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REVIEW

Ultrasound in the diagnosis of peripheralneuropathy structure meets function in theneuromuscular clinic

Elena Gallardo12

Yu-ichi Noto3

Neil G Simon45

1Service of RadiologyUniversity Hospital Marqueacutes deValdecilla Instituto deInvestigacioacuten Marqueacutes deValdecilla (IDIVAL) SantanderSpain2University of Cantabria (UC)and Centro de InvestigacioacutenBiomeacutedica en Red deEnfermedadesNeurodegenerativas(CIBERNED) Santander Spain3Department of Neurology

Graduate School of MedicalScience Kyoto PrefecturalUniversity of Medicine Japan4Prince of Wales ClinicalSchool University of NewSouth Wales Australia5Central Clinical School TheUniversity of Sydney Australia

Correspondence toDr Neil G Simon Prince of Wales Clinical SchoolUniversity of New South WalesAustraliansimonunsweduau

Received 16 October 2014

Revised 31 December 2014Accepted 8 January 2015Published Online First4 February 2015

To cite Gallardo E Noto YSimon NG J Neurol Neurosurg Psychiatry

2015861066ndash

1074

ABSTRACTPeripheral nerve ultrasound (US) has emerged as apromising technique for the diagnosis of peripheral nervedisorders While most experience with US has beenreported in the context of nerve entrapment syndromesthe role of US in the diagnosis of peripheral neuropathy(PN) has recently been explored Distinctive US 1047297ndingshave been reported in patients with hereditary immune-mediated infectious and axonal PN US may addcomplementary information to neurophysiological studiesin the diagnostic work-up of PN This review describes

the characteristic US 1047297ndings in PN reported to date anda classi1047297cation of abnormal nerve US patterns in PN isproposed Closer scrutiny of nerve abnormalities beyondassessment of nerve calibre may allow for more accuratediagnostic classi1047297cation of PN as well as contribute tothe understanding of the intersection of structure andfunction in PN

INTRODUCTIONPeripheral neuropathy (PN) contributes signi1047297cantlyto the neurological burden of disease worldwide1 2

Prevalence of PN is increasing particularly when

associated with the growing population affected bydiabetes3 and the rising incidence of drug-inducedneuropathy associated with chemotherapy andantiretroviral drugs4 5

Traditionally the diagnostic work-up of PNinvolves delineating a pattern of clinical involve-ment through history and examination with thediagnosis con1047297rmed by neurophysiological studiesIn some situations the clinical features and asso-ciated comorbidities may be enough to diagnose PNwithout further investigations6 although gradingof severity and monitoring of progression oftenincludes neurophysiological assessment However

the diagnosis of PN by clinical and neurophysio-logical grounds alone may be dif 1047297cult particularlyin those patients with atypical or proximal demye-linating PN7 It may also be dif 1047297cult to distinguishacquired from inherited demyelinating PN8 Hencethere is a need to develop novel strategies to aid inthe diagnosis and monitoring of patients with PNin particular the demyelinating forms

The peripheral nervous system was unavailable toimaging modalities prior to the 1990s because of insuf 1047297cient resolution and poor discrimination of nerves from surrounding soft tissues Howeverrecent technical developments have allowed imagingtechniques including MR neurography (MRN) and

ultrasound (US) to play an important role in the

diagnostic algorithm of peripheral nerve disordersMRN currently provides an excellent depiction of three-dimensional nerve anatomy and pathologyand development of diffusion tensor imagingand tractography may provide further functionaldata9 10 US provides superior spatial resolution thathas enabled detailed visualisation of even the smal-lest peripheral nerves Evolution of high-frequencybroadband transducers (up to 22 MHz) advances inimage postprocessing and sensitive Doppler technol-ogy that allows assessment of nerve vascularity

without contrast administration have improved theability of US to detect anatomic details and subtlestructural abnormalities in peripheral nerves In add-ition the acquisition of US is a real-time dynamicprocess and allows the examiner to explore theentire course of the nerve in a single sweep FinallyUS has the general advantages of being a painlessnon-invasive and inexpensive technique As suchUS may be considered to be an optimal tool to lookfor structural nerve pathology and hence serve as acomplementary technique to clinical and neuro-physiological diagnosis of patients with PN Thisreview will discuss the US features of PN focusing

on situations in which US studies may make a posi-tive contribution to the diagnosis

US FEATURES OF NORMAL PERIPHERAL NERVEThe US features of peripheral nerves correspond tomacroscopic and microscopic anatomy11 Peripheralnerves are visualised on US as tubular structureswith a characteristic fascicular appearance (1047297gures 1and 2) On longitudinal images linear hypoechoicfascicles are seen separated by bands of hyperechoicperineurial connective tissue On axial images theperipheral nerves demonstrate a lsquohoneycombrsquoappearance with ovoid hypoechoic fascicles embed-

ded in a hyperechoic background The dense epi-neurial connective tissue surrounding the nerve ishighly re1047298ective of sound waves which results in ahyperechoic rim that may provide a means of demarcating the nerve from surrounding structures

There are some situations where the US appear-ance of normal nerves differs from a typical fasci-cular pattern Nerves are more hypoechoic anddemonstrate fewer or no fascicles in very proximalnerves such as the brachial plexus and cervicalnerve roots12 because of reduced volume of con-nective tissue and more tightly packed fascicles13

Echogenicity and fascicle number may also bereduced where they cross osteo1047297brous tunnels such

as the ulnar nerve in the cubital tunnel14 The size

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of peripheral nerves decreases slightly proximal to distal in thelimb and it may be greater in entrapment sites in normalindividuals14 15

Commercially available US units are able to assess most per-ipheral nerves of the upper limbs lower limbs and brachialplexus However very deep nerves such as the proximal sciatic

nerve may be dif 1047297cult to image and the lumbar and sacralplexus cannot be visualised using US

US FEATURES OF INJURED PERIPHERAL NERVEUS 1047297ndings following peripheral nerve injury converge on anumber of common features These changes include alterations innerve size nerve echotexture de1047297nition of the epineurial marginsfascicle diameter and vascularity Much of the literature describingperipheral nerve changes following nerve injury is based on assess-ment of entrapment neuropathies16 In nerve compression theremay be focal nerve enlargement loss of the internal fascicularappearance and decrease in nerve echogenicity17

Nerve enlargement is most commonly quanti1047297ed using cross-

sectional area (CSA) traced within the hyperechoic epineurial

rim CSA is a reliable measure with a good intraobserver andinterobserver agreement and reproducibility18 therefore it hasbeen most frequently used to quantify changes in neuropathyand reference values have been established for the major limbnerves in several anatomic locations and for the brachialplexus15 19ndash21 It is worthwhile noting that some studies havedemonstrated that nerve size may be in1047298uenced by age genderbody mass index and height15 19 Temperature of the limb mayalso in1047298uence nerve calibre22 As such it is recommended that

comparison groups in studies of nerve US are matched for thosesubject characteristics and standardised environmental condi-tions are employed during the study

Measuring the size of individual nerve fascicles may also con-tribute important pathophysiological information for the nerveinjury and PN although presently there is very little publisheddata23 Fascicle size can differ between individuals nerves andanatomic regions of an individual nerve and hence a standar-dised approach would be required to systematically study this

Peripheral nerve echogenicity may be quanti1047297ed by measuringthe mean grey scale value of the nerve image Alternativelythresholding techniques may be applied to determine the pro-portion of the nerve that is relatively hypoechoic14 24 25 Data

obtained using each of these approaches is speci1047297

c to the USsystem being used and cannot be compared with data fromanother site unless the values are calibrated using a universalphantom

Nerve vascularity as measured by Doppler may also provideinsights into the pathophysiology of peripheral nerve disease Innormal nerves there is no detectable blood 1047298ow26 Increasedblood 1047298ow may be detected in compressive mononeuropathyand in1047298ammatory PN16 27 possibly re1047298ecting vascular prolifer-ation precipitated by chronic trauma or in1047298ammation (1047297gure 3)

US FINDINGS IN PNUS is emerging as a valuable tool in the diagnosis of PN and itis in this 1047297eld where it is anticipated that US will have a signi1047297-

cant impact in rationalising the diagnostic pathway potentiallyreducing the number of expensive investigations performed andfocusing the use of expensive immunomodulatory therapies28

In this section the US 1047297ndings documented to date in heredi-tary immune-mediated infectious and axonal neuropathies willbe discussed

Hereditary neuropathiesCharcot-Marie-Tooth diseaseCharcot-Marie-Tooth disease (CMT) is a clinically and genetic-ally heterogeneous hereditary neuropathy characterised by distalmuscle atrophy weakness and sensory loss with reduced tendonre1047298exes More than 60 different causative gene mutations have

been described

29

Nerve conduction studies still remain crucialboth for the diagnosis and the classi1047297cation of CMT (demyelin-ating type or axonal type) whereas US has emerged as a con-venient technique to assess morphological changes of peripheralnerves in patients with CMT as a complement to the neuro-physiological evaluation

Nerve US 1047297ndings of patients with CMT were 1047297rst describedin 1999 by Heinemeyer and Reimers 30 They examined nervediameter but not CSA in patients with CMT They concludedthat nerve diameter and echogenicity did not differ signi1047297cantlybetween patients with CMT and healthy subjects and noted thatthe visualisation of nerves with the 75 MHz linear array probewas often dif 1047297cult because of increased echogenicity of adjacentmuscles in patients with CMT The negative 1047297ndings of this

study may be explained by the limitations of resolution and

Figure 1 Ultrasound 1047297ndings in Charcot-Marie-Tooth disease type 1A(CMT1A) Ultrasound images of the median nerve (wristmdashAmid-forearmmdashB upper armmdashC) and C6 nerve root (longitudinalmdashDaxialmdashE) in a healthy subject and a patient with CMT1A (wristmdashFmid-forearmmdashG upper armmdashH C6 longitudinalmdashI C6 axialmdashJ) aredepicted Diffuse nerve enlargement was identi1047297ed in the patient withCMT1A

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recent studies using higher frequency probes (ge12 MHz) haveprovided further information regarding nerve morphology inpatients with various subtypes of CMT

CMT disease type 1ACMT1A the most common form of demyelinating CMT iscaused by a duplication of PMP22 that encodes peripheral

myelin protein 22 a transmembrane protein in the compact

myelin of the peripheral nerves Schwann cells and abundantconnective tissue around thinly myelinated axons (lsquoonion bulbsrsquo)are the main features of pathology in CMT1A In patients withCMT1A nerve US reveals that the CSA of peripheral nervesbrachial plexus and nerve roots are larger than those in healthysubjects Nerve CSA is uniformly increased throughout thecourse of the nerve and the CSA and diameter of the C6 nerve

root are also larger than those in controls (1047297gure 1) Martinoli

Figure 2 Patterns of nerve ultrasound changes in peripheral neuropathy (PN) Normal nerve ultrasound (US) appearances are shown in A (axialimage of the median nerve in the forearm cross-sectional area (CSA 7 mm 2) and B (longitudinal image of the tibial nerve in the popliteal fossaCSA 12 mm2) demonstrating a characteristic fascicular pattern A number of patterns of nerve US abnormalities may be seen in PN and examplesare shown in CndashH (C) An enlarged tibial nerve at the ankle (CSA 49 mm2) in a patient with CMT1A demonstrating heterogeneously enlargedhypoechoic fascicles (type 1amdashuniform or heterogenous enlargement of hypoechoic fascicles) (D) An enlarged median nerve in the forearm (CSA65 mm2) with mixed hyperechoic and hypoechoic fascicles in a patient with chronic in1047298ammatory demyelinating polyradiculoneuropathy (CIDP) (type1bmdashmixed hyperechoic and hypoechoic fascicles) (E) An enlarged median nerve at the elbow (CSA 91 mm 2) with disruption of the normalfascicular architecture in a patient with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (type 1cmdashobliteration of normal fascicular architecture) (F) An enlarged radial nerve (CSA 27 mm 2) in the spiral groove of a patient with CIDP a region in which US maydemonstrate a monofascicular or oligofascicular appearance of normal nerves (type 2mdashincrease CSA in monofascicular nerve) (G) Enlargement of the tibial nerve at the ankle (CSA 95 mm2) in a patient with hypertrophic neuropathy with prominent perineurial connective tissue and relativelynormal fascicular calibre (type 3mdashincreased CSA due to increased perineurial connective tissue) (H) The median nerve at the midpoint of the arm of a patient with amyloid neuropathy demonstrating normal calibre (CSA 8 mm2) but with loss of normal fascicular architecture (type 4mdashnormal CSAwith altered echotexture)

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et al31 reported that patients with CMT1A can be distinguishedfrom those with other types of CMT (CMT2 and CMTX1) by

either a larger CSA or a larger fascicular diameter in median

nerves Likewise Noto et al32 demonstrated that CSA was alsoincreased in the great auricular nerves and in C6 nerve roots in

patients with CMT1A Thus nerve US 1047297ndings demonstrate

Figure 3 Ultrasound (US) abnormalities in chronic in1047298ammatory demyelinating polyradiculoneuropathy (CIDP) A number of US abnormalities maybe detected in patients with CIDP (A) Focal enlargement and hypoechogenicity of the median nerve in the cubital fossa (black arrowhead) with arelatively normal fascicular pattern proximal and distal to the swelling (^)(B and C) Enlargement of the cervical nerve roots and brachial plexus(thin arrows) which is most commonly symmetric and may be associated with normal nerve calibre in more distal nerves (D) Increased nervecross-sectional area with prominent fascicular enlargement (thick arrow) In the patient nerve enlargement was diffuse and involved all studiedupper limb nerves The cervical nerve roots (between anterior and middle scalene muscles) are depicted in a patient with multifocal acquireddemyelinating sensory and motor neuropathy (MADSAM E and F) US abnormalities were asymmetric with marked enlargement on the right (E) andrelatively normal nerve calibre on the left (F) This corresponded with the clinical de1047297cits which were more severe in the right upper limb (G)Increased nerve vascularity on Doppler US in the median nerve at the midpoint of the arm in a patient with CIDP (H) The C6 nerve root in a patientwith CIDP showing reduced de1047297nition of its epineurial margin

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why CMT1A was previously classi1047297ed as a hypertrophic neur-opathy based just on nerve palpation

Regarding the CSAs of the sural nerves two con1047298ictingdescriptions have been reported Pazzaglia et al33 found that theCSA in the sural nerve was not increased in the majority of patients with CMT1A Noto et al32 found that the CSA in thesural nerve was increased in their population with CMT1AOne possible reason for this discrepancy can be attributed to thedifferent methods of CSA measurement between their studies

Pazzaglia et al tracked the nerve circumference inside the hyper-echoic rim whereas Noto et al traced the nerve circumferenceincluding hyperechoic rim

In terms of the correlation between US clinical and electro-physiological 1047297ndings in CMT1A there is an inverse relation-ship between the CSA and the nerve conduction parameterssuch as motor conduction velocity and compound muscle actionpotentials amplitude2 3 3 2 There is also a positive correlationbetween the CSAs in the median nerve and CMT neuropathyscore (CMTNS) that quanti1047297es the disease severity in patientswith CMT1A32 Taken together in patients with CMT1A theextent of nerve enlargement assessed by US paralleled not onlythe physiological function of peripheral nerves but also the clin-

ical disease severity

CMT disease type 1BCMT1B another demyelinating form of CMT is caused bymutations of MPZ gene that encodes myelin protein zero amajor constituent of peripheral myelin proteins In a studyinvolving a large family with CMT1B enlargement of themedian and vagus nerves was detected in affected familymembers34 Conversely sural nerve calibre was reduced pos-sibly re1047298ecting length-dependent axonal loss

CMT disease type 2CMT2 a group of axonal forms of autosomal dominant CMT

includes more than 19 distinct types Among them the mostcommon form is CMT2A that is caused by mutations of mitofu-sin 2 ( MFN2) gene In axonal neuropathies axonal loss is pre-dicted to result in decreased nerve caliber however mediannerve CSA in patients with CMT2 is slightly larger than that of normal subjects23 31 This discrepancy may be related to histo-pathological 1047297ndings that include Schwann cell hyperplasia withpseudo onion bulb formations and endoneurial swelling seen insome genetic subtypes of CMT235

CMT disease type X1CMTX1 the second most common form of CMT is caused bypoint mutations of gap junction-associated protein B1 (GJB1)

gene which encodes connexin-32 protein Although a statistic-ally signi1047297cant difference was not demonstrated the mediannerve CSAs in patients with CMTX1 were larger than those inhealthy subjects in one study but were smaller in anotherreport23 31 Both studies included a small number of patientstherefore a further study with larger number of patients will beneeded

With the accumulation of future studies of US 1047297ndings invarious types of CMT nerve US in combination with results of nerve conduction studies may provide tools to facilitate moretargeted gene analysis in patients with suspected CMT NerveUS is also useful for the diagnosis of hypertrophic-type CMT inthe rare instance when compound muscle action potentials arenot evoked in demyelinating CMT due to severe atrophy in

distal muscles or marked increase in stimulation threshold

Hereditary neuropathy with liability to pressure palsiesHereditary Neuropathy with liability to pressure palsies (HNPP) iscaused by a deletion of PMP22 and nerve biopsies in such patientsreveal focal thickening of myelin that is tomacula Beekman andVisser36

1047297rst reported focal and multiple nerve enlargements in apatient with HNPP not only at typical nerve entrapment sites butalso outside the entrapment sites Non-uniform nerve enlargementpatterns have been reported in some studies of patients withHNPP23 37 38 Gianneschi et al37 revealed that no morphometric

changes were seen in the distal nerve segments where entrapmentis unlikely while the distal motor latencies were increasedMorphological abnormalities identi1047297ed on US were not alwayscorrelated to the neurophysiological parameters in patients withHNPP unlike those in patients with CMT1A

Immune-mediated neuropathiesChronic in1047298ammatory demyelinating polyradiculoneuropathy (CIDP)Typical CIDP The clinical features of typical chronic in1047298ammatory demyelinat-ing polyradiculoneuropathy (CIDP) are well recognised includingprogressive symmetric weakness involving proximal more than the

distal muscles sensory impairment and reduced or absent deeptendon re1047298exes Histopathologically nerves in patients with CIDPdemonstrate segmental demyelination and remyelination resultingin onion bulb formation and varying degrees of interstitial oedemaand endoneurial in1047298ammation39 There are also a number of atypical or variant presentations such as multifocal acquireddemyelinating sensory and motor neuropathy (MADSAM)sensory-predominant CIDP and distal forms such as distalacquired demyelinating sensory neuropathy (DADS)40ndash42

In the majority of patients with CIDP abnormalities aredetected on nerve US However just as there is clinical variabil-ity there is a wide range of nerve US 1047297ndings reported in CIDP(1047297gure 3) Increased CSA of peripheral nerves andor cervicalnerve roots is most frequently reported43ndash48 Hypertrophy of

the vagus nerve has also been reported in CIDP49 50

While nerve enlargement is frequently identi1047297ed there may bemarked variability in the nerve CSA both between-patients andwithin a patient In some cases there may be massive enlargement(1047297gure 3) but in other patients nerve calibre may be normal ormildly enlarged Variability in nerve enlargement may be seenwhen different nerves of the same patient are compared andalong the course of the same nerve and identifying intranerveand internerve variability of CSA may be of diagnostic bene1047297t51

Three separate classes of US morphological 1047297ndings havebeen described in CIDP depending on the CSA and echogeni-city52 Class 1 nerves were enlarged with hypoechoic fasciclesClass 2 nerves were enlarged with mixed hypoechoic and hyper-

echoic fascicles Class 3 nerves were of normal calibre butdemonstrated abnormal hyperechoic fascicles which were lesseasily distinguished from the perineurial connective tissue Thenerve US patterns correlated with disease duration (class 3 wasassociated with longer disease duration) As such variations inUS 1047297ndings in CIDP may re1047298ect different pathophysiologicalstages of the disease although further histopathological correl-ation is needed As CIDP is a chronic segmental disorder oftenwith a relapsing course it is expected that different classes of nerve changes may coexist in some patients

Nerve vascularity may also be increased in patients with CIDPas assessed with Doppler US studies (1047297gure 3)53 Nerve blood1047298ow strongly correlates with cerebrospinal 1047298uid protein and thenumber of enlarged nerves suggesting that nerve vascularity

may re1047298ect disease activity

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The correlation between the US 1047297ndings and neurophysiologyfeatures or functional disability remains controversial43 52

although correlation between the extent of nerve enlargementand the duration of the disease has been reported15 52 Moredetailed comparisons between US clinical and neurophysio-logical 1047297ndings are needed to clarify this point Nerve US abnor-malities may improve with treatment response45

CIDP variants

The extent and nature of US abnormalities in CIDP variants areless well de1047297ned although changes overlap with typical CIDP

Multifocal acquired demyelinating sensory and motor neuropathy Patients with MADSAM present with asymmetric motor andsensory de1047297cits often with patchy neurophysiological abnormal-ities in nerve conduction studies US demonstrates multifocalnerve enlargements (1047297gure 3) that may be identi1047297ed at sites of current or previous electrophysiological conduction blocks54

Distal acquired demyelinating symmetric neuropathy The US features of DADS have not been systematically studiedNeuropathy associated with antimyelin-associated glycoprotein

(MAG) antibodies is most commonly categorised with DADSand one study has evaluated US 1047297ndings in this patient popula-tion55 Patchy enlargement of nerves was identi1047297ed most com-monly at entrapment sites Of interest distal nerve enlargementwas not prominent and this contrasts with the characteristicneurophysiological 1047297ndings of prominent slowing of distal nerveconduction56

POEMS syndromeThe demyelinating neuropathy associated with POEMS (poly-neuropathy organomegaly endocrinopathy M-protein skinchanges) syndrome may be confused with CIDP early in thecourse of the disease Distinguishing clinical features includepoor treatment response and the associated systemic features

that contribute to the acronym Increased serum vascular endo-thelial growth factor is a marker of the disease US may alsohelp distinguish POEMS syndrome neuropathy from CIDP InPOEMS syndrome nerve enlargement may be seen at sites of nerve entrapment but is uncommon in other parts of thenerve57 which is distinct from the 1047297ndings in CIDP

Multifocal motor neuropathyMultifocal motor neuropathy (MMN) is a rare neuropathycharacterised by slowly progressive limb weakness most com-monly starting in the distal upper limb with most patientsresponding to treatment with intravenous immunoglobulinFrom a practical perspective in some cases MMN can be dif 1047297-

cult to distinguish from patients with progressive muscularatrophy US studies identify focal nerve enlargement in themajority of patients with MMN including in limbs withoutneurophysiological dysfunction45 58 59 This is in contrast to themild reduction of nerve CSA seen in MND60 As such USstudies have been suggested as one method to select appropriatepatients for treatment28

Guillain-Barreacute syndromePresently there are few studies reporting the US 1047297ndings inpatients with Guillain-Barreacute syndrome (GBS) and no studies todate comparing demyelinating with axonal GBS variants Nerveenlargement has been reported in 47ndash83 of patients withearly GBS and may be present in peripheral nerves andor cer-

vical nerve roots15 61 The distribution of nerve changes may be

patchy within an individual61 and may be seen early beforeneurophysiological changes have developed15 Alterations of the fascicular architecture have been reported with heteroge-neous focal enlargement of single fascicles noted in one casereport62

In a detailed study Gallardo et al61 described clinical neuro-physiological and US 1047297ndings in six consecutive early GBSpatients with pathological correlation with autopsy material intwo patients US of the cervical nerve roots and major upper

and lower limb peripheral nerves was reported US abnormal-ities were only detected in 88 of the scanned nerveshowever cervical nerve root abnormalities were identi1047297ed in themajority of patients consisting of increased CSA and reducedde1047297nition of epineurial margins Indistinct margins of cervicalnerve roots was a novel US 1047297nding and was correlated withnerve oedema demonstrated on corresponding pathologicalstudies which suggested that US 1047297ndings may re1047298ect the patho-genesis of the disease

While longitudinal studies are generally lacking a single casereport demonstrated that US changes normalised during recov-ery in keeping with clinical and neurophysiological improve-ment62 However increased nerve CSA was identi1047297ed in

patients with residual de1047297

cits years after the onset of GBS butthese US changes did not correlate with functional disability 63

Infectious polyneuropathiesLeprosy is the most common infectious cause of neuropathyworldwide Nerve enlargement and loss of fascicular pattern areseen on US27 64 These abnormalities are most frequent atcommon sites of nerve entrapment in particular the cubitaltunnel However generally the nerve enlargement tends to bemore extensive and less circumscribed Thickened and hypoe-choic epineurium is a characteristic 1047297nding Immunologicallymediated reversal reactions are a common cause of skin andnerve injury in leprosy and Doppler US at this stage may dem-

onstrate increased nerve vascularity which suggests rapid pro-gression of nerve damage and a poor prognosis 64

Axonal neuropathyThe role of US may be less well de1047297ned in axonal PN Intuitivelyone may expect reduced CSA in axonal PN due to loss of myelin-ated 1047297bres However this is seldom apparent with the exceptionof modest reduction of nerve calibre in amyotrophic lateral scler-osis (ALS)6 0 6 5 6 6 In fact US of axonal PN may detect nerveenlargement in approximately 20 of patients15

Studies of US in diabetic PN most of them focused on theevaluation of tibial and median nerves have demonstrated evi-dence of nerve and fascicle enlargement and loss of fascicular

pattern

67ndash70

Correlation with electrophysiological parametershas been noted in some but not in all studies Speci1047297callyinverse relationships between nerve CSA and compound muscleaction potential amplitude and motor nerve conduction velocityhave been identi1047297ed69 Increased water content due to conver-sion of glucose into sorbitol in the nerve was suggested as acause of the increased nerve CSA67 Nerve enlargement may bean interesting marker of diabetic PN severity in future studiesalthough it is noted that this 1047297nding has not been reported in allstudies of diabetic PN15 71

Oxaliplatin-induced neuropathy which has axonal features onneurophysiological studies72 is not associated with reducedCSA on US but rather nerve enlargement at sites of nerveentrapmentmdasha 1047297nding suggesting increased susceptibility to

mechanical nerve injury73

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Nerve tumoursWhen only imaging data is considered hypertrophic neuropathymay be mistaken for a peripheral nerve tumour and viceversa particularly when nerve enlargement is segmental orwhen tumours are multifocal for example neuro1047297bromatosismultiple schwannomatosis and intraneural perineurioma7 4 7 5

A comprehensive review of US in peripheral nerve tumours isbeyond the scope of this review (and readers are directed to spe-ci1047297c reviews on the topic7 6 7 7) However characteristic lesion

features are noted in some peripheral nerve tumours whichmay help distinguish them from hypertrophic neuropathy

A comprehensive US study of proximal and distal peripheralnerves combined with clinical and neurophysiological informa-tion should satisfactorily distinguish each disease processhowever fascicular nerve biopsy may sometimes be needed

PRACTICAL APPROACH TO US DIAGNOSISMapping nerve abnormalities

An important aspect of the US examination of suspected PN isanalysis of the topographic distribution of nerve abnormalitiesThis includes the number of nerves involved (diffuse multi-focal or localised) the presence of a proximal or distal predom-

inance and the uniformity of the involvement along the courseof the nerve Comprehensive US assessment of the peripheralnervous system is the recommended approach which mayinclude examination of the brachial plexus upper extremitynerves (median radial and ulnar) and lower extremity nerves(femoral sciatic peroneal tibial and sural) with the compos-ition of the study guided by the clinical phenotype but alsoincluding clinically unaffected regions

Distinguishing CMT from CIDPOne issue experienced in the neuromuscular clinic is distinguish-ing some acquired neuropathies from hereditary demyelinatingneuropathies and broad diagnostic test batteries and empirical

treatment trials are often employed to con1047297rm a diagnosisNerve US may contribute to the diagnosis of demyelinating neu-ropathies in a number of ways

US may help differentiate CMT from mimicking acquireddemyelinating neuropathies such as in those patients in whomclinical features and nerve conduction studies remain inconclu-sive Evaluation of CSAs at intermediate nerve segments helpeddistinguish demyelinating CMT from CIDP because the CSAs inpatients with demyelinating CMT were uniformly enlargedwhile those in patients with CIDP demonstrated variableenlargement78 However care must be taken because patientswith demyelinating CMT other than CMT1A do not alwaysexhibit nerve enlargement32

In addition US studies facilitate assessment of proximal nerve

segments that may be dif 1047297cult to assess with nerve conductionstudies and hence may improve the detection of PN with demye-linating features in a predominantly proximal distribution

Identifying the contribution of nerve compressionDespite non-speci1047297c 1047297ndings in patients with axonal PN USdoes have an important role in the diagnosis or exclusion of superimposed entrapment neuropathy in these patients whichcan be dif 1047297cult to diagnose using electrophysiological studiesalone US is able to con1047297rm the diagnosis of compressive neur-opathy and to rule out anatomical contributions to nerve injury

As an example increased CSA of the median nerve withoutchange in wrist-to-forearm ratio might be compatible with dia-

betic PN while it would not be indicative of carpal tunnel

syndrome79 Many causes of PN do not lead to altered nervemorphology on US but may predispose to secondary entrap-ment neuropathy For example 70 of patients with systemicsclerosis and sensory complaints have US evidence of carpaltunnel syndrome or ulnar neuropathy at the elbow 80

FUTURE DIRECTIONS BEYOND CSARecent publications have demonstrated the utility of US in thework-up of patients with PN However many studies to date

have examined heterogeneous populations In addition moststudies have focused on the measurement of CSA at differentsites and there is overlap of values with healthy populationsUnlike 1047297ndings in entrapment mononeuropathy there is fre-quently no correlation between the changes in nerve calibre inPN and clinical severity although detailed clinical information isoften not reported More detailed exploration of the USchanges in PN may provide a more powerful assessment of nerve pathology which may help in the diagnosis of PN

The high resolution of US allows accurate assessment of dif-ferent morphological characteristics of the nerve independent of CSA and these features have seldom been mentioned in pub-lished studies The features that may warrant further exploration

include fascicle diameter fascicle-to-connective tissue ratio epi-neurial demarcation and nerve blood 1047298ow23 52 53

Proposed classi1047297cation of nerve US abnormalities Although the angle of insonation and other technical factorsimpact on the nature of the nerve image acquired by US infor-mation regarding the histopathological processes occurringwithin the nerve may be available with closer scrutiny of the USappearance of the nerve Taking into account the different mor-phological aspects that can be evaluated at present the previousreports and our personal observations we propose the follow-ing patterns of nerve involvement (1047297gure 2) Type 1 Increased CSA in multifascicular nerves due to fasci-

cular enlargement

ndash Type 1a With uniform or heterogeneous enlargement of hypoechoic fascicles as seen in hereditary demyelinatingneuropathies and CIDP

ndash Type 1b With mixed hyperechoic and hypoechoic fasciclesas seen in longstanding CIDP

ndash Type 1c With obliteration of normal sonographic fascicu-lar appearance as seen in in1047298ammatory PN nerve traumaHNPP leprosy and some axonal neuropathies mild exam-ples of this pattern are also common in entrapment sites innerves of asymptomatic normal individuals

Type 2 Increased CSA in monofascicular nerves Thispattern may be seen in the brachial plexus and cervical nerveroots in in1047298ammatory neuropathies such as GBS and CIDP

and hereditary neuropathies such as CMT Type 3 Increased CSA in multifascicular nerves due to

increased perineurial connective tissue This may be seen inunusual neuropathies such as hypertrophic mononeuropathyand leprosy and may contribute to US changes in diabeticneuropathy

Type 4 Normal CSA with fascicular enlargement or alteredechotexture as seen in CIDP and deposition disorders suchas amyloid neuropathy

Type 5 Decreased CSA Reduced CSA has been reported in ALS and rarely in studies of patients with axonal PN

CONCLUSIONSUS has a complementary role in the diagnosis of PN US has

the advantage of excellent resolution of super1047297cial nerves

1072 Gallardo E et al J Neurol Neurosurg Psychiatry 2015861066ndash1074 doi101136jnnp-2014-309599

Neuromuscular

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7232019 USG in Peripheral Neuropathy Jnnp

httpslidepdfcomreaderfullusg-in-peripheral-neuropathy-jnnp 810

and the dynamic nature of image acquisition makes it a natural1047297t for the neuromuscular and electrodiagnostic clinicsNeurophysiological studies have long been considered to be anextension of the clinical examination81 It is expected that asimilar assertion will be increasingly relevant for US and theaddition of anatomic and structural information may provideimportant complementary diagnostic information

Further US may be useful to distinguish between differenttypes of neuropathy in particular the demyelinating neuropa-

thies by identifying patterns of morphological changesIncorporating US features into diagnostic algorithms may ration-alise the process of diagnostic testing with inherent time andcost savings Exploration of nerve US features in addition toCSA may provide additional pathophysiological and diagnosticinsights Further correlation between US and MRI in PN mayallow the roles of each of these techniques to be betterdelineated

Presently correlations between nerve morphology and elec-trophysiological function are emerging in demyelinating neuro-pathies such as CMT and CIDP and diabetic neuropathyhowever further exploration is needed to determine the rela-tionship between structure and function in other neuropathy

subtypes Understanding of this emerging diagnostic tool will bebetter developed by detailed comparisons of US 1047297ndings withclinical neurophysiological and histopathological features andthis is recommended as a focus of future research

Acknowledgements NGS gratefully acknowledges funding from the NationalHealth and Medical Research Council and the Motor Neurone Disease ResearchInstitute of Australia (grant 1039520)

Competing interests None

Provenance and peer review Commissioned externally peer reviewed

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with polyneuropathy an ultrasound study Muscle Nerve 200940960ndash6

16 Martinoli C Bianchi S Gandolfo N et al US of nerve entrapments in osteo1047297broustunnels of the upper and lower limbs Radiographics 200020S199ndash213

17 Cartwright MS Walker FO Neuromuscular ultrasound in common entrapmentneuropathies Muscle Nerve 201348696ndash704

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24 Taglia1047297co A Taglia1047297co G Martinoli C Nerve density a new parameter to evaluateperipheral nerve pathology on ultrasound Preliminary study Ultrasound Med Biol 2010361588ndash93

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26 Joy V Therimadasamy AK Chan YC et al Combined Doppler and B-modesonography in carpal tunnel syndrome J Neurol Sci 201130816ndash20

27 Jain S Visser LH Praveen TL et al High-resolution sonography a new technique todetect nerve damage in leprosy PLoS Negl Trop Dis 20093e498

28 Simon NG Ayer G Lomen-Hoerth C Is IVIg therapy warranted in progressivelower motor neuron syndromes without conduction block Neurology 2013812116ndash20

29 Rossor AM Polke JM Houlden H et al Clinical implications of genetic advances inCharcot-Marie-Tooth disease Nat Rev Neurol 20139562ndash71

30 Heinemeyer O Reimers CD Ultrasound of radial ulnar median and sciatic nervesin healthy subjects and patients with hereditary motor and sensory neuropathiesUltrasound Med Biol 199925481ndash5

31 Martinoli C Schenone A Bianchi S et al Sonography of the median nerve inCharcot-Marie-Tooth disease Am J Roentgenol 20021781553ndash6

32 Noto YI Shiga K Tsuji Y et al Nerve ultrasound depicts peripheral nerveenlargement in patients with genetically distinct Charcot-Marie-Tooth disease J Neurol Neurosurg Psychiatry 201486378ndash84

33 Pazzaglia C Minciotti I Coraci D et al Ultrasound assessment of sural nerve inCharcot-Marie-Tooth 1A neuropathy Clin Neurophysiol 20131241695ndash9

34 Cartwright MS Brown ME Eulitt P et al Diagnostic nerve ultrasoundin Charcot-Marie-Tooth disease type 1B Muscle Nerve 200940

98ndash10235 Vallat JM Ouvrier RA Pollard JD et al Histopathological 1047297ndings in hereditary

motor and sensory neuropathy of axonal type with onset in early childhoodassociated with mitofusin 2 mutations J Neuropath Exp Neurol 2008671097ndash102

36 Beekman R Visser LH Sonographic detection of diffuse peripheral nerveenlargement in hereditary neuropathy with liability to pressure palsies J ClinUltrasound 200230433ndash6

37 Ginanneschi F Filippou G Giannini F et al Sonographic and electrodiagnosticfeatures of hereditary neuropathy with liability to pressure palsies J Periph Nervous System 201217391ndash8

38 Hooper DR Lawson W Smith L et al Sonographic features in hereditaryneuropathy with liability to pressure palsies Muscle Nerve 201144862ndash7

39 Dyck PJ Lais AC Ohta M et al Chronic in1047298ammatory polyradiculoneuropathyMayo Clin Proc 197550621ndash37

40 Katz JS Saperstein DS Gronseth G et al Distal acquired demyelinating symmetricneuropathy Neurology 200054615ndash2041 Lewis RA Sumner AJ Brown MJ et al Multifocal demyelinating neuropathy with

persistent conduction block Neurology 198232958ndash6442 Oh SJ Joy JL Kuruoglu R ldquoChronic sensory demyelinating neuropathyrdquo chronic

in1047298ammatory demyelinating polyneuropathy presenting as a pure sensoryneuropathy J Neurol Neurosurg Psychiatry 199255677ndash80

43 Kerasnoudis A Pitarokoili K Behrendt V et al Correlation of nerve ultrasoundelectrophysiological and clinical 1047297ndings in chronic in1047298ammatory demyelinatingpolyneuropathy J Neuroimaging 2014

44 Kerasnoudis A Pitarokoili K Behrendt V et al Nerve ultrasound score indistinguishing chronic from acute in1047298ammatory demyelinating polyneuropathyClin Neurophysiol 2014125635ndash41

45 Zaidman CM Harms MB Pestronk A Ultrasound of inherited vs acquireddemyelinating polyneuropathies J Neurol 20132603115ndash21

46 Zaidman CM Pestronk A Nerve size in CIDP varies with disease activity andtherapy response over time a retrospective ultrasound study Muscle Nerve

201450733ndash8

Gallardo E et al J Neurol Neurosurg Psychiatry 2015861066ndash1074 doi101136jnnp-2014-309599 1073

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47 Goedee HS Brekelmans GJF van Asseldonk JTH et al High resolution sonographyin the evaluation of the peripheral nervous system in polyneuropathymdasha review of the literature Eur J Neurol 2013201342ndash51

48 Matsuoka N Kohriyama T Ochi K et al Detection of cervical nerve roothypertrophy by ultrasonography in chronic in1047298ammatory demyelinatingpolyradiculoneuropathy J Neurol Sci 200421915ndash21

49 Grimm A Thomaser AL Peters N et al Vagal hypertrophy in immune-mediatedneuropathy visualised with high-resolution ultrasound (HR-US) J Neurol NeurosurgPsychiatry 2014 doi101136jnnp-2014-308271

50 Jang JH Cho CS Yang KS et al Pattern analysis of nerve enlargement usingultrasonography in chronic in1047298ammatory demyelinating polyneuropathy Clin

Neurophysiol 20141251893ndash951 Padua L Martinoli C Pazzaglia C et al Intra- and internerve cross-sectional area

variability new ultrasound measures Muscle Nerve 201245730ndash352 Padua L Granata G Sabatelli M et al Heterogeneity of root and nerve ultrasound

pattern in CIDP patients Clin Neurophysiol 2014125160ndash553 Goedee HS Brekelmans GJ Visser LH Multifocal enlargement and increased

vascularization of peripheral nerves detected by sonography in CIDP a pilot studyClin Neurophysiol 2014125154ndash9

54 Scheidl E Bohm J Simo M et al Ultrasonography of MADSAM neuropathy focalnerve enlargements at sites of existing and resolved conduction blocksNeuromuscular Disord 201222627ndash31

55 Lucchetta M Padua L Granata G et al Nerve ultrasound 1047297ndings in neuropathyassociated with anti-myelin-associated glycoprotein antibodies Eur J Neurol 201522193ndash202

56 Capasso M Torrieri F Di Muzio A et al Can electrophysiology differentiatepolyneuropathy with anti-MAGSGPG antibodies from chronic in1047298ammatory

demyelinating polyneuropathy Clin Neurophysiol 2002113346ndash

5357 Lucchetta M Pazzaglia C Granata G et al Ultrasound evaluation of peripheralneuropathy in POEMS syndrome Muscle Nerve 201144868ndash72

58 Beekman R van den Berg LH Franssen H et al Ultrasonography showsextensive nerve enlargements in multifocal motor neuropathy Neurology 200565305ndash7

59 Kerasnoudis A Pitarokoili K Behrendt V et al Multifocal motor neuropathycorrelation of nerve ultrasound electrophysiological and clinical 1047297ndings J PeriphNervous System 201419165ndash74

60 Cartwright MS Walker FO Grif 1047297n LP et al Peripheral nerve and muscle ultrasoundin amyotrophic lateral sclerosis Muscle Nerve 201144346ndash51

61 Gallardo E Sedano MJ Orizaola P et al Spinal nerve involvement in earlyGuillain-Barre syndrome a clinico-electrophysiological ultrasonographic andpathological study Clin Neurophysiol 2014 doi101016jclinph201406051

62 Almeida V Mariotti P Veltri S et al Nerve ultrasound follow-up in a child withGuillain-Barre syndrome Muscle Nerve 201246270ndash5

63 Kerasnoudis A Pitarokoili K Behrendt V et al Correlation of nerve ultrasound

electrophysiological and clinical 1047297ndings in post Guillain-Barre syndrome J PeriphNervous System 201318232ndash40

64 Martinoli C Derchi LE Bertolotto M et al US and MR imaging of peripheral nervesin leprosy Skel Radiol 200029142ndash50

65 Nodera H Takamatsu N Shimatani Y et al Thinning of cervical nerve roots andperipheral nerves in ALS as measured by sonography Clin Neurophysiol 20141251906ndash11

66 Schreiber S Abdulla S Debska-Vielhaber G et al Peripheral nerve ultrasound inALS phenotypes Muscle Nerve 2014 doi101002mus24431

67 Riazi S Bril V Perkins BA et al Can ultrasound of the tibial nerve detect diabeticperipheral neuropathy A cross-sectional study Diabetes Care 2012352575ndash9

68 Liu F Zhu J Wei M et al Preliminary evaluation of the sural nerve using 22-MHzultrasound a new approach for evaluation of diabetic cutaneous neuropathy PLoS

ONE 20127e3273069 Watanabe T Ito H Sekine A et al Sonographic evaluation of the peripheral nerve

in diabetic patients the relationship between nerve conduction studies echointensity and cross-sectional area J Ultrasound Med 201029697ndash708

70 Zheng Y Wang L Krupka TM et al The feasibility of using high frequencyultrasound to assess nerve ending neuropathy in patients with diabetic foot Eur JRadiol 201382512ndash7

71 Hobson-Webb LD Massey JM Juel VC Nerve ultrasound in diabeticpolyneuropathy correlation with clinical characteristics and electrodiagnostic testingMuscle Nerve 201347379ndash84

72 Park SB Lin CS Krishnan AV et al Oxaliplatin-induced neurotoxicity changes inaxonal excitability precede development of neuropathy Brain 20091322712ndash23

73 Briani C Campagnolo M Lucchetta M et al Ultrasound assessment of oxaliplatin-induced neuropathy and correlations with neurophysiologic 1047297ndingsEur J Neurol 201320188ndash92

74 Wang LM Zhong YF Zheng DF et al Intraneural perineurioma affecting multiple

nerves a case report and literature review Int J Clin Exp Pathol 201473347ndash

5475 Koontz NA Wiens AL Agarwal A et al Schwannomatosis the overlookedneuro1047297bromatosis Am J Roentgenol 2013200W646ndash53

76 Gruber H Glodny B Bendix N et al High-resolution ultrasound of peripheralneurogenic tumors Eur Radiol 2007172880ndash8

77 Reynolds DL Jr Jacobson JA Inampudi P et al Sonographic characteristics of peripheral nerve sheath tumors Am J Roentgenol 2004182741ndash4

78 Sugimoto T Ochi K Hosomi N et al Ultrasonographic nerve enlargement of themedian and ulnar nerves and the cervical nerve roots in patients with demyelinatingCharcot-Marie-Tooth disease distinction from patients with chronic in1047298ammatorydemyelinating polyneuropathy J Neurol 20132602580ndash7

79 Moon HI Kwon HK Kim L et al Ultrasonography of palm to elbow segment of median nerve in different degrees of diabetic polyneuropathy Clin Neurophysiol 2014125844ndash8

80 Taglia1047297co A Panico N Resmini E et al The role of ultrasound imaging in theevaluation of peripheral nerve in systemic sclerosis (scleroderma) Eur J Radiol 201177377ndash82

81 Simon NG Dynamic muscle ultrasoundmdashanother extension of the clinicalexamination Clin Neurophysiol 2014 doi101016jclinph201410153

1074 Gallardo E et al J Neurol Neurosurg Psychiatry 2015861066ndash1074 doi101136jnnp-2014-309599

Neuromuscular

groupbmjcomon November 23 2015 - Published by httpjnnpbmjcom Downloaded from

7232019 USG in Peripheral Neuropathy Jnnp

httpslidepdfcomreaderfullusg-in-peripheral-neuropathy-jnnp 1010

neuromuscular clinicneuropathy structure meets function in theUltrasound in the diagnosis of peripheral

Elena Gallardo Yu-ichi Noto and Neil G Simon

doi 101136jnnp-2014-309599online February 4 2015

2015 86 1066-1074 originally publishedJ Neurol Neurosurg Psychiatry

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These include

References BIBLhttpjnnpbmjcomcontent86101066

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