Over the last few years, more and more attention has been focused on neuromuscular changes that present during a patient's stay in the Intensive Care. The literature refers to different types: critical illness myopathy (CIM), thin-filament myopathy, necrosing myopathy, a mixed type of necrosing myopathy and thin-filament neuropathy, critical illness polyneuropathy (CIP), sensory neuropathy, motor or mixed, polyneuropathy, demyelinating and axonal, and neuropathy as a result of prolonged neuromuscular block once non-depolarizing neuromuscular blocking agents have been suspended [1-11].
It is very difficult to differentiate on a clinical level between myogenic and neurogenic types, especially in critically ill patients, as it is so difficult, or sometimes impossible, to do a complete neurological examination. These patients are often not very cooperative, sedated or intubated, and their central nervous system may also be compromised as a result of trauma, meningo-encephalitis, septic shock, epilepsy, etc. To discriminate between the pathology of the nervous system as opposed to that of the muscular system in patients like these, we need to use technical approaches like electromyography and neuromuscular biopsy.
It must also be remembered, however, that, apart from problems associated with diagnosis, the group of neuromuscular pathologies affecting patients in the Intensive Care are so similar that most authors group all the different types listed above under the same heading ‘weakness associated with critically ill patients' .
CIP or CIM? That is the question
Standard nerve conduction tests and electromyographs, which are normally used to differentiate between myopathies and neuropathies, are often not sufficiently specific for differentiating between different types of neuromuscular pathologies in critically ill patients. This discrepancy can be attributed to the following:
- CIP and CIM both lead to reduction in amplitude of the compound motor action potential (CMAP) and in both cases fibrillation potentials and/or positive sharp waves can be seen indicating denervation or primary muscular problems.
- The voluntary recruitment of motor units is often not possible because the muscle is too weak or the patient is unable to cooperate.
- Disturbances to the action potentials of sensory nerves (SNAP) are often used to discriminate neuropathies from myopathies. Study of the sensory nerves, however, may be unreliable because of the peripheral oedema affecting many of the patients. When the soft tissue is engorged it leads to a reduction or absence of the action potential.
It is important to differentiate between CIP and CIM and formulate a specific diagnosis from both an epidemiological and a prognostic point of view. Some writers have found that CIP is more prevalent than CIM, while others maintain that the opposite is true, suggesting that CIM is at least three times more frequent than CIP [8,10,13-15].
From the few studies available in the literature, it would appear that nerve disturbances are associated with slower functional recovery and with residual electrophysiological disturbances even years after the event, while recovery would appear to be more rapid with myopathies [16-19].
How to do a differential diagnosis?
The ‘Gold Standard' test, to date, for diagnosing the presence of neuropathies and/or myopathies is neuromuscular biopsy. Unfortunately, this is an expensive and invasive test and therefore cannot be routinely used on patients in critical condition [10,20,21].
In 1996, Rich and colleagues  proposed a technique involving direct stimulation of the muscle belly to study, separately from the nerve, the excitability of the muscle fibre and conduction speed along the fibre to obtain specific values, which would enable CIP to be differentiated from CIM.
The technique involves using a unipolar electrode as the cathode and a subdermal needle, positioned 2 cm laterally, as the anode. The stimulating electrodes need to be positioned on a level with the distal-third of the muscle and away from the neuromuscular plate. Once the electrodes are in place, the muscle is stimulated with increasing intensity (10-100 mA) until a clearly visible muscle contraction is obtained. The recording electrodes are then placed on the twitch pathway: the first subdermal needle at a distance of 2-3 cm from the stimulating needle, the second subdermal needle or surface electrode as reference a few centimetres down from the first needle. The position of the recording needle can be changed to obtain the biggest amplitude of the action potential. If a potential cannot be evoked, the position of the recording electrode can be changed as well. Stimulation is applied through small but steady increases in intensity until a maximum response is achieved. Maximum amplitude is usually reached at values of approximately 70-80 mA. In this way, a compound muscle action potential is obtained (direct muscle stimulation (dm) CMAP). A supramaximal stimulus is subsequently applied to the trunk of the nerve innervating the muscle under study, and the action potential is measured using the same electrodes used for the dmCMAP. In this way, the compound nerve action potential is obtained (nerve stimulation (ne) CMAP). The amplitude of both CMAPs is measured from peak to peak. In patients with CIP, muscle excitability is preserved so the parameters of the action potential appear normal. With CIM, the muscle fibres lose their excitability and both dmCMAP and neCMAP are reduced. Rich and colleagues do not use absolute reference values for the two CMAPs, but calculate the neCMAP/dmCMAP ratio. With CIP, since only the nerve potential is reduced, the ratio is <0.5, or even zero if the denervation is severe. If it measures between 0.5 and 0.9 it is not possible to differentiate neuropathy from myopathy (indeterminate), whereas if the ratio is >0.9 the clinical picture is compatible with myopathy or normality depending on the amplitude values during standard electroneurography (ENG). When the nerve/muscle ratio is close to 1, the amplitude of the two potentials is similar: proportionally reduced or normal [22,23] Figure 1.
Over the following years, Trojaborg and colleagues  and Bednarik and colleagues , in 2001 and 2003, respectively, used direct muscular stimulation (SDM) and biopsy to study neuromuscular weakness in patients in critical condition. They are both very similar, prospective cohort studies, using different electrophysiological techniques (standard electromyography (EMG), SDM, quantitative EMG (QEMG)) and biopsy. The objective of both works was, primarily, to assess the frequency of CIP and CIM and, secondly, to compare methods. From the summary of their results in Table 1, we can see that there was some discrepancy between the diagnosis achieved through SDM and that based on the biopsy.
In this 2003 study, four myopathies that were diagnosed through biopsy were not picked up by the SDM. The electrophysiological studies, in fact, show two normal subjects and two with neuropathies. Other authors found similar discrepancies  and several factors may account for this. The most important of these is the co-presence of both CIP and CIM and, secondly, the difference between the diagnostic tools used. SDM analyses the excitability of the muscle membrane, which is the result of complex pathophysiological processes, including the inactivation of sodium channels [27,28]. Biopsy, on the other hand, does not analyse electrical but histological aspects. Another difference is with the type of muscle used in the study. SDM was mainly carried out on tibialis anterior (distal muscle), whereas neuromuscular biopsy is usually carried out on the quadriceps femoris (proximal muscle).
We can see from this small amount of data that despite diagnostic overlap, when SDM indicates myopathy, this needs to be confirmed through histological testing.
In a more recent work, Lefaucher and colleagues in 2006  used SDM without any other electrophysiological techniques. They proposed a diagnostic algorithm that would enable doctors to differentiate between CIP and CIM solely on the basis of the amplitude of the action potential and the neCMAP/dmCMAP ratio. SDM identifies the patients with either normal or reduced amplitude. Neuropathies belong to the first group and myopathies to the second. Once the ratio is calculated, as Rich and colleagues described, we can see whether these are pure or mixed cases.
Ratio versus absolute values
SDM, according to Rich and colleagues [22,23], uses the neCMAP/dmCMAP ratio rather than absolute values for differentiating between neuropathies, myopathies and a normal clinical picture. This ratio can cause confusion, which is why some authors have tried to find absolute reference values.
Trojaborg and colleagues  were the first in 2001 to use the values obtained from 18 healthy subjects as the reference values. Bednarik and colleagues , then, in 2003 defined amplitudes of less than 2 mV as pathological. Lefaucher and colleagues  were the last to obtain absolute values from 12 control subjects. They are small series, and vary in the mean values they put forward. If absolute values are to be found that could be used in clinical practice, larger sample sizes need to be used.
Other diagnostic techniques apart from SDM are:
- QEMG: described by Buchtal and Kamieniecka, and Trojaborg and colleagues for testing, when possible, action potentials in 20 different motor units (motor unit potentials (MUPs)) with random insertion of concentric needles in different areas of the muscle being tested. Average duration and amplitude of the MUPs from each muscle are compared to reference values, which vary according to age. The duration of MUPs is expressed as a percentage variation from the reference values. This method is not, however, specific to the diagnosis of CIP and is not very sensitive as far as recognizing myopathies is concerned [24,30,31].
- MUNE (motor unit number estimation): this tests enables us to assess the number of motor axons connected to the muscle and to see whether there is any pathology of the second motor neurone. It can be used as an exclusion criterion in the diagnosis of myopathy [24,32,33].
SDM is quick, simple, non-invasive and can be carried out at the patient's bedside. Even more importantly, it is reliable even when the patients cannot cooperate or are comatose. From the small amount of data available, it seems to be as accurate as neuromuscular biopsy in diagnosing CIM. It would therefore be advisable to use it in everyday clinical practice.
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