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ournal of Neuroradiology (2014) 41, 124—130

Available online at

www.sciencedirect.com

RIGINAL ARTICLE

T diffusion tensor imaging and electroneurographyf peripheral nerve: A morphofunctional analysis inarpal tunnel syndrome

arianna Brienzaa,∗, Francesco Pujiaa, M. Chiara Colaiacomob,. Grazia Anastasioa, Francesco Pierelli a, Claudio Di Biasib,hiara Andreoli b, Gianfranco Gualdib, Gabriele O.R. Valentea

Department of Medico-Surgical Sciences and Biotechnologies Neurology section, ‘‘Sapienza’’ University of Rome, v.leell’Università 30, 00185 Rome, ItalyRadiology DEA Department, Umberto I Hospital, ‘‘Sapienza’’ University of Rome, Rome, Italy

KEYWORDSDiffusion tensorimaging;Median nerve;Fractional anisotropy;Apparent diffusioncoefficient;Electroneurography

SummaryObjective: The aim of the study was to assess the diagnostic potential of diffusion tensorimaging (DTI) for pathologies of the peripheral nervous system (PNS) through clinical, elec-trophysiological and morphological evaluation of the median nerve.Methods: The present work was a multilevel prospective study involving 30 subjects, 15 ofwhom had carpal tunnel syndrome (CTS) and 15 healthy controls. All subjects underwentclinical evaluation through administration of the Boston Carpal Tunnel Questionnaire (BCTQ),electroneurography (ENG), 3-Tesla magnetic resonance imaging with DTI, and calculation offractional anisotropy (FA) and the apparent diffusion coefficient (ADC) at the flexor retinacu-lum. Tractography was also performed for three-dimensional reconstruction of the route of themedian nerve through the carpal tunnel. The degree of functional impairment was comparedwith the anatomical damage to the median nerve according to ENG and DTI.Results: FA and ADC were significantly correlated with ENG parameters of CTS and BCTQ data.Mean FA and ADC values in the CTS patients were 0.359 ± 0.06 and 1.866 ± 0.050 × 10−3 mm2/s,

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respectively, vs 0.59 ± 0.014 and 1.395 ± 0.035 × 10 mm /s, respectively, in the controls. FAwas decreased and ADC increased in patients with CTS compared with healthy controls (P < 0.05).Conclusion: DTI parameters were clearly confirmed by both clinical and ENG data and, there-fore, may be used for the diagnosis of CTS.© 2013 Elsevier Masson SAS. All rights reserved.

∗ Corresponding author. Tel.: +39 0649914815.E-mail address: marianna.brienza@gmail.com (M. Brienza).

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150-9861/$ – see front matter © 2013 Elsevier Masson SAS. All rights rettp://dx.doi.org/10.1016/j.neurad.2013.06.001

ntroduction

arpal tunnel syndrome (CTS) is a peripheral ‘entrapment’europathy caused by compression of the median nerve as it

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passes through the carpal tunnel, an inextensible anatomicalstructure, that is characterized by potentially disabling painand paresthesia affecting the hand and forearm [1,2]. CTSis the most frequent entrapment neuropathy of the mediannerve, affecting approximately 2—3% of the general popula-tion [3,4].

If clinically suspected, a final diagnosis of CTS maybe confirmed by electroneurography (ENG), which assessesconduction delay in the median nerve by comparing sen-sory and motor electrophysiological parameters betweenthe ulnar and median nerves of the affected and contralat-eral hand [5,6].

Diffusion tensor imaging (DTI) is the only non-invasivein vivo magnetic resonance imaging (MRI) technique for map-ping white-matter fiber tracts in the human brain. In whitematter, diffusion of free water molecules is not the same inall directions of a three-dimensional (3D) space (anisotropy)[7]. Diffusion anisotropy is predominantly determined bythe orientation of fiber tracts in white matter, and influ-enced by both its micro- and macrostructural properties[8].

The purpose of the present research was to compare thedegree of functional impairment, as determined by ENG,with microstructural alterations of the median nerve, asfound by DTI, in CTS patients and to assess the potentialof DTI for the diagnosis of peripheral neuropathies suchas CTS. Indeed, this multilevel prospective study outlinedthe clinical, functional and microstructural features of themedian nerve in CTS patients and in healthy matched con-trols.

Materials and methods

Study design

Clinical evaluation was assessed by anamnesis and physicalexamination using Tinel’s and Phalen’s provocation tests. Inaddition, every patient underwent the Boston Carpal TunnelQuestionnaire (BCTQ) to obtain an objective evaluation ofsymptoms and functional limitations in everyday activities.Functional evaluation of the sensory and motor componentsof the median nerve was carried out with ENG and thedetection of distal sensory latency (DSL) and distal motorlatency (DML), amplitude of sensory action potential (SAP)and compound motor action potential (cMAP), and nerveconduction velocity (NCV). Microstructural evaluation wasperformed by DTI. Diffusion data were used to obtain quanti-tative values such as the apparent diffusion coefficient (ADC)and fractional anisotropy (FA). In addition, fiber tractogra-phy, a method that visualizes nerve bundles on color-coded3D images, was performed [9]. Finally, the clinical, ENGand DTI data were compared to determine whether DTI val-ues (ADC and FA) correlated with the clinical and functionaldamage demonstrated by ENG.

Patients

The study enrolled 15 CTS patients (11 women andfour men), aged between 30 and 45 years (average age37.5 ± 3.43 years) and with body mass index (BMI) scoresranging from 21.8 to 24.2 kg/m2 (mean 23.1 ± 1.12 kg/m2),

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etween November 2011 and February 2012. In addition,5 healthy age- and gender-matched controls were alsonrolled.

Inclusion criteria were established on the basis of anam-esis, physical examination and BCTQ scores. Patients andontrols with additional concurrent pathologies (such as cer-ical radiculopathy, trigger finger, tenosynovitis, arthrosis,iabetes and arthritis) and those taking pharmacologicalreatments (such as steroids and estrogen therapy) werexcluded.

The BCTQ (Italian version) [10] is a patient-based out-ome measure developed specifically for patients with CTS.t comprises two distinct scales: the Symptom Severity ScaleSSS), which poses 11 questions and uses a five-point rat-ng scale; and the Functional Status Scale (FSS), whichonsists of eight items rated by degree of difficulty on a five-oint scale. Each evaluation generates a final score (sum ofndividual scores divided by the number of items) rangingrom 1 to 5, with higher scores indicating greater disability11,12].

Physical examination was performed to detect anywellings, painful areas or congenital/acquired anomalies,nd to evaluate the strength of abduction/opposition ofhe thumb, as well as sensitivity tests of the innervationerritory of the median nerve, looking in particular forypoesthesia and dysesthesia.

Tinel’s test (percussion of the median nerve at the wristo create tingling in the median-innervated fingers) andhalen’s test (wrist flexion to provoke tingling in the median-nnervated fingers within 60 s) [13] were also performed asrovocation tests. These clinical evaluations and functionalests were all carried out by the same neurologist in all studyarticipants.

Only patients with a clinical suspicion of an idiopathiconolateral form of CTS and a BCTQ score greater than 1.1ere included in the study, which ultimately enrolled 11

ight hands and four left hands affected by CTS.Patients and controls were informed of the study pro-

ocol, and gave their written informed consent to undergooth ENG and MRI examinations. The study had the approvalf the local ethics committee.

lectroneurography

ll patients underwent standard ENG examination of theedian and ulnar nerves bilaterally, using a Mendelec Syn-

rgy EMG Monitoring System (Oxford Instruments Medical,ld Woking, Surrey, UK). Sensory nerve conduction velocity

SNCV; in m/s) and motor nerve conduction velocity (MNCV;n m/s), DSL and DML (both in ms), and SAP and cMAP (bothn �V) were assessed by orthodromic stimulation. All sub-ects also underwent F-wave nerve conduction studies inhe upper and lower limbs to exclude radiculopathy andolyneuropathy.

According to data from our laboratory, the follow-ng values are considered diagnostic of CTS: DSL ≥ 2.9 ms;ML ≥ 3.9 ms; and SNCV ≤ 46 m/s. All tests were carried out

hile maintaining the subjects’ skin temperature at 34 ◦C.

ENG examination was performed by the same neurologistn all patients and healthy controls. The average examina-ion time was 25 min.

126 M. Brienza et al.

Table 1 Parameters used for the magnetic resonance imaging protocol.

Sequence Orientation Phaseencoding

Phaseoversam-pling

Slice over-sampling

Gap Slices Slicethickness(mm)

FOVread(mm)

FOVphase(%)

VIBE 3D Coronal RL 25% 20% 0 120 per slab 0.50 210 75DTI DWI—EPI Axial AP 0 0 0.5 40 5 272 100

Sequence TR/TE (ms) Flip angle (◦) Average Matrix BW (Hz/px) Ipat b value Fat sat Acquisitiontime (min)

VIBE 3D 10.8/4.65 10 1 384 × 384 150 2 Yes 03.58DTI DWI—EPI 7600/87 0 4 150 × 150 1450 2 0 and 1000 Yes 03.56

FOV: field of view; VIBE: volumetric interpolated breath-hold examination; 3D: three-dimensional; DTI: diffusion tensor imaging;DWI—EPI: diffusion-weighted imaging—echo-planar imaging; Fat sat: fat saturation.

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iffusion tensor imaging

RI was performed on a 3T Verio whole-body MRI systemSiemens, Erlangen, Germany), equipped with a 45 mT/mnd 200 T/m/s slew rate gradient coil. Patients werecanned in a prone position with the arm abducted and handlongside the head, head first, and the contralateral wristexed in the most comfortable position.

Also, the forearm and hand, wrapped in cushionsnd bandages, were positioned inside an eight-channel,hased-array, head-coil scanner. The imaging protocolonsisted of diffusion-weighted single-shot echo-planarmaging (DWI—EPI) and gradient-echo volumetric interpo-ated breath-hold examination (VIBE) 3D sequences; thearameters are summarized in Table 1.

The examination started with the gradient-echo VIBED sequence to obtain an anatomical reference. Sequencearameters were: phase encoding RL; phase oversampling5%; slice oversampling 20%; slice for slab 120; FOV read10 mm; FOV phase 75%; TR/TE 10.8/4.65 ms; average 1;ip angle 10◦; fat saturation (sat); slice thickness 0.5 mm;atrix 288 × 384; BW 150 Hz/px; and TA 3:58 min.The DTI series was acquired by DWI—EPI with the fol-

owing parameters: slices 40; gap 0.5 mm; orientation axial;hase encoding AP; FOV 272; slice thickness 5 mm; TR/TE600/87 ms; average 4; matrix 150 × 150; Fat sat; IPAT 2;W = 1450 Hz/px; b values 0 and 1000 at six gradient direc-ions; and TA 3:56 min. All images were acquired in the axiallane to optimize reconstruction of the median nerve, whichs perpendicular to nerve fibers in the carpal tunnel.

The DWI—EPI sequence was set to automatically pro-uce four series of images: b = 0 traces; b = 1000 traces; ADCaps; and FA maps. A b value of 1000 was used because,

ccording to Ohana et al. [14], 3T DTI sequences with = 1000 s/mm2 provide the best results for any given rea-onable acquisition time.

ost-processing

ll images were analyzed using Neuro 3D software on aeonardo workstation (Siemens) by two senior radiologists.A and ADC were measured using a single region of interest

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ROI) beneath the flexor retinaculum. The software com-ined the anatomical data obtained by gradient-echo VIBED sequences with an FA color-coded map.

Tractography used the Runge—Kutta fiber assignment byontinuous tracking (FACT) algorithm that follows the vec-or’s angle found in each pixel through straightforward linearropagation to its neighboring pixel. A threshold FA greaterhan 0.2 was applied to start the tracking. In the CTSatients, if a reduction in FA was present, the algorithm waspplied using the ‘brute-force’ approach to assess whetherhere was a minimum threshold of recognition of the nerve.

The brute-force approach goes through all pixels to findvery tract originating from every one of them, then choosesnly those going through the selected seed tractography ROI10 mm2; range: 4.7—17.9 mm2). In this case, our survey wasonducted on the median nerve at the flexor retinaculum, aslready described in previous studies (Figs. 1 and 2) [15,16].

tatistical analysis

PSS software for Windows, version 15.0, was used for allnalyses (SPSS Inc., Chicago, IL, USA). FA and ADC parame-ers in the healthy controls and CTS patients were evaluatedy paired Student’s t-test, while a P value < 0.05 was con-idered a statistically significant difference. Correlationsetween DTI parameters and electrophysiological resultsere calculated using linear regression.

esults

ontrol subjects

or the healthy controls, their average ENG values for sen-ory and motor action potentials (Table 2) were comparedith the CTS patients’ results. At the ulnar nerve, theseere: DSL 2.3 ± 0.2 ms; SAP 15 ± 3 �V; SNCV 52 ± 4 m/s; DML

.6 ± 1 ms; cMAP 11 ± 3 �V; and MNCV 60 ± 3 m/s. Also, theirverage values for FA and ADC calculated at the flexor reti-aculum were 0.59 ± 0.014 and 1.395 ± 0.035 × 10−3 mm2/s,espectively.

3T diffusion tensor imaging and electroneurography of peripheral nerve 127

Figure 1 A. Reformatted isotropic VIBE 3D imaging of the wrist on the axial plane showing the carpal tunnel and the median nerve(circle). B: ADC and C: FA images of the median nerve (arrow) calculated from EPI diffusion-weighted imaging.

Figure 2 Tractography of the median nerve in a normal subject. A: axial and B: coronal view of the median nerve illustrating the3D course of the nerve through the carpal tunnel with an excellent correlation with the anatomic VIBE 3D image.

128

Table 2 Mean electroneurography (ENG) values ± SD inhealthy controls and patients with carpal tunnel syndrome(CTS).

Healthy controls CTS patients

DSL (ms) 2.4 ± 0.2 4.05 ± 1.626SAP (�V) 18 ± 5 4.26 ± 2.2SNCV (m/s) 52 ± 5 37.5 ± 9.192DML (ms) 2.8 ± 1 5.65 ± 2.474cMAP (�V) 16 ± 4 11.8 ± 6MNCV (m/s) 59 ± 5 45 ± 7.071

DSL: distal sensory latency; SAP: sensory action potential; SNCV:sensory nerve conduction velocity; DML: distal motor latency;

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TS patients

ach patient’s BCTQ score was calculated as the mean ofesponses to each individual item. Patients were dividednto four groups according to their mean score: group

= extreme (4.1—5 points); group 3 = severe (3.1—4 points);roup 2 = moderate (2.1—3 points); and group 1 = minimal1.1—2 points) [11]. No patients had a negative score onhe self-administered questionnaire. Their average ENG val-es (Table 2) were compared with those from the healthyubjects. Results at the ulnar nerve were within the nor-al range. In addition, their average FA and ADC values at

he flexor retinaculum were, respectively, 0.359 ± 0.06 and.866 ± 0.050 × 10−3 mm2/s. Their FA and ADC results werelso compared with those of the healthy controls (Table 3)nd the clinical stage of CTS derived from their BCTQ scores.orrelations between BCTQ scores (SSS and FSS) and FA/ADCalues are shown in Figs. 3 and 4.

iscussion

ur present results show significant correlations across clin-cal, electrophysiological and DTI data. As the CTS diagnosiss essentially a clinical one, the use of the BCTQ allowedor the selection and objectification of anamnestic data,endering them more quantifiable and comparable amonghemselves and with ENG and DTI results.

ENG can provide objective data on the functionality ofhe median nerve through analysis of sensory and motorerve conduction. Electrophysiological signs of CTS were

ound in all of our study patients to varying degrees; in par-icular, there was an increase of DSL and DML, a reduction ofAP and cMAP amplitude, and a slowing of SNCV and MNCV.

Table 3 Difference (P < 0.05) between mean diffusion ten-sor imaging (DTI) values ± SD in healthy controls and patientswith carpal tunnel syndrome (CTS).

Healthy controls CTS patients

FA 0.59 ± 0.014 0.359 ± 0.06ADC × 10−3 mm2/s 1.395 ± 0.035 1.866 ± 0.050

FA: fractional anisotropy; ADC: apparent diffusion coefficient.

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Our study used DTI because of its validated diagnosticotential in CNS disorders [17,18], especially demyelinat-ng diseases [19]. Directionally ordered cellular structuresuch as cell membranes and myelin that limit random waterotion can also influence water mobility, guiding it in a pref-

rential direction [20]. DTI relies on the random thermallyriven motion of water molecules to supply microscopictructural information in vivo [20,21]. Using DTI, the levelf anisotropy and local organization of fibers can be mappedoxel by voxel, providing an excellent opportunity to studyhite matter in vivo [22]. Several indices may be used foruantitative analysis of DTI data. In particular, two parame-ers are generally used to describe the diffusion propertiesf tissues: the ADC provides information on the degree ofestriction of water molecules, using a scalar value reflect-ng molecular diffusivity under motion restriction [23], ands independent of magnetic field strength [7]; while FAescribes the degree of directionality and is one of the mostommon anisotropy measures, ranging from 0 to 1, where 0s isotropic and 1 is fully anisotropic [23]. Highly directionalbers are revealed as hyperintense on an FA map [24].

In our healthy controls, the FA and ADC mean val-es calculated underneath the flexor retinaculum were.59 ± 0.014 and 1.395 ± 0.035 × 10−3 mm2/s, respectively.here were some differences compared with other previoustudies carried out in healthy subjects: our present FA valuesere lower than those of Yao and Gai [1] (FA 0.70 ± 0.13),ut fitted well with the results of Kabakci et al. [15,25] (FA.59 ± 0.07, ADC 0.97 ± 0.03 × 10−3 mm2/s), Tasdelen et al.26] (FA 0.599 ± 0.063, ADC 1.046 ± 0.271 × 10−3 mm2/s)nd Andreisek et al. [23] (FA 0.50—0.73, ADC.43—1.61 × 10−3 mm2/s). These differences may haveeen due to the anatomical site of measurement: theedian nerve as it runs beneath the flexor retinaculumay be constricted by flexor tendons, thereby affecting

he motion of water molecules through the myelin sheathnd causing variation in diffusion values. By a similarechanism, as CTS refers to pathological compression of

he median nerve in the carpal tunnel, this might also causeathological changes in FA values, as already suggested byabakci et al. [15,25].

In our CTS patients, DTI showed a significant reductionn FA and an increase in ADC compared with the healthyontrols; this result is consistent with both Khalil et al.16], who found significant changes in diffusion proper-ies of the median nerve in CTS, and Stein et al. [27],ho demonstrated that FA decreased and ADC increasedhen the nerve passed through the carpal tunnel. In fact,hen nerve fibers are subjected to mechanical tension, theemyelination process, which initially involves the paran-dal site of compression and thereafter the whole length ofhe internodal segment, leads to a reduction in the randomovement of water molecules and a consequent reduction in

A compared with surrounding tissues [28]. Thus, our presentesults are consistent with histopathological changes inhe myelin coating during chronic compression (segmen-al demyelination, Wallerian degeneration and eventuallyxonal damage).

In addition, as suggested by Khalil et al. [16], our findingsave confirmed the potential of DTI in the diagnosis of CTS byomparisons with ENG data to establish whether DTI valuesFA and ADC) correlate with the degree of functional damage

3T diffusion tensor imaging and electroneurography of peripheral nerve 129

Figure 3 Correlation between Boston Carpal Tunnel Questionnaire (BCTQ) scores and (a) fractional anisotropy (FA) and (b) apparentdiffusion coefficient (ADC) according to Symptom Severity Scale (SSS).

Figure 4 Correlation between Boston Carpal Tunnel Questionnaire (BCTQ) scores and (a) fractional anisotropy (FA) and (b) apparent (FSS

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diffusion coefficient (ADC) according to Functional Status Scale

demonstrated by ENG. Indeed, our study is the first to pro-pose a threefold comparison of clinical, ENG and DTI data,using BCTQ scores to quantify clinical results. On compar-ing FA and ADC with DSL, DML, SNCV and MNCV in patientswith CTS, there was a significant correlation between DTIand ENG parameters: FA decreased and ADC increased inpatients compared with healthy controls. Moreover, a con-sistent correlation was observed between anatomical andfunctional damage, as lower FA values and higher ADC valueswere found in patients who had ENG confirmation of moresevere CTS. A particular correlation was also noted betweenFA and DSL. Although there was an increase in ADC valuesin CTS patients that was positively correlated with sever-ity of damage, it was not as much as with the FA, whichwas consistent with the observations of Kabakci et al. [25],Stein et al. [27] and Wang et al. [29]. This might be becausethe ADC is an isotropic value that assesses the diffusion ofwater molecules in all directions, whereas FA assesses dif-fusion in only one preferential direction. In any case, it canbe asserted that FA is a more reliable parameter than theADC in the diagnosis of CTS.

Nevertheless, our study has some limitations. One is therelatively small number of patients investigated. In future,more patients need to be enrolled to optimize the technique

and exploit the results. The study could also be extended topatients who have undergone decompression surgery of themedian nerve to assess changes in FA and ADC both pre-and post-surgical, and to identify the potential use of DTI in

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heir follow-up, as suggested by the study of Hiltunen et al.30]. To this end, evaluation of the surgical implications ofractography might represent an interesting development,s it provides 3D reconstruction of the course of the medianerve through the carpal tunnel.

The application of DTI to the peripheral nervous systemould also be of interest considering the possibility of iden-ifying pathological changes and submicroscopic lesions ofhe myelin sheath, even when they are not clinically evi-ent. For this reason, another limitation of this study washe enrolment of only patients with moderate-to-severe CTSas clinically revealed), as the primary aim of our work athis initial stage was to assess the potential of DTI in theiagnosis of CTS by comparison with other instruments atur disposal. A further step might be the assessment of itsotential in the early diagnosis of CTS by enrolling patientst a preclinical stage. In fact, evidence suggests that chronicerve compression induces concurrent Schwann cell prolif-ration and apoptosis in the early stages of the disorder28].

onclusion

ur present results suggest that DTI values can offer signifi-ant confirmation of both clinical and ENG data, and may besed for the diagnosis and evaluation of structural damagef the median nerve in patients with CTS.

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isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

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