J. Neurol. Neurosurg. Psychiat., 1970, 33, 55-61

The incidence of abnormality in control humanperipheral nerves studied by single

axon dissectionN. ARNOLD AND D. G. F. HARRIMAN

From the Neuropathology Laboratory, The General Infirmary, Leeds

Dissection and staining of single myelinated axonsfrom peripheral nerves is a procedure useful fol thestudy of peripheral neuropathies, and has beenrevived in recent years (Cavanagh and Jacobs, 1964;Thomas and Lascelles, 1966) after a long period ofneglect. The method demands qualities of patienceand artistic agility more readily available when itwas introduced over a century ago, and the beautifulpictures published by such workers as Gombault(1880/1), whose demonstration of segmental de-myelination in lead poisoning is well known, havenot since been equalled. Later observers relied onconventional histological methods for the exam-ination of peripheral nerves, but these often fail toshow demyelination adequately, especially segmentaldemyelination, in which it is necessary to see aportion of nerve long enough to demonstrate intactmyelin both proximal and distal to the demyelinatedinternode or internodes. With revival ofthe techniquesegmental demyelination has been shown in diabeticneuropathy (Thomas and Lascelles, 1966), liverdisease (Dayan and Williams, 1967), diphtheria(Cavanagh and Jacobs, 1964), peroneal muscularatrophy (Gutrecht and Dyck, 1966), and in myx-oedema (Harriman, 1968), and knowledge has beengained of the pathogenesis of those disorders.However, it has also been realized that segmentaldemyelination may occur in normal nerves (Lubinska1958), so that it becomes difficult to evaluate itssignificance in routine nerve biopsies unless it isextensive.To help to assess the value of this technique as a

routine procedure for nerve biopsy a control seriesof 51 nerves has been examined. Of these, 46 wereobtained at necropsy of patients with no knownperipheral neurological abnormality, without evi-dence of chronic disease or of cardiac failure withoedema. It was obviously necessary to avoid bed-ridden subjects in whom pressure palsies might haveoccurred. The specimens were obtained from a wideage range. Patients suffering from acute disease were

selected, dying after a short illness, and the causesof death were as follows: acute head injury (15);cerebral aneurysm (six); cerebral haemorrhage orthrombosis (six); myocardial infarction (six); CNSmalfoimation (children) (four); acute infection(four); cerebral tumour (two); pulmonary embolism(two); and thrombotic microangiopathy (one).Fascicular specimens were also available from fiveperipheral sensory nerves obtained at motor pointmuscle biopsy, in which no abnormality had beendetected in fascicles of the same nerve examined bythe Marchi, Palade, and routine paraffin methods.Myelinated axons were dissected and measurementsmade of internodal length and fibre diameter, andthe data from different age groups were compared.Any abnormalities found were recorded. It wasfound that segmental demyelination occurred in asignificant proportion, but rarely more than oncein 24 axons. Internode lengths at first increased andthen decreased during the life span.

MATERIALS AND METHODS

The majority of nerve funiculi were taken from themusculocutaneous branch of the lateral popliteal nerve3 in. above the lateral malleolus; many of our routinenerve biopsies are taken from this site, which convenientlyoverlies the peroneus brevis, often used for motor-pointmuscle biopsy. Other sites examined were the mediannerve at least 3 in. proximal to the carpal ligament, acutaneous nerve overlying the palmaris longus, a cu-taneous nerve overlying the vastus intemus, and the suralnerve from the dorsum of the foot. The nerves wereclassified as follows: group 1: musculo-cutaneous nervesat necropsy (34); group 2: musculo-cutaneous nerves atbiopsy (three); group 3: median nerves at necropsy (10);group 4: other nerves-two at necropsy and two at biopsy(four).Each specimen 1 to 2 cm long was placed on a piece of

card, allowed to adhere to it, and then fixed in Paladesolution (1 % buffered osmium tetroxide) for 18 to 24hours. It was then washed in running tap water for 24hours and stored in 60% glycerol solution until required

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Dissection of each nerve was carried out using a Zeissstereomicroscope with twin transillumination at mag-nifications of x 20 and x 60. Three or four bundles ofnerve fibres selected at random from each funiculus wereteased out and individual fibres placed on a glass slide.Fibres of varying calibre from each bundle were selectedwithout regard for the presence or absence of abnormality.The individual fibres on the glass slide were dehydratedand cleared in creosote. Most of the creosote was thenremoved with filter paper, the fibres straightened, someremaining creosote allowed to evaporate, and the axonsthen mounted in balsam. Twenty-four fibres of varyingcalibre were mounted from each nerve.The diameter of each fibre was measured (see below),

and the internode lengths were determined. Abnormalitiesincluding the number of demyelinated or regeneratedsegments were noted.

FIBRE DIAMETER The diameter of individual fibres wasnot always constant, and presented a problem in selectionof the site for diameter measurement. As most variationocurred in the paranodal region, the most vulnerable partof the nerve fibre (Lubinska and Lukaszewska, 1956) andliable to myelin retraction and swelling, it was decided torestrict measurements to the more central parts of theinternodes. Several measurements were made along thecourse of the internode and the mean recorded.

Greatest variation in diameter was found in somefibres ofnarrow calibre (6 p), which had a beaded catenateappearance throughout most or all of their length (Fig. 3).Here maximum diameter was recorded. Ochs (1965)showed that beading of myelinated fibres in rat sciaticnerve could result from stretching of the nerve: whentension was removed, the beading disappeared. In a fibrein which beading occurred only in part of its length, thediameter of the beaded or catenate area was greater thanthe diameter of the non-beaded section of the fibre, andthis we confirmed in human nerve. We are uncertain ofthe cause of beading in our material, but consider it isartifactual. Care taken to avoid stretching did notprevent its occurrence.

INTERNODE LENGTH This was measured at a magnificationof x 100, except for small calibre fibres, where a greatermagnification was sometimes necessary in order todetermine the site of the node. Where the myelin hadretracted from the node, it was normally possible todetect the constriction of the endoneurium at the nodeitself. In any one fibre, internode length was found tovary considerably, up to 200 ,u from the mean for thatparticular fibre. In abnormal fibres the variation ininternode length was usually greater.

HISTOGRAMS For each nerve examined, a histogram wascharted recording the internode length of each fibreagainst the fibre diameter (Fig. 1). Each point representsone intemode length, as measured from the base line, andeach line represents one fibre-this is a slight modificationof the method used by Fullerton, Gilliatt, Lascelles, andMorgan-Hughes (1965). Wide variations in internodelengths in one fibre indicate an abnormality, such assegmental demyelination, and such fibres can be rec-ognized on the histograms (C45, C48).

RESULTS

EFFECT OF AGE AND SITE Representative histogramsin Fig. 1 illustrate the findings at four different ages,and Figs. 2 and 3 include normal nerve fibres atdifferent ages.

800

400

-C_s

a)

01)00

0)C-

1600

1200

800

400

A. lyr 11months

Ia a a

2 4 6 8 10 12 14

D. 70 years

II I.2 4 6 8 10 12 14

Fibre diameter (,u)FIG. 1. Representative histograms showing increase andvariation in internode length with increasing age (see text).Ordinate: internode length (it), abscissa:fibre diameter (IL).A. (C31) 1 year 11 months. B. (C45) 18 years. C. (C51)48 years. D. (C48) 70 years.

4

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.............

I

I I

C 31

c 27

X C 42

4 1 l 1 1 1 1 I lc7

1000 mu

FIG. 2. 1. Normalfibre, age I year 11 months, calibre 6,. 2. Normalfibre, age 25 years, calibre JOp,. 3. Short and longinternodes. 4. Paranodal oedema and short internodes.

a. From 4 weeks to 5 years In this age group thereis very little variation in internode length in fibresof different calibre-for example, the 4 ,u fibres haveinternodes of the same length as the 8 p fibres andthere are very few internodes longer than 600 s. At5 years there is a little more variation in internodelength. In the youngest case the greatest calibrerecorded is 9 p, whereas at 5 years two fibres withcalibres of 10 and 11 t have been isolated.b. From 12 years to 23 years There is now a definiteincrease in internode length commensurate withincreased fibre calibre. Fibre calibre varies from 4 ,to 12 ,u, and internode lengths up to 1,600 ,u are

recorded indicating considerable growth.c. From 34 years to 50 years The histograms showthe same graded relationship between fibre calibreand internode length as in the previous group. Thegreatest internode lengths recorded are of 1,500 ,t

and fibre calibres of 13 to 14 ,u are common.

d. From 60 years to 75 years There is a definitepreponderance of fibres with short internode lengthsespecially in the fibres of 6 to 10 ,u calibre. Thesemay indicate regeneration when present throughoutthe fibre, and are common findings in this age group.

The results are similar to those of Lascelles and

Thomas (1966), who reported on the effect ofincreasing age on internode length, and their findingswere confirmed by Dyck, Gutrecht, Bastron, Karnes,and Dale (1968) in nine normal sural nerves. Inearly development internodes are all of the same

short size, and this increases in proportion to thefibre diameter as growth takes place. Vizoso (1950)showed that the growth of the part from which thenerve is taken has an important influence on inter-node length, and in this connection it is noteworthythat we found no difference between the internodelengths of the median nerve in the forearm and themusculo-cutaneous nerve above the ankle at corre-

sponding ages.

ABNORMALITIES Table 1 shows the number of cases

in each group affected by the following abnormalities:1 Pale internodes between normal segments Myelinwas minimal or absent in these internodes, and theirinternodal length and calibre were usually less thanthose of the adjacent normal segments (Fig. 3).For example, a fibre (case C61) was composed ofinternodes of the following lengths in micra: 840872-656-368-776-872-710. The undeilinedinternodes were pale.

I I I I

2 l

3 1

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W%MWAOP Q -.W-'w;-' -WPB - ..i W

i.

FIG. 3. 1. Normal fibre, age I year 1I months, calibre 6,u. 2. Normal fibre, age S years, calibre 8,u. 3. Normal fibre.age 25 years, calibre 1O,u. 4. Segmental demyelination. 5. Fibre with intercalated short internode. 6. Paranodal oedema,7. Wallerian-type degeneration. 8. Catenate fibre.

This indicated segmental demyelination affectingone or more segments; one fibre was isolated inwhich five segments were involved. The abnormalinternodes were either in sequence or separated bynormal internodes.No fibres of the nerves in Group 3 (median nerves)

showed segmental demyelination, but the group wasrelatively small and the subjects mainly young.2 Short internodes between normal segments Fibreswith normally myelinated but short internodes,intercalated between normal segments (Fig. 3). Forthe purpose of this study a 'short' internode was

TABLE 1INCIDENCE OF ABNORMALITIES IN EACH GROUP OF NERVES EXAMINED1

Nerve Paleinter- Shortinter- Short inter- Wallerian- Short Paranodal Catenatenodes nodes nodes type internodes oedema fibresbetween between enclosed by degeneration alonenormal normal normal

segments segments segments(1) (2) (3) (4) (5) (6) (7)

1. Musculo-cutaneous (necropsy) 12 (34) 6 (34) 6 (34) 3 (34) 13 (34) 23 (34) 30 (34)2. Musculo-cutaneous (biopsy) 0 (3) 1 (3) 0 (3) 0 (3) 1 (3) 3 (3) 2 (3)3. Median (necropsy) 0 (10) 2 (10) 1 (10) 0 (10) 6 (10) 9 (10) 7 (10)4. (a) Other nerves (necropsy) 0 (2) 0 (2) 0 (2) 0 (2) 0 (2) 2 (2) 2 (2)

(b) Other nerves (biopsy) 1 (2) 0 (2) 1 (2) 0 (2) 2 (2) 1 (2) 1 (2)

Total 13 (51) 9 (51) 8 (51) 3 (51) 22 (51) 38 (51) 42 (51)

"The figure in parentheses shows the total number of nerves in each group.

III N iiiiiiijoll W41. 0 mm=M- I.."o- -:a---n--:M::....

0 I WIN ---wommillip 1111 111,1111 will .-

iiiiiinii pillimilNW&IA*

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defined as an internode not more than half as long asthe average internode length of the fibre concerned.As in demyelinated segments, the short internodeswere usually slightly narrower than normal. Theywere thought to be due to remyelination by one ormore Schwann cells of previously demyelinatedsegments, and hence to indicate previous segmentaldemyelination. Significantly, two cases showingactive segmental demyelination also demonstratedshort intercalated internodes.3 Short internodes not enclosed by normal segmentsHere short internodes occurred at either end of adissected fibre, in sequence with anormal internode butnot intercalated (Fig. 2). There was, thus, no indica-tion whether the short segments were due to previoussegmental demyelination or to previous Wallerian-type1 degeneration. If the latter, all segments in theregenerated portion of nerve would have been shortand more or less equal (Vizoso and Young, 1948),whereas the former would have been intercalatedbetween normal segments, no matter how far apart.In these specimens intercalation could not be deter-mined. Seven of the eight cases in this group alsohad fibres with short internodes alone (see section 5),suggesting that Wallerian-type degeneration was themore likely cause.4 Wallerian-type degeneration Active Wallerian-type degeneration was seen in only three nerves, allin necropsy musculo-cutaneous nerves. In one of thenerves concerned, two fibres with only a few rem-nants of myelin were seen. In the other two nerves,the appearances of the degeneration were more con-ventional (Fig. 3).5 Short internodes alone In these fibres all theinternodes were 'short' in comparison with normalfibres in the same funiculus (Fig. 2). It was notuncommon, occurring in 22 out of 51 cases, andindicated regeneration of the fibre after Wallerian-type degeneration.6 Paranodal oedema Paranodal oedema was verycommon, and more frequent in necropsy than inbiopsy material. When present, it affected most nodesin the fibre concerned. The 'oedema' was more oftenwithin myelin adjacent to the node, but occasionallywas manifest as a retraction of myelin from thenode (Figs. 2 and 3).7 Catenate fibres Catenate fibres were smallcalibre fibres with a marked beaded appearance(Fig. 3).

INCIDENCE OF ABNORMALITIES Table 2 shows thenumber of fibres in each specimen affected by thevarious abnormalities.

'This term is used in preference to 'Wallerian' degeneration, which,strictly speaking, refers to the sequence of events following nervesection only.

It will be seen that segmental demyelination andremyelination occurred infrequently, and thenusually once only per 24 fibres. The three specimenswith two affected fibres were from patients withmyocardial infarction, pulmonary embolism, andcerebral haemorrhage respectively, and the specimenwith four affected fibres was from a case of myo-cardial infarction.

Wallerian-type degeneration or its effects (columns4 and 5 respectively) was rather more common, butdid not usually affect more than three fibres perspecimen unless the patient was over 60 years in age.The patient who had five fibres/24 with short inter-nodes was aged 75 years (myocardial infarction),and the two patients with eight fibres/24 affected bythis change were aged 68 years and 70 years (bothmyocardial infarction). Paranodal oedema andcatenate fibres were frequent and occurred in morethan two-thirds of the cases in up to six fibres/specimen.

AGE AT WHICH ABNORMALITIES DEVELOP Table 3shows the incidence of abnormalities in different agegroups.

It will be seen that segmental demyelinationoccurred only once in the first decade, and showed alow incidence thereafter, becoming commoner over60. The effects of Wallerian-type degenerationappeared after 10 and rose steadily with age. Para-nodal oedema and catenate fibres did not appear tobe age related in incidence.

DISCUSSION

If dissection of individual axons is to have a placein routine examination of nerves taken at motor-point muscle biopsy, it must be able to provideinformation not available in the paraffin sections. Itis an ideal method for the demonstration of seg-mental demyelination, which can only be imperfectlyseen in sectioned material and may go unrecognizedin embedded nerves. However, in any given nerve,the investigator requires to know how much emphasismay be put on the discovery of, say, a single fibreshowing segmental demyelination, when it is realizedthat it may occur normally (Lubinska, 1958), andwhat significance can be attributed to paranodaloedema or to beading of myelin sheaths (catenatefibres).The present study was designed to provide evidence

of the incidence of abnormalities in 'normal' nervesat sites commonly used for biopsy in our hospital. Itmay be objected that the main nerve selected, themusculocutaneous branch of the lateral poplitealnerve, is not ideal for biopsy, as its parent nerve isliable to compression at the head of the fibula. We

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TABLE 2THE INCIDENCE OF ABNORMAL FIBRES IN EACH NERVE (PER 24 FIBRES DISSECTED)

Affected fibres Pale internodes Short internodes Short internodes Wallerian- Short Paranodal Catenatein each between between not enclosed by type internodes oedema fibres

specimen normal segments normal segments normal segments degeneration alone(no.) (1) (2) (3) (4) (5) (6) (7)

0 38 42 43 48 28 12 91 9 8 5 2 9 2 62 3 1 3 0 5 9 103 0 0 0 1 6 8 104 1 0 0 0 0 4 65 0 0 0 0 1 6 36 0 0 0 0 0 2 57 0 0 0 0 0 0 18 0 0 0 0 2 3 19 0 0 0 0 0 1 010 or more 0 0 0 0 0 4 0

Total 51 51 51 51 51 51 51

believe that the risks of misinterpretation of a effects are, perhaps, unavoidable and may be re-biopsy for this reason are real, but have been sponsible for the abnormalities seen in the presentexaggerated. One of us (D.H.) has used the mus- series of nerves as a wear and tear phenomenon.culocutaneous nerve for fascicular biopsy routinely The results show that segmental demyelinationsince 1958 without inconsistent findings, whereas was seen in 12 out of 37 musculocutaneous nerves,sural nerve branches on the dorsum of the foot, used and in the majority was seen in only one fibre out ofbefore then, were not infrequently misleading, 24 dissected. In three cases, two fibres were affected,because of perineurial fibrosis and fibre loss. The and in one case, four fibres. This would indicate thatmost popular site for neive biopsy in the leg now- on dissection of 24 fibres from a given biopsy noadays is the sural neive, behind and above the lateral diagnostic significance should be attributed tomalleolus, but even it is subject to fascial compression segmental demyelination in one or two fibres, andproximally and distally, and it is joined in midcalf increasing significance to three or more. In the caseby a branch of the lateral popliteal nerve. No long of Wallerian-type degeneration, unless the patient isnerve is ideal for biopsy towards the periphery of its over 60 years of age, the discovery of two fibres/24course, and it is better to be aware of the risks of showing active degeneration would be significant,abnormality being present as a result of local whereas no diagnostic importance would be attachedpressures and to assess their incidence in a 'control' to evidence of former Wallerian-type degenerationseries than to assume normality in controls. Ander- unless it occurred in three or more fibres/24. Evenson, Fullerton, Gilliatt, and Hern (1969) have this would not be significant in patients over 60recently shown that distal nerve compression may years old, when it is a moie frequent finding.lead to retrograde degeneration, and this must The other abnormalities of paranodal oedemaincrease our awareness of the risks of misinter- and catenate fibres are much less likely to indicatepretation of nerve biopsies. Minor compressive disease, the latter not at all, and the former only if it

TABLE 3INCIDENCE OF ABNORMALITIES BY AGE

Age groups Pale internodes Short internodes Short internodes Wallerian- Short Paranodal Catenate(yr) between between not enclosed by type internodes oedema fibres

normal segments normal segments normal segments degeneration alone(1) (2) (3) (4) (5) (6) (7)

0- 9 0 (9) 1 (9) 0 (9) 0 (9) 0 (9) 4 (9) 4 (9)10-19 3 (7) 0 (7) 1 (7) 1 (7) 1 (7) 7 (7) 7 (7)20-29 1 (9) 1 (9) 2 (9) 0 (9) 4 (9) 8 (9) 9 (9)30-39 2 (9) 2 (9) 0 (9) 0 (9) 4 (9) 6 (9) 7 (9)40-59 0 (4) 2 (4) 1 (4) 1 (4) 2 (4) 4 (4) 4 (4)60-89 7 (13) 3 (13) 4 (13) 1 (13) 11 (13) 9 (13) 11 (13)

Total 13 (51) 9 (51) 8 (51) 3 (51) 22 (51) 38 (51) 42 (51)

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Incidence of abnormality in control human peripheral nerves

occurs in more than two-thirds of the dissectedfibres.

SUMMARY

Peripheral nerves obtained at biopsy or necropsy of51 subjects were examined by single axon dissectionin order to provide a control series for biopsies ofdiseased nerve studied by the same method.

Evidence of past or present segmental demyelin-ation and also of active or preceding Wallerian-type degeneration was found in a small number offibres. Their incidence suggested that on dissecting24 fibres, diagnostic significance should be ascribedto three or more abnormal fibres, whether the ab-normality consisted of previous or current segmentaldemyelination or active or preceding Wallerian-typedegeneration. If the patient is over 60, precedingWallerian-type degeneration should be present insix or more fibres before it is considered abnormal.The influence of increasing age on internode

length and on the incidence of abnormalities wasdemonstrated and the known relationships of inter-node length and fibre diameter confirmed.

Grants from the Muscular Dystrophy Group of GreatBritain and from the National Fund for Research intoCrippling Diseases are gratefully acknowledged.

REFERENCES

Anderson, M. H., Fullerton, P. M., Gilliatt, R. W., and Hern, J. E. C.(1970). Changes in the forearm associated with median nervecompression at the wrist in the guinea-pig. J. Neurol. Neuro-surg. Psychiat., 33, 70-79.

Cavanagh, J. B., and Jacobs, J. M. (1964). Some quantitative aspectsof diphtheritic neuropathy. Brit. J. exp. Path., 45, 309-322.

Dayan, A. D., and Williams, R. (1967). Demyelinating peripheralneuropathy and liver disease. Lancet, 2, 133-134.

Dyck, P. J., Gutrecht, J. A., Bastron, J. A., Karnes, W. E., andDale, A. J. D. (1968). Histologic and teased-fiber measurementsof sural nerve in disorders of lower motor and primary sensoryneurons. Mayo Clin. Proc., 43, 81-123.

Fullerton, P. M., Gilliatt, R. W., Lascelles, R. G., and Morgan-Hughes, J. A. (1965). The relation between fibre diameter andinternodal length in chronic neuropathy. J. Physiol. (Lond.),178, 26 P-28 P.

Gombault, M. (1880/1). Contribution a l'etude anatomique de lanevrite parenchymateuse subaigue et chronique-nevritesegmentaire peri-axile. Arch. Neurol. (Paris), 1, 11-38.

Gutrecht, J. A., and Dyck, P. J. (1966). Segmental demyelination inperoneal muscular atrophy: nerve fibres teased from sural nervebiopsy specimens. Mayo Clin. Proc., 41, 775-777.

Harriman, D. G. F. (1968). Unpublished observations.Lascelles, R. G., and Thomas, P. K. (1966). Changes due to age in

internodal length in the sural nerve in man. J. Neurol. Neuro-surg. Psychiat., 29, 40-44.

Lubinska, L., and Lukaszewska, I. (1956). Shape of myelinated nervefibres and proximo-distal flow of axoplasm. Acta Biol. exp.(Warszawa), 17, 115-133.

(1958). 'Intercalated' internodes in nerve fibres. Nature (Lond.),181, 957-958.

Ochs, S. (1965). Beading of myelinated nerve fibres. Exp. Neurol.,12,84-95.

Thomas, P. K., and Lascelles, R. G. (1966). The pathology of diabeticneuropathy. Quart. J. Med., 35, 489-509.

Vizoso, A. D., and Young, J. Z. (1948). Internode length and fibrediameter in developing and regenerating nerves. J. Anat. (Lond.)82,110-134.

(1950). The relationship between internodal length and growthin human nerves. J. Anat. (Lond.), 84, 342-353.

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