Post-ischaemic in diabetes mellitus · age groups. Comparison ofthe results obtained from the...

Journal of Neurology, Neurosurgery, and Psychiatry, 1973, 36, 288-295

Post-ischaemic paraesthesiae in diabetes mellitusK. N. SENEVIRATNE, N. SENANAYAKE, AND A. NIMALASURIYA

From the Departments ofPhysiology and Medicine, Faculty of Medicine,University of Ceylon, Colombo

SUMMARY A quantitative assessment of post-ischaemic paraesthesiae has been made in 50 diabeticsubjects and in a group of healthy age-matched controls. The results show a highly significantdiminution of the paraesthetic response in the diabetic subjects. The degree of depression of theparaesthetic response was associated with the duration of the disease and the severity of the meta-bolic abnormality as determined by the degree of insulin dependence. Diabetics with the juvenileonset type of the disease were more adversely affected than those with the maturity onset type. Therewas no consistent relationship between the degree of depression of the paraesthesiae and the presenceof peripheral neuropathy. The significance of these results is discussed in relation to the factors whichdetermine the composition of the ionic micro-environment of myelinated nerve and the level ofelectrical excitability of the nerve fibre.

Although paraesthesiae consequent on ischaemiaof a limb have long attracted interest and manyfeatures have suggested their possible value inthe study ofperipheral nerve disease, the observa-tions of Poole (1956a, b) have received lessattention than they merit. Occlusion of thecirculation with a sphygmomanometer cuffapplied above the elbow elicits ischaemic paraes-thesiae within a few minutes, being perceivedas a faint tingling, buzzing, or vibrating sensationin the hand before dying away some minuteslater (Weddell and Sinclair, 1947). Release of thecuff and restoration of the circulation gives riseto the more distinct post-ischaemic paraesthesiaein which Merrington and Nathan (1949) recog-nize four elements-thermal, cramp, tingling,and a pricking 'pins and needles' sensation.Poole (1956a) determined the features suitable ascriteria of normality in the clinical application ofparaesthesiae tests, and showed that post-ischaemic paraesthesiae of the pricking 'pins andneedles' type occurred with such great con-stancy in the upper limbs of healthy subjectsbetween the ages of 12 and 60 years that theirdiminution or absence might readily attractattention as evidence of abnormality of peri-pheral nerve function. He studied three groupsof subjects comprising those with acute infec-tive polyneuritis, chronic and recurrent neuro-

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pathies, and those with megaloblastic anaemia,and confirmed the view that paraesthetic re-sponses were disturbed in these conditions, andthat the extent of the depression provided asensitive index which defined the presence andprogress of neuropathies in such conditions asintoxications, vitamin deficiencies, alcoholism,malignant disease, and diabetes (Poole 1956b).In an attempt to obtain objective evidence ofPoole's observation, Seneviratne and Peiris(1968a) measured excitability changes in thesensory fibres of the median nerve during andafter 30 minute periods of vascular occlusion ofthe upper limbs of healthy subjects. They ob-served that the low threshold fibres of the nervewent through a transient phase of hyperexcit-ability before being inactivated by the ischaemicprocess, while release of the cuff and restorationof the circulation were followed by a rapid in-crease in the excitability of the fibres whichlasted for several minutes before the nerveregained its resting level of excitability. All con-trol subjects experienced paraesthesiae duringthe ischaemic and post-ischaemic phases ofnerve hyperexcitability. Measuring excitabilitychanges in the nerves of 12 diabetic subjectsSeneviratne and Peiris (1968b) observed that themost characteristic difference between normaland diabetic nerves was the very limited extent

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Post-ischaemic paraesthesiae in diabetes mellitus

to which the diabetic nerve was inactivated by a30 minute period of complete vascular occlu-sion. The nerves of the diabetic subjects did notexhibit the phases of ischaemic and post-ischaemic hyperexcitability that are character-istic of the normal subject, nor did any of thesediabetic subjects experience ischaemic or post-ischaemic paraesthesiae. Comparing the re-sponses obtained from six diabetic subjects whohad clinical and electrophysiological evidence ofperipheral neuropathy with those of six age-matched diabetic subjects who had no evidenceof neuropathy as judged by clinical testing andby conventional electrophysiological techniques,they found that both groups behaved in anidentical manner. None of these diabetic sub-jects experienced paraesthesiae nor did any ofthem show the transient phases of nerve hyper-excitability during the ischaemic or post-ischaemic periods. The results obtained from thislimited sample led Seneviratne and Peiris(1968b) to suggest that the absence of paraes-thesiae evoked by vascular occlusion in thediabetic subject indicated the existence of someabnormality of peripheral nerve function whichpreceded the development ofthe signs, symptoms,and electrical criteria characteristic of a peri-pheral neuropathy.

Since the advantages of such a simple bedsidediagnostic procedure are obvious, the experi-ments described in this paper were designed toassess the validity of the test. A larger group ofcontrol and diabetic subjects has been studiedwith a view to correlating the response with theseverity of the diabetic state, the type of diabetes,the presence of peripheral neuropathy, and theduration of the diabetic state. These experimentswere also designed to elicit information whichwould help to elucidate the basic problemsrelating to the normal production of ischaemicand post-ischaemic paraesthesiae and to thepathophysiology of the processes that lead to theabsence of such paraesthesiae.

METHODS

Fifty diabetic patients whose ages ranged from 15 to60 years were studied in this series, while 50 healthysubjects of a comparable age group served as con-trols. A diagnosis of diabetes mellitus was establishedusing the criteria recommended by WHO (1965).All the diabetic subjects were in an adequate state of

metabolic control for at least two weeks before theirinclusion in this group. The severity of the diabeticstate was assessed in terms of the quantity of astandard preparation of insulin which was requiredto maintain each patient in a state of metaboliccontrol. Three grades of severity were recognized.Those who required no insulin and could be main-tained in a state of control by dietary adjustmentalone were considered as having 'mild' diabetes,those who required up to 40 units of insulin per daywere in the 'moderately severe' group, while thosewho required over 40 units of insulin daily foradequate control were considered as having 'severe'diabetes.The duration of the diabetic state was used to

classify the subjects into three groups. The firstgroup included those subjects who were known to bediabetic for less than five years, a second groupthose with diabetes for five to 10 years, and a thirdgroup included subjects whose history of diabetesextended for more than 10 years. These patientswere also classified on the basis of the type ofdiabetes, the criteria recommended by Fajans andConn (1965) being used to differentiate the juveniletype from the maturity onset type of diabetes.A careful clinical examination was carried out on

all diabetic subjects in order to assess peripheralnerve function, and all such tests were done by oneof us. A system of scoring was designed so that eachpositive symptom or sign from a list was allotted onepoint, the mraximum possible score being 15 points.The following symptoms and signs were containedin the list: pain in the legs, spontaneous paraesthesiaein arms or legs, loss of sensation in arms or legs,muscular weakness, sensory loss to pin prick in thelegs only, sensory loss to pin prick in both arms andlegs, loss of light touch sensation, loss of vibrationsense at the ankle, at the iliac crest or at the wrist,calf tenderness, loss of deep reflexes, and muscularwasting. This system of scoring was used to differen-tiate the diabetic subjects into four groups. Subjectswith a score 0 had no clinical evidence of peripheralneuropathy, those with scores of 1-5 had mildneuropathy, scores of 6-10 a moderate neuropathy,while those with scores of 11-15 had evidence ofsevere peripheral neuropathy.

In the control and diabetic subjects vascularocclusion was obtained by using an ordinary sphyg-momanometer cuff placed on the upper arm withthe lower border of the cuff 2 cm above the medialepicondyle of the elbow. In all cases the restingsystolic blood pressure was measured, and vascularocclusion applied by rapid inflation of the cuffpressure to 60 mmHg above the resting systolicpressure. Ischaemia of the limb was maintained for20 minutes, after which the cuff pressure was

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K. N. Seneviratne, N. Senanayake, and A. Nimalasuriya

released. All subjects were instructed at the beginningof the vascular occlusion to report the time of onset,site, nature, and time of cessation of any subjectivesensations they experienced during the ischaemic andpost-ischaemic periods. During the post-ischaemicperiod itself they were reminded at regular intervalsof the need to report the details of any paraesthesiaethey experienced, special attention being paid to the'pins and needles type' of post-ischaemic paraes-thesiae.A quantitative assessment of the 'pins and

needles' paraesthesiae was made by determining apost-ischaemic paraesthesiae (PIP) index. The indexwas numerically equal to the product of the durationof the 'pins and needles' paraesthesiae in minutesand the PIP score, which was determined by theseverity of the paraesthesiae as experienced by thesubject. This scoring was done on a 3 point scale.Score 0-no post-ischaemic 'pins and needles'paraesthesiae; score 1 -mild pins and needlesparaesthesiae confined to the fingers; score 2-severe paraesthesiae felt in the fingers and palmusually accompanied by other reactions of discomfortor distress-for example, grimaces or whistling.

RESULTS

Of the sensations that healthy subjects experienceduring the post-ischaemic period, the 'pins andneedles' sensation is the component which ismost easily recognized by the subject. Pre-liminary observations provided evidence that

TABLE 1POST ISCHAEMIC PARAESTHESIAE INDEX (PIP INDEX) IN

CONTROL AND DIABETIC SUBJECTS

Age (yr)

Less th/an 30 30-40 41-50 51-60

Healthy controlsSubjects (no.) 10 16 16 8Mean PIP index 24 2 23-4 22 1 20-6Range of index 21-28 16-30 16-28 15-28SD +3 4 +6 1 +3-7 +6-2

Diabetic subjectsSubjects (no.) 12 8 18 12Mean PIP index 1 3 4-6 4-3 3-4Range of index 0-6 0-9 0-24 0-13SD ±22 ±38 ±54 +4-4

Significance of differenceof PIP index betweencontrol and diabeticgroup

Student's t testSignificance (P) < 0 001 < 0 001 < 0001 < 0001

the times of onset and cessation of this varietyof paraesthesia could be easily recognized by allsubjects and that the results obtained on oneoccasion could be reproduced some days laterwhen the other arm was tested. All healthy con-trols reported that thermal paraesthesiae occur-red with great constancy, but though its time ofonset was easily perceived, its duration could notbe determined as the time of cessation of thethermal sensation could not be determined withany certainty. All healthy subjects also experi-enced some tingling, vibration, or 'buzzing'sensation immediately after the thermal paraes-thesiae but neither the times of onset nor timesof cessation of these sensations could be deter-mined reliably. The sensation of post-ischaemicmuscle cramp was experienced by only some ofthe healthy controls. The PIP index was thereforedetermined with respect to the duration andseverity of the pricking, 'pins and needles'sensation alone.The results expressed in Table 1 and Fig. I

show that all healthy controls had uniformlyhigh PIP indices and that there was no significantdifference in the indices between the separateage groups. Comparison of the results obtainedfrom the healthy controls with that of the 50diabetics shows a very highly significant differ-ence of the PIP indices between the two groups.

x30-L1J

0 _z

Q_-20-CL

zLL

10-

15-30 31-40 41-70AGE

I51-60

FIG. 1. Age distr-ibution of PIP inidices in contr-ol(blank bar) and diabetic (solid bar) subjects.

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020-

z

0 -5 6-10 >10P I P INDEX

FIG. 2. Effects ofseverity of the diabetic state on thepercentage distribution ofPIP indices in subjects withmild diabetes (blank bar), moderate (stippled bar), andsevere diabetes (solid bar).

In the diabetic patients the mean index was uni-formly low in all age groups, there being nosignificant difference in the distribution of theindex between the different age groups. Only oneof the 50 diabetic subjects had a PIP index

lLIU)

mD3i) 40-U-00 20-z

0 l-5 6-10P I P INDEX

FIG. 3. Effects of duration of diabetic state on

percentage distribution ofPIP indices in subjects withdiabetes of less than five years duration (blank bar),5 to 10 years (stippled bar), and over 10 years'duration (solid bar).

which was of normal magnitude. This was a 45year old man who had a very mild diabetes oftwo years' duration, and was being maintainedin an adequate state of metabolic control bydietary restrictions alone.When the severity of the metabolic state of the

diabetics is determined in terms of the degree ofdependence on insulin, the frequency histogramof Fig. 2 shows that the severity of the diabeticstate seems to be a factor relating to the degreeof diminution of the PIP index. Thus 65% ofthose with severe diabetes had an index of 0,

80-

U-)

U60

co:DU)4.U-00520-z

0 1-5 6-10P P INDEX

>10

FIG. 4. Distribution of PIP indices in diabetic sub-jects with the juvenile onset type of disease (solid bar)and maturity onset type (blank bar).

while all the rest had indices of less than 10. Incontrast, only 33.300 of the mild diabetics hadindices of 0, 330 had indices of 1-5, 26.7°/ hadindices of 6-10, while 6.700 of this group hadindices over 10. These results indicate that evensubjects with the mildest grade of diabetes had amean PIP index which was significantly smallerthan that of the healthy control group, whilewithin the diabetic group itself, increasingseverity of the diabetic state was associated withdiminution of the PIP index.

Figure 3 shows that the duration of the dia-betic state is another factor related to thediminution of the PIP index. Thus 8000 of the

I

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TABLE 2PIP INDICES IN DIABETICS OF THE MATURITY AND

JUVENILE ONSET TYPES

Juvenile onset type Maturity onset type

No. of Mean PIP No. of Mean PIPsubjects index subjects index

Duration of diabetes (yr)Less than 5 14 1-0 16 5-15-10 6 0 6 9 3-2Over 10 2 00 3 2-0

Severity of diabetesMild 3 1 2 10 6-2Moderately severe 7 0-6 9 4-3Severe 12 0 5 9 2-1

subjects who had been diabetic for over 10 yearshad no paraesthesiae, while the remaining 20%had indices of less than 10. In contrast, the sub-jects whose diabetes was of shorter duration haduniformly higher indices. Of those with diabetesof less than five years duration 450 had indicesof 0, 47.5%0 had indices between 1-10, while7.5o% had indices over 10. Here, too, it is evidentthat even those with diabetes of very short dura-tion had indices significantly smaller than thoseof the control group, while increasing durationof the diabetic state related to increasing diminu-tion of the PIP index.

Figure 4 shows that the type of diabetic lesion,whether it was of the juvenile or maturity onsettype, seemed to relate to the diminution of thePIP index: those with the juvenile type havingsignificantly lower indices than the maturityonset types. A further comparison was thereforemade between the subjects of these two groups,to determine whether this difference was in factdue to the nature of the diabetic lesion, since theearlier results have shown that the severity ofthe diabetic state and the duration of the diseaseare both factors which relate to the diminutionof the PIP index.The results expressed in Table 2 show that the

diabetics of the juvenile onset type have con-sistently lower PIP indices than the maturityonset types when comparison is made betweenthe two groups, whether in respect of the severityof the diabetes or the duration of the diabeticstate.The results of Table 3 show that there does not

TABLE 3PIP INDICES IN DIABETICS WITH NEUROPATHY

PIP Total Percentage distribution of subjectsindex no. of

subjects No Mild Moderate Severeneuropathy neuropathy neuropathy neuropathy

0 25 20 28 44 81-5 1 1 36 36 18 106-10 9 33 55 12 0OverI 0 5 20 60 20 0

seem to be a consistent relationship between theseverity of the peripheral neuropathy and thedegree of diminution of the PIP index. Thusamong the 25 subjects who had a completeabsence of post-ischaemic paraesthesiae werefive subjects who had no clinical evidence ofneuropathy. Among the five diabetics who hadthe severest paraesthesiae and highest PIPindices were four who had evidence of mild ormoderate degrees of peripheral neuropathy.

DISCUSSION

These results confirm the observations of Poole(1956a) that paraesthesiae can be elicited inhealthy subjects with great constancy. In thisstudy, an attempt has been made to obtain aquantitative assessment of the post-ischaemicparaesthesiae response by determining the dura-tion and severity of the paraesthesiae. This post-ischaemic paraesthesiae index (PIP index) hasbeen determined with reference to the 'pins andneedles' component only, because this was theelement which occurred with the greatest con-stancy in the healthy controls, and because it wasthe component whose duration could be assessedwith some certainty. Even though this index isdetermined on the basis of a subjective assess-ment of the severity and duration of a sensoryexperience, it achieves a measure of reliabilityand validity in that the results obtained from anindividual are reproducible, and because of thedegree of uniformity which occurs within thecontrol group. All control subjects had con-sistently high indices, while the duration of theparaesthesiae was in good agreement with theresults obtained by Poole (1956a). The durationsof the post-ischaemic paraesthesiae in the healthysubjects of this study were also in close accord

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with the duration of the phase of post-ischaemichyperexcitability of the peripheral sensory fibresofthe median nerve as determined by Seneviratneand Peiris (1968a).The differences between the PIP indices of the

control and diabetic group are very highlysignificant, only one of the 50 diabetic subjectshaving an index that lay within the range ofnormal values. The results also show that thedegree of diminution of the PIP index seemedrelated to the duration of the diabetes and theseverity of the metabolic state as determined bythe degree of insulin dependence-increasingduration and severity of the disease beingassociated with greater lowering of the PIPindex. The results also indicate that diabeticswith the juvenile onset type of the disease aremore adversely affected than those with thematurity onset type, this distinction persistingeven when the two groups are made comparablewith respect to the duration and severity of thedisease. Increasing age is itself not a factorrelating to the diminution of paraesthesiae insubjects who are between the ages of 15 and 60years, nor is there any consistent relationshipbetween the diminution of the PIP index and thepresence of clinical evidence of peripheralneuropathy. The results show that diabetic sub-jects with neuropathy tend to have lower indicesthan those without it, but this is a relationshipwhich could also be due to the association whichis known to occur between the presence ofneuropathy and the duration of the diabeticstate.

This pattern of diminution of the paraestheticresponse among diabetic subjects is of interestbecause it throws some light on the problemsrelating to the mechanisms which are responsiblefor the causation of post-ischaemic paraes-thesiae in healthy subjects. Although there is,as yet, no consensus of opinion regarding thesemechanisms, the available evidence (Merringtonand Nathan, 1949; Nathan, 1958; Seneviratneand Peiris, 1968a) suggests that the 'pins andneedles' sensation arises as a result of an in-creased excitability of low threshold sensoryfibres of peripheral nerve which occurs duringischaemic and post-ischaemic periods. Sene-viratne and Peiris (1969, 1970a, b) have sug-gested that nerve ischaemia leads to the efflux ofK' from the axon and that the accumulation of

this K' in a periaxonal space leads to the pro-gressive depolarization of the axon which passesthrough a transient phase of ischaemic hyper-excitability before further depolarization resultsin conduction block. Restoration of the circula-tion leads to the rapid reabsorption of the K'from the periaxonal space into the axon, and re-polarization of the fibre which once again passesthrough a transient phase of post-ischaemichyperexcitability before the repolarization iscomplete. This hypothesis postulates the exist-ence of a periaxonal diffusion barrier whichserves to hold the K' effilux in close proximity tothe axon membrane and to limit the rate at whichit diffuses into the endoneurial spaces of thenerve trunk. Seneviratne and Peiris (1968b) havedemonstrated that the absence of ischaemic andpost-ischaemic paraesthesiae of diabetic subjectsis due to the reduced rate ofchange of excitabilityof the peripheral nerve during the ischaemic andpost-ischaemic periods, and suggest that this isthe cause of its resistance to inactivation byischaemia. Seneviratne and Peiris (1969, 1970a)attribute this abnormality of the diabetic nerveto an increase in the permeability of its peri-axonal diffusion barrier to K'. In a recent paper,Seneviratne, Peiris, and Weerasuriya (1972) havecited evidence which suggests that the poly-anionic mucopolysaccharide gap substance whichsurrounds the bare axon at the node of Ranvierserves as the periaxonal diffusion barrier. Theincreased permeability of the diffusion barriermay be due to a reduction in the quantity of thisgap substance at the node, or to a qualitativechange in the nature of the mucopolysaccharidematrix which results in a reduction in its capacityto bind K' ions and hold them in close proximityto the axon at the node. Preliminary evidence(Seneviratne, 1972) indicates that such a reduc-tion in the K' binding property of the nodal gapsubstance can, in fact, be demonstrated in nervesofhumans and alloxan diabetic rats. This suggeststhat the increased resistance of peripheral nerveto inactivation by ischaemia is due primarily toan alteration in the immediate ionic environmentof the axon itself, rather than to an alteration inthe energy metabolism of the axon which enablesit to maintain its function under anaerobic con-ditions, and lends support to Simpson's (1962)concept of an ionic micro-environment of thenerve fibre. Simpson drew attention to the fact

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that the micro-environment within the nervesheath was an important factor in maintainingthe normal function of nerve, that it was keptrelatively constant in healthy nerves despite widefluctuations in plasma constitution, and thatchanges in the ionic environment of the axoncould be the ultimate cause of excitabilitychanges.The hypothesis that the resistance of nerve to

ischaemic inactivation is determined by factorswhich alter the ionic environment of the nerve issupported by several lines of evidence. Absenceof the paraesthetic response and resistance of theperipheral nerve to inactivation by ischaemiaoccurs not only in diabetes but in several otherconditions which are not associated with a grossabnormality of carbohydrate metabolism. Poole(1956b) observed the absence or diminution ofparaesthetic response in patients with megalo-blastic anaemia, acute infective polyneuritis andbronchial carcinoma; Seneviratne and Peiris(1970b) demonstrated increased resistance ofperipheral nerve to ischaemic inactivation inpatients with chronic liver disease who hadnormal glucose tolerance curves; Christensenand 0rskov (1969) observed these features inpatients with uraemia, while Shahni and Russell(1969) suggest that it occurs in patients withmotor neurone disease. A second line of evidencederives from the fact that the degree of resistancecan be changed by experimental alterations ofthe periaxonal K' ion concentration. Seneviratne,Peiris, and Weerasuriya (1972) have shown thatan increase in the serum K' ion concentrationproduces a significant reduction of the ischaemicinactivation time of cat peripheral nerve. Insulinincreases the resting intra-axonal K' ion con-centration, and nerves from healthy animals pre-treated with insulin show an increased rate of K'efflux when they are exposed to anoxic condi-tions, leading to a local increase of the peri-axonal K' ion concentration. These nerves haveinactivation times in anoxia which are con-siderably shorter than that of control nerves(Seneviratne and Peiris, 1970a). Steiness (1961)and Gregersen (1968) have demonstrated anormalization of the ischaemic vibration per-ception threshold in early diabetics during activeinsulin therapy, and the results of this studyshow that the degree of diminution of theparaesthetic response is related to the severity of

the diabetic state as determined by the degree ofinsulin dependence. These relationships could bedue to the role of insulin in determining the rateand amount of K' ion efflux from the axonsduring ischaemic conditions. The results of thisstudy also indicate that diabetics with thejuvenile onset type of the disease have con-sistently smaller paraesthesiae indices thandiabetics with the maturity onset type of disease.This relationship, too, may be due to the greatersensitivity to insulin of the diabetic with thejuvenile onset form of the disease.

Further evidence that the resistance of a nerveto ischaemia is determined by the ionic micro-environment of the axon is provided by theobservations of Gregersen and Pilgaard (1971).They recognized that the serum calcium ionconcentration was also a factor determining theresistance of nerve to ischaemia; hypercalcaemicstates being associated with an increase of in-activation time. They noticed, however, that a sixhour calcium infusion into a normocalcaemicpatient, raising the serum Ca" ion level from 9-6to 13-8 mg/100 ml., was without effect inchanging ischaemic vibration perception thresh-old. Frankenhaeuser and Hodgkin (1957) haveshown that the action of Ca' ions on the systemcontrolling membrane Na-K permeability ex-plains its effect on excitability; the nerve be-coming more excitable in low Ca" ion concentra-tions because a smaller depolarization is nowrequired {o increase its Na' conductance to thecritical level at which the inward Na' currentexceeds the outward current carried by the K'.Using the isolated squid axon, Frankenhaeuserand Hodgkin (1957) showed that changing theexternal Ca" ion concentration produced immedi-ate changes in the fibre threshold. The muchlonger time lag observed by Gregersen andPilgaard (1971) may hence be a measure of theeffectiveness of the buffer properties of the nodalgap substance of healthy myelinated nerve, whichbecause of its polyanionic characteristics servesto maintain the constancy of an ionic micro-environment in the immediate vicinity of thenode.The evidence cited above suggests that the

diminution of the paraesthetic response and theincreased resistance of nerve to inactivation byischaemia are due primarily to changes in theproperties of the nodal gap substance which in

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turn determines the changes in the ionic environ-ment of the nerve. The pathogenesis and natureof this change are quite unknown. Althoughsegmental demyelination of peripheral nerve iscommonly associated with the increased resist-ance of nerve to ischaemia, the experimentalobservations of Seneviratne and Peiris (1968b)and Gregersen and Pilgaard (1971) show thatincreased resistance to ischaemia does notnecessarily follow demyelination and, conversely,that nerves which exhibit no clinical or conven-tional electrophysiological evidence of dysfunc-tion may exhibit increased resistance to in-activation by ischaemia. This view is supportedby the results of this study which show no con-sistent relationship between the presence ofneuropathy and diminution of the paraestheticresponse.

REFERENCES

Christensen, N J., and 0rskov, H. (1969). Vibratory percep-tion during ischaemia in uraemic patients with mildcarbohydrate intolerance. Journal of Neurology, Neuro-surgery, and Psychiatry, 32, 519-524.

Fajans, S. S., and Conn, J. W. (1965). Prediabetes, sub-clinical diabetes and latent clinical diabetes: interpretation,diagnosis and treatment. In On the Nature and Treatmentof Diabetes, pp. 641-656. Edited by B. S. Leibel and G. A.Wrenshall. International Congress Series No. 84. ExcerptaMedica Foundation: Amsterdam.

Frankenhaeuser, B., and Hodgkin, A. L. (1957). The actionof calcium on the electrical properties of squid axons.Journal of Physiology, 137, 218-244.

Gregersen, G. (1968). A study of the peripheral nerves indiabetic subjects during ischaemia. Journal of Neurology,Neurosurgery, and Psychiatry, 31, 175-181.

Gregersen, G., and Pilgaard, S. (1971). The effect of ischaemiaon vibration sense in hypo- or hypercalcaemia and on de-myelinated nerves. Acta Neurologica Scandinavica, 47, 71-79.

Merrington, W. R., and Nathan, P. W. (1949). A study ofpost-ischaemic paraesthesiae. Journal of Neurology, Neuro-surgery, and Psychiatry, 12, 1-18.

Nathan, P. W. (1958). Ischaemic and post-ischaemic numb-ness and paraesthesiae. Journal of Neurology, Neuro-surgery, and Psychiatry, 21, 12-23.

Poole, E. W. (1956a). Ischaemic and post-ischaemic paraes-thesiae: normal responses in the upper limb with specialreference to the effect of age. Journal of Neurology, Neuro-surgery, and Psychiatry, 19, 148-154.

Poole, E. W. (1956b). Ischaemic and post-ischaemic paraes-thesiae in polyneuritis. Journal of Neurology, Neuro-surgery, and Psychiatry, 19, 281-288.

Seneviratne, K. N., and Peiris, 0. A. (1968a). The effect ofischaemia on the excitability of human sensory nerve.Journal of Neurology, Neurosurgery, and Psychiatry, 31,338-347.

Seneviratne, K. N., and Peiris, 0. A. (1968b). The effect ofischaemia on the excitability of sensory nerves in diabetesmellitus. Journal of Neurology, Neurosurgery, and Psy-chiatry, 31, 348-353.

Seneviratne, K. N., and Peiris, 0. A. (1969). The effects ofhypoxia on the excitability of the isolated peripheral nervesofalloxan-diabetic rats. JournalofNeurology, Neurosurgery,and Psychiatry, 32, 462-469.

Seneviratne, K. N., and Peiris, 0. A. (1970a). The role ofdiffusion barriers in determining the excitability ofperipheral nerve. Journal of Neurology, Neurosurgery, andPsychiatry, 33, 310-318.

Seneviratne, K. N., and Peiris, 0. A. (1970b). Peripheralnerve function in chronic liver disease. Journal ofNeurology,Neurosurgery, and Psychiatry, 33, 609-614.

Seneviratne, K. N., Peiris, 0. A., and Weerasuriya, A. (1972).The effects of hyperkalaemia on the excitability of peri-pheral nerve. Journal of Neurology, Neurosurgery, andPsychiatry, 35, 149-155.

Seneviratne, K. N. (1972). Unpublished results.Shahani, B., and Russell, W. R. (1969). Motor neurone

disease. An abnormality of nerve metabolism. Journal ofNeurology, Neurosurgery, and Psychiatry, 32, 1-5.

Simpson, J. A. (1962). Conduction velocity of peripheralnerves in human metabolic disorders. Electroencephalo-graphy and Clinical Neurophysiology, Suppl. 22, 36-43.

Steiness, I. (1961). Influence of diabetic status on vibratoryperception during ischaemia. Acta Medica Scandinavica,170, 319-338.

Weddell, G., and Sinclair, D. C. (1947). 'Pins and needles':observations on some of the sensations aroused in a limbby the application of pressure. Journal of Neurology,Neurosurgery, and Psychiatry, 10, 26-46.

WHO (1965). Diabetes mellitus. Report of a WHOexpert committee. World Health Organization TechnicalReport Series, 310.

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