Pa tho physiology /Comp Ii cations
`ORIGINAL ARTICLE
`
`Carcal Tunnel Syndrome in Patients With
`Dia etic Polyneuropathy
`
`BRUCE A. PERKINS, FRCPc
`3
`DAVID 0LALEYE, PHD
`4
`VERA BRIL, MD. FRCPC
`
`1
`
`2
`•
`
`OBJECTIVE - Carpal tunnel syndrome (CTS) and diabetic polyneuropathy (DPN) are com(cid:173)
`mon conditions in patients with diabetes and therefore frequently occur concomitantly. Diag(cid:173)
`nosis of CTS in patients with DPN is important, as therapeutic interventions directed toward
`relief of CTS may be effective irrespective of diffuse neuropathy. The prevalence of clinical CTS
`and the most efficient electrodiagnostic discriminators of CTS from diffuse neuropathy are
`uncertain.
`
`RESEARCH DESIGN AND METHODS - A total of 4 78 subjects, including reference
`subjects (without diabetes and without neuropathy), nonneuropathic subjects with diabetes,
`and diabetic subjects with mild, moderate, and severe neuropathy, were evaluated in a cross(cid:173)
`sectional design for clinical features of CTS. In the ascertainment of the cohort, a clinical
`stratification method was used to ensure a broad spectrum of neuropathy severity. All subjects
`underwent nerve conduction study determinations of median, ulnar, and sural nerve parame(cid:173)
`ters.
`
`RESULTS- The prevalence of clinical CTS was 2 % in the reference population, 14% in
`diabetic subjects without DPN, and 30% in those with DPN. Multiple linear regression analysis
`revealed that mean electrodiagnostic parameters are not significant predictors of clinical CTS in
`patients with diabetes. Generally, the parameters worsened with severity of neuropathy, but
`none reliably distinguished diabetic patients with and without CTS.
`
`CONCLUSIONS- Given the high prevalence of CTS in patients with DPN and that elect(cid:173)
`rodiagnostic criteria cannot distinguish those with clinical CTS, it is recommended that thera(cid:173)
`peutic decisions for CTS be made independently of electrodiagnostic findings.
`
`Diabetes Care 25:565-569, 2002
`
`C arpal tunnel syndrome ( CTS) and
`
`curate electrodiagnostic discriminator of
`diabetic polyneuropathy (DPN) are
`the two conditions is unknown, the diag(cid:173)
`nosis of CTS in those with DPN is com(cid:173)
`common conditions in patients with
`plex (7). Electrophysiological criteria
`type 1 and type 2 diabetes (1,2) The
`prevalence of CTS is thought to be higher
`designed to discriminate CTS in subjects
`in patients with DPN (3-6) than in the
`with and without DPN are available, but
`general population, and the treatment less
`their reliability is uncertain. The common
`successful (2, 7-10). Because the most ac-
`practice is to apply nerve conduction
`•••••••••••••••••••••••••••••••••••••••••••••••••
`From the 1Beth Israel Deaconness Medical Center. Harvard Medical School. Boston. Massachusetts; 2Joslin
`Diabetes Center. Boston. Massachusetts; 3iBiomatics, Cary, North Carolina; and 4Toronto General Hospital,
`University Health Network, University of Toronto, Toronto, Canada.
`Address correspondence and reprint requests to Dr. Vera Bril, EN 11-209, TGH, University Health
`Network, 200 Elizabeth St., Toronto, Ontario, Canada MSG 2C4. E-mail: vera.bril@utoronto.ca.
`Received for publication 2 August 2001 and accepted in revised form 7 December 2001.
`Abbreviations: CTS, carpal tunnel syndrome; DMMA, distal median nerve motor amplitude; DMML,
`distal median nerve motor latency; DMSA, distal median sensory amplitude; DMSCV, distal median sensory
`conduction velocity; DMSL, distal median sensory latency; DPN, diabetic polyneuropathy; DUMA, distal
`ulnar motor amplitude; DUML, distal ulnar motor latency; DUSA, distal ulnar sensory amplitude; DUSCV,
`distal ulnar sensory conduction velocity; DUSL, distal ulnar sensory latency; NCS, nerve conduction study;
`PMSCV, proximal median sensory conduction velocity; PMSL, proximal median sensory latency; SA, sural
`amplitude; SCV, sural conduction velocity; SL, sural latency; UHN, University Health Network.
`A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion
`factors for many substances.
`
`study (NCS) criteria to diagnose CTS in
`diabetic subjects without DPN in the
`same manner as in the nondiabetic pop(cid:173)
`ulation.
`Commonly applied criteria are a dis(cid:173)
`proportionate increase of the median
`nerve latency compared with other up(cid:173)
`per-limb latencies; a difference in side-to(cid:173)
`side median nerve conduction studies
`with more abnormality on the affected
`side, if clinical CTS is unilateral; and ab(cid:173)
`sent median nerve responses when other
`upper-limb responses are present (7). An(cid:173)
`other criterion is a difference in the distal
`sensory nerve conduction velocities such
`that the median nerve is < 10 mis com(cid:173)
`pared with the ulnar nerve. However,
`these criteria for the diagnosis of CTS
`have generally been developed with the
`deliberate exclusion of subjects with both
`DPN and CTS, thus excluding a potential
`interaction effect on NCS measurements
`(11). In addition, therapeutic trials in
`DPN exclude subjects with CTS based on
`NCS criteria of uncertain reliability, call(cid:173)
`ing into question the generalizability of
`results obtained from studies using these
`selected populations. The lack of reliable
`information on electrodiagnostic discrim(cid:173)
`inators of CTS from DPN therefore has
`major implications in both clinical and re(cid:173)
`search contexts.
`The current study has two objectives:
`to estimate the point prevalence of clinical
`CTS in a population of subjects with dia(cid:173)
`betes and a broad spectrum of DPN sever(cid:173)
`ity, and to identify the most valid
`electrodiagnostic test for discriminating
`CTS from DPN in different stages of se(cid:173)
`verity of DPN.
`
`RESEARCH DESIGN AND
`METHODS- The study was con(cid:173)
`ducted at the Toronto General Hospital
`University Health Network (UHN) in the
`Diabetic N europathy Research Clinic
`from June 1998 to August 1999. Ap(cid:173)
`proval from the UHN Research Ethics
`Board was obtained before commencing
`the study.
`
`Selection of patients
`The inception cohort was ascertained
`from four different sources: unselected
`
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`CTS in diabetic polyneuropathy
`
`Table I-Clinical stratification method
`
`Symptom scores
`
`Reflex scores
`
`Sensory test scores
`
`Knee reflexes
`Ankle reflexes
`
`foot pain
`Numbness
`Tingling
`Weakness
`Ataxia
`Upper-limb symptoms
`Symptom scores graded as present= 1 or absent= 0 (numbness, tingling as perceived at toes and in feet),
`Reflex scores graded as absent = 2, reduced = 1, or normal = 0 for each side, Sensory test scores graded as
`abnormal= 1 or normal= 0, Maximum score is 19,
`
`Pinprick
`Temperature
`Light touch
`Vibration
`Position sense
`
`patients attending a diabetes clinic with(cid:173)
`out known neuropathy status, patients re(cid:173)
`f erred to the Diabetic Neuropathy
`Research Clinic for suspected neuropa(cid:173)
`thy, responders to advertisements in the
`community for patients with diabetes
`without known neuropathy status, and
`reference subjects (healthy volunteers
`without diabetes and without known
`neuropathy), Informed consent for the
`study was obtained from each subject,
`
`Study protocol
`All subjects underwent the following:
`
`• A comprehensive medical and neuro(cid:173)
`logical evaluation in order to exclude
`neuropathy of other etiologies (e,g,, fa(cid:173)
`milial, alcoholic, nutritional, and ure(cid:173)
`mic) performed by the individual who
`obtained the informed consent,
`• Carpal tunnel evaluation: specific clin(cid:173)
`ical evaluation for CTS using generally
`accepted criteria (7,10), The presence
`of any four of the following six criteria
`established a diagnosis of CTS: history
`of paresthesia in hands and/or marked
`preponderance of sensory symptoms in
`the hands, nocturnal hand symptoms
`awakening patient, symptoms precipi(cid:173)
`tated by activities such as holding a
`newspaper or driving a car and relieved
`by hand shaking, predilection for radial
`digits, weak thenar muscles, or upper(cid:173)
`limb sensory loss solely within the dis(cid:173)
`tribution of the median nerve,
`• Standardized bilateral N CS by three
`technologists blinded to the compre(cid:173)
`hensive medical and neurological eval(cid:173)
`uation, as well as the carpal tunnel
`evaluation, Counterpoint (Medtronic,
`Mississauga, Canada) was used for N CS
`in all patients, Standardized techniques
`for NCS with temperature control and
`fixed distances were applied, Measure(cid:173)
`ments of latencies, distances, and am-
`
`plitudes were done in a standard
`fashion using onset latencies and base(cid:173)
`line-to-peak amplitudes, or for sensory
`curves using initial positive peak (if
`present) to negative peak measure(cid:173)
`ments, Conduction velocities were cal(cid:173)
`culated automatically by Counterpoint,
`The NCS included 1) distal median
`nerve motor latency (DMML) and distal
`median nerve motor amplitude
`(DMMA) of the evoked motor response
`over the thenar muscles; 2) distal me(cid:173)
`dian nerve sensory conduction studies,
`with distal latency (distal median sen(cid:173)
`sory latency [DMSL]), distal median
`sensory amplitude (DMSA), and distal
`median sensory conduction velocity
`(DMSCV); 3) proximal median nerve
`sensory conduction, with proximal la(cid:173)
`tency (proximal median sensory la(cid:173)
`tency [PMSL]), proximal amplitude
`(proximal median sensory amplitude
`[PMSA]), and proximal conduction ve(cid:173)
`locity (proximal median sensory con(cid:173)
`duction velocity [PMSCV]); 4) distal
`ulnar nerve motor conduction, with
`distal motor latency (distal ulnar motor
`latency [DUML]) and amplitude (distal
`ulnar motor amplitude [DUMA]) of the
`evoked motor response over the hy(cid:173)
`pothenar muscles; 5) distal ulnar nerve
`sensory conduction, with distal latency
`(distal ulnar sensory latency [DUSL]),
`distal ulnar sensory amplitude (DUSA),
`and distal ulnar sensory conduction ve(cid:173)
`locity (DUSCV); and 6) sural nerve la(cid:173)
`tency (SL), sural amplitude (SA), and
`sural conduction velocity (SCV), All
`sensory nerve conduction studies were
`antidromic, The tern perature of the
`limbs was controlled such that the min(cid:173)
`imum upper limb value was 32°C, and
`the lower limb value was 31°C Low
`interobserver and intraobserver vari(cid:173)
`ability have been established for these
`measurements using the rigorous tech-
`
`niques described (12,13) The coeffi(cid:173)
`cients of variation for sensory nerve
`potentials are 11 and 16% in the upper
`and lower limb, respectively, For motor
`amplitudes, the values are 10 and 12%
`in the upper and lower limb, respec(cid:173)
`tively, Motor nerve conduction veloci(cid:173)
`ties have a variation of 3% in upper and
`lower limbs, whereas sensory conduc(cid:173)
`tion velocities show 4-5% variation,
`These figures represent interobserver
`variability and interlaboratory vari(cid:173)
`ability from a 60-site study, These vari(cid:173)
`ances are the same for intraobserver
`variability within this laboratory,
`
`ln the presence of CTS, the expectation is
`that the DMML and DMSL are prolonged
`and the DMMA, DMSA, and DMSCV are
`reduced, The PMSL is prolonged, and the
`PMSCV and motor conduction velocity
`may be reduced, Other NCS parameters
`are normaL The ratios of median-to-ulnar
`or median-to-sural N CS parameters
`would change in the direction of the me(cid:173)
`dian nerve changes noted above, The de(cid:173)
`gree of change in the NCS parameters
`depends on the severity of the CTS and
`the specific nerve fibers involved, as some
`patients primarily have motor impair(cid:173)
`ments, whereas others mainly have sen(cid:173)
`sory changes, Many patients have changes
`in both motor and sensory fibers,
`
`Clinical stratification method
`Subjects were graded as to neuropathy se(cid:173)
`verity using six symptom scores, i,e,, foot
`pain, numbness, tingling, weakness, im(cid:173)
`balance, and upper limb symptoms, all as
`present or absent; eight reflex scores, i,e,,
`bilateral knee and ankle reflexes, each
`graded as absent, reduced, or normal; and
`five physical examination scores, i,e,, pin(cid:173)
`prick, tern perature, light touch, vibration,
`and position sense, as present or absent,
`for a total of 19 possible points (Table l),
`Assessment of numbness and tingling in
`this scoring system was referable to the
`toes and feet, The clinical sensory exami(cid:173)
`nation was done at the first toe bilaterally,
`Grading was stratified such that 0-5 in(cid:173)
`dicated no neuropathy, 6-8 indicated
`mild neuropathy, 9-11 indicated moder(cid:173)
`ate neuropathy, and 212 indicated severe
`neuropathy, The demographic data for
`the 4 78 participants are shown in Table 2,
`The presence of complications was deter(cid:173)
`mined by the history provided by the pa(cid:173)
`tient without further testing,
`
`566
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`Perkins, Olaleye, and Bril
`
`Table 2-Demographic data for 478 subjects
`
`Variable
`
`Reference
`
`Diabetes
`
`None
`Neuropathy status
`52 (11)
`n(%)
`Sex(% male)
`46
`Age (years)
`37.6 ±: 10.4
`NIA
`Type 1 diabetes(%)
`Diabetes duration (years)
`0
`5.5 ±: 0.04
`HbA1c (%)
`NIA
`Neuropathy duration (years)
`Clinical CTS (%)
`2
`Foot ulcer history(%)
`0
`Retinopathy (%)
`0
`Nephropathy (%)
`0
`Erectile dysfunction(% male)
`1.9
`Orthostatic hypotension (%)
`0
`Data are means ± SD unless otherwise indicated. NA. not applicable.
`
`None
`81 (17)
`68
`51.0 ±: 10.8
`19
`9.4 ±: 9.9
`8.3 ±: 1.4
`NIA
`14
`0
`11
`18
`27
`9
`
`Mild
`94 (20)
`65
`56.8 ±: 8.5
`13
`11.2 ±: 11.0
`8.1 ±: 1.9
`2.9±4.1
`31
`9
`10
`14
`43
`16
`
`Moderate
`109 (23)
`75
`57.7 ±: 10.1
`13
`13.3 ±: 10.7
`8.0 ±: 1.7
`4.2 ±: 4.3
`23
`27
`20
`25
`56
`27
`
`Severe
`134 (30)
`65
`57.0 ±: 9.5
`20
`15.8 ±: 11.7
`8.7 ±: 1.6
`5.1 ±: 5.0
`34
`64
`36
`43
`49
`28
`
`Statistical analyses
`Ratios of electrophysiological para(cid:173)
`meters were calculated as follows:
`DMML-to-DUML, DMSL-to-DUSL,
`DMMA-to-DUMA, DMSA-to-DUSA, DM(cid:173)
`SCV-to-DUSCV, PMSCV-to-DMSCV,
`DMSL-to-SL, DMSA-to-SA, DMSCV-to(cid:173)
`SCV, DMML-to-SL, and DMMA-to-SA Sta(cid:173)
`tistical analyses were performed using
`Statview version 5.0 (SAS Institute, Cary,
`NC) for MacIntosh. The point estimates of
`clinical CTS were obtained by the propor(cid:173)
`tion of patients with clinical CTS in a par(cid:173)
`ticular category. ANOVA was used to
`calculate the mean values of NCS parame(cid:173)
`ters and ratios in different clinical groups.
`The multiple linear regression method, or
`method of generalized least squares, was
`used to determine whether CTS or DPN
`was the major determinant of the electrodi(cid:173)
`agnostic values in patients with clinical
`CTS. The analysis was repeated for different
`patient clusters: CTS + DPN, CTS - DPN,
`and no CTS regardless of DPN status.
`
`RESULTS- Significant differences
`were observed among the defined clinical
`neuropathy strata in patient age (refer(cid:173)
`ence group as younger, P < 0.0001), in
`duration of diabetes (longer for more se(cid:173)
`vere neuropathy, P < 0.0001), and in du(cid:173)
`ration of neuropathy (longer for more
`severe neuropathy, P < 0.0001). Contin(cid:173)
`gency table analyses revealed a signifi(cid:173)
`cantly increasing prevalence of history of
`foot ulcer, retinopathy, nephropathy, and
`erectile dysfunction with stage of neurop(cid:173)
`athy, as previously described (14)
`The frequency of clinical CTS was 2 %
`
`in the reference stratum, 14% in nonneu(cid:173)
`ropathic diabetic subjects, and 30% in
`those with DPN. The presence of CTS was
`related to the duration of diabetes such
`that those with CTS had diabetes for a
`mean of 14.0 :::'::: 12.5 years compared with
`those without CTS who had diabetes for
`10.8 :::'::: 10. 7 years. Metabolic control was
`not different in the two groups; both had
`a mean glycosylated hemoglobin value of
`8.1 % with an SD of 1.7 and 1.9%.
`Table 3 shows a sampling of the elec(cid:173)
`trodiagnostic results for the different clin(cid:173)
`ical categories of subjects studied. Mean
`values in each category for those with and
`without CTS were not different other than
`the DMSA-to-DUSA for reference sub(cid:173)
`jects. ln this stratum, the subjects with
`clinical CTS had an abnormal ratio of
`DMSA-to-DUSA of ~ 112 that of those
`without CTS. All other parameters are the
`same in both groups. The reference pop(cid:173)
`ulation is limited in that only one subject
`had clinical CTS. Mean values for electro(cid:173)
`diagnostic parameters tended to worsen
`with worsening neuropathy status, as
`shown by the changes in mean values of
`the different parameters in Table 3.
`Among patients with DPN, having CTS is
`not a major determinant of the outcome
`variables other than for DMML-to-SA.
`The significance of this finding is lost
`when the association is adjusted for clin(cid:173)
`ical neuropathy stratum.
`
`CONCLUSIONS- These results
`demonstrate that electrodiagnostic pa(cid:173)
`rameters in subjects with diabetes are not
`different in those with and without CTS,
`
`placing a limit on the value of N CS in the
`diagnosis of clinical CTS in these subjects.
`The assumption that the electrodiagnostic
`criteria for CTS are the same in diabetic
`subjects without DPN as in the general
`nondiabetic, reference population (7) is
`therefore misleading and can result in the
`inaccurate diagnosis of CTS in subjects
`with diabetes. The electrodiagnostic fea(cid:173)
`tures for CTS in the reference population
`cannot be ascertained from this study,
`given that only 1 of 50 reference subjects
`had clinical CTS in this subgroup. An
`older reference population without diabe(cid:173)
`tes might have more frequent CTS than
`observed in the younger reference popu(cid:173)
`lation in this study. Cohorts of nondia(cid:173)
`betic subjects with clinical CTS have been
`extensively studied in the past in order to
`evaluate the different electrodiagnostic
`parameters associated with clinical CTS
`(15,16)
`The cross-sectional prevalence of
`clinical CTS in a mixed population of sub(cid:173)
`jects with diabetes and varying degrees of
`DPN is remarkably high. Our finding of a
`point prevalence of 30% CTS in subjects
`with DPN is higher than in previous re(cid:173)
`ports, although many studies report the
`prevalence of CTS in those with diabetes
`without considering the presence of DPN
`(7). Some of the difficulty in comparing
`series is that the diagnostic approaches for
`CTS are not uniform (7). More recently,
`Dyck et al. (2) reported the prevalence of
`symptomatic CTS in those with diabetes
`as 11 and 6% in type 1 and type 2 diabetic
`patients, respectively, but these are not
`subjects with DPN. The prevalence of
`
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`asymptomatic CTS in both type 1 and
`type 2 diabetes was considerably higher.
`The frequency of electrophysiological and
`clinical CTS in diabetic subjects with and
`without DPN demands an etiological ex-
`planation. It is hypothesized that the me-
`dian nerve is made more susceptible to
`the pressure effects existing in the carpal
`tunnel when underlying DPN, a length-
`dependent axonopathy, is present. The
`anatomy of the carpal tunnel may pro-
`duce local vascular compromise, which is
`superimposed on the metabolically disor-
`dered nerve or a nerve with established
`endoneurial ishemia, leading to frequent
`dysfunction in this short nerve segment.
`This combination of insults may result in
`impaired axonal transport (17), produc-
`ing local pathology and retrograde nerve
`dysfunction.
`A further implication of these results
`relates to the selection of subjects with
`DPN for research studies. Patients with
`clinical or electrophysiological criteria for
`CTS have commonly been excluded from
`clinical trials. The results of this study in-
`dicate that the presence of clinical CTS
`does not modify the electrophysiological
`measure of DPN. We therefore recom-
`mend that CTS criteria not be used as ex-
`clusion criteria in clinical trials using NCS
`as an outcome measure for DPN.
`NCS has a clear role in determining
`the presence and severity of DPN (18,19)
`but does not reliably distinguish the pres-
`ence or the absence of CTS in subjects
`with diabetes. Given the high prevalence
`of clinical CTS in subjects with DPN, it is
`recommended that therapeutic decisions
`in patients with clinical criteria for CTS
`should be made independently from NCS
`findings. Specifically, a trial of therapy
`should be strongly considered in patients
`with both diabetes and clinical CTS with-
`out undue reliance on electrodiagnostic
`results .
`
`Acknowledgments- We thank M. Ngo, E.
`Ng, T. Ganeshram, S. Gogov, K. Than Nwe,
`and S. Skandarajah for assistance in data col-
`lection and David Liang for assistance in data
`management.
`
`References
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`
`DIABETES CARE, VOLUME 25, NUMBER 3, MARCH 2002
`
`Sanofi Exhibit 2173.004
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`IPR2018-01676
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`

`

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