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Sub-clinical entrapment neuropathy in man
Journal of the neurological Sciences, 1975, 24:283-298
283
,~ Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Sub-clinical Entrapment Neuropathy in Man D. NEARY, J. OCHOA* AND R. W. GILLIATT Institute of Neurology and the National Hospital for Nervous Diseases, Queen Square, London WC1N3BG (Great Britain) (Received 17 July, 1974)
I NTRODUCTION
As a result of the increasing sensitivity of electrophysiological techniques, nerve conduction studies may sometimes suggest a mild entrapment lesion in a nerve which is clinically normal. In patients with unilateral ulnar nerve lesions, for example, Payan (1969) found several examples of abnormal sensory conduction in the clinically unaffected nerve of the opposite arm. In order to look for anatomical evidence of sub-clinical entrapment, we have obtained peripheral nerves at routine autopsies on patients without known disease of the peripheral nervous system. The present paper describes our preliminary findings in relation to the median nerve at the wrist and the ulnar nerve at the elbow. MATERIAL AND METHODS
Nerves were taken from patients undergoing routine autopsies at the Middlesex Hospital, University College Hospital, and St. Pancras Coroner's Court, as well as at the National Hospital, Queen Square. Those suffering from general medical or neurological disorders which might affect the peripheral nervous system were excluded. All nerves were obtained within 24 hr of the stated time of death; in 2 cases, nerves were obtained within 8 hr. The present paper is based on the findings in 12 median and 12 ulnar nerves; the cause of death in each case is shown in Table 1. The median nerve and its digital branches were exposed from the lower forearm to the palm, the site of the upper border of the flexor retinaculum being marked by a stitch in the epineurium. The length of nerve removed, including the digital branches, was approximately 15 cm. After removal, the specimen was gently stretched on a perspex frame by nylon threads stitched through the epineurium at either end. The This work was carried out while J. Ochoa was holding a Wellcome Senior Research Fellowship. Support from the Brain Research Trust is also gratefully acknowledged. * Present address: Division of Neurology, Dartmouth Medical School~ Hanover, N.H., U.S.A.
284
D. NEARY, J. OCHOA, R. W. GILLIATJ ]['ABLE
I
( A U S E 0 1 DI'iA I H IN PATIENTS STUI)IF.I)
Case No. 1 2 3 4 5 6 7 8 9 10 11 12
Age (years)
Sex
Cause o[ death
73 63 59 60 36 80 60 84 40 39 61 51
M M M F M M M F M F M M
hypertension hypertension myelofibrosis coronary thrombosis cerebral haemorrhage coronary thrombosis coronary thrombosis coronary thrombosis cerebral glioma cerebral atrophy coronary thrombosis coronary thrombosis
ulnar nerve was exposed throughout its course at the elbow and for 5 7 cm above it. The point at which the nerve passed deep to the origin of flexor carpi ulnaris to enter the cubital tunnel was marked by a stitch in the epineurium. A length of approximately 15 cm was removed and mounted in the same way as the median nerve. Nerves were fixed in buffered glutaraldehyde (4~o) at pH 7.4 for 3 4 hr. During this time the specimens were further divided and excess epineurium was removed. After treating with 1~o osmium tetroxide in buffered veronal acetate for 3 hr, the nerves were dehydrated, transferred to fluid Epoxyresin (Epon) and stored at - 15°C. Single myelinated fibres from some portions of the nerves were teased apart in fluid Epon, examined under the light microscope and photographed. Selected single fibres were prepared for electron microscopy as described by Ochoa (1972). Other portions of nerve were transferred to fresh Epon and embedded: from these blocks, 1-/~m transverse sections were cut on an ultramicrotome and stained with 1~0 toluidine blue. Additional sections were taken for electron microscopy. For the estimation of fibre density, photographic prints were obtained at a magnification of x 1000. From these, areas were selected at random, on which total fibre counts and measurements of fibre diameter were made. For the latter a modification of the counter originally devised by Espir and Harding (1961) was used. Four fascicles were sampled from each nerve, and not less than 300 fibres were counted in each case. RESULTS
Macroscopic appearances Most of the ulnar nerves showed some enlargement in the ulnar groove compared with the nerve proximal and distal to it. However, this was not more marked in those with nerve fibre damage than in those without it. In the case of the median nerve there was no visible swelling at the wrist or under the flexor retinaculum but the nerve was usually flattened in this region.
Interstitial changes In the ulnar nerve transverse sections confirmed that the cross-sectional area was
S U B - C L I N I C A L E N T R A P M E N T N E U R O P A T H Y IN MAN
285
I II W
Fig. 1. Case 9. T r a n s v e r s e sections of the u l n a r nerve. A : 6 cm p r o x i m a l to the e l b o w ; B : in the u l n a r g r o o v e at the e l b o w ; C : 4 cm distal to the elbow. Bar 1 mm.
286
o. NEARY, J. O('HOA, R. W. (HLLIATq TABLE 2
C R O S S - S E C T I O N A L AREA OF W H O L E NERVE, T O T A L I N T R A F A S C I C U L A R AREA A N D M Y E I d N A T E I ) FIP, RI- I ) k N S l l 5
"~
D I F F E R E N T LEVELS
Case No.
Level
Area of whole nerve ( mm 2)
lntrajascicular area (ram z )
Fibre density (fibre.~/mm 2 j
proximal elbow distal
6.0 10.3 5.7
3.9 8.7 3.4
6,500 3.900 6.700
proximal elbow distal
5.3 12.8 6.4
4.3 9.8 3.9
9,900 3,900 8,000
proximal wrist
5.9 10.9
4.0 5.4
7,400 6,500
proximal wrist
5.0 9.6
3.8 5.5
9,600 7,400
Ulnar nerves
7
Median nerves 9
10
increased in the ulnar groove, particularly in its lower part just proximal to the upper border of flexor carpi ulnaris. In the 2 most marked examples the total intrafascicular area was approximately doubled at this level, although the thickness of the perineurial sheath and epineurium was less increased (Fig. 1). The cross-sectional area of the whole nerve and the total intrafascicular area were measured at 3 levels for each of the 2 nerves, and are shown in Table 2, which also contains values for myelinated fibre density. It can be seen that the increased intrafascicular area at the level of the elbow produced a corresponding reduction in fibre density, when this is compared with values for the nerve proximal and distal to it. In 4 other ulnar nerves there was a slight increase in intrafascicular area at the elbow, and, in addition, the amount of perineurial and epineurial tissue was definitely increased compared with the appearances in proximal and distal sections. The severity of these interstitial changes showed little relation to the presence or absence of nerve fibre damage. For example, 1 of the 2 ulnar nerves with the marked increase in cross-sectional area in Table 2 showed nerve fibre changes while the other did not. In the case of the median nerve, transverse sections showed that the cross-sectional area was usually slightly increased under the flexor retinaculum compared with that of sections taken proximal to it. The cross-sectional area distal to the retinaculum could not be estimated as the nerve starts to divide into its digital branches at this level. The 2 median nerves showing the most marked increases in cross-sectional area are shown in Table 2, from which it can be seen that the increase was mainly due to perineurial and epineurial thickening, the intrafascicular area and fibre density showing less change. As for the ulnar nerve, there was little correlation with parenchymatous changes. Of the 2 median nerves in Table 2, for example, only 1 showed nerve fibre pathology.
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
287
Fig. 2. Case 10. Transverse sections of the median nerve. A : under the retinaculum to show numerous Renaut bodies; B: 2.5 cm proximal to the flexor retinaculum. Bar 200 #m.
A striking feature of both the median and ulnar nerves was the presence of Renaut bodies at the sites of entrapment. As an example, the median nerve of Case 10 is shown in Fig. 2. At the level of the flexor retinaculum each fascicle contained 1 or more Renaut bodies (Fig. 2A) whereas few were present in the section taken 2.5 cm proximal to this (Fig. 2B). Renaut bodies were seen at the site of entrapment in most of the median and ulnar nerves examined; their numbers showed no correlation with the presence or absence of nerve fibre damage.
288
D. NI!ARY, J. ()('HOA, R. W. GILL1AT7
Blood vessels Normal capillaries were present m the endoneurium and were also found togethe~ with small arterioles in the epineurium. No consistent differences were detected between the vessels at sites of entrapment and those elsewhere. In the older cases in particular, hyaline changes in the vessel walls were prominent at all levels studied. In some nerves, structures with features of both Renaut bodies and capillaries were occasionally seen at sites of entrapment. In such cases the absence of a definite lumen and the presence of some whorling made identification uncertain. Changes in myelinated nerve fibres In teased preparations it soon became clear that specimens taken within 24 hr of death showed good structural preservation, with minimal post-mortem change in the form of retraction of myelin from the nodes of Ranvier or swelling of SchmidtLanterman clefts. This was in contrast to specimens taken more than 24 hr after death, which showed irregularity of fibre contour and the formation of myelin ellipsoids, making proper assessment impossible. Such material has been excluded from the present study. In seeking evidence of nerve fibre damage, we were particularly influenced by the results of previous animal studies. In chronic median nerve compression in the guineapig, first described by Fullerton and Gilliatt (1967), the characteristic early change in myelinated fibres proximal to the site of entrapment consisted ofa polarised distortion of the internodes, which became bulbous at one end and tapered at the other (Anderson, Fullerton, Gilliatt, and Hern 1970). A similar distortion of the internodes but with a reversed polarity was subsequently demonstrated in fibres distal to the site of entrapment (Ochoa and Marotte 1973). This change appeared to lead to demyelination which was followed by remyelination, indicated by the presence of thinly-myelinated intercalated segments.
(;iiill
~ ~,i~~ii~ i ~~=?~)?ii~!~ ? ~ ii
iii)/ , ~
•
!i
i
:;'
~
~
iii;ii ii+
i ~ .....
Fig. 3. Case 11. Loosely-teased bundle of median nerve fibres from the region of the upper border of the flexor retinaculum, to show bulbous swellings of the proximal ends of the internodes. Bar 200/am.
289
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
A
PROX
i~ !i!i¸i~i~ ¸I •
.....
..................
~iill 2,_~
~i~! !!ili!• ¸ ~
i ¸
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i!!ii!,iiiii!B?i¸ ~ ~ii'i~i~i~ ~ !!~ ~!i! ~i~~ii
~
~ ~ ~ i(~i~~i~~, i'ii~iiii ~ ~i~
i ~!~ ~!~ i
ii~ i~I~
Fig. 4. Case 10. Median nerve. A: two consecutive nodes from a single fibre proximal to the flexor retinaculum; B: two consecutive nodes from a (different) single fibre distal to the upper border of the retinaculum. In each case the fibres are m o u n t e d with their proximal portions to the left• Bar 50 ~m.
On the basis of the animal results described above, we have paid particular attention to the following changes in the present study : (1) Bulbous swelling of one end of the internode, with or without thinning and retraction of the myelin at the opposite end. In some cases the swellings were present on many fibres in a single fascicle, the change having a constant polarity in different fibres (Fig. 3). The change could also be shown to affect successive internodes on a single fibre (Fig. 4A). On the opposite side of the suspected site of entrapment the polarity of the swellings would be reversed (Fig. 4B). (2) Demyelination and remyelination. In some nerve fibres showing bulbous swelling of one end of the internode, thinning and retraction of the myelin at the
290
D. NEARY, J. OCHOA, R. W. GILLIAIT
PROX
A
B
t2 Fig. 5. Case 10. Median nerve proximal to the flexor retinaculum. Three fibres with bulbous swellings to show: A : normal myelin thickness proximal to node of Ranvier; B: demyelination proximal to node: C: part of an intercalated segment, with thin myelin and prominent Schmidt Lantermann incisures, proximal to node. Bar 50 itm.
opposite end appeared to lead to complete myelin loss extending for a variable distance from the node of Ranvier (Fig. 5B). Remyelination, with the formation of intercalated segments, was also seen. Short intercalated segments can occasionally occur in apparently normal nerves (Lubinska 1958: Lascelles and Thomas 1966: Fullerton 1969) but in the present material they were situated either on fibres which also showed bulbar swellings (Fig. 5C) or on other fibres at the same level (Fig. 6). When several thinly-myelinated intercalated segments were present on a single fibre, separated by regions of apparently normal myelin, as in Fig. 6, it was presumed that there had been previous paranodal demyelination affecting successive internodes. Results for the 24 nerves are shown in Table 3, and it can be seen that bulbous swellings having a consistent polarity in different fibres, and sometimes accompanied by intercalated segments, were seen in 5 ulnar and 5 median nerves. In all cases the
SUB-CLINICAL
ENTRAPMENT
NEUROPATHY
291
IN MAN
F i g . 6. C a s e 9. U l n a r n e r v e a t t h e e l b o w . T w o i n t e r c a l a t e d s e g m e n t s f r o m t h e s a m e f i b r e m o u n t e d o n e b e l o w t h e o t h e r . 0.8 m m o f n o r m a l m y e l i n s e p a r a t i n g t h e t w o p o r t i o n s h a s b e e n o m i t t e d . B a r 50 # m .
TABLE
3
INCIDENCE OF NERVE FIBRE PATHOLOGY IN MEDIAN NERVE (UNDER FLEXOR RETINACULUM) AND IN ULNAR NERVE (AT ELBOW)
Case No.
Age (years)
Median nerve bulbous swellings
Ulnar nerve
intercalated segments
bulbous swellings
intercalated segments
1
73
-
-
+
+
2
63
+
+
+
-
3 4 5
59 60 36
. + .
-
-
6 7
80 60
. .
8 9 10 11 12
84 40 39 61 51
+ + + -
+ + +
+ -
.
.
.
.
.
.
. .
. .
. .
+
+ -
abnormalities were localised to the elbow region in the ulnar nerve and to the region of the flexor retinaculum in the median nerve. Reversal of polarity of the swellings on the opposite sides of the lesions was seen in all specimens except for 2 ulnar nerves which were taken early in the series, in which the specimen did not include the portion of the nerve under the upper border of flexor carpi ulnaris. If the point of reversal of polarity is taken to indicate the centre of the lesion,this appeared to lie, in the case of the ulnar nerve, under the tendinous arch joining the ulnar and humeral origins of m. flexor carpi ulnaris, the lesion extending for 1-2 cm on either side of it. This localisation fits well with the macroscopic appearances
292
D. NEARY, J. OCHOA, R. W. GILLIATT
observed at o p e r a t i o n by Feindel a n d Stratford (1958) a n d by O s b o r n e (1959) in patients with u l n a r nerve lesions t h o u g h t to be due to e n t r a p m e n t at this level. In the case of the m e d i a n nerve, the site of the lesion and its extent were m o r e variable. In 2 cases the lesion was clearly centred u n d e r the u p p e r edge of the flexor r e t i n a c u l u m , 2(3
20
B
bo %,
,o m
20
..0
E I0 ..Q u_
D i a m e t e r (#m)
Fig. 7. Case 9. On the left, enlarged portions of transverse sections of ulnar nerve shown in Fig. 1. On the right, histograms of fibre diameter from the same sections. A : proximal to the elbow; B: in the ulnar groove ; C: distal to the elbow. Bar 50 #m.
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
293
extending 1-2 cm above and below this point. In the remaining 3 cases the bulbous swellings extended for at least 1 cm above and below the retinaculum, suggesting a long lesion, 4-5 cm in length. Owing to the difficulty of obtaining single fibres in continuity from such a long length of nerve, the exact po;nt of reversal under the retinaculum could not be established. Quantitative studies of transverse sections Teased fibre preparations do not allow a very satisfactory assessment of the extent or severity of a pathological process, as only a small proportion of the myelinated fibres in a nerve trunk can be examined. Further information has therefore been obtained from quantitative studies of transverse sections. Fibre diameter histograms were prepared from transverse sections taken at different levels in 2 nerves which had shown marked changes in teased fibres. The results for the ulnar nerve of Case 9 are shown in Fig. 7, and it can be seen that although the myelinated fibre density was grossly reduced in the ulnar groove, the fibre diameter spectrum remained normal. A few fibres with inappropriately thin myelin sheaths were present at the level of the elbow (Fig. 7B) but there was no osmiophilic debris to suggest degeneration either at this level or distal to it. Thus it seems likely that the markedly reduced myelinated fibre density was due to fibre dispersion in the swollen fascicles, rather than to demyelination or degeneration. This interpretation is supported by the fact that further distally fibre density returned to a figure similar to that in the nerve proximal to the lesion (See Table 2). In transverse sections of the median nerve of Case 10, taken at the level of the lesion, there was again little demyelination or degeneration and fibre density was not reduced more than would be expected from the increased intrafascicular area (see Table 2). The fibre diameter histogram was normal. From these results it appears that in both the nerves described above, the changes observed in single fibres, while sufficient to indicate the presence of a local lesion, had not led to significant fibre loss. Clusters of thinly-myelinated fibres in transverse sections are generally recognised as evidence of regeneration (Schr6der 1968; Ochoa and Mair 1969; Ochoa 1970; Thomas 1970). In the present material occasional clusters were seen in the ulnar and median nerves examined. Since, however, they were present in the proximal parts of the nerves as well as distally, their relation to the localised changes at the elbow and wrist is uncertain. Acute nerve compression One median nerve in the series appeared to show the changes of acute compression. The patient (Case 5) was a 30-year-old man who died of intracerebral haemorrhage. For several hours before death he had been in a state of decorticate rigidity, with extension of the elbows and flexion of the wrists. This posture, which was maintained after death, appeared to have resulted in pressure on the median nerve under the distal part of the flexor retinaculum. The nerve was not macroscopically abnormal but loosely teased bundles showed abnormalities extending over a distance of approximately 7 mm. Single fibres showed the characteristic changes seen previously after
294
D. NEARY, J. OCHOA, R. W. (;ILL1Aq]'
site
of compression
A
B
j
B
n
Fig. 8. Case 5. Single fibres from the median nerve under the distal part of the flexor retinaculum, to show displacement of the nodes of Ranvier. i = Sehwann cell junction; n = new position of node. Bar 30/~m.
acute compression in experimental animals (Ochoa, Fowler and Gilliatt 1972). These consisted of displacement of the nodes of Ranvier from their normal positions under
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
295
the Schwann cell junctions, the direction of displacement being away from the presumed site of compression. Examples are shown in Fig. 8, in which the original sites of the nodes can be identified by indentations of the myelin under the Schwann cell junctions 0'). The new positions of the nodes are labelled n and indicate displacement away from the centre of the lesion. It can also be seen that the displacement has caused distortion and partial rupture of the paranodal myelin. As in the previous study, these light-microscopic appearances were confirmed by electron microscopy. No demyelination had occurred, suggesting that the lesion was only a few days old. An early cellular reaction was present, indicating that the lesion had occurred during life.
DISCUSSION
The present study of a group of patients without known peripheral nerve disease has shown that pathological changes at two common sites of entrapment were present in a high proportion. Comparable changes were not present at other levels in the nerves studied. The changes themselves were of considerable interest. In the first place, there were interstitial changes affecting the endoneurium, the perineurium and epineurium. Enlargement of the ulnar nerve at the elbow has been found previously in routine necropsy examinations by Chang, Low, Chan, Chuang and Pooh (1963) who commented that this was due to "an absolute increase of the connective tissue in both the extra-funicular and intra-funicular areas". Similar changes have been described in the nerve to teres minor (Gitlin 1957) and in the lateral cutaneous nerve of the thigh (Nathan 1960). In the median nerve Sunderland and Bradley (1952) observed a relative increase in perineurial thickness at the wrist as compared with the axilla; in 1 case this was accompanied by swelling of the whole nerve. In none of these cases did the authors associate the changes with nerve fibre damage. Our finding of Renaut bodies localised to the sites of entrapment is in keeping with the experience of others. The literature on Renaut bodies has recently been reviewed by Asbury (1973) who concludes that while they may be found in otherwise normal nerves, "they occur more frequently in nerve trunks normally subject to some compression, such as the digital nerves of the feet, the median nerve at the wrist, and the brachial plexus". Their presence in compressive neuropathies has been emphasised by Krficke (1955). Distinct from the interstitial changes described above, and not necessarily occurring in the same nerves, were parenchymatous changes, best seen in teased nerve fibres. The appearance of the internodes was altered, due to bulbous swelling at one end and thinning and retraction of myelin at the other; in some nerves intercalated segments indicative of previous demyelination were also present. The changes were much more difficult to detect in transverse sections and it is not surprising that, without the additional information provided by teased fibres, previous authors have noted the connective tissue changes without commenting on abnormalities of the nerve fibres themselves. What is the significance of the changed configuration of the internodes which we
296
1). NEARY. J, ( ) ( : H O A , R. W . (;ILI.1AT-I
have found in teased fibres'? From previous studies of the guinea-pig this would seem to be the earliest change to occur in nerve fibres subject to chronic or recurren! compression: demyelination was seen when this process was advanced but not m ils early stages (Ochoa and Marotte 1973). In the guinea-pig model, electron microscope studies of single fibres indicated that the distortion of the internodes resulted from slippage of myelin lamellae away from the site of the pressure, the bulbous ends of the internodes consisting of redundant folds of myelin. This process was followed by demyelination of the axon, beginning in each internode at the end nearer to the ccnlre of the lesion. Owing to the presence of postmortem artefact, electron-microscopic studies of the present material proved more difficult, but in 1 median nerve (frona Case 8) it was possible to confirm the main ultrastructural features of the guinea-pig model. The findings in this nerve will be described in detail elsewhere. The actual cause of myelin slippage is uncertain. Ochoa and Marotte (1973) suggested that it might be the result of recurrent trauma or pressure sufficient 1o cause detachment of the inner myelin lamellae. The concept of intermittent or recurrent pressure is an attractive one since sustained pressure over a prolonged period appears to produce a different histological picture (Duncan 1948 ; Aguayo, Nair and Midgley 1971}. Sustained pressure sufficient to produce an acute lesion within 1 2 hr results in yet another type of lesion with displacement of the nodes of Ranvier (Ochoa et al. 1972). This latter change is easily identifiable in single fibres and is quite distinct from the chronic lesion seen in guinea-pigs and in the majority of the present cases. There was however, 1 example of the acute lesion in the present series (Case 5) and it is interesting that this occurred under the flexor retinaculum where the chronic type of change would be expected. This raises the question as to whether both types of pathological lesion may not occur in entrapment syndromes. Since both lead to paranodal or segmental demyelination, the end-result would be similar. There is some support for this concept from clinical studies. For example, Payan (1970) found that a proportion of chronic ulnar nerve lesions requiring decompression had begun as acute lesions following a single identifiable episode of compression. When our present findings are compared with the guinea-pig material of Ochoa and Marotte (1973), and with the few histological studies which have been made of human entrapment lesions, it seems likely that the mild changes seen in the present series represent the earliest stage of a compressive lesion, before much demyelination or degeneration has followed. This early picture may be contrasted with the median nerve lesion described by Thomas and Fullerton (1963) from a patient with the carpal tunnel syndrome, in which there was a marked change in the fibre diameter histogram, not only under the flexor retinaculum, but also distal to it. Even grosser changes were described by Marie and Foix (1913) in their specimen. Further studies of nerves from patients with known entrapment lesions would clearly be of considerable interest. ACKNOWLEDGEMENTS
We wish to thank Mrs. M. A. Nylk and Mr. H. Long for technical assistance. We are also grateful to Dr. Rosemary Eames for helpful criticism and discussion.
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
297
SUMMARY
Twelve median and 12 ulnar nerves were obtained at routine autopsies from patients without known disease of the peripheral nervous system. Enlargement of cross-sectional area due to an increase in connective tissue elements was commonly present in the ulnar nerve at the elbow and in the median nerve under the flexor retinaculum. Renaut bodies were also prominent at these two sites. The connective tissue changes did not appear to be related to the presence or absence of nerve fibre damage. When nerve fibres were teased apart and examined individually, localised changes were found at the elbow in 5 ulnar nerves and under the flexor retinaculum in 5 median nerves. The changes were mild and transverse sections at the same levels showed few abnormalities. However, the changes were similar in character to those described previously in experimental animals with entrapment syndromes. They are therefore considered to be valid evidence of sub-clinical entrapment in apparently unaffected human subjects. REFERENCES AGUAYO. A., C. P. U. NAIR AND R. MIDGLEY (1971) Experimental progressive compression neuropathy in the rabbit, Arch. Neurol. (Chic.j, 24:357 364. ANDERSON, M. H., P. M. FULLERTON, R. W. GILUATr AND J. E. C. HERN (1970) Changes in the forearm associated with median nerve compression at the wrist in the guinea-pig, J. Neurol. Neurosurg. Psychiat., 33 : 7(~79. ASBURV,A. K. (1973) Renaut bodies. A forgotten endoneurial structure. J. Neuropath. exp. Neurol., 32: 2, 334-343. CHANG, K. S. F., W. D. Low, S. T. CHAN, ADSON CHUANGAND K. T. POON (1963) Enlargement of the ulnar nerve behind the medial epicondyle, Anat. Rec., 145: 149-153. DUNCAN, D. (1948) Alterations in the structure of nerves caused by restricting their growth with ligatures, J. Neuropath. exp. Neurol., 7: 261-273. EsPm, M. L. E. AND D. T, C. HARDING (1961) Apparatus for measuring and counting myelinated nerve fibres, J, Neurol. Neurosurg. Psychiat., 24: 287-290. FEINDEL, W. AND J. STRATFORD(1958) The role of the cubital tunnel in tardy ulnar palsy, Canad. J. Surg., 1: 287-300. FULLERTON, P. M. (1969) Electrophysiological and histological observations on peripheral nerves in acrylamide poisoning in man, J. Neurol. Neurosurg. Psychiat., 32: 186-192. FULLERTON, P. M. AND R. W. GILLIATT (1967) Median and ulnar neuropathy in the guinea-pig, J. NeuroL Neurosurg. PsTchiat,, 30: 393402. GITLXN, G. (1957) Concerning the gangliform enlargement ("pseudoganglion") on the nerve to the teres minor muscle, J. Anat. (Lond.), 91 : 466-470. KR~CKE, W. (1955) Erkrankungen der peripheren Nerven. In: O. LUBARSCH,F. HENKE AND R. R6SSLE (Eds.), Handbuch der speziellen pathologischen Anatomie und Histolo#ie, Vol. 13 (Nercensvstem). Part 5 [Erkrankungen des peripheren und vegetativen Nervensystems), Springer, Berlin, pp. 35 36. LASCELLES, R. G. AND P. K. THOMAS(1966) Changes due to age in internodal length in the sural nerve in man, J. Neurol. Neurosurg. Psychiat., 29: 40~4. LUBINSKA, L. (1958) "Intercalated" internodes in nerve fibres, Nature (Lond.j, 181: 957-958. MArnE, P. AND C. Forx (1913) Atrophic isol6e de l'6minence th6nar d'origine neuritique, r61e du ligament annulaire ant6rieur du carpe dans la pathog6nie de la 16sion, Rev. neurol., 21 (ii), 647. NATHAN, H. (1960) Gangliform enlargement on the lateral cutaneous nerve of the thigh, J. Neurosurg., 17 : 843-849. OCHOA, J. (1970) Isoniazid neuropathy in man : quantitative electron microscope study, Brain, 93 : 831-850. OCHOA, J. (1972) Ultrathin longitudinal sections of single myelinated fibres for electron microscopy, J. neurol. Sci., 17:103 106. OCHOA, J. AND W. G. P. MAre (1969) The normal sural nerve in man, Part 2 (Changes in the axons and Schwann cells due to ageing), Acta neuropath. (BerL), 13: 217-239.
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OCHOA, J. AND [,. MAROTTE (1973) The nature of the nerve lesion caused by chronic entrapment in the: guinea-pig, J. neurol. Sci., 19:491-495 OCHOA, J., T. J. FOWLERAND R. W. GILLIATT (1972) Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet, J. Anat. (Lond.), 113: 3, 433-455. OSBORNE, G. V, (1959) Ulnar neuritis. Postyrad. reed. J., 35:392--396 PAYAN, J. (1969) Electrophysiological localisation of ulnar nerve lesions, J. Neurol. Neurosur#, Psvchiat.. 32 : 208-220. PAYAN, J. (1970) Anterior transposition of the ulnar nerve: an electromyographical study, J. Neurol. Neurosur 9. Psychiat., 33: 157- 165. SCHRODER, J. M. (I 968) Die Hyperneurotisation Bungnerscher B~inder bei der expefimentellen lsoniazidNeuropathie: Phasenkontrast- und elektronen-mikroskopisehe Untersuehungen. Virchows Arch. path. Anat., Abt. B (Zellpath.), 1: 131-156. SUNDERLAND, S. aYl~ K. C. BRADLEY (1952) The perineurium of peripheral nerves, Anat. Rec.. 113: 2. 125-141. THOMAS, P. K. (1970) The cellular response to nerve injury, Part 3 (The effect of repeated crush injuries), J. Anat. (Lond.), 106: 463~70. THOMAS, P. K. AND P. M. FULLERrO~ (1963) Nerve fibre size in the carpal tunnel syndrome, J. Neurol. Neurosur,q. Psychiat., 26 : 520- 527.
283
,~ Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Sub-clinical Entrapment Neuropathy in Man D. NEARY, J. OCHOA* AND R. W. GILLIATT Institute of Neurology and the National Hospital for Nervous Diseases, Queen Square, London WC1N3BG (Great Britain) (Received 17 July, 1974)
I NTRODUCTION
As a result of the increasing sensitivity of electrophysiological techniques, nerve conduction studies may sometimes suggest a mild entrapment lesion in a nerve which is clinically normal. In patients with unilateral ulnar nerve lesions, for example, Payan (1969) found several examples of abnormal sensory conduction in the clinically unaffected nerve of the opposite arm. In order to look for anatomical evidence of sub-clinical entrapment, we have obtained peripheral nerves at routine autopsies on patients without known disease of the peripheral nervous system. The present paper describes our preliminary findings in relation to the median nerve at the wrist and the ulnar nerve at the elbow. MATERIAL AND METHODS
Nerves were taken from patients undergoing routine autopsies at the Middlesex Hospital, University College Hospital, and St. Pancras Coroner's Court, as well as at the National Hospital, Queen Square. Those suffering from general medical or neurological disorders which might affect the peripheral nervous system were excluded. All nerves were obtained within 24 hr of the stated time of death; in 2 cases, nerves were obtained within 8 hr. The present paper is based on the findings in 12 median and 12 ulnar nerves; the cause of death in each case is shown in Table 1. The median nerve and its digital branches were exposed from the lower forearm to the palm, the site of the upper border of the flexor retinaculum being marked by a stitch in the epineurium. The length of nerve removed, including the digital branches, was approximately 15 cm. After removal, the specimen was gently stretched on a perspex frame by nylon threads stitched through the epineurium at either end. The This work was carried out while J. Ochoa was holding a Wellcome Senior Research Fellowship. Support from the Brain Research Trust is also gratefully acknowledged. * Present address: Division of Neurology, Dartmouth Medical School~ Hanover, N.H., U.S.A.
284
D. NEARY, J. OCHOA, R. W. GILLIATJ ]['ABLE
I
( A U S E 0 1 DI'iA I H IN PATIENTS STUI)IF.I)
Case No. 1 2 3 4 5 6 7 8 9 10 11 12
Age (years)
Sex
Cause o[ death
73 63 59 60 36 80 60 84 40 39 61 51
M M M F M M M F M F M M
hypertension hypertension myelofibrosis coronary thrombosis cerebral haemorrhage coronary thrombosis coronary thrombosis coronary thrombosis cerebral glioma cerebral atrophy coronary thrombosis coronary thrombosis
ulnar nerve was exposed throughout its course at the elbow and for 5 7 cm above it. The point at which the nerve passed deep to the origin of flexor carpi ulnaris to enter the cubital tunnel was marked by a stitch in the epineurium. A length of approximately 15 cm was removed and mounted in the same way as the median nerve. Nerves were fixed in buffered glutaraldehyde (4~o) at pH 7.4 for 3 4 hr. During this time the specimens were further divided and excess epineurium was removed. After treating with 1~o osmium tetroxide in buffered veronal acetate for 3 hr, the nerves were dehydrated, transferred to fluid Epoxyresin (Epon) and stored at - 15°C. Single myelinated fibres from some portions of the nerves were teased apart in fluid Epon, examined under the light microscope and photographed. Selected single fibres were prepared for electron microscopy as described by Ochoa (1972). Other portions of nerve were transferred to fresh Epon and embedded: from these blocks, 1-/~m transverse sections were cut on an ultramicrotome and stained with 1~0 toluidine blue. Additional sections were taken for electron microscopy. For the estimation of fibre density, photographic prints were obtained at a magnification of x 1000. From these, areas were selected at random, on which total fibre counts and measurements of fibre diameter were made. For the latter a modification of the counter originally devised by Espir and Harding (1961) was used. Four fascicles were sampled from each nerve, and not less than 300 fibres were counted in each case. RESULTS
Macroscopic appearances Most of the ulnar nerves showed some enlargement in the ulnar groove compared with the nerve proximal and distal to it. However, this was not more marked in those with nerve fibre damage than in those without it. In the case of the median nerve there was no visible swelling at the wrist or under the flexor retinaculum but the nerve was usually flattened in this region.
Interstitial changes In the ulnar nerve transverse sections confirmed that the cross-sectional area was
S U B - C L I N I C A L E N T R A P M E N T N E U R O P A T H Y IN MAN
285
I II W
Fig. 1. Case 9. T r a n s v e r s e sections of the u l n a r nerve. A : 6 cm p r o x i m a l to the e l b o w ; B : in the u l n a r g r o o v e at the e l b o w ; C : 4 cm distal to the elbow. Bar 1 mm.
286
o. NEARY, J. O('HOA, R. W. (HLLIATq TABLE 2
C R O S S - S E C T I O N A L AREA OF W H O L E NERVE, T O T A L I N T R A F A S C I C U L A R AREA A N D M Y E I d N A T E I ) FIP, RI- I ) k N S l l 5
"~
D I F F E R E N T LEVELS
Case No.
Level
Area of whole nerve ( mm 2)
lntrajascicular area (ram z )
Fibre density (fibre.~/mm 2 j
proximal elbow distal
6.0 10.3 5.7
3.9 8.7 3.4
6,500 3.900 6.700
proximal elbow distal
5.3 12.8 6.4
4.3 9.8 3.9
9,900 3,900 8,000
proximal wrist
5.9 10.9
4.0 5.4
7,400 6,500
proximal wrist
5.0 9.6
3.8 5.5
9,600 7,400
Ulnar nerves
7
Median nerves 9
10
increased in the ulnar groove, particularly in its lower part just proximal to the upper border of flexor carpi ulnaris. In the 2 most marked examples the total intrafascicular area was approximately doubled at this level, although the thickness of the perineurial sheath and epineurium was less increased (Fig. 1). The cross-sectional area of the whole nerve and the total intrafascicular area were measured at 3 levels for each of the 2 nerves, and are shown in Table 2, which also contains values for myelinated fibre density. It can be seen that the increased intrafascicular area at the level of the elbow produced a corresponding reduction in fibre density, when this is compared with values for the nerve proximal and distal to it. In 4 other ulnar nerves there was a slight increase in intrafascicular area at the elbow, and, in addition, the amount of perineurial and epineurial tissue was definitely increased compared with the appearances in proximal and distal sections. The severity of these interstitial changes showed little relation to the presence or absence of nerve fibre damage. For example, 1 of the 2 ulnar nerves with the marked increase in cross-sectional area in Table 2 showed nerve fibre changes while the other did not. In the case of the median nerve, transverse sections showed that the cross-sectional area was usually slightly increased under the flexor retinaculum compared with that of sections taken proximal to it. The cross-sectional area distal to the retinaculum could not be estimated as the nerve starts to divide into its digital branches at this level. The 2 median nerves showing the most marked increases in cross-sectional area are shown in Table 2, from which it can be seen that the increase was mainly due to perineurial and epineurial thickening, the intrafascicular area and fibre density showing less change. As for the ulnar nerve, there was little correlation with parenchymatous changes. Of the 2 median nerves in Table 2, for example, only 1 showed nerve fibre pathology.
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
287
Fig. 2. Case 10. Transverse sections of the median nerve. A : under the retinaculum to show numerous Renaut bodies; B: 2.5 cm proximal to the flexor retinaculum. Bar 200 #m.
A striking feature of both the median and ulnar nerves was the presence of Renaut bodies at the sites of entrapment. As an example, the median nerve of Case 10 is shown in Fig. 2. At the level of the flexor retinaculum each fascicle contained 1 or more Renaut bodies (Fig. 2A) whereas few were present in the section taken 2.5 cm proximal to this (Fig. 2B). Renaut bodies were seen at the site of entrapment in most of the median and ulnar nerves examined; their numbers showed no correlation with the presence or absence of nerve fibre damage.
288
D. NI!ARY, J. ()('HOA, R. W. GILL1AT7
Blood vessels Normal capillaries were present m the endoneurium and were also found togethe~ with small arterioles in the epineurium. No consistent differences were detected between the vessels at sites of entrapment and those elsewhere. In the older cases in particular, hyaline changes in the vessel walls were prominent at all levels studied. In some nerves, structures with features of both Renaut bodies and capillaries were occasionally seen at sites of entrapment. In such cases the absence of a definite lumen and the presence of some whorling made identification uncertain. Changes in myelinated nerve fibres In teased preparations it soon became clear that specimens taken within 24 hr of death showed good structural preservation, with minimal post-mortem change in the form of retraction of myelin from the nodes of Ranvier or swelling of SchmidtLanterman clefts. This was in contrast to specimens taken more than 24 hr after death, which showed irregularity of fibre contour and the formation of myelin ellipsoids, making proper assessment impossible. Such material has been excluded from the present study. In seeking evidence of nerve fibre damage, we were particularly influenced by the results of previous animal studies. In chronic median nerve compression in the guineapig, first described by Fullerton and Gilliatt (1967), the characteristic early change in myelinated fibres proximal to the site of entrapment consisted ofa polarised distortion of the internodes, which became bulbous at one end and tapered at the other (Anderson, Fullerton, Gilliatt, and Hern 1970). A similar distortion of the internodes but with a reversed polarity was subsequently demonstrated in fibres distal to the site of entrapment (Ochoa and Marotte 1973). This change appeared to lead to demyelination which was followed by remyelination, indicated by the presence of thinly-myelinated intercalated segments.
(;iiill
~ ~,i~~ii~ i ~~=?~)?ii~!~ ? ~ ii
iii)/ , ~
•
!i
i
:;'
~
~
iii;ii ii+
i ~ .....
Fig. 3. Case 11. Loosely-teased bundle of median nerve fibres from the region of the upper border of the flexor retinaculum, to show bulbous swellings of the proximal ends of the internodes. Bar 200/am.
289
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
A
PROX
i~ !i!i¸i~i~ ¸I •
.....
..................
~iill 2,_~
~i~! !!ili!• ¸ ~
i ¸
~i~ ~
~
~
i!!ii!,iiiii!B?i¸ ~ ~ii'i~i~i~ ~ !!~ ~!i! ~i~~ii
~
~ ~ ~ i(~i~~i~~, i'ii~iiii ~ ~i~
i ~!~ ~!~ i
ii~ i~I~
Fig. 4. Case 10. Median nerve. A: two consecutive nodes from a single fibre proximal to the flexor retinaculum; B: two consecutive nodes from a (different) single fibre distal to the upper border of the retinaculum. In each case the fibres are m o u n t e d with their proximal portions to the left• Bar 50 ~m.
On the basis of the animal results described above, we have paid particular attention to the following changes in the present study : (1) Bulbous swelling of one end of the internode, with or without thinning and retraction of the myelin at the opposite end. In some cases the swellings were present on many fibres in a single fascicle, the change having a constant polarity in different fibres (Fig. 3). The change could also be shown to affect successive internodes on a single fibre (Fig. 4A). On the opposite side of the suspected site of entrapment the polarity of the swellings would be reversed (Fig. 4B). (2) Demyelination and remyelination. In some nerve fibres showing bulbous swelling of one end of the internode, thinning and retraction of the myelin at the
290
D. NEARY, J. OCHOA, R. W. GILLIAIT
PROX
A
B
t2 Fig. 5. Case 10. Median nerve proximal to the flexor retinaculum. Three fibres with bulbous swellings to show: A : normal myelin thickness proximal to node of Ranvier; B: demyelination proximal to node: C: part of an intercalated segment, with thin myelin and prominent Schmidt Lantermann incisures, proximal to node. Bar 50 itm.
opposite end appeared to lead to complete myelin loss extending for a variable distance from the node of Ranvier (Fig. 5B). Remyelination, with the formation of intercalated segments, was also seen. Short intercalated segments can occasionally occur in apparently normal nerves (Lubinska 1958: Lascelles and Thomas 1966: Fullerton 1969) but in the present material they were situated either on fibres which also showed bulbar swellings (Fig. 5C) or on other fibres at the same level (Fig. 6). When several thinly-myelinated intercalated segments were present on a single fibre, separated by regions of apparently normal myelin, as in Fig. 6, it was presumed that there had been previous paranodal demyelination affecting successive internodes. Results for the 24 nerves are shown in Table 3, and it can be seen that bulbous swellings having a consistent polarity in different fibres, and sometimes accompanied by intercalated segments, were seen in 5 ulnar and 5 median nerves. In all cases the
SUB-CLINICAL
ENTRAPMENT
NEUROPATHY
291
IN MAN
F i g . 6. C a s e 9. U l n a r n e r v e a t t h e e l b o w . T w o i n t e r c a l a t e d s e g m e n t s f r o m t h e s a m e f i b r e m o u n t e d o n e b e l o w t h e o t h e r . 0.8 m m o f n o r m a l m y e l i n s e p a r a t i n g t h e t w o p o r t i o n s h a s b e e n o m i t t e d . B a r 50 # m .
TABLE
3
INCIDENCE OF NERVE FIBRE PATHOLOGY IN MEDIAN NERVE (UNDER FLEXOR RETINACULUM) AND IN ULNAR NERVE (AT ELBOW)
Case No.
Age (years)
Median nerve bulbous swellings
Ulnar nerve
intercalated segments
bulbous swellings
intercalated segments
1
73
-
-
+
+
2
63
+
+
+
-
3 4 5
59 60 36
. + .
-
-
6 7
80 60
. .
8 9 10 11 12
84 40 39 61 51
+ + + -
+ + +
+ -
.
.
.
.
.
.
. .
. .
. .
+
+ -
abnormalities were localised to the elbow region in the ulnar nerve and to the region of the flexor retinaculum in the median nerve. Reversal of polarity of the swellings on the opposite sides of the lesions was seen in all specimens except for 2 ulnar nerves which were taken early in the series, in which the specimen did not include the portion of the nerve under the upper border of flexor carpi ulnaris. If the point of reversal of polarity is taken to indicate the centre of the lesion,this appeared to lie, in the case of the ulnar nerve, under the tendinous arch joining the ulnar and humeral origins of m. flexor carpi ulnaris, the lesion extending for 1-2 cm on either side of it. This localisation fits well with the macroscopic appearances
292
D. NEARY, J. OCHOA, R. W. GILLIATT
observed at o p e r a t i o n by Feindel a n d Stratford (1958) a n d by O s b o r n e (1959) in patients with u l n a r nerve lesions t h o u g h t to be due to e n t r a p m e n t at this level. In the case of the m e d i a n nerve, the site of the lesion and its extent were m o r e variable. In 2 cases the lesion was clearly centred u n d e r the u p p e r edge of the flexor r e t i n a c u l u m , 2(3
20
B
bo %,
,o m
20
..0
E I0 ..Q u_
D i a m e t e r (#m)
Fig. 7. Case 9. On the left, enlarged portions of transverse sections of ulnar nerve shown in Fig. 1. On the right, histograms of fibre diameter from the same sections. A : proximal to the elbow; B: in the ulnar groove ; C: distal to the elbow. Bar 50 #m.
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
293
extending 1-2 cm above and below this point. In the remaining 3 cases the bulbous swellings extended for at least 1 cm above and below the retinaculum, suggesting a long lesion, 4-5 cm in length. Owing to the difficulty of obtaining single fibres in continuity from such a long length of nerve, the exact po;nt of reversal under the retinaculum could not be established. Quantitative studies of transverse sections Teased fibre preparations do not allow a very satisfactory assessment of the extent or severity of a pathological process, as only a small proportion of the myelinated fibres in a nerve trunk can be examined. Further information has therefore been obtained from quantitative studies of transverse sections. Fibre diameter histograms were prepared from transverse sections taken at different levels in 2 nerves which had shown marked changes in teased fibres. The results for the ulnar nerve of Case 9 are shown in Fig. 7, and it can be seen that although the myelinated fibre density was grossly reduced in the ulnar groove, the fibre diameter spectrum remained normal. A few fibres with inappropriately thin myelin sheaths were present at the level of the elbow (Fig. 7B) but there was no osmiophilic debris to suggest degeneration either at this level or distal to it. Thus it seems likely that the markedly reduced myelinated fibre density was due to fibre dispersion in the swollen fascicles, rather than to demyelination or degeneration. This interpretation is supported by the fact that further distally fibre density returned to a figure similar to that in the nerve proximal to the lesion (See Table 2). In transverse sections of the median nerve of Case 10, taken at the level of the lesion, there was again little demyelination or degeneration and fibre density was not reduced more than would be expected from the increased intrafascicular area (see Table 2). The fibre diameter histogram was normal. From these results it appears that in both the nerves described above, the changes observed in single fibres, while sufficient to indicate the presence of a local lesion, had not led to significant fibre loss. Clusters of thinly-myelinated fibres in transverse sections are generally recognised as evidence of regeneration (Schr6der 1968; Ochoa and Mair 1969; Ochoa 1970; Thomas 1970). In the present material occasional clusters were seen in the ulnar and median nerves examined. Since, however, they were present in the proximal parts of the nerves as well as distally, their relation to the localised changes at the elbow and wrist is uncertain. Acute nerve compression One median nerve in the series appeared to show the changes of acute compression. The patient (Case 5) was a 30-year-old man who died of intracerebral haemorrhage. For several hours before death he had been in a state of decorticate rigidity, with extension of the elbows and flexion of the wrists. This posture, which was maintained after death, appeared to have resulted in pressure on the median nerve under the distal part of the flexor retinaculum. The nerve was not macroscopically abnormal but loosely teased bundles showed abnormalities extending over a distance of approximately 7 mm. Single fibres showed the characteristic changes seen previously after
294
D. NEARY, J. OCHOA, R. W. (;ILL1Aq]'
site
of compression
A
B
j
B
n
Fig. 8. Case 5. Single fibres from the median nerve under the distal part of the flexor retinaculum, to show displacement of the nodes of Ranvier. i = Sehwann cell junction; n = new position of node. Bar 30/~m.
acute compression in experimental animals (Ochoa, Fowler and Gilliatt 1972). These consisted of displacement of the nodes of Ranvier from their normal positions under
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
295
the Schwann cell junctions, the direction of displacement being away from the presumed site of compression. Examples are shown in Fig. 8, in which the original sites of the nodes can be identified by indentations of the myelin under the Schwann cell junctions 0'). The new positions of the nodes are labelled n and indicate displacement away from the centre of the lesion. It can also be seen that the displacement has caused distortion and partial rupture of the paranodal myelin. As in the previous study, these light-microscopic appearances were confirmed by electron microscopy. No demyelination had occurred, suggesting that the lesion was only a few days old. An early cellular reaction was present, indicating that the lesion had occurred during life.
DISCUSSION
The present study of a group of patients without known peripheral nerve disease has shown that pathological changes at two common sites of entrapment were present in a high proportion. Comparable changes were not present at other levels in the nerves studied. The changes themselves were of considerable interest. In the first place, there were interstitial changes affecting the endoneurium, the perineurium and epineurium. Enlargement of the ulnar nerve at the elbow has been found previously in routine necropsy examinations by Chang, Low, Chan, Chuang and Pooh (1963) who commented that this was due to "an absolute increase of the connective tissue in both the extra-funicular and intra-funicular areas". Similar changes have been described in the nerve to teres minor (Gitlin 1957) and in the lateral cutaneous nerve of the thigh (Nathan 1960). In the median nerve Sunderland and Bradley (1952) observed a relative increase in perineurial thickness at the wrist as compared with the axilla; in 1 case this was accompanied by swelling of the whole nerve. In none of these cases did the authors associate the changes with nerve fibre damage. Our finding of Renaut bodies localised to the sites of entrapment is in keeping with the experience of others. The literature on Renaut bodies has recently been reviewed by Asbury (1973) who concludes that while they may be found in otherwise normal nerves, "they occur more frequently in nerve trunks normally subject to some compression, such as the digital nerves of the feet, the median nerve at the wrist, and the brachial plexus". Their presence in compressive neuropathies has been emphasised by Krficke (1955). Distinct from the interstitial changes described above, and not necessarily occurring in the same nerves, were parenchymatous changes, best seen in teased nerve fibres. The appearance of the internodes was altered, due to bulbous swelling at one end and thinning and retraction of myelin at the other; in some nerves intercalated segments indicative of previous demyelination were also present. The changes were much more difficult to detect in transverse sections and it is not surprising that, without the additional information provided by teased fibres, previous authors have noted the connective tissue changes without commenting on abnormalities of the nerve fibres themselves. What is the significance of the changed configuration of the internodes which we
296
1). NEARY. J, ( ) ( : H O A , R. W . (;ILI.1AT-I
have found in teased fibres'? From previous studies of the guinea-pig this would seem to be the earliest change to occur in nerve fibres subject to chronic or recurren! compression: demyelination was seen when this process was advanced but not m ils early stages (Ochoa and Marotte 1973). In the guinea-pig model, electron microscope studies of single fibres indicated that the distortion of the internodes resulted from slippage of myelin lamellae away from the site of the pressure, the bulbous ends of the internodes consisting of redundant folds of myelin. This process was followed by demyelination of the axon, beginning in each internode at the end nearer to the ccnlre of the lesion. Owing to the presence of postmortem artefact, electron-microscopic studies of the present material proved more difficult, but in 1 median nerve (frona Case 8) it was possible to confirm the main ultrastructural features of the guinea-pig model. The findings in this nerve will be described in detail elsewhere. The actual cause of myelin slippage is uncertain. Ochoa and Marotte (1973) suggested that it might be the result of recurrent trauma or pressure sufficient 1o cause detachment of the inner myelin lamellae. The concept of intermittent or recurrent pressure is an attractive one since sustained pressure over a prolonged period appears to produce a different histological picture (Duncan 1948 ; Aguayo, Nair and Midgley 1971}. Sustained pressure sufficient to produce an acute lesion within 1 2 hr results in yet another type of lesion with displacement of the nodes of Ranvier (Ochoa et al. 1972). This latter change is easily identifiable in single fibres and is quite distinct from the chronic lesion seen in guinea-pigs and in the majority of the present cases. There was however, 1 example of the acute lesion in the present series (Case 5) and it is interesting that this occurred under the flexor retinaculum where the chronic type of change would be expected. This raises the question as to whether both types of pathological lesion may not occur in entrapment syndromes. Since both lead to paranodal or segmental demyelination, the end-result would be similar. There is some support for this concept from clinical studies. For example, Payan (1970) found that a proportion of chronic ulnar nerve lesions requiring decompression had begun as acute lesions following a single identifiable episode of compression. When our present findings are compared with the guinea-pig material of Ochoa and Marotte (1973), and with the few histological studies which have been made of human entrapment lesions, it seems likely that the mild changes seen in the present series represent the earliest stage of a compressive lesion, before much demyelination or degeneration has followed. This early picture may be contrasted with the median nerve lesion described by Thomas and Fullerton (1963) from a patient with the carpal tunnel syndrome, in which there was a marked change in the fibre diameter histogram, not only under the flexor retinaculum, but also distal to it. Even grosser changes were described by Marie and Foix (1913) in their specimen. Further studies of nerves from patients with known entrapment lesions would clearly be of considerable interest. ACKNOWLEDGEMENTS
We wish to thank Mrs. M. A. Nylk and Mr. H. Long for technical assistance. We are also grateful to Dr. Rosemary Eames for helpful criticism and discussion.
SUB-CLINICAL ENTRAPMENT NEUROPATHY IN MAN
297
SUMMARY
Twelve median and 12 ulnar nerves were obtained at routine autopsies from patients without known disease of the peripheral nervous system. Enlargement of cross-sectional area due to an increase in connective tissue elements was commonly present in the ulnar nerve at the elbow and in the median nerve under the flexor retinaculum. Renaut bodies were also prominent at these two sites. The connective tissue changes did not appear to be related to the presence or absence of nerve fibre damage. When nerve fibres were teased apart and examined individually, localised changes were found at the elbow in 5 ulnar nerves and under the flexor retinaculum in 5 median nerves. The changes were mild and transverse sections at the same levels showed few abnormalities. However, the changes were similar in character to those described previously in experimental animals with entrapment syndromes. They are therefore considered to be valid evidence of sub-clinical entrapment in apparently unaffected human subjects. REFERENCES AGUAYO. A., C. P. U. NAIR AND R. MIDGLEY (1971) Experimental progressive compression neuropathy in the rabbit, Arch. Neurol. (Chic.j, 24:357 364. ANDERSON, M. H., P. M. FULLERTON, R. W. GILUATr AND J. E. C. HERN (1970) Changes in the forearm associated with median nerve compression at the wrist in the guinea-pig, J. Neurol. Neurosurg. Psychiat., 33 : 7(~79. ASBURV,A. K. (1973) Renaut bodies. A forgotten endoneurial structure. J. Neuropath. exp. Neurol., 32: 2, 334-343. CHANG, K. S. F., W. D. Low, S. T. CHAN, ADSON CHUANGAND K. T. POON (1963) Enlargement of the ulnar nerve behind the medial epicondyle, Anat. Rec., 145: 149-153. DUNCAN, D. (1948) Alterations in the structure of nerves caused by restricting their growth with ligatures, J. Neuropath. exp. Neurol., 7: 261-273. EsPm, M. L. E. AND D. T, C. HARDING (1961) Apparatus for measuring and counting myelinated nerve fibres, J, Neurol. Neurosurg. Psychiat., 24: 287-290. FEINDEL, W. AND J. STRATFORD(1958) The role of the cubital tunnel in tardy ulnar palsy, Canad. J. Surg., 1: 287-300. FULLERTON, P. M. (1969) Electrophysiological and histological observations on peripheral nerves in acrylamide poisoning in man, J. Neurol. Neurosurg. Psychiat., 32: 186-192. FULLERTON, P. M. AND R. W. GILLIATT (1967) Median and ulnar neuropathy in the guinea-pig, J. NeuroL Neurosurg. PsTchiat,, 30: 393402. GITLXN, G. (1957) Concerning the gangliform enlargement ("pseudoganglion") on the nerve to the teres minor muscle, J. Anat. (Lond.), 91 : 466-470. KR~CKE, W. (1955) Erkrankungen der peripheren Nerven. In: O. LUBARSCH,F. HENKE AND R. R6SSLE (Eds.), Handbuch der speziellen pathologischen Anatomie und Histolo#ie, Vol. 13 (Nercensvstem). Part 5 [Erkrankungen des peripheren und vegetativen Nervensystems), Springer, Berlin, pp. 35 36. LASCELLES, R. G. AND P. K. THOMAS(1966) Changes due to age in internodal length in the sural nerve in man, J. Neurol. Neurosurg. Psychiat., 29: 40~4. LUBINSKA, L. (1958) "Intercalated" internodes in nerve fibres, Nature (Lond.j, 181: 957-958. MArnE, P. AND C. Forx (1913) Atrophic isol6e de l'6minence th6nar d'origine neuritique, r61e du ligament annulaire ant6rieur du carpe dans la pathog6nie de la 16sion, Rev. neurol., 21 (ii), 647. NATHAN, H. (1960) Gangliform enlargement on the lateral cutaneous nerve of the thigh, J. Neurosurg., 17 : 843-849. OCHOA, J. (1970) Isoniazid neuropathy in man : quantitative electron microscope study, Brain, 93 : 831-850. OCHOA, J. (1972) Ultrathin longitudinal sections of single myelinated fibres for electron microscopy, J. neurol. Sci., 17:103 106. OCHOA, J. AND W. G. P. MAre (1969) The normal sural nerve in man, Part 2 (Changes in the axons and Schwann cells due to ageing), Acta neuropath. (BerL), 13: 217-239.
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