Troni et
al.45 DMS of tibialis anterior (TA) muscle fibers with
a monopolar needle was performed in 7 patients
(age 14 –71 years) and in 5 control subjects (age
25–35 years) who had no known neuromuscular dis-
ease. This muscle was chosen specifically because of
its size, accessibility, longitudinally orientated mus-
cle fibers, and the eccentric location of the endplate
in relation to the muscle belly. Other muscles were
therefore not studied with this technique for these
reasons.
The endplate zone of the muscle was identified
using liminal surface stimulation, so this region was
avoided. A monopolar stimulating needle electrode
(26G, surface area 0.34 mm2; Teca, Oxford Instru-
ments, Old Woking, UK) was placed approximately
at the junction of the proximal two thirds with the
distal one third of the TA muscle belly. A concentric
recording needle electrode (26G; Teca, Oxford In-
struments, Old Woking, UK) was then inserted 50
mm proximally. Both needles were inserted to a
depth of about 20 mm perpendicular to the skin
surface and maintained in a perpendicular position
by taping the looped electrode leads to the skin
surface. A surface ground electrode was placed be-
tween the needles and a surface anode electrode was
placed 30 mm distal to the monopolar needle (Fig.
1). Fine needle manipulation and variation of the
stimulus strength resulted in recording a complex of
multiple single muscle-fiber action potentials
(MFAPs) (Fig. 2). Responses earlier than 8 ms were
likely to be conducted via intramuscular nerve twigs
and were not included.11 Sequential sweeps were
recorded to demonstrate that the responses were
stimulus-induced, all-or-none, stable, and reproduc-
ible. The technique took approximately 20 – 60 min-
utes to perform. Responses were frequently acquired
FIGURE 1. Electrode arrangement for MFCV studies in the tibi-
alis anterior.
MUSCLE & NERVE January 2008 15
 measured as the interval between CMAP onset and
the first zero crossing. CMAP parameters were mea-
sured in 26 patients and in 27 age-matched controls.
Although care was taken to obtain data from these

FIGURE 2. Multiple muscle-fiber action potentials obtained by DMS

and recording with a concentric needle placed at a 50-mm distance.

with stimulation at low intensity, typically between 1

and 3 mA (with stimulus duration of 0.1 ms). Muscle-
fiber action potentials were recorded using filter
settings between 500 Hz and 10 kHz. The needle was
repositioned along the 50-mm arc to exclude vari-
able muscle-fiber alignment in case of lack of re-
sponse. If still no response was seen at an interelec-
trode distance of 50 mm, the recording electrode
was moved toward the stimulating electrode (to a
measured distance between 20 and 30 mm). If after
repositioning no responses were obtained, the mus-
cle was assumed to be inexcitable. The latency to
each muscle-fiber action potential was measured and
MFCV calculated. The ratio of the fastest to the
slowest MFCV was also determined. The ambient
temperature in the ICU and the use of thermal
blankets ensured that the limbs tested were warm.
Hence, temperature was not measured routinely.
We assessed muscle-fiber excitability in 7 patients
and 5 normal controls using a paired stimulus pro-
tocol to measure muscle-fiber absolute refractory
period. We used the same electrode arrangement
and further manipulated needle tip positions (by
rotational and depth movements) and reduced stim-
ulus intensity in order to obtain a single, stable, and
well-defined muscle-fiber action potential. Paired
stimuli were applied and the interstimulus interval
(ISI) was then reduced in a stepwise fashion, to
predetermined intervals of 20, 10, 8, 6, 5, 4, 3, and 2
ms. The effect on the second response was observed
(Fig. 3). By a bracketing procedure, the refractory
period was measured where possible to the nearest
0.1 ms.

CMAP Measurements. CMAP duration in the abduc-
tor pollicis brevis (APB) and abductor hallucis (AH)
muscles from supramaximal stimulation of the me-
dian and posterior tibial nerves, respectively, was
FIGURE 3. Single muscle-fiber action potential response to
paired stimuli. The top trace is the response to a single stimulus
and below are responses to paired stimuli at intervals of 20, 10,
8, 6, 5, 4, 3, 2.5, and 2 ms, respectively. Note: The second action
potential is absent at an ISI of 2 ms.

16 Critical Illness Myopathy MUSCLE & NERVE January 2008

two chosen muscles, in 6 patients the CMAP data
were not available for the aforementioned muscles.
This was due either to inexcitability (2 patients) or
inaccessibility (4 patients) due to dressings, vascular
access, and other obstacles. Although it might have
seemed prudent to measure CMAP parameters from
TA, the considerable variability in normal responses
and the often-present initial positive component
would make such measurements unreliable. Further-
more, stimulation near the fibular head might inad-
vertently result in direct muscle stimulation, and
more proximal stimulation of the peroneal nerve is
unreliable.
We used unpaired t-tests to compare nerve con-
duction data and MFCVs. Non-parametric Mann–
Whitney U-tests were used for comparing results of
excitability studies.
RESULTS
Of the 32 patients included, 20 were still alive at the
time of writing. Twelve patients died secondary to
the underlying critical illness, although sometimes
weeks or even months after the onset of quadriple-
gia. The patients were in the ICU for variable peri-
ods of time, with most being referred for neurophys-
iological evaluation after difficult ventilatory
weaning. The precise duration of illness was not
available for most patients because of the difficulty in
dating the onset of the weakness, which had several
reasons. None of the patients had pre-existing or
other confounding neuromuscular disorders. Al-
though several patients had received some steroid
therapy, often early on during ICU admission, none
received them on a long-term or regular basis. None
of the patients had an elevated serum creatine kinase
(CK) to suggest a necrotic myopathy; the serum CK
ranged from 23 to 620 IU/L, at an average of 233
IU/L (normal: ⬍150 IU/L). Clinical and electro-
physiological findings suggested no alternative diag-
nosis.
CMAP Duration. CMAP durations were frequently
prolonged in CIM patients and possessed smooth
contours (Fig. 4). The mean CMAP duration record-
ing over APB in 25 patients was 9.0 ms (range 5.3–
30.3, SD 4.9 ms) compared with 5.0 ms in 26 controls
(SD 0.6, mean ⫹ 2 SD ⫽ 6.2 ms, range 3.9 – 6.3 ms)
(P ⬍ 0.0005). The mean CMAP duration over APB
was greater than the mean ⫹ 2 SD of the control
group in 18 of 25 (72%) patients. The mean CMAP
duration over AH in 16 patients was 9.4 ms (range
5.0 –17.1, SD 3.96) compared with 5.0 ms in 21 con-
trols (range 3.2– 6.7, SD 0.9, mean ⫹ 2 SD ⫽ 6.8 ms),
Critical Illness Myopathy
FIGURE 4. Synchronous dispersion causing a prolonged CMAP
in a patient with severe CIM (B) compared with a CMAP from a
control subject (A). Note the absence of the positive phase and
the long “tail” of the negative phase in the CMAP from the patient.
also significant (P ⬍ 0.0005). In 10 of 16 (63%)
patients, tibial CMAP duration values exceeded the
mean ⫹ 2 SD of the control group. No significant
difference in CMAP duration was noted between
proximal and distal stimulation sites; that is, there
was no abnormal temporal dispersion of nerve ori-
gin.
SNAP Amplitude and Duration. SNAP amplitude and
durations were not statistically different between pa-
tients and controls. Mean SNAP durations in pa-
tients were 1.1 ms, 1.2 ms, and 1.2 ms on median,
ulnar, and sural nerve stimulation. The correspond-
ing values for the controls were 1.1 (SD 0.11) ms, 1.1
(SD 0.08) ms, and 1.3 (SD 0.16) ms, respectively.
EMG. Needle EMG studies revealed spontaneous
activity, usually fibrillation potentials and positive
sharp waves, in 15 (47%) patients. Twenty-four pa-
tients (75%) had short-duration, low-amplitude mo-
tor unit potentials and early recruitment patterns at
some stage during their illness. In seven patients it
was not possible to assess motor units due to severe
weakness. In severely affected patients, no volitional
electrical activity was seen and the muscle was inex-
citable to direct simulation. Some of these patients
did, however, have abnormal spontaneous activity.
MFCV. We measured MFCV in 7 CIM patients and 5
controls. Two of the 7 patients had repeat examina-
tions during the recovery phase of the illness. Several
fibers were assessed in each patient and the MFCV
for each muscle fiber was calculated. In total, 146
muscle fibers were assessed in patients and 66 fibers
in controls. The mean MFCV in patient fibers was
MUSCLE & NERVE January 2008 17
2.32 m/s (SD 1.12, range 0.4 – 4.8), compared with a
mean of 4.02 m/s (SD 0.6, range 3.0 –5.5) in controls
(P ⫽ 0.004). However, this average value included
data from patients with a spectrum of clinical severity
ranging from mild–moderate to very severe. In ad-
dition, this value only included data when muscle
fibers were excitable; hence, data from the most
severely affected muscle fibers were not included. In
2 patients, muscle fibers were inexcitable at any dis-
tance. In 3 others, muscle-fiber action potentials
could only be obtained at shorter interelectrode dis-
tances (25 mm). Plotting MFCV values against the
CMAP duration values obtained during the same
examination for individual patients reveals an in-
verse correlation between them (Fig. 5). The mean
(⫾SD) ratio of fastest to slowest fibers was 3.02
(⫾0.71) in CIM patients compared with 1.65
(⫾0.15) in controls. This implies significantly larger
variation in MFCV in CIM patients (P ⬍ 0.003). No
significant difference in this ratio was observed be-
tween the moderate and severe groups of patients.
Excitability Studies. We defined muscle-fiber excit-
ability using the interstimulus interval (ISI) at which
the fiber identified became inexcitable to the second
of the paired stimuli. This reflects the absolute re-
fractory period of the fiber. The higher the ISI value,
the less excitable the fiber. We assessed 11 fibers in 6
patients and 12 fibers in 5 controls. The mean ISI at
which the second stimulus failed to generate an
action potential in patient fibers was 4.7 ms (range
2.2–20 ms) with more than half of the values being
⬎3.0 ms. This value included one outlier where the
ISI was 20 ms. This is in comparison to a mean of 2.5
ms (SD 0.33) for controls. To give a more meaning-
ful comparison of the groups, we recalculated the
statistics with this outlier excluded; the calculated
patient mean was 3.18 ms (SD 1.14). When the two
groups were compared, either with or without the
FIGURE 5. MFCV plotted against duration of CMAP recorded
over the abductor hallucis. MFCV of 0 indicates inexcitable mus-
cle.
18 Critical Illness Myopathy
20-ms outlier, there was no significant difference
(P ⬎ 0.05) between them, but in some patients’
muscles the fibers were completely inexcitable and
these data could not be included in the aforemen-
tioned analysis.
Case History. We include a brief case history to
emphasize the overall pattern of electrophysiological
findings in relation to the evolution of the illness.
A 30-year-old man was admitted to the ICU with
liver failure. He developed severe weakness diag-
nosed as CIM. We examined him on three occasions.
Normal SNAPs were recorded on each of these ex-
aminations. Needle EMG on the first examination
revealed electrical silence and inexcitable muscle
fibers to direct stimulation. On this occasion, CMAP
durations were 14.5 ms (median), 9.9 ms (ulnar),
and 13.0 ms (tibial), with amplitudes of 0.2 mV, 0.3
mV, and 1.2 mV, respectively. On the second exam-
ination 1 month later, when he was still very weak,
motor studies revealed a median CMAP amplitude of
0.1 mV with a duration of 30.3 ms, and tibial CMAP
amplitude of 1.5 mV with a duration of 17.1 ms. At
this stage, needle EMG revealed fibrillation poten-
tials and positive sharp waves in TA and biceps
brachii. Voluntary recruitment of APB was possible
and revealed low-amplitude, early-recruited motor
unit potentials. Muscle fibers remained inexcitable
to direct stimulation. A third examination after a
further 2 months during rehabilitation showed a
median CMAP amplitude of 3.3 mV with a duration
of 7.7 ms, and tibial CMAP amplitude of 1.4 mV with
a duration of 8.6 ms. Muscle fibers at this stage were
excitable and the mean MFCV at this time was 3.4
m/s. Clinically, the patient had power graded at 1 in
the right TA, 3 in left APB, and 4 in right AH. EMG
of the right TA and biceps brachii revealed early
motor-unit recruitment but no spontaneous activity
and no evidence of chronic partial denervation.
DISCUSSION
In this study we have demonstrated dysfunction at
the level of the muscle-fiber membrane in CIM. We
found a significant reduction in MFCV in CIM mus-
cle, which correlates inversely with significant pro-
longation of the surface-recorded CMAP duration.
We also found that muscle-fiber excitability is af-
fected in CIM.
CIM and CIP were both first described over 20
years ago.13,28 Both have been reported with a rela-
tively high incidence in ICU patients.8,14,17,21,49,51 In a
series of 92 patients with neuromuscular disorders in
the ICU, a myopathy consistent with CIM was three
MUSCLE & NERVE January 2008
times as common as axonal polyneuropathy (42% vs.
13%).21 Severe illness in itself can cause acute quad-
riplegic myopathy.40 Neither sepsis nor multiorgan
failure is a prerequisite to developing CIM.19 Mortal-
ity rates of 50% have been reported.8 In our series,
mortality was 38%, usually as a consequence of the
underlying illness. When biopsies are performed,
CIM patients have clear histological evidence of my-
opathy, in the presence of normal nerves.25,38 It is
possible that some patients have a “neuromyopathy.”
Differentiating muscle disease from a pure motor
neuropathy is challenging and relies on direct dem-
onstration of muscle dysfunction. There is dispute
over which are the most useful tests to distinguish
CIM and CIP.44
Nerve and muscle biopsy, including electron mi-
croscopy, can aid in the differentiation of CIP from
CIM, revealing normal peripheral and intramuscular
nerves and selective loss of myosin in
CIM.20,21,23,24,29,38 However, this is frequently neither
available nor practical in most ICUs. Myosin loss in
itself cannot explain muscle inexcitability, and myo-
sin loss itself lags behind the development of weak-
ness.40,50 Calpains may increase degradation of myo-
sin filaments and show enhanced expression in CIM
muscle biopsies.40 Additionally, severe illness, sepsis,
glucocorticoid therapy, and paralysis also stimulate
muscle protein catabolism.37 Weakness in CIM can
develop very rapidly but can also show rapid im-
provement. Despite rapid early improvement, how-
ever, recovery can be prolonged. Severe CIM paral-
ysis may result in greater muscle protein loss, and
regaining ambulation after CIM may take several
months,8 presumably in part due to secondary mus-
cle atrophy. Atrophy is a likely consequence of the
systemic illness but cannot account for the sudden
onset of paralysis or the electrical inexcitability of
the muscles. Secondary atrophy, however, is likely
and is commensurate with the delayed recovery and
chronically reduced MFCV, reflecting the now
smaller muscle-fiber diameter.
Although serum CK may be elevated, it is fre-
quently normal or only mildly increased in CIM. In
the recent study by Lefaucheur et al.,25 when the
single patient with a serum CK of 12,000 IU/L was
excluded, most patients with pure or predominant
myopathy had an average CK of 127 IU/L, with a
range of 17–700 IU/L. It appears that an elevated
serum CK should be considered a supportive but not
a major diagnostic finding.22 Coexistent scattered
necrosis has been noted in CIM muscle biopsies.8,24
It is likely that this causes the increased serum CK
observed in some CIM cases. This, in turn, is prob-
ably related to critical illness as opposed to primary
Critical Illness Myopathy
muscle pathology. In the present series, the serum
CK elevation was disproportionately low relative to
the degree of weakness. This further supports the
notion that weakness is due to muscle-fiber mem-
brane dysfunction and not to structural muscle
changes at onset. Subsequent structural changes may
occur due to changes at the level of the muscle-fiber
membrane and other factors.
Some investigators suggested that myopathic-
appearing motor units, associated with an often
nearly normal serum CK, could be due to a distal
axonopathy,50 an argument potentially supported by
abnormal single-fiber EMG findings.39 These find-
ings, however, could also be explained by abnormal-
ities of the postsynaptic membrane. Normal intra-
muscular nerves have been demonstrated on
biopsy.22 MUP duration analysis in CIM has indi-
cated myopathic changes, whereas mean MUP am-
plitudes, quantitative electromyography, and motor
unit number estimates were within normal limits in
one study.43 In common with other acquired muscle
disorders, the pathology is likely to be diffuse, affect-
ing most skeletal muscles, but patchy in any given
muscle. This would explain why some fibers are
nearly normal but others are very abnormal with
respect to MFCV and excitability.
Direct intramuscular stimulation of muscle fibers
is not a new technique.6,32,41,45,53 Rich et al. reported
that the motor nerve stimulation (MNS)/DMS ratio
was useful in distinguishing myopathy and neuropa-
thy in ICU quadriplegia.33 A ratio of ⬎0.5 was asso-
ciated with myopathy. Others have also used the
DMS technique to distinguish myopathy and neu-
ropathy.2,25,43 However, there are potential disadvan-
tages to DMS. The whole muscle is not necessarily
stimulated and the CMAP amplitudes used in the
calculation are likely derived from unequal or differ-
ent muscle-fiber populations. The results are semi-
quantitative, only indirectly demonstrating dysfunc-
tion of muscle. DMS also has limited utility in mildly
affected patients, as only large changes in amplitude
can be detected and there is a lack of normative data
in ICU controls. A high ratio will not distinguish
between abnormal and normal muscle.
Estimation of MFCV using methods based on
voluntary contraction will be biased toward the slow-
est fibers, which are recruited first.1 However, inva-
sive MFCV study is a relatively easy technique to
perform, provides objective, quantitative results, and
has been found to be more sensitive than surface
EMG measurement in hypokalemic periodic paraly-
sis (HPP) carriers.48 Using an invasive method, Troni
et al. found normal values of MFCV to be 3.53– 4.24
m/s (male) and 2.96 –3.74 m/s (female).45 Also,
MUSCLE & NERVE January 2008 19
using an invasive technique, normal values of 2.6 –
5.3 m/s (mean 3.7) were reported specifically for the
TA muscle.1 Our normal control data agree, provid-
ing a mean of 4.0 m/s, with a range of 3.0 –5.5 m/s.
Trojaborg et al. used an invasive DMS technique to
measure the MFCV and the evoked response ampli-
tude. MFCV was 30% lower in 5 CIM patients com-
pared with controls (4.5 ⫾ 0.2 m/s vs. 6.4 ⫾ 0.3
m/s).43 Although their study showed a relative dif-
ference between these two groups, the absolute
MFCV values were higher than those reported by us
and others for controls and by us for CIM patients.
This may reflect technical differences in measure-
ment and possibly differences in the spectrum of
CIM severity assessed.
The technique used could introduce error in the
form of interelectrode distance variation. Although
inserted at a measured distance (usually 50 mm),
needle angulation within the tissues could result in
the needle tips being closer together or further apart
than the surface measurement. We estimated that,
on visual inspection, a 5-degree angle of the needle
could be missed and not corrected by re-placement.
This would result in a 4% shortening of the distance
(4% of 50 mm) with needle insertion to a depth of
20 mm. If both needles were angulated their relative
separation would be reduced or exaggerated by ap-
proximately 8%. If it was assumed that this effect
overestimated MFCV by 8% for all control subjects
and underestimated the MFCV by 8% for all pa-
tients, we calculated that the new mean for controls
would be 3.84 m/s (SD 0.23) and for patients would
be 2.56 m/s (SD 1.17). This difference would still
reach a statistically significant level (P ⫽ 0.0278).
This scenario is, however, unlikely as we took care to
maintain perpendicular needle positions during the
studies.
Reduced MFCV values can be obtained from histo-
logically normal muscle, such as in HPP.11,46 Small
atrophic fibers would be expected to show a reduced
MFCV,3 but the commonly observed rapid deteriora-
tion and resolution as seen in CIM would not be ex-
pected if atrophy were the cause. Furthermore, the
degree of slowing is greater than that found in other
myopathies, which is further evidence of sarcolemmal
dysfunction. Inaccuracy of MFCV calculation could re-
sult from uncertainty regarding the site of muscle-fiber
activation. However, evidence suggests that, with weak
stimulation, muscle fibers are activated at discrete low-
threshold sites close to the needle tip.47 In the pres-
ence of a normal nerve and neuromuscular junction,
the amplitude of MUPs can be affected by dispersion
between action potentials of fibers in single motor
units, amplitude decline of a single fiber action poten-
20 Critical Illness Myopathy
tial due to a decrease in MFCV, and blocking of action
potentials.13 We believe that all three of these mecha-
nisms may play a role in CIM. We found in several
patients that muscle fibers were unable to conduct
action potentials over the standard 50-mm distance.
They were, however, able to conduct action potentials
over shorter distances, albeit at reduced velocities, sug-
gesting that there might be conduction block along
muscle fibers. This finding has not been described
prior to our study, at least to our knowledge.
With respect to the excitability of normal human
muscle fibers, a few studies have found a mean ab-
solute refractory period of 4.12 ms (range 2.69 – 8.13
ms) and a relative refractory period of 5.99 ms
(2.88 –12.40 ms).30 Our data fall within these limits,
with our mean normal absolute refractory period
being 2.5 ms and that for patients tending to be
higher at 4.7 ms, notably above the normal mean for
the other studies. The method used by us is likely to
stimulate the fibers close to the stimulating electrode
with the lowest threshold for activation. This tech-
nique may therefore underestimate the degree of
inexcitability of muscle fibers in close proximity to
the needle tip, as the most inexcitable fibers may
simply not be activated.
Trojaborg et al. recently highlighted previous
studies showing CMAP prolongation in CIM.44 One
patient with histologically confirmed CIM had nor-
mal intramuscular nerves and marked CMAP pro-
longation. The smoothly outlined but prolonged
CMAPs were thought to be due to slowing of MFCV,
as a result of impairment or blockade of voltage-
gated ion channels, although this was not demon-
strated.9 Another study of 9 possible CIM cases re-
vealed prolonged CMAP duration, again with
smooth and synchronous waveforms. The investiga-
tors suggested that this observation might be useful
as a simple diagnostic test.31 However, those findings
could not be replicated in a subsequent study,43
perhaps reflecting milder CIM severity. As we have
shown, abnormalities in CIM, namely reduced
MFCV and prolonged CMAP duration, are inversely
correlated and related to the clinical severity and
clinical phase of the illness.
The smooth contour of the markedly prolonged
CMAP probably reflects the synchronous depolariza-
tion of muscle fibers, which are not only slowed but
also have a wider-than-normal distribution of MFCV.
Another feature seen in these patients is that the
positive phase of the CMAP is often prolonged or
even replaced by a long “tail” of the negative phase.
This is probably the effect of the few muscle fibers
within the diseased muscle with markedly slowed
conduction velocities (Fig. 4). However, altered
MUSCLE & NERVE January 2008
membrane repolarization dynamics, as part of the
overall membrane dysfunction, may also contribute.
CMAP measurements represent the whole muscle
and, although the MFCV studies sample only a very
small proportion of fibers within a single muscle, it is
logical that these findings are complementary.
In vitro studies have shown that serum fractions
from patients with CIM affect the excitability of intact
muscle-fiber membranes and calcium release from the
sarcoplasmic reticulum.15 Rich and Pinter demon-
strated that depolarization of the resting membrane
potential and a hyperpolarizing shift in the voltage
dependence of sodium-channel gating is the principal
factor underlying inexcitability in an animal model of
CIM. In their model, depolarization of the resting
membrane potential following denervation was one of
the most important factors because it increased inacti-
vation of sodium channels.35,36 In the critically ill, de-
nervation may not be a prerequisite, as the resting
membrane potential may be reduced (depolarized)
due to raised intracellular sodium, possibly due to a
generalized cellular dysfunction related to critical ill-
ness.10 In vitro intracellular recording of individual
muscle fibers by Rich and Pinter showed failure of
muscle fibers to generate action potentials when stim-
ulated electrically, possibly due to reduced sodium cur-
rent.34 Sodium-channel dysfunction in the muscle-fiber
membrane can lead to inexcitability and is well known
in type 2 HPP, which is associated with SCNA4 muta-
tions.7,42 These mutations also result in enhanced in-
activation and reduced current through the muscle
sodium channel.18
Drawing parallels between CIM and HPP may
help to define the pathophysiology of CIM and also
offer common therapeutic opportunities. In HPP,
surface recordings between attacks revealed reduced
MFCV.52 Sensory and motor nerve studies between
attacks are normal as are needle EMG findings, al-
though chronically some may develop myopathic
changes.16 During a paralytic attack the CMAP am-
plitude declines secondary to muscle-membrane in-
excitability52 and invasive recordings show low MF-
CVs (mean 2.0, range 0.9 –3.0 m/s), which improves
within hours to days.27 Early during an attack, fibril-
lation potentials are evident, indicating depolarized
muscle membranes.16 Single-fiber EMG during an
attack shows an increase in jitter and occasional
potential blocking, but there is no jitter between
attacks.12,52 Troni et al. reported that DMS in one
patient was not possible for a long period during
recovery from paralysis. Muscle showed near electri-
cal silence during paralysis. When power increased
to MRC grade 3 in biceps, the MFCV was still slow at
1.7 m/s.46 In HPP, paralysis is caused by membrane
Critical Illness Myopathy
depolarization triggering sodium-channel inactiva-
tion, rendering the muscle membrane inexcitable.26
In CIM, a similar shift in membrane potential, due to
critical illness and perhaps serum factors,15 may con-
tribute to sodium-channel inactivation and a similar
pattern of pathophysiology. Depolarization of the mus-
cle membrane initially gives rise to spontaneous activ-
ity, and slowed MFCV; as this progresses, conduction
block ensues, and finally the fibers become inexcitable.
“Synchronized dispersion” of the CMAP, in con-
trast to the well-known asynchronous dispersion seen
in demyelinating neuropathy is, we suggest, a char-
acteristic feature of CIM. We agree with previous
studies that monitoring of this is simple to perform
and may be useful for diagnosis. It may also predict
recovery but requires further systematic study. The
techniques used for MFCV and excitability measure-
ment are technically demanding. They are powerful
research tools but are unlikely to become standard
diagnostic testing techniques. Our experience sug-
gests that CIM is more common than CIP and that
there is a spectrum of severity within CIM. Some
patients are moderately weak, have characteristic
neurophysiological changes, and improve quickly.
Other patients have more profound weakness, which
requires a longer recovery period. These patients
have inexcitable muscles, reduced MFCV, and pre-
dictable CMAP abnormalities. In CIM, changes at
the level of the muscle-fiber membrane correlate
with CMAP parameters and the clinical phases.
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