Multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are acquired immune-mediated peripheral neuropathies (PN). MMN is a pure motor neuropathy syndrome usually beginning in one or both hands and principally affecting the upper extremities, characterized by a chronic or stepwise progressive asymmetrical limb weakness and muscle atrophy [
The neurophysiological hallmark of MMN is conduction blocks (CB) outside the usual sites of nerve compression [
Neuromuscular ultrasound (US) is a noninvasive, painless, and radiation-free complementary imaging technique for the diagnostic work-up of PN [
The aim of this study is to analyze US findings in patients with CIDP and MMN at different functional disability, in order to correlate US qualitative and quantitative measures with clinical and neurophysiological features.
This cross-sectional observational study includes 22 CIDP (5 females; 17 males) and 10 MMN (4 females; 6 males) patients recruited from the Neuromuscular Unit of Turin University Hospital between May 2014 and May 2015 and 70 healthy controls (43 men and 27 women).
Patients were evaluated by means of a clinical, US, electrophysiological assessment, and a structured clinical interview. All subjects fulfilled the European Federation of Neurological Society/Peripheral Nerve Society (EFNS/PNS) criteria for CIDP or MMN [
A complete neurological examination was performed by means of the inflammatory neuropathy cause and treatment (INCAT) disability scale [
According to the INCAT disability scale, upper limb activities were scored as “no/minimal impairment” (not affected), “moderate impairment” (affected but not prevented), or “severe impairment” (prevented), while the evaluation of walking difficulties was based on the use of aids: “no/minimal impairment” (no/minimal gait impairment); “moderate impairment” (moderate gait impairment, independent or with unilateral support); “severe impairment” (severe gait impairment, bilateral supports or wheelchair).
The US assessment was performed by means of a SonoSite M-Turbo Ultrasound Machine equipped with a broadband linear transducer (frequency band 6–15 MHz). The US scan was performed the same day of the neurological assessment by an evaluator (Michela Rosso), who was blinded to the clinical and neurophysiological data.
The following quantitative and qualitative US parameters were collected for the median, ulnar, peroneal, tibial, and sural nerves bilaterally.
Normative US reference values were obtained by the assessment of healthy controls (Table
Control group ultrasonographic data (70 subjects).
Nerve | Site | Average CSA (mm2) | Standard deviation |
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Peroneal | Popliteal fossa | 8.91 | 1.82 |
Fibular head | 7.42 | 2.11 | |
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Tibial | Popliteal fossa | 9.62 | 3.20 |
Ankle | 8.89 | 2.05 | |
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Sural | Ankle | 2.15 | 0.62 |
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Median | Wrist | 8.07 | 1.30 |
Middle third of the forearm | 7.05 | 1.98 | |
Elbow | 9.62 | 1.45 | |
Middle third of the arm | 8.50 | 1.67 | |
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10.33 | 1.22 | |
Intranerve variability | 1.76 | 0.47 | |
Side-to-side intranerve variability | 1.27 | 0.17 | |
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Ulnar | Wrist | 4.82 | 1.04 |
Middle third of the forearm | 6.07 | 1.42 | |
Elbow | 5.94 | 1.82 | |
Middle third of the arm | 7.31 | 1.79 | |
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8.75 | 2.09 | |
Intranerve variability | 1.74 | 0.71 | |
Side-to-side intranerve variability | 1.25 | 0.13 |
CSA: cross-sectional area.
Nerve conduction studies were performed by means of a KeyPoint (Natus Medical Incorporated, San Carlos, CA, USA) electromyography (EMG) machine by evaluators blinded to the US study, assessing the bilateral peroneal, tibial, ulnar, and median motor nerves and the bilateral sural, median, and ulnar sensory nerves. Nerve conduction velocities (CV), compound muscle action potentials (CMAP), and sensory action potentials (SNAP) were collected and compared to the normality cut-off values of our laboratory; all patients were checked for skin temperature with a probe on the EMG machine. If needed, the body temperature was maintained above +34°C by means of an infrared lamp.
CB was defined in accordance with the EFNS/PNS criteria [
Descriptive statistics (mean, standard deviation, and range) were used for continuous variables. Mann-Whitney and Cramer’s
Complete clinical, US, and neurophysiological data were available for 22 CIDP and 10 MMN patients with similar age (
According to the INCAT disability score (Table
INCAT, ONLS, and MRC scores in CIDP and MMN patients.
Upper limbs | Lower limbs | Total score | ||
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INCAT | CIDP |
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MMN |
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ONLS | CIDP |
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MMN |
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MRC | CIDP |
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MMN |
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Results are reported as average ± standard deviation (minimum-maximum).
INCAT: inflammatory neuropathy cause and treatment.
MRC: medical research council.
ONLS: overall neuropathy limitation scale.
The upper limbs score showed that 9/32 subjects had a severe impairment in daily living activities (CIDP = 23%; MMN = 40%); 12/32 reported a moderate impairment (CIDP = 41%; MMN = 30%); and 11/32 did not report any significant impairment (CIDP = 36%; MMN = 30%). No differences were observed between CIDP and MMN patients at the INCAT (
A total of 320 nerves (220 CIDP and 100 MMN) were evaluated by means of nerve conduction studies and US assessments: neurophysiological alterations were found in 78.0% of CIDP nerve segments (predominant myelin damage = 41.6%; predominant axonal damage = 36.4%) and in 62.5% of MMN nerve segments (predominant myelin damage = 35.0%; predominant axonal damage = 27.5%). Quantitative and/or qualitative US alterations were observed in 43.2% (95/220) of CIPD nerve segments and in 40.0% (40/100) of MMN nerve segments. In both cases these alterations were found more frequently in nerves with predominantly myelin versus axonal damage (CIDP = 74.6% versus 25% [
As shown in Figure
Clinical, neurophysiological, and ultrasonographic data: lower limbs.
No/minimal impairment |
Moderate impairment |
Severe impairment |
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Motor CV (m/sec) | CIDP |
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MMN |
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0.099 | |
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CMAP amplitude (mV) | CIDP |
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MMN |
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0.110 | |
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CSA popliteal fossa (mm2) | CIDP |
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MMN |
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0.114 | |
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CSA fibular head (mm2) | CIDP |
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0.227 |
MMN |
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0.112 | |
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Motor CV (m/sec) | CIDP |
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0.121 |
MMN |
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0.234 | |
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CMAP amplitude (mV) | CIDP |
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MMN |
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CSA popliteal fossa (mm2) | CIDP |
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MMN |
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0.241 | |
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CSA ankle (mm2) | CIDP |
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0.254 |
MMN |
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Sensory CV (m/sec) | CIDP |
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0.255 |
MMN |
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0.441 | |
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SNAP amplitude ( |
CIDP |
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0.111 |
MMN |
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0.638 | |
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CSA ankle (mm2) | CIDP |
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0.928 |
MMN |
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0.958 |
Results are reported as average ± standard deviation.
CMAP: compound muscle action potential.
CSA: cross-sectional area.
CV: conduction velocity.
SNAP: sensory action potential.
INCAT (inflammatory neuropathy cause and treatment) lower limbs score: no/minimal impairment = 0; moderate impairment = 1-2; severe impairment = 3–5.
CSA values in relation to functional disability and neurophysiological alterations. Higher CSA values were observed in patients with intermediate functional disability and in nerves with predominant demyelinating features, both at the lower (a, c) and at the upper (b, d) limbs. Normalized cross-sectional area (
The quantitative US analyses showed higher
The qualitative US analyses revealed abnormal fascicles in 40% of MMN versus 22.7% of CIDP peroneal nerve segments (
Additionally, a significant correlation was found between abnormal nerve fascicles and CB (peroneal nerve: tau = 0.411 [
Median and ulnar nerves CSA were significantly higher in patients with moderate impairment compared to subjects with either a more severe functional impairment (
Clinical, neurophysiological, and ultrasonographic data: upper limbs.
No/minimal impairment | Moderate impairment | Severe impairment |
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Motor CV (m/sec) | CIDP |
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0.129 |
MMN |
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0.631 | |
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CMAP amplitude (mV) | CIDP |
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MMN |
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Sensory CV (m/sec) | CIDP |
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0.509 |
MMN |
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0.738 | |
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SNAP amplitude ( |
CIDP |
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0.236 |
MMN |
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0.267 | |
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CIDP |
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0.163 |
MMN |
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0.129 | |
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Intranerve variability | CIDP |
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0.462 |
MMN |
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0.263 | |
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Motor CV (m/sec) | CIDP |
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0.091 |
MMN |
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0.099 | |
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CMAP amplitude (mV) | CIDP |
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MMN |
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Sensory CV (m/sec) | CIDP |
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0.133 |
MMN |
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0.688 | |
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SNAP amplitude ( |
CIDP |
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MMN |
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0.256 | |
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CIDP |
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MMN |
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0.362 | |
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Intranerve variability | CIDP |
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MMN |
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Results are reported as average ± standard deviation.
CMAP: compound muscle action potential.
CSA: cross-sectional area.
CV: conduction velocity.
SNAP: sensory action potential.
INCAT (inflammatory neuropathy cause and treatment) upper limbs score: no/minimal impairment = 0-1; moderate impairment = 2; severe impairment = 3–5.
Median nerve axial ultrasound scan in CIDP patients at different disability state. (a) Male, 60 years old; disease duration 64 months; INCAT upper limbs score: 1. (b) Male, 63 years old; disease duration 72 months; INCAT upper limbs score: 2. (c) Male, 62 years old; disease duration 79 months; INCAT upper limbs score: 4.
The quantitative US analyses showed higher
The correlation between abnormal fascicles and CB was also confirmed for the upper limbs (median nerve: tau = 0.310 [
There was a direct correlation between axonal damage and gait impairment at the lower limbs (CIDP:
No linear correlations were observed between US data and INCAT score (CIDP:
Correlations between MRC score and corresponding ultrasonographic data in different muscles/nerves.
Muscle | Ultrasonographic data | Correlation coefficient |
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Flexor carpi radialis (median nerve) |
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CIDP |
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0.223 |
MMN |
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0.654 | ||
Abnormal fascicles | CIDP |
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0.674 | |
MMN |
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0.378 | ||
Intranerve variability | CIDP |
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MMN |
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0.993 | ||
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First dorsal interosseous (ulnar nerve) |
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CIDP |
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0.276 |
MMN |
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0.932 | ||
Abnormal fascicles | CIDP |
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0.717 | |
MMN |
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0.813 | ||
Intranerve variability | CIDP |
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MMN |
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0.834 | ||
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Tibialis anterior (peroneal nerve) | CSA popliteal fossa | CIDP |
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0.145 |
MMN |
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0.737 | ||
CSA fibular head | CIDP |
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0.228 | |
MMN |
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0.954 | ||
Abnormal fascicles | CIDP |
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0.324 | |
MMN |
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0.194 | ||
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Gastrocnemius/soleus (tibial nerve) | CSA popliteal fossa | CIDP |
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0.132 |
MMN |
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0.868 | ||
CSA ankle | CIDP |
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0.250 | |
MMN |
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0.213 | ||
Abnormal fascicles | CIDP |
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0.146 | |
MMN |
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0.423 |
CSA: cross-sectional area (mm2).
MRC: medical research council.
CSA values were not influenced by age (CIDP:
This study reports the peripheral nerve US findings of 32 CIDP and MMN patients at different functional disabilities. Lower CSA values were associated with more severe clinical alterations and/or axonal damage, while higher CSA values were associated with intermediate functional disability (clinical alterations without loss of functionality) and/or demyelinating damage.
These data are in accordance with the findings reported by Di Pasquale et al. [
In addition, we found some differential aspects between MMN and CIDP: greater side-to-side intranerve variability was observed in MMN, in line with the pattern of heterogeneous and multifocal involvement characteristic of the disease; patients with CIDP showed higher CSA values, potentially indicating more prominent demyelinating processes; qualitative US analyses revealed a different distribution of abnormal fascicles in the upper and lower limbs, with more prominent US alterations in district affected by predominantly demyelinating damage (frequently associated with a less marked functional impairment) compared to district affected by secondary axonal degeneration.
The majority of literature data reported increased CSA values in CIDP, with a possible association between intranerve variability and functional scores [
Our data support the complementary role of US in the assessment of CIDP and MMN, suggesting a different pattern in nerves with demyelinating versus axonal damage and in CIDP versus MMN patients, in possible relationship with the different pathological processes involved.
Previous studies reported a correlation between disease duration and CSA values [
Other factors, such as IVIg pharmacological treatment and/or individual inflammatory response, might also be implicated in the morphological modifications of peripheral nerves [
Taken together, these findings suggest variable applications for US in the field of immune-mediated peripheral neuropathies, ranging from the more accurate clinicopathophysiologic phenotyping to the early detection of morphological changes associated with critical disease milestones. In addition innovative US score, such as the Bochum Ultrasound Score [
Our findings suggest that CIDP and MMN patients with an intermediate functional disability may present more pronounced quantitative and qualitative US alterations than patients with higher disability. Moreover, some differential aspects can be recognized in CIDP versus MMN and greater US alterations might be observed in nerve segments with demyelinating versus axonal damage.
The strength of our findings is partially limited by the relatively small sample size and the lack of serial prospective follow-up assessments. In addition, two aspects should be considered in the interpretation of data: (a) the “U-shaped” relationship between US findings and functional impairment, which might result in a similar US pattern in patients with either minimal or severe disability; (b) the association of CSA reduction with two different factors (axonal damage and functional impairment), indicating the need of further prospective studies to analyze which of the two features primarily correlates with nerve size reduction.
The authors declare that they have no competing interests.
The authors acknowledge the contributions of Agustina Vaccaro for the help with neurophysiological recording and data collection and Benjamin D. Wissel (University of Cincinnati, USA) for the help with the organization and presentation of data and linguistic editing.