Jtournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:509-514

Subclinical diabetic polyneuropathy: earlydetection of involvement of different nerve fibretypes

P H Hendriksen, P L Oey, G H Wieneke, B Bravenboer, A C van Huffelen

AbstractNerve conduction studies, tests of auto-nomic function and terminal nerve

branches, and soleus muscle H reflexeswere applied to 60 patients with insulindependent diabetes mellitus who had no

clinical symptoms but abnormal vibrato-ry or temperature perception thresholdsindicating subclinical neuropathy. Inmost patients neurophysiological exami-nation yielded a broad spectrum of neur-al dysfunction. The perception thresholdfor cold stimuli was sometimes selective-ly impaired and abnormal pupillometryresults were common, suggesting thatsmall fibres are vulnerable in the earlystage of diabetic neuropathy. The arms

were less frequently and less severelyaffected than the legs, an effect that maybe related to nerve length. The neuro-

physiological test results did not changein 30 patients followed up for one year.

(J Neurol Neurosurg Psychiatry 1993;56:509-514)

Department ofClinicalNeurophysiology,University HospitalUtrecht, TheNetherlandsP H HendriksenP L OeyG H WienekeA C van HuffelenDepartment ofInternal Medicine,University HospitalUtrecht, TheNetherlandsB BravenboerCorrespondence and reprintrequests to:Dr P L Oey, Department ofClinical Neurophysiology,University Hospital Utrecht,Heidelberglaan 100, 3584CX Utrecht,The Netherlands.Received 6 January 1992and in revised form23 June 1992 and4 September 1992.

Accepted 17 September1992

Diabetic neuropathies include a variety of dis-tinct disorders affecting individual nerves or

nerve roots, but more commonly the effectsare seen in different nerve types and at multi-ple sites. The neuropathy is generally assessedwith electrophysiological tests. Most of thecommonly used methods for the detection ofdiabetic neuropathy, however, reflect only theloss of large fibres.' Because unmyelinatedfibre loss precedes abnormalities of largefunction,2 and because the extent of smallfibre loss in most cases of asymptomaticpolyneuropathy is not known,' simultaneousassessment of different neurological functionsmediated by different nerve fibre types mighthelp to detect nerve involvement related tofibre type. Several classes of motor, sensory,and autonomic fibres must be considered.Dyck et al have shown that there are strongcorrelations between clinical abnormalitiesand neurophysiological indices in diabeticneuropathy, and they found a highly signifi-cant association between sural sensory nerve

action potential amplitude and neuropathicsymptoms.4 Sundkvist and Young et al study-ing asymptomatic patients with insulindependent diabetes mellitus, found only a

weak relation between peripheral somatic andautonomic abnormalities. Conflicting opin-ions exist on whether large myelinated(peripheral somatic), small myelinated, andunmyelinated (autonomic) nerve fibres are

damaged in parallel by diabetes.To evaluate nerve dysfunction related to

fibre type and to compare the results of auto-nomic, motor end plate, sensory, and motornerve function tests in a well defined group of60 insulin dependent diabetic patients with-out symptoms of polyneuropathy, we per-formed H reflex of the soleus muscle, singlefibre electromyography of the anterior tibialmuscle, and pupillometry in addition to theestablished methods for the quantification ofperipheral nerve dysfunction.7To study the natural course of subclinical

diabetic polyneuropathy, we followed up 30diabetic patients for 12 months. Neurophysio-logical tests included psychophysical testingand pupillometry (reflecting small nerve fibrefunction), nerve conduction examination(reflecting large nerve fibre function), andsingle fibre electromyography (reflecting neuro-muscular junction transmission function).

Subjects and methodsPATIENT SELECTIONSixty patients, (37 men) with type I (insulindependent) diabetes mellitus participated inthis study. The mean (SD) age was 47 (12)years, range 20-71 years; the known durationof illness was 24 (10) years, range 4-50 years,and mean glycosylated haemoglobin Al(HbA,)was 9 3 (2A4)%. To study progress ofpolyneuropathy, 30 of these patients (22men) were selected at random (mean age47 (11) years, range 31-71 years; mean dura-tion of illness 25 (11) years, range 6-50years). The 30 other patients participated in adrug trial. Detailed information was presentfor all patients relating to duration of illnesssince diagnosis, concomitant drug therapy,and measures of diabetic control at onset.The patients were selected on the basis of thepresence of a subclinical form of polyneu-ropathy according to the criteria of Dyck.5They had no evidence of clinical neuropathywhen evaluated with the neuropathy symp-tom score (NSS) and neurological symptomprofile (NSP)4 but all had an abnormal vibra-tory perception threshold or an abnormalthermal discrimination threshold as a sign ofpolyneuropathy.

EXAMINATIONSClinical examination-Before the patientsentered the study they were physically exam-ined. They were admitted only if no abnor-malities of sensation and muscle weaknesswere present on neurological examination or

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when laboratory data, including biochemicaland haematological variables as well as urineanalysis and electrocardiography, were nor-mal. During the experimental period themetabolic state of all patients was controlledevery four months. Concentrations of HbAl,serum glucose, total bilirubin, y glutamyl-transferase, aspartate aminotransferase(SGOT), alanine amino transferase (SGPT),and lactate dehydrogenase did not changesignificantly during the twelve month studyperiod (Wilcoxon signed rank test, twotailed).

Vibration perception threshold was measuredat the dorsum of the second metacarpal of theright hand with an electromagnetic vibrame-ter (Somedic AB Vibrameter type III). Thevibration threshold was determined by themethod of limits. The stimulus strength wasincreased gradually from zero to the pointwhere sensation was first perceived. Thestimulus was then decreased to the pointwhere the sensation first disappeared. Thisprocedure was repeated, and the thresholdwas calculated from the average of the per-ception and disappearance thresholds. Theresults were compared with reference values.9

Thermal discrimination threshold was mea-sured at the carpal site of the right forearm(Medelec Triple-T, Old Woking, Surrey).Heat threshold and cold threshold valueswere determined with a microcomputer con-trolled system and the two alternative forcedchoice method of psychophysical analysis.Results more than 2-5 SD above the agematched mean value for normal individualswere considered abnormal.'0

Nerve conduction studies of the left sural sen-sory nerve, the left posterior tibial motornerve and the right motor and sensory ulnarnerve were performed with standard surfacestimulating and recording techniques (Vikingapparatus, Nicolet, Madison, Wisconsin).Results were considered abnormal if theydeviated from the normal mean by more than2-5 SD, on the basis of data published byOh." To minimise the effects of temperaturefluctuation the limbs were warmed in waterbaths at 34°C for 30 minutes before the testand kept at this temperature with an infraredheat lamp during the examination. TheHoffmann (H) reflex of the soleus muscle wasevoked by transcutaneous bipolar electricalstimulation of the tibial nerve in the poplitealfossa.'2 For normal data, Hoffmann reflexlatencies (H-M interval) in relation to ageand height as published by Visser et al3 wereused.

Single fibre electromyography (SFEMG) ofthe anterior tibial muscle was recorded(Dantec Counterpoint apparatus, Skovlunde,Denmark) by inserting the electrode intoweakly contracting muscle as described byStalberg et al.'4 Mean neuromuscular jitterwas expressed as the mean consecutive differ-ence for 20 pairs of potentials and was con-sidered abnormal if the value exceeded 60-2,us. The mean fibre density was calculated for20 sampled recording potentials and was con-sidered abnormal if it exceeded 2-28.

Autonomic fiunction testing-Static anddynamic pupillometry were performed indarkness. For static pupillometry the pupildiameter was measured after 2 and 4 minutesof dark adaptation by infrared photography.'5The mean pupil diameter was determinedfrom the two photographs in relation to thehorizontal iris diameter and expressed as per-centage of pupil diameter (PD%). Fordynamic pupillometry the infrared light reflextechnique (IRIS) was used.'6 With infraredlight emitting diodes and sensors mounted ona frame in front of both eyes, variations inpupil size were recorded after a light stimuluswas placed in front of the right eye. Theblock shaped stimulus, which was given every5 seconds, had an intensity of 3-7 log Troland(Troland = retinal illuminance) and a dura-tion of 1 2 seconds. Measurement of thelatency between the onset of the stimulus andthe start of the constriction started from thefirst deflection in the differentiated signal.'7The latency of pupillary constriction (LC)was determined from at least 10 artefact freeresponses for both eyes. Values more than 2-5standard deviations beyond means for controlsubjects of the same age, as published bySmith and Dewhurst'8 for PD% and Lantinget al,'9 for LC were regarded as abnormal.

PROCEDURESixty patients were examined electrophysio-logically; 30 of these were selected at randomfor longitudinal monitoring. The examina-tions took place after 4, 8, and 12 months. Allneurophysiological evaluations consisted ofdetermining vibration and temperaturethresholds, motor and sensory conductionstudies, H reflex measurement, and static anddynamic pupillometry. During the first exam-ination, and after 12 months, SFEMG of theanterior tibial muscle was performed as well.

Before each neurophysiological examina-tion the patients underwent a physical exami-nation and laboratory data (haematologicaland biochemical data, blood glucose profile,and ECG) were collected to ensure that thepatient's condition had not changed. Allexaminations were done by the same investi-gator.

ANALYSISTwenty three variables were used for the sta-tistical analyses (see table 4). For perceptionthreshold we used vibration threshold (VT),heat discrimination threshold (HT), and colddiscrimination threshold (CT); for motorulnar and tibial nerve, distal motor latency(DML) (distance of distal stimulation to theactive recording electrode, 8 cm for both theright ulnar and left tibial nerve), amplitude ofthe compound muscle action potential fromdistal stimulation (AMP), ratio of amplitudeof compound muscle action potential fromproximal and distal sites (AR), and motornerve conduction velocity (MNCV); for sen-sory ulnar and sural nerve, sensory nerve con-duction velocity (SNCV); (distance of distalstimulation to the active electrode, approxi-mately 14 cm for both the right ulnar and left

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Subclinical diabetic polyneuropathy: early detection of involvement ofdifferent nerve fibre "ypes

Table 1 Results of clinical neurophysiological examinations

Test No with test response Mean (SD)

Tibial nerve (MNCV) 53 33-5 (7-9) m/sH reflex (soleus muscle)* 44 32-2 (15-3) msPupil diameter percentaget 53 44-0 (8 9)%Latency of pupil constrictiont 53 244-1 (33) msSural nerve (SNCV) 45 35-9 (10-1) m/sSFEMG:Mean jitter 57 71-1 (162) usFibre densityt 57 3-01 (1-8)

Ulnar nerve:SNCV 56 42-5 (15-1) m/sMNCV 60 53-4 (5 6) m/s

MNCV = motor nerve conduction velocity; SNCV = sensory nerve conduction velocity*Latency H reflex minus latencyM response; value depends on age and height.tValue depends on age.

sural nerve) and amplitude of the sensorynerve action potential (AMP); for soleusmuscle, H-M interval (H-M) and H-M ratioamplitude from H reflex; from SFEMG, fibredensity (FD) and mean of mean consecutivedifference (MJ); and for pupillometry, pupildiameter as a percentage of iris diameter(PD%) and constriction latency of the pupilto light (LC).

Although the selection criteria usedimplied that the 60 patients had no clinicalsymptoms of polyneuropathy, the presence ofneurophysiological abnormalities had to beassessed. Therefore we compared measure-ments on 18 variables with normal valuesreported in the literature. Measurementsmore than 2-5 SD from the mean were con-sidered abnormal; when a response could notbe elicited the result was interpreted asabnormnal.

Correlations among the different tests wereexamined. When no response had been

Table 2 Percentage ofpatients with abnormal results (values >25 SDfrom mean)

No ofpatients

Response notTotal obtained Limit value % Abnormal

Perception threshold:Cold threshold (CT) 60 <0.280 C 98Heat threshold (HT) 60 <0.320 C 58Vibration threshold (VT) 60 <1 00* 33

Pupillometry:Dynamic (LC) 53 <225 ms 80Static (PD%) 53 >42%* 76

H reflex soleus muscle:H-M interval 60 16 <31-8 ms* 66

SFEMG:Mean jitter 57 <62-5 Is 58Fibre density 57 <2-28 48

Peripheral nerve conduction fimction:Tibial nerveMNCV 60 7 >34-1 m/s 53AMP 60 7 >4 5 mV 32DML 60 7 <54ms 12

Sural nerveSNCV 60 20 >37-6 m/s 50AMP 60 20 >4-5 g V 48

Ulnar nerve (sensory)SNCV 60 4 >41-9 m/s 27AMP 60 4 >4-5,uV 24

Ulnar nerve (motor)MNCV 60 >45-4 m/s 20AMP 60 >7-2 mV 10DML 60 <4-5 ms 10

*Value depends on age or height, or both.DML = distal motor latency; AMP = amplitude of distal compound muscle action potential orsensory nerve action potential; MNCV = motor nerve conduction velocity; SNCV = sensorynerve conduction velocity; LC = latency of pupil constriction to light; PD% = pupil diameter aspercentage of iris diameter.

obtained, the result was placed at the abnor-mal end of the distribution for that test. Non-parametric correlation analysis was performedwith Spearman's rank correlation.

Thirty patients were assessed longitudi-nally to monitor functional changes. AFriedmann two way analysis of variance wasused to evaluate possible changes in the val-ues of each variable. To assess the effect ofexaminations in which abnormality was toolarge to elicit a response, the analysis wasrestricted to the repeatedly measurable data.In this analysis data from patients in whomthe sural nerve conduction velocity or H-Minterval of the H reflex of the soleus musclecould not be elicited during the first examina-tion were excluded. The variation in repeatedexaminations was calculated by expressingthe change in these results from baseline as apercentage, and the absolute changes in thethree follow up examinations were averaged.

ResultsThe mean (SD) values of the baseline dataare shown in table 1. The percentage ofpatients with abnormal test results (valuesmore than 2-5 SD from the mean) are shownin table 2.The psychophysical examinations (WT,

HT, CT) were used as selection criteria,yielding an overall abnormality of 100%, andwere therefore not included in the analyses.However, the thermal threshold was selective-ly impaired in some patients, suggesting thatsmall fibres are more prone to damage in dia-betic neuropathy. Static and dynamic pupil-lometry, which are also considered as tests todetermine the function of small nerve fibres,were often abnormal as well. The nerve con-duction studies did not follow a definite pat-tern of involvement. Clustering of tests withunobtainable responses or tests with pro-nounced abnormalities were not found. Forexample, only four of the 30 patients inwhom a suralis response could not be elicitedhad an unrecordable H reflex. Generally, theH-M interval of the Hoffnann reflex wasmost likely to be affected and the ulnar nervedistal motor latency was the least likely to beaffected. Nerve conduction abnormalitieswere most pronounced in motor nerves of theleg, (Tib MNCV), followed, in order ofseverity, by sensory nerves of the leg (suralSNCV), sensory nerves of the arm (ulnarSNCV), and motor nerves of the arm (ulnarMNCV). It thus seems that the thin myeli-nated and unmyelinated autonomic nerveswere most often affected, followed by thefibres conducting the H reflex.

Spearman's rank correlation coefficientsbetween variables are presented in table 3. Ingeneral, the different conduction systemswere poorly correlated. However, the correla-tions between the conduction function of therelatively short nerves in the arms with thoseof the longer nerves in the legs were moderate(0-61-0-71), suggesting that there was still nodifference related to nerve length at this stageof polyneuropathy.

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Table 3 Correlations between different electrophysiological variables on nerve fui60 patients with insulin dependent diabetes

CT/HTPT/MNCVArmsLegs

PT/H reflexPT/pupillometry

PD%/LC

Pupillometry/MNCV:ArmsLegs

Pupillometry/SFEMG

H-M interval/AMP (H/M) ratioH-M interval/MNCV:ArmsLegs

Fibre density/mean jitterSFEMG/MNCV:ArmsLegs

PerilMNCV arms/MNCV legsMNCV arms/SNCV armsMNCV arms/AMP (CMAP) armsMNCV legs/AMP (CMAP) legs

Perception threshold (PT)0-53* TT/VT

PT/SNCV0-18 Arms

- 0-32 Legs0.10 PT/SFEMG

-0-19

Pupillomet0 37

0-290 30

-0-18

Pupillometry/H reflex

Pupillometry/SNCV:ArmsLegs

H reflex (soleus muscle)0-33 H-M interval/SFEMG

H-M interval/SNCV:-0-14 Arms-0-09 Legs

Singlefibre EMG (SFEMG)0-66*

-0-46- 0-60*

SFEMG/SNCV:ArmsLegs

ipheral nerve conduction function0-71* SNCV arms/SNCV legs0.54* MNCV legs/SNCV legs0.70* SNCV arms/AMP (SNAP) arms0-76* SNCV legs/AMP (SNAP) legs

CT = cold threshold; HT = hot threshold; TT = temperature threshold; VT =threshold; MNCV = motor nerve conduction velocity; SNCV = sensory nerve ccvelocity; LC = latency of pupil constriction; PD% = pupil diameter as percentage of ixter; AMP = amplitude of distal CMAP (compound muscle action potential) or SNAInerve action potential).*p < 0 001; regression analysis, least squares method.

Table 4 Comparison of electrophysiological variables in longitudinal assessment Xfiunction

MezNo with Mean % cpain Mean (SD) at correlation in pmeasurements start (n = 30) coefficient mea

Perception threshold:Cold threshold (CT) 30 0-68 (0 37) 0-61 21-4Heat threshold (HT) 30 0 73 (0-41) 0-68* 16-fVibration (VT) 30 2-19 (1-21) 0-67 14-

Pupillometry:Dynamic (latency) 29 245-1 (27 0) 0-64** 2-!Static (PD%) 28 47-4 (6 59) 0-86** 241

H reflex (soleus muscle):H-Minterval 23 29-90 (3-34) 0-64 4-Amplitude ratio 23 0-1 (0-06) 0-83** 18-

SFEMG:Fiber density 29 2-21 (0-38) 0-78** 5.(Mean jitter 29 66-14 (13-9) 0-60** 2-1

Peripheral nerve conduction function:Tibial nerve:DML 26 4-19 (0-63) 0 75** 2-4AMP 26 6-11 (2-01) 0-89** 7.AR 26 0-61 (0 20) 0-75 1 'MNCV 26 37-98 (4-83) 0-92** 1-5

Sural nerve:LAT 19 2-09 (0 76) 0-66** 9.4AMP 19 3-89 (2-12) 0-80** 5.SNCV 19 36-45 (4 92) 0.77** 2-'

Ulnar nerve (motor):DML 30 3-38 (0 60) 0-88** 3.(AMP 30 8-74 (1-97) 0-90* 4-'AR 30 0-89 (0-14) 0-51* 1 lMNCV 30 53-47 (5 63) 0-78** 1.]

Ulnar nerve (sensory):LAT 27 2-96 (1-06) 0.47* 10 'AMP 27 5-54 (2-00) 0.73** 6-.SNCV 27 43-73 (3-48) 0-81** 2-

*p <0-01; **p <0-001.DML = distal motor latency; AMP = amplitude of distal compound muscle action pesensory nerve action potential; AR = amplitude ratio form proximal and distal sites; Imotor nerve conduction velocity; LAT = sensory latency; SNCV = sensory nerve ccvelocity.

ction in The results of the changes in the variablesin the longitudinal assessment in comparisonwith the starting results are shown in table 4.

0-80* Although the values showed fluctuations over- 035 the period, no general trends were evident.- 0-38 When the changes for each variable were0-27 analysed (Friedmann two way analysis of

variance, p > 0-10), none of the electrophysi-ological variables changed significantly over

-0-16 the test period. The fluctuations could pre-sumably be attributed to measurement errors.

0239 Reproducibility was tested in two ways.Firstly, for each variable the correlation of therepeated examinations was determined. The

0-10 averaged correlation coefficients indicate thevariation in repeated examinations. Secondly,

- 0-08 for all variables the mean percentage of- 0-20 change from baseline value during longitudi-

nal assessment was calculated (table 4). Forthe temperature and vibration threshold tests,

-0-41 the variation seemed to be high, whereas it- 0.62* was lowest for nerve conduction velocity tests

in the arms. On repeated measurement the0.61* variation ranged from 1-1% (ulnar MNCV)0.47* to 21% (CT). Overall, the variation was0.69* lower in the arms than in the legs. The tests

on neuromuscular transmission and thinvibration myelinated and unmyelinated (autonomic)indudioen- nerve fibres, SFEMG, and pupillometry? (sensory showed variations of about 2-5% (MJ, PD%,

LC).Comparison of the amplitudes of the proxi-

mal and distal ulnar compound muscle actionpotential showed a decrease in amplitude of1 1% (table 4: amplitude ratio (AR) 0-89(±0'14)). However, a relatively high correla-tion was found between distal amplitude and

of nervi conduction velocity (table 3: 0 70 for theulnar nerve). This implies that there were no

an indications of segmental demyelination mani-,hange fested by a decrease in amplitude ratio ofPaired 2,surements more than 20%20 in this population.

8 DiscussionSubclinical diabetic neuropathy was assessed

5 by evaluating psychophysical deficits, abnor-6 malities of neuromuscular transmission, sen-I sory and motor nerve conduction function,5 and quantitative autonomic function in the

absence of clinical symptoms. Quantitation of°6 vibratory sensation and determination of

thermal discrimination thresholds were usedto select the study population. These tests

7 examined large and small fibre function sepa-7 rately.21 The results depend on the local

intergrity of nerve endings as well as on nerve0 conduction.22 This study is not unique in3 finding a discrepancy between the lack of

symptoms and the results of the measure-0 ments of psychophysical functions.23 Thermal9 sensitivity was sometimes selectively affected,

suggesting that in the subclinical form of dia-betic neuropathy the small fibres are more

2 vulnerable. Ali et al reported similar results.247 It was our aim to evaluate the diagnosis of

subclinical polyneuropathy and the extent of)tential or nerve involvement at this stage of illness byMNCV:= examining the function of all types of nervenduction fibres. Many tests have been used to detect

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Subdinical diabetic polyneuropathy: early detection of involvement of different nerve fibre types

and characterise diabetic polyneuropathy, butthe value of simultaneous and extensive test-ing for detecting and monitoring early nervedysfunction in diabetic patients has beeninadequately assessed. Dyck published anoverview of the literature and devices todetect and assess diabetic polyneuropathy.8The present study is a clinical approach inline with these devices. Patients with a sub-clinical form of neuropathy were selected aswe expected that histopathological changeswould not be advanced. Only in this earlystage of illness would extensive neurophysio-logical examination help to assess the possibleinvolvement of selective nerve fibres.The technique most commonly used is the

measurement of motor and sensory nerveconduction velocity. Conduction velocity is afunction of a number of physiological proper-ties. Fibre size, myelination, nodal andinternodal length, and external and internalaxonal resistance have a role in the speed ofconduction. Nerve conduction testing usessupramaximal stimuli, thereby recruitingnon-selectively all available fibres. Only thestate of the largest, most rapidly conducting,myelinated fibres is examined.

In an attempt to examine all fibre typesselectively, pupillometry, H reflex of thesoleus muscle, and single fibre EMG wereperformed in addition to the methods mostcommonly used. In our patients the pupildiameter in relation to the iris diameter(PD%) and the latency of constriction of thepupil to light were often abnormal. Thesefindings indicate impairment of the reflex arcsinvolving small myelinated and unmyelinatedparasympathetic nerves to the eye and sympa-thetic nerves to the iris.'9 The weak correla-tion between autonomic pupillary functionand peripheral nerve conduction functiontests suggests a lack of association betweenautonomic neuropathy and peripheral nervefibre dysfunction. With the H reflex (H-Minterval) it is possible to determine motor andsensory fibre function simultaneously. Thistest is a sensitive means of detecting proximalnerve trunk dysfunction and is valuablebecause it can reveal abnormalities before theneuropathy becomes clinically manifest.25Our data confirm this assumption, as twothirds of the patients showed an increase inthe H-M interval. SFEMG was performed aspart of the electrophysiological examinationto assess terminal axonal function and mea-sure neuromuscular transmission.26 This is arelatively new test in clinical use and showedabnormal findings in 48% of the patients.Most of our diabetic patients had, despite

the absence of clinical symptoms, signs ofperipheral nerve dysfunction, as well as evi-dence of impairment of the reflex arcs involv-ing parasympathetic nerves to the eye andsympathetic nerves to the iris. Nerve conduc-tion abnormalities were widespread, involvingproximal and distal parts of the nerve trunks.The relative involvement of large and smallfibres was not uniform.

In longitudinal studies, the reproducibilityof the tests is of major importance. However,

before interpreting neurophysiological dataon serial determinations and drawing conclu-sions about examination variation, two asso-ciated problems should be addressed. Thefirst problem is the lack of knowledge aboutthe natural progress of diabetic polyneuropa-thy. In the present study, where all nerve fibretypes were selectively examined, the results ofthe longitudinal clinical neurophysiologicaltests did not change throughout the examina-tion period. No support was found for theconcept of a progression of neuropathic dam-age, or from small fibre dysfunction initiallyto loss of function in large fibres later on.The second problem focuses on the obser-

vation that measurements of nerve functionshould be objective, sensitive, specific, andreproducible and therefore useful in a followup evaluation of diabetic neuropathy. In thisstudy the psychophysical tests showed consid-erable variation at follow up examination: onrepeated testing, patients with borderline nor-mal perception thresholds could becomeabnormal, and vice versa. High examinationvariations for vibratory perception thresholdsand thermal discrimination thresholds havebeen reported previously.3 This variabilitymay be partly due to fluctuations in roomtemperature and in the patient's attention. Ofthe nerve conduction measurements, motorand sensory nerve conduction velocities anddistal motor latencies were the most repro-ducible, with only 1-1% to 4 1% variation;amplitude had the lowest reproducibility(4-9% to 7-7% variation). Although the nervefunction of the legs seemed to show a greatermagnitude of abnormality, in the longitudinalassessment the variation was greater than thatof tests assessing the function of the armnerves and seemed inversely proportional tothe length of the tested nerve. Main sourcesof this variation might be the error in latencyreadings and distance measurements.27 It maybe because of the relatively short length of thetested nerve segment that the H reflex (H-Minterval) showed considerable interexamina-tion stability.One of our objectives in this study was to

assess which combination of clinical neuro-physiological tests could be used for evaluat-ing the diagnosis reliably and for the earlydetection of diabetic neuropathy. Reliabilityof the neurophysiological evaluation dependson the sensitivity and the selectivity of thetests to assess the function of different typesof nerve fibre. The present data show thenecessity of extensive clinical neurophysiolog-ical testing rather than the standard tech-niques to detect selective nerve fibreinvolvement in patients with a subclinicalform of diabetic neuropathy. Because nervesare not affected to the same extent, even inthe early stage of illness, we suggest the use ofa combination of methods to examine allnerve fibres selectively, not restricting theexamination to thick myelinated nerve fibres.The choice of tests and their diagnostic use

for detecting and monitoring nerve dysfunc-tion is a matter of discussion as the results ofeach test and their reproducibility reflect an

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interaction between test sensitivity and bio-logical expression. In this study the H reflexof the soleus seemed to be a sensitive andreproducible test. Other sensitive and repro-ducible tests were pupillometry and motor orsensory conduction velocity in tibial and suralnerves. These three tests were not correlatedand thus provided information on differentnerve systems. The nerve conduction func-tion tests in nerves of the arms and the legswere highly correlated. Evaluation of motorand sensory nerve conduction function cantherefore, be restricted to the most sensitivetest.The diagnostic yield and also the discom-

fort to the patient are important factors toconsider when choosing a method. SFEMG(reflecting motor end plate function) maytherefore not be useful for routine examina-tion. Furthermore, SFEMG of tibial anteriormuscle was highly correlated with motornerve conduction velocity of the tibial nerve.We suggest that a combination of testsreflecting function of small nerve fibres aswell as of thick and fast conducting myelinat-ed nerves should be used for early and selec-tive detection of diabetic polyneuropathy.

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3 Levy DM, Abraham RR, Abraham RM. Small- and large-fiber involvement in early diabetic neuropathy: a studywith the medial plantar response and sensory thresh-olds. Diabetes Care 1987;10:441-7.

4 Dyck PJ, Karnes JL, Daube J, O'Brien P, Service FJ.Clinical and neuropathological criteria for the diagnosisand staging of diabetic polyneuropathy. Brain1985;108:861-80.

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10 Jamal GA, Weir AI, Hansen S, Ballantyne JP. Animproved automated method for the measurement ofthermal thresholds: two patients with peripheral neu-ropathy. J Neurol Neurosurg Psychiatry 1985;48:361-6.

11 Oh SJ. Clinical electromyography: nerve conduction studies.Baltimore; University Park Press, 1984:93-113.

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