ORIGINAL RESEARCHRapid Screening for Carpal Tunnel Syndrome: A Novel Methodand Comparison With Established OthersPanagiotis Zis,* Vassilios Zis,* Sophia Xirou,* Elissavet Kemanetzoglou,*Thomas Zambelis,* and Nikolaos Karandreas*Purpose: The authors have observed that in healthy people, the Ulnar wrist-to-rst dorsalinterosseousdistalmotorlatencydoesnotdiffersignicantlycompared with median wrist-to-abductor pollicis brevis distal motor latency.The aim of our study was to investigate whether the difference between thesetwolatenciescanbeusedasascreeningtool fordiagnosingcarpal tunnelsyndrome and how this technique compares with other establishedtechniques.Methods: The study was set up as a prospective observational study. As goldstandard for the clinical diagnosis of carpal tunnel syndrome, the authors usedthe opinion of two neurologists who independently examined the patients. Athird neurologist, also independently, performed the electrophysiologicalstudy.Results: Eighty-four subjects, 42 patients and 42 age- and sex-matchedcontrols, participated in the study. Among all subjects using a receiveroperatingcharacteristiccurveanalysis, theareaunderthecurvewas0.924(95%CI, 0.8570.991; SE, 0.034; P,0.001). Todetect carpal tunnelsyndrome, at a cutoff score of equal to or greater than 0.575 milliseconds, ourtechnique showeda sensitivityof 91%, a specicityof 93%, a positivepredictive value of 93%, and a negative predictive value of 91%. Comparedwith other classical techniques, our technique showed better area under thereceiver operating characteristic curve and better Youden index.Conclusions: The median wrist-to-abductor pollicis brevis motorlatencyminusulnarwrist-to-rst dorsal interosseousmotorlatencymaybeused as a novel rapid screening tool of patients suffering from carpal tunnelsyndrome.Key Words: Carpal tunnel syndrome, Screening, Ulnar nerve, Median nerve.(J Clin Neurophysiol 2015;32: 375379)Carpal tunnel syndrome (CTS) is an entrapment neuropathy of themedian nerve that causes symptoms such as pain, paresthesia andnumbness in the areas innervated by the median nerve because of itscompressionasit passesthroughthecarpal tunnel. Carpal tunnelsyndrome is the most frequent mononeuropathy with a 10% lifetimerisk (Atroshi et al., 1999; Zambeliset al., 2010).Carpal tunnel syndrome is a clinical diagnosis with thehallmarkof classicCTSbeingpainor paresthesia(numbnessandtingling) inadistributionthat includesthemediannerveterritorywithinvolvement oftherst threedigitsandtheradial halfofthefourth digit. The symptoms of CTS are typically worse at night andoften awaken patients fromsleep. Some patients react to thesesymptomsbyshakingorwringingtheirhandsorbyplacingthemunder warm running water (Preston and Shapiro, 1998).Electrophysiologically, several techniques for diagnosingCTShavebeendescribed. TheAmericanAssociationof Electro-diagnostic Medicine (AAEM) has summarized results across studiesand has estimated the pooled sensitivities and specicities fromindividual studiesby calculatinga weightedaverage. In calculatingthe weighted average, studies enrolling more patients received moreweight thanstudiesenrollingfewerpatients. Thisanalysisshowedthat thetwotechniqueswiththecombination ofthehighest pooledsensitivity and specicity were the comparison of the mediansensoryconductionbetweenthewristandpalmsegmentcomparedwith digit segment and the comparison of median and ulnar sensoryconduction (AAEM et al., 2002).We have observed that in healthy people, the Ulnar wrist-to-rstdorsalinterosseous(FDI)distalmotorlatencydoesnotdiffersignicantly compared with median wrist-to-abductor pollicisbrevis (APB) distal motor latency. Therefore, the aim of our studywas to investigate whether the difference between these twolatenciescanbeusedasascreeningtoolfordiagnosingCTSandhow this technique compares with the other established techniquesrecommended by the AAEMshowing the combination of thehighestpooledsensitivityandspecicity.METHODSParticipantsAll consecutive patients with symptoms consistent with CTSwho were referred for neurophysiological studies to the Departmentof Neurophysiologyof AeginitionHospital, Universityof Athens,were invited to participate in the study. Healthy controls wereselected during the period of the study, they were age andsexmatched, andtheyhadtofulll thesameinclusionandexclusioncriteria as the patients.Tobeenrolled, theparticipants hadtomeet thefollowinginclusion criteria: (1) age equal to or greater than 18 years, (2) beingrst-time visitors and not previously diagnosed by the investigators,(3)nogrossintellectual disabilityorcognitivedecits, and(4)bewilling to provide a written informed consent to undergo theexperimental procedures.Exclusioncriteria were (1) havinghistoryof anyformofpolyneuropathy, idiopathic, or secondary, (2) suffering from diseasesassociated with polyneuropathy, such as diabetes mellitus, renalfailure, and hypothyroidism, (3) receiving or having receivedmedication associated with neuropathy, such as oxaliplatin, (4)receivingcortisone, (5)havinghistoryofcervical myelopathy, (6)suffering fromamyotrophic lateral sclerosis, (7) suffering frombromyalgia, (8) having history of trauma in the examined arm, suchFrom the *1st Department of Neurology, National and Kapodistrian University ofAthens,Aeginition Hospital, Athens,Greece;andDepartment ofNeurology,Evangelismos General Hospital, Athens, Greece.AddresscorrespondenceandreprintrequeststoPanagiotisZis, MD, MSc, PhD,DepartmentofNeurology,AeginitionHospital,72-74Vas,SophiasAvenue,Athens11528, Greece;e-mail: takiszis@gmail.com.Copyright 2015 by the American ClinicalNeurophysiology SocietyISSN: 0736-0258/15/3204-0375Journal ofClinical Neurophysiology

Volume32,Number4,August2015 375as bone fractures or brachial plexus trauma, (9) suffering from ulnarentrapment neuropathyeither at thewrist at theelbow, and(10)suffering from any form of myopathies.StudyDesignThe study was designedas aprospective study. During thevisit, twoneurologistsexaminedindependentlythepatientsanddiagnosed them CTS based on the carpal tunnel consensus criteria(Rempel et al., 1998). Participants who were diagnosed withdenite CTS by both physicians were included in the patientgroup. Similarly, participantswhowerenotdiagnosedwithCTSby both physicians were included in the healthy control group. Athird physician has collected the demographic data of the patientsand has performed, also independently, the neurophysiologicalstudies to the patients. The study was approved by the localscienticcommittee.ElectrophysiologicalStudiesThefollowingparametersweremeasuredusingaKeyPoint(Medtronic, Sweden) electromyography:1. Median wrist-to-APB distal motor latency. RecordingelectrodeswereplacedoverthemotorpointofAPBandstimulation 2 cm proximal to the wrist crease andapproximately7cmproximal tothe recordingcathode.Distalmotorlatencywasmeasuredtotheinitialnegativedeection from the baseline.2. Median sensory conduction velocity from the 2nd digit towristmeasuredantidromicallywiththerecordingcathodeat the proximal interphalangeal joint and anode 2 cmdistally.Thestimulationwas exactlyatthesamepoint asfor parameter (1).3. Median sensory conduction velocity from the 2nd digit topalmmeasuredantidromicallywiththerecordingcathodeat the proximal interphalangeal joint and anode 2 cmdistally. The stimulation was 5 cm distal to the wrist creaseand between the 2nd and 3rd metacarpal head.4. Ulnar wrist-to-FDI distal motor latency. Recording electro-des were placed over the motor point of FDI andstimulation 2 cmproximal to the wrist crease. Distalmotor latency was measured to the initial negativedeection from the baseline.5. Ulnar sensoryconductionvelocityfromthe5thdigit towristmeasuredantidromicallywiththerecordingcathodeat the proximal interphalangeal joint and anode 2 cmdistally.Thestimulationwas exactlyatthesamepoint asfor parameter (4).StatisticalAnalysesAdatabasewas developedusingtheStatistical PackageforSocial Science (version 16.0 for Mac; SPSS, Chicago, Illinois).Frequencies and descriptive statistics were examined for each variable.Receiver operatorcharacteristics(ROC)analysiswascalcu-latedtoassesstheutilityoftheDN4total scoretodistinguishthediagnosis of CTS dened by the gold-standard diagnosis of thersttwo physicians. Area under the curve (AUC) and its 95% condenceintervals for the ROC curve were calculated. The AUC is a measureof the diagnostic power of the test independent of cutoff points. AnAUC,0.60isconsiderednegative,0.61to0.80asdoubtful,0.81 to 0.90 asgood, and .0.91 asvery good (Altman, 1999).TheYoudenIndexwas calculatedas thesumof sensitivityplusspecicity minus 1 for all possible cutoff points to identify the mostrelevant cutoff values (Youden, 1950).Avalue of P ,0.05 was considered to be statisticallysignicant.RESULTSBetween June 2014andNovember 2014, 84subjects, 42patients,and42sex-andage-matchedcontrolsfullledtheabove-mentioned inclusion criteria. The mean age of the patient group was46.1612.9years, rangingfrom21yearsto74years. Out of42subjects in each group, 31 subjects were women (73.8%).MedianWrist-To-abductorPollicisBrevisMotorLatencyMinusUlnarWrist-To-rstDorsalInterosseousMotorLatencyWecalculatedthedifferencebetweenmedianwrist-to-APBdistalmotor latencyand ulnarwrist-to-FDIdistalmotorlatency foreach subject.Among all subjects using an ROC curve analysis, as shown inFig. 1, the AUC was 0.924 (95% condence intervals, 0.8570.991;SE, 0.034; P ,0.001). To detect CTS, at a cutoff score of equal to orgreater than 0.575 milliseconds,ourtechnique showed a sensitivityof 91%, a specicity of 93%, a positive predictive value of 93%, anda negative predictive value of 91% (Table 1).UlnarDigit-to-WristSensoryLatencyMinusMedianDigit-to-WristSensoryLatencyWe calculated the difference between ulnar digit-to-wristsensory latency minus median digit-to-wrist sensory latency for eachsubject.Among all subjects using an ROC curve analysis, as showninFig. 2, theAUCwas0.906(95%condenceintervals, 0.8400.972; SE, 0.034; P , 0.001). To detect CTS, at a cutoff score ofequal to or greater than 8.6 m/s, the difference between ulnar digit-to-wrist sensory latency minus median digit-to-wrist sensorylatency showed a sensitivity of 79%, a specicity of 95%,a positive predictive value of 94%, and a negative predictivevalueof82%(Table2).MedianDigit-to-PalmSensoryLatencytoMedianDigit-to-WristSensoryLatencyRatioWecalculatedthemediandigit-to-palmsensorylatencytomedian digit-to-wrist sensory latency ratio for each subject.Among all subjects using an ROC curve analysis, as shown inFig. 3, the AUC was 0.895 (95% condence intervals, 0.8250.966;SE, 0.036; P ,0.001). To detect CTS, at a cutoff score of equal to orgreater than 1.15, the median digit-to-palmsensory latency tomediandigit-to-wrist sensorylatencyratioshowedasensitivityof79%, aspecicityof 91%, apositivepredictive value89%, anda negative predictive value of 81% (Table 3).DISCUSSIONSeveral electrodiagnostic studies have been found to be highlysensitive and specic for the diagnosis of CTS (AAEM et al., 2002).The AAEM published recommendations regarding neurophysiolog-ical studies to conrm a clinical diagnosis of CTS suggesting that theP. Zis et al. Journal ofClinical Neurophysiology

Volume32,Number4,August2015376 Copyright 2015 by the American Clinical Neurophysiology Societytwo techniques showing the higher pooled sensitivity and specicitywere the median sensory conduction study (wrist and palm segmentcomparedwithdigit segment) andthecomparisonof medianandulnar sensoryconductionbetweenwrist andring nger (AAEMet al., 2002). Our study presents a novel electrophysiological way ofscreeningforCTS, whichwecomparedwiththesetwotechniquesrecommended by the AAEM.The ROC analysis showed that our technique (median wrist-to-APB motor latency minus ulnar wrist-to-FDI motor latency) provideshigherAUC(0.924) comparedwiththeAUCprovidedbythetwoclassical methods of ulnar digit-to-wrist sensory latency minus mediandigit-to-wrist sensory latency (0.906) and median digit-to-palm sensorylatency to median digit-to-wrist sensory latency ratio (0.895). The samesuperioritywasalsounderpinnedbythebetter Youdenindex(0.83,0.74, and 0.69, respectively).Additionally, our technique has three major advantagescomparedwithanyother electrophysiological techniquecurrentlybeing used:1. It is more rapid, as it only needs two studies to be done, themedianwrist-to-APBdistal motor latencyandtheulnarwrist-to-FDI distal motor latency.2. It is not pronetomeasurement bias, whichis likelytooccurwhenmeasuringthedistancesbetweenthepoint ofstimulation and the recording electrode.3. As bothrecordings arefrommuscles of thethenar, themeasurements are not affectedbythe difference inthetemperature between the thenar and the hypothenar, whichmay affect thendings in theclassical techniques.Denitely many other techniques have been described andinclude comparison of other motor latencies, such as median wrist-to-APB versus ulnar wrist-to-abductor digiti minimi (Werner and Andary,2011) or median latency to the second lumbrical versus ulnar latency tothe interossei (Sheean et al., 1995). Additionally, other techniques usesensoryconductionstudies, suchas comparisonof themedianandulnar sensory velocity measured antidromically with palmar stimulation(Werner andAndary, 2011). Wefollowedtherecommendationsforfuture research studies in CTS published by the AAEM (AAEM et al.,FIG.1. Receiveroperatingcharacteristic(ROC)curveformedianwrist-to-abductorpollicisbrevis motorlatencyminusulnarwrist-to-rstdorsalinterosseousmotorlatencyforthediagnosisofcarpaltunnelsyndrome.TABLE1. DiagnosticEfciencyofMedianWrist-to-APBMotor Latency Minus Ulnar Wrist-to-FDI Motor Latency for theDiagnosisofCarpalTunnelSyndromeCutoffScoreYoudenIndex Sensitivity Specicity PPV NPV$0.175 0.33 95.2% 35.7% 59.7% 88.2%$0.490 0.69 92.9% 76.2% 79.6% 91.4%$0.575 0.83 90.5% 92.9% 92.7% 90.7%$0.775 0.80 81.0% 97.6% 97.1% 83.7%$1.395 0.50 50.0% 100% 100% 66.7%Journal ofClinical Neurophysiology

Volume32,Number4,August2015 RapidScreeningforCarpal TunnelSyndromeCopyright 2015 by the American Clinical Neurophysiology Society 3772002), and we compared our proposed technique with the twotechniques that showthe highest pooledsensitivityandspecicitycombination according to the AAEM analysis.In addition to the numerous different techniques that are beingused, previousstudieshavealsoshownthatusingtwocomparisontechniques lower the risk of false positives or false negatives and thatone comparative study by itself may not sufce (Werner and Andary,2011). Therefore, comparisonof our technique withother estab-lished techniques alone or in combination would be of great interestin future studies.To be able to obtain a pure CTS population withoutcomorbidities likelytoaffect theelectrophysiological studies, ourinclusion and exclusion criteria were very strict. Therefore, it wouldbe of great interest if in future studies our technique was also testedinpopulationswithCTSandcomorbiditiesthatinthisstudywerethe exclusion criteria.Another advantage of our design is that by using age- and sex-matchedcontrols, we limited the possible confoundingeffect ofthesevariables. Of course, our results shouldbeinterpretedwithsome caution given the fact that our population comprised patients ofone hospital and results may not be generalizable to other settings. Amulticenter replicationvalidationstudyis advisedtoconrmourndings.Choosing the optimal cutoff point is difcult (Budczieset al., 2012). When evaluating a screening tool, a balance betweensensitivity and specicity is necessary as the tool should not onlycorrectlydiagnose the conditionwhenpresent (sensitivity) butalsocorrectlyexclude the presence of the conditionwhennotpresent (specicity). UsingtheYoudenindex, wefoundthat atthe optimumcutoff point (0.575 milliseconds), our techniqueshowed a sensitivity of 91%and a specicity of 93%. Thesensitivity is higher compared with the pooled sensitivitycalculatedbytheAAEMintheir review(AAEMet al., 2002).Although the specicity is slightly lower, one could choosea higher cutoff point to increase the specicity; however, thesensitivity will drop. For example, at a cutoff point of 0.775milliseconds, the specicity of our technique would be 98%meaningthatalmostallpatientshavingadifferencebetweentheTABLE2. DiagnosticEfciencyofUlnarDigit-to-WristSensory Latency Minus Median Digit-To-Wrist Sensory LatencyfortheDiagnosisofCarpalTunnelSyndromeCutoffScoreYoudenIndex Sensitivity Specicity PPV NPV$4.30 0.71 85.7% 85.7% 85.7% 85.7%$6.15 0.72 81.0% 90.5% 89.5% 82.6%$8.60 0.74 78.6% 95.2% 94.4% 81.6%$15.55 0.43 45.2% 97.6% 95.0% 64.1%$16.85 0.41 40.5% 100% 100% 62.7%FIG.2. Receiveroperatingcharacteristic(ROC)curveforulnardigit-to-wristsensorylatencyminusmediandigit-to-wristsensorylatencyforthediagnosisofcarpaltunnelsyndrome.P. Zis et al. Journal ofClinical Neurophysiology

Volume32,Number4,August2015378 Copyright 2015 by the American Clinical Neurophysiology Societymedianwrist-to-APBmotor latencyandtheulnar wrist-to-FDImotor latencylower than0.775milliseconds wouldnot sufferfrom clinical CTS. However, in this case, the specicity would be81%meaningthat almost oneout of vescreenedpositiveforCTSwouldactuallybehealthy.Denitely, a diagnosis of CTS is clinical, and a singleelectrophysiological technique cannot set a diagnosis. A rapidscreening tool, as the one we are introducing, may be used inidentifyingsubjects verylikelytosuffer fromCTSand, insuchcases, proceed in further investigations to conrm the diagnosis.ACKNOWLEDGMENTSTheauthors aresincerelythankful tothepatients andthehealthy controls who participated in the study.REFERENCESAltmanDG. Practicalstatisticsformedical research. Washington:Chapman&Hall,1999.American Association of Electrodiagnostic Medicine, American Academy ofNeurology, and American Academy of Physical Medicine and Rehabilitation.Practiceparameter forelectrodiagnosticstudiesincarpal tunnel syndrome:summary statement.MuscleNerve 2002;25:918922.Atroshi I, Gummesson C, Johnsson R, et al. Prevalence of carpal tunnel syndromein a general population.JAMA 1999;282:153158.BudcziesJ, KlauschenF, SinnBV, et al. Cutoff Finder: acomprehensiveandstraightforwardWebapplicationenablingrapidbiomarkercutoffoptimiza-tion. PLoS One 2012;7:e51862.Preston DC, Shapiro BE. Median neuropathy. In: electromyography andneuromuscular disorders: clinical-electrophysiologic correlations. Boston,MA: Butterworth-Heinemann, 1998;231.Rempel D, Evanoff B, Amadio PC, et al. Consensus criteria for the classicationof carpal tunnel syndrome in epidemiologic studies.1998.Sheean GL, Houser MK, Murray NM. Lumbrical-interosseous latency comparisonin the diagnosis of carpal tunnel syndrome. Electroencephalogr Clin Neuro-physiol1995;97:285289.WernerRA,AndaryM.Electrodiagnosticevaluationofcarpaltunnelsyndrome.MuscleNerve2011;44:597607.Youden WJ.Index for rating diagnostictests. Cancer 1950;3:3235.ZambelisT, TsivgoulisG, KarandreasN. Carpal tunnel syndrome: associationsbetween risk factorsand laterality.Eur Neurol 2010;63:4347.FIG.3. Receiveroperatingcharacteristic(ROC)curveforthemediandigit-to-palmsensorylatencytomediandigit-to-wristsensorylatency ratio for the diagnosis of carpaltunnelsyndrome.TABLE3. DiagnosticEfciencyoftheMedianDigit-to-PalmSensoryLatencytoMedianDigit-to-WristSensoryLatencyRatiofortheDiagnosisofCarpalTunnelSyndromeCutoffScoreYoudenIndex Sensitivity Specicity PPV NPV$1.07 0.64 90.5% 73.8% 77.6% 88.6%$1.12 0.64 83.3% 81.0% 81.4% 82.9%$1.15 0.69 78.6% 90.5% 89.2% 80.9%$1.23 0.62 66.7% 95.2% 93.3% 74.1%$1.32 0.48 47.6% 100% 100% 65.6%Journal ofClinical Neurophysiology

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