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 .
cidp is an immune - mediated peripheral neuropathy that may cause weakness , paralysis , and/or impairment in both motor and sensory functions , usually affecting both sides of the body ( symmetrical ) .
the neurophysiological hallmark of mmn is conduction blocks ( cb ) outside the usual sites of nerve compression [ 1 , 3 ] , while cidp typical features are cb , slowed motor , and sensory nerves conduction velocities and prolonged distal latencies .
in addition , both diseases may present a variable extent of axonal loss [ 5 , 6 ] , which has been attributed both to recurrent demyelinating insults and intrinsic pathogenic features , especially in the case of mmn .
neuromuscular ultrasound ( us ) is a noninvasive , painless , and radiation - free complementary imaging technique for the diagnostic work - up of pn [ 7 , 8 ] .
focal nerve enlargements can be observed in the majority of mmn patients and generalized nerve enlargements can be observed in cidp patients , interestingly showing alterations also in limbs without signs of neurophysiological dysfunction [ 911 ] .
however , the correlation between us , neurophysiological findings , and functional disability is still partially controversial [ 1214 ] .
some authors have found an association between disease duration and the extent of nerve enlargement , while others have suggested a specific us pattern in relation to different mechanisms of injury : demyelinating insults might result in swollen , enlarged , and hypoechoic nerves , while axonal damage may be characterized by hyperechoic atrophic bundles of fascicles .
in addition , a variable combination of axonal and demyelinating insults may also coexist , resulting in hyperechoic and hypertrophic nerves .
most of literature data have been collected on cidp patients , while a few sonographic - clinical - electrophysiological studies have been currently reported in mmn [ 9 , 11 , 1618 ] .
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 [ 3 , 19 ] and , at the time of us examination , were receiving a monthly treatment with intravenous immunoglobulin ( ivig ) ( 1 - 2  g / kg / month ) for at least 6 months .
written informed consent and local ethical committee ( aou san giovanni battista di torino ) approval were obtained .
the authors acted in accordance with the ethical standards laid down in the 1964 declaration of helsinki .
a complete neurological examination was performed by means of the inflammatory neuropathy cause and treatment ( incat ) disability scale , the medical research council ( mrc ) score in 8 muscle groups bilaterally ( shoulder abduction , elbow flexion , wrist flexion , first dorsal interosseous , hip flexion , knee extension , and ankle flexion / extension ) , and the overall neuropathy limitation scale ( onls ) . 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 
( 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 615  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 . 

csa was measured by tracing the nerve just inside the hyperechoic rims with the  ellipse method  when applicable ( when the nerve in the transverse scan had an elliptical or roundish shape ) or alternatively tracing the nerve shape ( when the nerve had an irregular shape ) .
csa was evaluated for each nerve at predetermined sites : median nerve was evaluated at wrist ( entrance of carpal tunnel ) , middle third of the forearm , elbow ( before penetrating the pronator teres muscle next to the brachial artery ) , and middle third of the arm ( middle of the distance between medial epicondyle and axillary fossa ) ; ulnar nerve at wrist ( guyon 's canal ) , middle third of the forearm , elbow ( between medial epicondyle and olecranon ) , and middle third of the arm ( middle of the distance between medial epicondyle and axillary fossa ) ; peroneal nerve at the fibular head and popliteal fossa ; tibial nerve at popliteal fossa and at medial malleolus before its division into plantar nerves ( ankle ) ; sural nerve at the ankle .
maximal csa ( csa ) enlargement was recorded for each nerve ; median and ulnar nerves were scanned along the entire viewable tract , from the wrist to the middle third of the arm .
abnormal csa values at entrapment sites ( wrist , elbow , and fibular head ) were excluded to avoid confounding local neuropathies . 
 intranerve csa variability .
intranerve csa variability was calculated as the ratio between csa / csa , for each nerve ( available for median and ulnar nerves ) . 

side - to - side intranerve variability was calculated as the  side - to - side  ratio of the intranerve csa variability . 
 qualitative analysis of nerve fascicles .
nerves were classified as abnormal if  3 fascicles showed a cross - sectional area  2  mm , regardless of the csa value .
normative us reference values were obtained by the assessment of healthy controls ( table 1 ) , considering the upper threshold of the normality range ( ut ) to be the average value + 2 standard deviations .
then , in order to compare the csa of different nerves taking into account their relative normative values , a normalized csa ( csa ) was calculated by dividing the csa of each nerve to the corresponding ut value ( csa = csa / csa ) .
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 + 34c by means of an infrared lamp .
cb was defined in accordance with the efns / pns criteria [ 3 , 19 ] , excluding possible sites of entrapment ( wrist , elbow , and fibular head ) to avoid confounding focal neuropathies .
moreover , neurophysiological alterations of nerve segments were stratified in predominantly  myelin damage  or 
axonal damage  in accordance with the classification already proposed by di pasquale et al . .
descriptive statistics ( mean , standard deviation , and range ) were used for continuous variables .
mann - whitney and cramer 's v tests were used for comparison between patients with different disease severity and neurophysiological alterations and between cidp and mmn patients .
spearman 's rho , kendall 's tau - b , and pearson 's correlations were used to estimate correlations between clinical , us , and electrophysiological characteristics , while a linear regression model was applied to estimate the influence of age , disease and treatment duration , and ivig doses on csa values .
bonferroni 's correction for multiple comparisons was applied to avoid statistical biases of repeated testing effects .
the average csa values in bilaterally measured nerves were obtained pooling together data of the two sides . however , in order to take into account the asymmetrical involvement typical of mmn , we also considered the side - to - side intranerve variability , calculated by dividing the intranerve variability of the most affected side with the intranerve variability of the less affected side .
complete clinical , us , and neurophysiological data were available for 22 cidp and 10 mmn patients with similar age ( 62.7  13.8 versus 55.1  14.9 years old ; p : 0.119 ) and disease duration ( 81.5  60.0 versus 87.3  46.6 months ; p : 0.734 ) . us data of 70 healthy controls ( 58.4  16.1 years old ; range 3082 ) with normal clinical and neurophysiological assessments were used as normative reference values ( table 1 ) . according to the incat disability score ( table 2 ) , 7/32 subjects required a bilateral support / wheelchair ( cidp = 18% ; mmn = 30% ) ; 17/32 required a unilateral support ( cidp = 64% ; mmn = 30% ) ; and 8/32 did not show any significant impairment of gait ( cidp = 18% ; mmn = 40% ) .
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 ( p : 0.519 ) , onls ( p : 0.724 ) , and mrc ( p : 0.327 ) scores ( table 2 ) .
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% [ p : 0.001 ] ; mmn = 78.3% versus 20% [ p : 0.010 ] ) . us
abnormal features were additionally observed in 14.4% of cidp and 10.1% of mmn nerve segments without significant neurophysiological alterations . as shown in figure 1(a ) and
table 3 , cidp and mmn patients with intermediate functional disability ( gait disturbance that might require a unilateral support ) showed higher csa values than patients with no / minimal gait difficulties ( p : 0.001 for cidp and p : 0.002 for mmn ) or higher functional disability ( p : 0.041 for cidp and p : 0.034 for mmn ) . moreover , higher csa values were observed ( figure 1(c ) ) in nerves with demyelinating features versus axonal damage ( p : 0.048 for cidp and p : 0.049 for mmn ) .
the quantitative us analyses showed higher csa in cidp than in mmn patients in peroneal nerve ( 16.81  3.01  mm versus 13.60  2.27  mm ; p : 0.024 ) , tibial nerve ( 23.46  2.23  mm versus 18.64  2.66  mm ; p : 0.027 ) , and sural nerve ( 3.56  0.31  mm versus 2.60  0.49  mm ; p : 0.047 ) .
the qualitative us analyses revealed abnormal fascicles in 40% of mmn versus 22.7% of cidp peroneal nerve segments ( p : 0.171 ) and in 35% of mmn versus 15.9% of cidp tibial nerve segments ( p : 0.087 ) .
additionally , a significant correlation was found between abnormal nerve fascicles and cb ( peroneal nerve : tau = 0.411 [ p : 0.015 ] in cidp and tau = 0.302 [ p : 0.046 ] in mmn ; tibial nerve : tau = 0.365 [ p : 0.042 ] in cidp and tau = 0.282 [ p : 0.048 ] in mmn ) and between abnormal nerve fascicles and csa values , both in cidp ( peroneal nerve : rho = 0.329 [ p : 0.033 ] ; tibial nerve : rho = 0.296 [ p : 0.049 ] ) and in mmn ( peroneal nerve : rho = 0.229 [ p : 0.046 ] ; tibial nerve : rho = 0.454 [ p : 0.044 ] ) .
median and ulnar nerves csa were significantly higher in patients with moderate impairment compared to subjects with either a more severe functional impairment ( p : 0.037 for cidp and p : 0.047 for mmn ) or milder disability ( p : 0.042 for cidp and p : 0.037 for mmn ) ( table 4 , figures 1(b ) and 2 ) .
the quantitative us analyses showed higher csa in cidp than in mmn patients in median nerve ( 18.70  2.30 versus 14.85  2.58 ; p : 0.042 ) and ulnar nerve ( 13.27  2.64 versus 10.75  2.23 ; p : 0.040 ) , while the side - to - side intranerve variability was higher in mmn ( median nerve : 1.9  0.6 versus 1.5  0.6 [ p : 0.035 ] ; ulnar nerve : 1.8  0.4 versus 1.4  0.4 [ p : 0.007 ] ) ( table 4 ) .
the correlation between abnormal fascicles and cb was also confirmed for the upper limbs ( median nerve : tau = 0.310 [ p : 0.046 ] in cidp and tau = 0.213 [ p : 0.045 ] in mmn ; ulnar nerve : tau = 0.260 [ p : 0.049 ] in cidp and tau = 0.271 [ p : 0.048 ] in mmn ) , as was for the correlation between altered fascicles and csa , both in cidp ( median nerve : rho = 0.315 [ p : 0.037 ] ; ulnar nerve : rho = 0.447 [ p : 0.002 ] ) and in mmn subjects ( median nerve : rho = 0.331 [ p : 0.043 ] ; ulnar nerve : rho = 0.564 [ p : 0.001 ] ) .
qualitative us analyses showed an inverse pattern compared to that observed at the lower limbs , with a moderately higher prevalence of altered fascicles in cidp than in mmn nerve segments ( median nerve : 38.6% versus 15% [ p : 0.059 ] ; ulnar nerve : 36.4% versus 20% [ p : 0.194 ] ) .
as observed in the lower limbs , the csa values were higher in nerve segments with predominantly demyelinating features versus axonal damage ( p : 0.001 for cidp and p : 0.049 for mmn ) ( figure 1(d ) ) . there was a direct correlation between axonal damage and gait impairment at the lower limbs ( cidp : r = 0.456 [ p : 0.002 ] ; mmn : r = 0.450 [ p : 0.036 ] ) and between axonal damage and functional disability at the upper limbs ( cidp : r = 0.402 [ p : 0.001 ] ; mmn : r = 0.325 [ p : 0.047 ] ) .
no linear correlations were observed between us data and incat score ( cidp : r = 0.121 [ p : 0.110 ] ; mmn : r = 0.239 [ p = 0.190 ] ) or between us data and onls score ( cidp : r = 0.053
[ p = 0.415 ] ; mmn : r : 0.211 [ p : 0.140 ] ) , while an inverse correlation was observed in cidp patients between mrc scores of muscles innervated by median and ulnar nerves and the corresponding intranerve variability ( table 5 ) .
csa values were not influenced by age ( cidp :  = 0.141 [ p : 0.456 ] ; mmn :  = 0.205 [ p : 0.437 ] ) , disease duration ( cidp :  = 0.005 [ p : 0.954 ] ; mmn :  = 0.195 [ p : 0.305 ] ) , treatment duration ( cidp :  = 0.027 [ p : 0.749 ] ; mmn :  = 0.295 [ p : 0.247 ] ) , or ivig dose ( cidp :  = 0.023 [ p : 0.809 ] ; mmn :  = 0.186 [ p : 0.663 ] ) .
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 . , who observed that nerve segments characterized by predominantly myelin damage had greater csa than nerves with predominantly axonal damage and normal nerves , which virtually overlapped .
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 [ 23 , 24 ] .
less data are available for mmn , where asymmetric and focal csa enlargements have also been reported in nerves without neurophysiological alterations , suggesting disease processes that could extend beyond the sensitivity of standard diagnostic techniques [ 9 , 11 , 1618 ] .
several complex phenomena , such as segmental demyelination , proliferation of schwann cells in response to repeated inflammatory insults , onion bulbs formation , and a variable degree of axonal loss might underlie these us findings [ 22 , 25 , 26 ] .
however , their correlation with the mechanisms of nerve damage and repair still remains to be clarified .
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 [ 14 , 22 , 27 ] , while in our heterogeneous sample of patients we observed a 
we speculate that different disease phases might be associated with different us patterns , with an initial / intermediate phase of inflammation and myelin damage , characterized by increased csa and enlarged swollen fascicles and a late phase of severe axonal degeneration , characterized by small atrophic fascicles , reduced csa and greater functional impairment .
other factors , such as ivig pharmacological treatment and/or individual inflammatory response , might also be implicated in the morphological modifications of peripheral nerves .
however , the similar therapeutic regimen ( ivig ) administered to our patients did not allow a post hoc analysis of treatment effects on csa values .
finally , patients with cidp , characterized by more prominent inflammatory and demyelinating features , might display greater nerve enlargement compared to mmn or to peripheral neuropathies characterized by primary axonal degeneration ( i.e. , chronic idiopathic axonal polyneuropathy ) .
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 , will likely allow a more accurate differentiation between cidp and other acquired or inherited peripheral neuropathies .
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 .
 
 objective . 
 this cross - sectional study analyzes the pattern of ultrasound peripheral nerve alterations in patients with chronic inflammatory demyelinating polyradiculoneuropathy ( cidp ) and multifocal motor neuropathy ( mmn ) at different stages of functional disability . 
 material and methods . 
 22 cidp and 10 mmn patients and a group of 70 healthy controls were evaluated with an ultrasound scan of the median , ulnar , peroneal , tibial , and sural nerves . 
 results were correlated with clinical disability scales and nerve conduction studies . 
 results . 
 patients with intermediate functional impairment showed relatively larger cross - sectional areas than subjects with either a milder ( p < 0.05 ) or more severe impairment ( p < 0.05 ) , both in cidp and in mmn . in addition , mmn was associated with greater side - to - side intranerve variability ( p < 0.05 ) , while higher cross - sectional areas were observed in cidp ( p < 0.05 ) and in nerve segments with predominantly demyelinating features ( p < 0.05 ) . 
 higher csa values were observed in nerves with demyelinating features versus axonal damage ( p < 0.05 for cidp ; p < 0.05 for mmn ) . 
 discussion and conclusions . 
 greater extent of quantitative and qualitative us alterations was observed in patients at intermediate versus higher functional disability and in nerves with demyelinating versus axonal damage . 
 cidp and mmn showed differential us aspects , with greater side - to - side intranerve variability in mmn and higher cross - sectional areas in cidp . 
1. Introduction
2. Material and Methods
3. Results
4. Discussion
5. Conclusions