J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

J. Neurol. Neurosurg. Psychiat., 1967, 30, 215

Clinical and pathological study of ischaemic neuropathy

ROSEMARY A. EAMES AND L. S. LANGE From the Department ofAnatomy, St. Mary's Hospital Medical School, and the Department of Neurology, St. Mary's Hospital, Paddington, London

For many years a number of workers have studied (Joffroy and Achard, 1889; Woltman and Wilder, the relation between arterial occlusion or com- 1929). Cottrell (1940) found occlusive changes pression in man, produced by various pathological present in the vasa nervorum of the aged. Detailed processes, and peripheral abnormality. The examination of the smaller vessels has, however, whole subject was authoritatively reviewed by been neglected both by workers on nerve ischaemia Richards (1951). There is ample evidence, clinical, and by those studying arteriosclerosis. histological, and electrical, that ischaemia of a nerve It has been shown that there are two types of has an adverse effect upon it. Persisting nerve degenerative change that occur in nerve fibres: damage from ischaemia may be produced by arterial Wallerian degeneration and segmental demyelina- injury (Tinel, 1917; Holmes, Highet and Seddon, tion (Gombault, 1880; Vizoso and Young, 1948;

1944), by embolism (Blackwood, 1944; Haimovici, Thomas and Young, 1949; Vizoso, 1950; Lubin'ska, Protected by copyright. 1950), by chronic occlusive arterial disease (Joffroy 1958 and 1959). It is a common clinical experience and Achard, 1889; Priestley, 1931; Hutchinson and to find abolition of vibration sensitivity and Liversedge, 1956; Gairns, Garven, and Smith, 1960), diminution or loss of ankle jerks in the feet of the by polyarteritis nodosa (Kemohan and Woltman, aged (Pearson, 1928; Critchley, 1931). Lascelles and 1938), and by other, rarer, causes. Experimentally Thomas (1966) studied isolated nerve fibres from the ischaeiia has been produced in animal by sural nerves of subjects of various ages, and found variou means (Adams 1943; Roberts, 1948) and degenerative changes present in those over the age electrical studies have been carried out on ischaemic of 65 years, segmental demyelination being the nerves (Bentley and Schlapp, 1943; Porter and predominant abnormality. They suggested a possible Wharton, 1949). Lewis, Pickering, and Rothschild relationship between these clinical findings and (1931) showed in their classical experiments that nerve changes and atheromatous occlusion of the changes may be produced in nerve function by vasa nervorum. ischaemia. The present investigation was designed to The histological changes described in the nerves determine the degree of neurological abnormality, have been fairly consistent and non-specific, and as assessed clinically, in the affected limbs of patients involve patchy degeneration in nerve fibres together with chronic occlusive arterial disease of the legs. http://jnnp.bmj.com/ with endoneurial fibrosis. However, many reports This was combined with a study of the pathological have not distinguished between changes occurring in changes in sensory nerves from the affected limbs, nerves after an acute ischaemic episode and those by both light and electron microscopy, with particular resulting from chronic longstanding ischaemia, and reference to the alterations in the vasa nervorum no attempt has been made to determine the type of and the detailed study of the nerve fibres themselves. degeneration in ischaemic nerve fibres by individual In of the earlier reports MATERIALS AND METHODS examination. addition, many on September 29, 2021 by guest. on nerves in arteriosclerotic limbs were from cases complicated by diabetes mellitus. Some of the studies CLINICAL SURVEY Thirty-two patients with clear clinical on but it has and arteriographic evidence of peripheral arterial disease also were carried out digital nerves, of the lower limbs were studied. Two patients were been shown (Gairns et al., 1960) that the digital suffering from Buerger's disease, with histories dating nerves even of healthy young subjects may reveal back 27 and 13 years respectively, and the other 30 damage due to repeated minor injuries. patients had arteriosclerotic obliterative disease. All were The state of the vasa nervorum in peripheral in-patients, admitted under the care of the Surgical Unit arteriosclerosis has been commented upon incident- for surgery (endarterectomy, sympathectomy, by-pass ally by a few authors while studying the nerves procedures, or amputation). Their ages ranged from 215 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

216 Rosemary A. Eames and L. S. Lange 43 to 71 years, 28 patients falling into the 50-to-70-year and exclusions were made on the same basis as for the range (Table I). Twenty-six patients were smokers, and, patients with vascular disease. with one exception, all were male. LIGHT AND ELECTRON MICROSCOPY Eight of the 32 patients with arterial disease had amputations at the TABLE I knee joint while in hospital. All eight were biopsied for AGES OF PATIENTS AND DURATION OF SYMPTOMS OF electron microscopy; five of these also had pieces of nerve PERIPHERAL ARTERIAL DISEASE taken for light microscopy. At operation a 2 in. incision Patient Duration ofSymptoms Age (years) was made 1 in. behind the lateral malleolus immediately (years) before the leg was amputated. A small piece of sural nerve was removed and divided into three portions. a solution of 4% 2 2 The larger piece was placed in 3 2 formaldehyde in 09% sodium chloride for four days. 4 27 It was then transferred to a solution of 1% osmium 5 washed in distilled water, and 6 tetroxide for 24 hours, 7 3 macerated in a solution of 2:1 glycerol and water for three 8 13 days. Individual fibres were teased out in pure glycerol 9 4 with mounted needles under a dissecting microscope and 10 3 11 1 transferred to a few drops of creosote on a slide. For 12 1 1 each case, the first 45 fibres covering the range of fibre 13 7 diameter were teased out, no effort being made to obtain 14 2 fibres. The nerve fibres were 15 10 particularly pathological 16 3 arranged in parallel rows, and, after draining off the 17 3 creosote, mounted in Canada balsam. 18 5 Internodal length and fibre diameter were measured 19 7 was 7 using a micrometer eyepiece; each diameter recorded

20 Protected by copyright. 21 1 the mean of five measurements made along the internode. 22 For each case, internodal lengths were plotted against 23 5 of the widest internode on a given fibre, and 24 l the diameter 25 7 the points joined bya vertical line, accordingto themethod 26 5 suggested by Fullerton, Gilliatt, Lascelles, and Morgan- 27 2 Hughes (1965). 28 4 The second piece of sural nerve obtained at amputation 29 1* 30 II was placed in Flemming's fixative for 24 hours and, after 31 2i washing and dehydration in alcohols, embedded in 32 3 paraffin wax. Transverse sections were cut at 5p and stained in Kulschitsky's stain for myelin by the method of Every effort was made to exclude patients with other Gutmann and Sanders (1943). possible causes of or myelopathy, The smallest piece of nerve obtained was placed particularly diabetes, carcinoma, collagen diseases, a immediately in ice-cold 2% osmium tetroxide, buffered history of alcoholism or of neurotoxic drugs, vitamin at pH 7 4, for electron microscopy. Within 10 minutes of deficiencies, and lumbar disc prolapse. In addition being placed in the fixative, the nerve was teased into patients with a recent cerebrovascular accident or a individual fascicles with a sharp scalpel blade. After family history of neurological disease were excluded. two to three hours of fixation, the pieces were placed in http://jnnp.bmj.com/ Apart from exclusions on those grounds no selection 70% alcohol for 12 hours, dehydrated in absolute alcohol, was made. and embedded in Araldite. A few fascicles from each case Each patient was carefully examined by one of us, were stained in bulk in 1 % phosphotungstic acid in 95% particular attention being paid to the peripheral nervous alcohol before dehydrating. system. Careful note was made of complaints of Sections were cut using a Cambridge ultramicrotome, paraesthesiae or leg weakness, and the sensory exam- mounted on unfilmed copper grids, and examined in a ination was made as objectively as possible, in most cases Siemens Elmiskop I. Sections from those blocks which the findings being confirmed on more than one occasion. had not been stained in bulk were treated with lead Gangrenous areas were excluded from sensory testing. hydroxide on the grid before examination. on September 29, 2021 by guest. Intermittent claudication was severe in all the patients, the least affected being able to walk a distance of up to RESULTS 200 yards before pain forced them to stop. Thirteen patients had gangrene of the toes or feet, and 16 patients CLINICAL FINDINGS Table II summarizes the had pain at rest. abnormalities found, and shows a correlation Twelve control patients were also examined. These were in a between the incidence of neurological abnormalities were in hospital for various reasons. They All with similar age range to the patients with arterial disease. and the severity of ischaemia. patients None had any evidence of ischaemia of the lower limbs, claudication distances of less than 100 yards showed J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

Clinical andpathological study of ischaemic neuropathy 217

TABLE II some neurological abnormalities, which were severest SUMMARY OF CLINICAL FINDINGS in those who had pain at rest and claudication 20 or less. Patient Leg Pulses Sensory Ankle Motor distances of yards Present' Deficit2 Jerks3 Signs' The presence of palpable pulses distal to the femoral pulse in these patients was usually associated R F a + L F a with more minor degrees ofneurological abnormality, 2 R All a or none at all. The site of major arterial occlusion L F c 3 R F, DP did not appear to be related to the presence or L F b R severity of neuropathy. In 20 patients the superficial 4 R F c 5 R F, PT R femoral was occluded, while in the remainder L None d the occlusion was more proximal, although often 6 R F a associated with considerable atheroma distally. L All + 7 R F Sensory abnormalities In 28 (87-5%) patients L None d + one or more sensory modalities were impaired, 8 R F L All vibration sensation alone in four. Faulty joint 9 R F b + position sensation was demonstrable in nine patients, L F b l in all of whom superficial and vibration sensation 10 R F a L F a + was also impaired. Impaired superficial sensation 11 R F a varied from a patchy loss below the knee in 11 L F b 12 R F patients to an irregular stocking distribution of loss L F below the ankle or knee in one or both legs in 13 R F, P a L F c 15 patients. 14 R F, P Paraesthesiae were present in 21 patients (630%). L None b + The complaints were not prominent and were Protected by copyright. 15 R F a R L F a R elicited by direct questioning, except in three patients, 16 R F, DP who complained spontaneously of bursts of sharp L F, DP 17 R F + stabbing sensations resembling lightning pains. L None C Motor abnormalities Sixteen patients had weak- 18 R None d + L F a + ness of one or both legs, and in 10 there was muscle 19 R F c wasting. Two of the patients with weakness had L F c + 20 L None d suffered recent acute episodes, and the pattern in 21 R F a R one of them was that of a lateral popliteal nerve L F d R 22 R F d palsy following sudden occlusion of the common L All + femoral artery. One patient (case 25) presented the 23 L F d R picture of an almost symmetrical peripheral neuro- 24 R F c R L F c R pathy affecting the legs for which no cause other 25 R F d + + than that of ischaemia could be found. In the others, L F d 26 R F b the muscle wasting was diffuse and moderate in L F b + present only in the more severely ischaemic

degree, http://jnnp.bmj.com/ 27 R F b + +I limbs. L F b + 28 R F, P Reflex changes Thirteen patients had reduced or L F b 29 R F, DP c absent ankle jerks; those limbs in which the ankle L F c + jerks were merely reduced were not so ischaemic as 30 R All those in which these reflexes were absent. L F a 31 R F d Control patients Of the 12 control patients L None d 32 R F c examined, only one had impaired vibration sense in L F c the feet and sluggish ankle jerks. on September 29, 2021 by guest.

IF = femoral pulse, P = popliteal pulse, PT = posterior tibial pulse, LIGHT MICROSCOPY Figures 1 and 2 represent the DP = dorsalis pedis pulse. relations between internodal length and fibre 2a = absent vibration sense, b = superficial sensory loss, c = absent vibration sense and superficial sensory loss, d = impairment of all diameter in two of the cases where the nerve fibres sensory modalities. were examined in this way. There are several 'Ankle jerks are recorded as present (+), reduced (R), or absent (-). prominent features of the graphs that differ from

'Positive motor signs indicate definite muscle weakness with or graphs made from normal subjects of similar ages. without wasting. There is clear evidence that a considerable amount of

3 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

218 Rosemary A. Eames and L. S. Lange I* 2i

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0-2 Protected by copyright. I i I U'2 4 6 8 10 1'2 1'4 1.6 FIG. 1. diameter (p) FIGS. 1 and 2. Graphs showing the relation between internodal length andfibre diameter (see text). Figure 1: case 21. s = fibre showing evidence of segmental demyelination and remyelination; w = fibre having undergone Wallerian-type degeneration and regeneration. Figure 2: case 31. segmental demyelination and remyelination has greater than 0O80 mm. While teasing the fibres, occurred, as shown by the number of fibres present, evidence of recent Wallerian degeneration could be with some internodes of normal length and others of seen in each case; this was most notable in the patient http://jnnp.bmj.com/ very short length. This is shown most clearly in the illustrated in Figure 1. In this case several fibres of widest diameter, but is also present in those endoneurial tubes containing scattered osmiophilic of medium and small diameter. In addition a certain droplets were visible. amount of Wallerian-type degeneration and re- In a large number of fibres, abnormalities in the generation has taken place; this is shown by the myelin sheath were apparent. These were of several number of fibres in the medium and large diameter types: (a) widening of the nodal gap (Fig. 3a); range which have uniformly short internodes. (b) demyelination over part of an internode, with In a normal subject in the age range being apparently normal myelin on either side (Fig. 3b); on September 29, 2021 by guest. considered here, internodal length varies from (c) demyelination and partial remyelination over approximately 015 mm. at a diameter of 2 p, to a part of an internode (Fig. 3c); (d) demyelination and length of approximately 1-0 mm. at a diameter of partial remyelination over one or more internodes 12 it (Lascelles and Thomas, 1966). In the cases (Fig. 3d). This last abnormality was the commonest described here, most internodal lengths for the type seen. Often the abnormalities alternated with fibres of medium and large diameter were con- normal segments on a single fibre. The demyelinated siderably shorter than normal, with an average segments showed changes that ranged from complete length of 0 70 mm. at a diameter of 12 u. In all cases, disappearance ofmyelin to slight thinning only of the there were few fibres with internodal lengths sheath. In the partially remyelinated segments, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

Clinical andpathological study of ischaemic neuropathy 219

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Schmidt-Lantermann incisures were especially pro- collagen was present in the endoneurium of the minent. nerves examined, and few largemyelinated fibres were These changes correspond with those previously seen. Large numbers of Schwann cells were present, described for nerve fibres undergoing segmental most of which contained many profiles of endo- demyelination and remyelination. plasmic reticulum in their cytoplasm. In many http://jnnp.bmj.com/ Figure 4 shows a transverse section of an ischaemic Schwann cells there were cytoplasmic inclusions of nerve stained for myelin. The fibres are much less homogeneous lipid-like material (Fig. 5), and the numerous than in a normal sural nerve from a Golgi apparatus and ribosomes were prominent. subject of the same age (O'Sullivan, 1966), and Many Schwann cells contained lysosomes. Myelin some fibre loss was present in all the nerves examined. figures and clumps of degenerate myelin within The amount of endoneurial collagen was Schwann cells and processes were frequently seen moderately increased in all cases, and the perineur- (Fig. 6). Some Schwann cells entirely lacked an axon.

ium showed a probable slight increase in thickness. Collagen pockets of the various types described by on September 29, 2021 by guest. Both and small of the inter- Gamble and Eames (1964) were seen in association fascicular tissues showed thickening of their walls, with Schwann cells. Unmyelinated axons for the with some endothelial proliferation. Many arterioles most part appeared normal (Fig. 5); some axons of contained organized thrombus, and their lumens both myelinated and unmyelinated fibres, however, were occluded. The lumens of small arteries were showed loss of neurofibrils and contained large reduced in diameter, and thrombi were also present numbers of vacuoles and electron-dense vesicles. in many of these vessels. A few shrunken endoneurial tubes, consisting of Schwann cell processes surrounded by folded ELECTRON MICROSCOPY A considerable amount of basement membranes, were present. Other endo- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

220 Rosemary A. Eames and L. S. Lange a *b I c

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I http://jnnp.bmj.com/ FIG. 3a. Portion isolated nerve I of fibre showing widening ofthe nodal gap. FIG. 3d. Nerve fibre showing a long segment ofpartial remyelination. It is not possible to distinguish the nodes of FIG. 3b. Part offibre showing a short length ofdemyelina- Ranvier. tion, with apparently normal myelin on either side. The top end ofA is continuous with the lower end ofB, and similarly through C and D to E. FIG. 3c. Part offibre showing a short length ofincomplete Fibres stained with osmium tetroxide. Each x 600.

remyelination, in which Schmidv-Lantermann incisures are on September 29, 2021 by guest. prominent. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

Clinical and pathological study of ischaemic neuropathy 221

FIG. 4. Transverse section ofsural nerve from case 21, showing loss of myelinated fibres. Kulschitsky. x 60. FIG. 5. Electron- !k..:;.1T A micrograph showing two nucleated Schwann cells with unmyelinated axons (a). The cyto- *, ... > plasm ofboth cells contains numerous I vesicles, ribosomes (r), k. andprominent Golgi .t . 9 .r .a I apparatus (G); and ,;,s. ,., 5. .* > pio. d one cell also has three ... | U lipid-like inclusions X % Yi: K: ., C: = Schwann ... (1). N nucleus. Lead hydroxide f: @s,. .,i.Oij 2^*8''. x 21,000. FIG. 4. -..s. *-.u#i% ..X::JA Protected by copyright. http://jnnp.bmj.com/ on September 29, 2021 by guest.

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222 Rosemary A. Eames and L. S. Lange

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FIG. 6. Schwann cell process containing a myelin figure FIG. 7. Small endoneurial in which the nuclei with lamellae (ml) visible. The centre ofthe figure contains of two endothelial cells (ec) are visible. The endothelial large mitochondria (m) and a vacuole (v). Lead hydroxide. basement membranes (bm) are very thick. Phosphotungstic x 20,000. acid. x 2,000. neurial elements, fibroblasts and macrophages, were those in the endoneurium. The arterioles showed seen, the latter often containing myelin figures and marked abnormalities. The arteriolar lumen was lipid-like droplets. often occluded by fibrin or by proliferated endo- The endoneurial were of particular thelial cells. Smooth muscle cells were vacuolated http://jnnp.bmj.com/ interest. All those seen showed thickening of and oflowelectron density, with loss ofmyofilaments. basement membranes (Fig. 7), often considerable. Thickening of basement membranes was such as to In many cases the basement membranes were resemble hyalinization in many areas, and small multilayered (Fig. 8). An increase in pericapillary amounts of collagen were present between the cells collagen was commonly present, sometimes forming of the media. In some vessels the medial layers a layer 3 ,u thick or even more (Fig. 9). Many appeared proliferated, and the cells contained endothelial cells showed irregular internal surfaces, homogeneous inclusions. Adventitial collagen was with small villous projections into the vessel lumen, increased. Occasional small cellular constituents of on September 29, 2021 by guest. and lipid-like inclusions in the cytoplasm. Some the adventitia resembled Schwann cell processes, but capillaries consisted of several layers of endothelial contained no axons; these were believed to represent cells; these were believed to have proliferated. the Schwann cells of degenerate sympathetic nerve Occasionally the lumen of a capillary was occluded fibres. by an electron-dense granular material resembling A few small arteries were also present. Striking fibrin. features in these were the abundance of intercellular The epineurial tissue contained numbers of collagen in the media and smooth muscle cells arterioles and capillaries. The latter were similar to internal to the internal elastic lamina, often arranged J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

Clinical andpathological study of ischaemic neuropathy 223

A -F.

n' 8 Part of wall of endoneurial capillary showing FIG. 9. Part of wall of endoneurial capillary showing proliferated basement membranes (bin) Phosphotungstic grossly thickened perivascular collagenous layer (cl), up to acid. x 18,000. 3,u thick. Lead hydroxide. x 15,000. in a concentric layer. This was associated with some seldom encountered where there is a short history of fragmentation of the elastic sheets. vascular disease. In our patients, however, five out http://jnnp.bmj.com/ of six limbs in which the history of claudication was DISCUSSION under six months had evidence of sensory impair- ment, suggesting that severity of ischaemia is more The incidence (87-5 %) of sensory neuropathy in important than length of history in the aetiology of this group of patients is considerably higher than neurological abnormalities. that recorded by previous authors. Hutchinson and The subject of the blood supply of peripheral Liversedge (1956) found neurological abnormalities nerves has received considerable attention for some in 58-8% of patients and Mufson (1952) in 43%. years, and was reviewed by Adams (1942) and by on September 29, 2021 by guest. This discrepancy is most probably related to a greater Sunderland (1945). Briefly, it has been shown that severity of ischaemic disease in our patients, and to a peripheral nerve trunk receives a number of the fact that we have included estimates of vibration nutrient arteries from a main artery or a muscle sensitivity. Lightning pains, painful paraesthesiae, artery, and these anastomose longitudinally within and pain at rest were present in patients with more the nerve. Occlusion of one or its severe ischaemia, and in almost all these there was intraneural branches does not produce ischaemia as good evidence of sensory impairment. Richards a good collateral circulation is available. Animal (1951) has suggested that 'ischaemic neuritis' is experiments (Adams, 1943; Roberts, 1948) have J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

224 Rosemary A. Eames and L. S. Lange shown that it is necessary to occlude a number of diameter. Figure 1 shows several fibres which have vasa nervorum before significant ischaemia is clearly undergone Wallerian-type degeneration and produced. In cases of human peripheral arterial regeneration; the severity of the changes seen in disease associated with nerve ischaemia it seems transverse section (Fig. 3), however, suggests that likely that occlusive changes in the vasa nervorum axonal damage may be more widespread than would would produce a similar ischaemia, which may be appear from the presence of regenerated fibres in increased by occlusion of a main artery in a limb. It the teased preparations. Since ample time had is probable that such a degree of nerve ischaemia elapsed in these patients for regeneration of nerve contributes in no small measure to the pain at rest fibres to occur, it seems likely that ischaemic typical of severe arterial disease, and may also be neuropathy is a process in which axonal damage is responsible in part for the onset of trophic skin not always followed by regeneration. changes. The relation between our findings and those The pathology of chronic ischaemic changes in occurring in old age must be considered. Cottrell peripheral nerves was first described by Joffroy (1940) observed occlusive changes in the vasa and Achard (1889), and was later expanded by nervorum in old age, and showed that an increase in Buerger (1908) for cases of thrombo-angiitis endoneurial collagen is associated with a decrease obliterans, and by Priestley (1931) for arterio- in the number of nerve fibres present. Lascelles and sclerotic limbs. These workers described patchy Thomas (1966) have shown that over the age of 65 Wallerian-type degeneration in the nerve fibres, and years irregularities of internodal length occur, and endoneurial fibrosis, more marked distally than are common in the older age groups. Evidence of proximally. In particular, the nerve changes were both Wallerian-type degeneration and regeneration found to be directly proportional to the degree of and segmental demyelination and remyelination was arteriosclerotic change in the vessels, suggesting a observed. The presence of the latter type of change peripheral cause for the nerve degeneration which may well be ischaemic in origin, consequent upon Protected by copyright. was probably ischaemia. gradual vascular occlusion, in a similar manner to In our biopsies, there was evidence of extensive the changes produced in our patients. segmental demyelination and remyelination in It is well known that segmental demyelination and addition to Wallerian degeneration and regeneration. remyelination in a nerve produces a reduction in These two types of change cannot be distinguished conduction velocity (McDonald, 1963; Cragg and in ordinary transverse sections of the nerve, which Thomas, 1964; Gilliatt, 1966), and impairment, may account for the earlier reports of patchy or particularly of those functions that depend upon the slight degeneration in nerves subjected to con- ability of the nerve to transmit a synchronous volley siderable degrees of ischaemia. of impulses, namely, vibration sensitivity and the Recently attention has been drawn to the occur- tendon reflexes (Gilliatt and Willison, 1962; Lascelles rence of segmental demyelination in certain human and Thomas, 1966). As already mentioned, several peripheral neuropathies, such as those associated workers have observed that in old age vibration with diabetes (Thomas and Lascelles, 1965 and sensitivity is impaired in the legs (Pearson, 1928), 1966a) and in the Guillain-Barre syndrome (Thomas and that the tendon reflexes are diminished or lost, and Lascelles, 1966b). It has also been demonstrated particularly the ankle jerks (Critchley, 1931). in experimental allergic neuritis (Waksman and Similar changes were observed in many of our http://jnnp.bmj.com/ Adams, 1956; Cragg and Thomas, 1964), in experi- patients, supporting the view that loss of these mental diphtheritic neuropathy (McDonald, 1963), functions in the aged is at least partially due to and in lead neuropathy (Fullerton, 1966) in animals. segmental demyelination in the nerve fibres resulting The evidence presented in this paper shows that from peripheral ischaemia. Occlusive changes in the chronic ischaemia also produces segmental demyelin- vasa nervorum of the aged may well contribute to ation, and the presence of this change therefore the peripheral neuropathology of old age. indicates that ischaemia does affect Schwann cells, The question arises as to how far ischaemia either directly by anoxia or indirectly by accumu- contributes to the changes in the peripheral nerves on September 29, 2021 by guest. lation of toxic metabolites. of . Although 'earlier workers Regenerating fibres that have undergone Wal- (Woltman and Wilder, 1920; Dry and Hines, 1941) lerian-type degeneration are only recognizable as attributed diabetic neuropathy to peripheral arterio- such by teasing methods when the regeneration sclerosis, recent work has cast doubt upon this process has reached a certain stage. Before this stage, explanation (Dolman, 1963; Greenbaum, Richard- it is not possible to distinguish between normal small son, Salmon, and Urich, 1964) and has suggested myelinated fibres and those which have partially that the changes may be of metabolic origin. regenerated but have not yet regained their normal However, in patients with diabetic neuropathy and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

Clinical andpathological study of ischaemic neuropathy 225 marked peripheral vascular disease it seems likely were rare, most of the demyelinated regions having that ischaemia contributes to the segmental become at least thinly remyelinated. demyelination and to the loss of axons that is also encountered (Greenbaum et al., 1964; Thomas and SUMMARY Lascelles, 1966a). Dreyfus, Hakim, and Adams (1957) have put forward some evidence to suggest Thirty-two patients with obliterative arterial disease that the cause of the ocular palsies occasionally of the lower limbs were examined neurologically. seen in association with diabetes may be ischaemia. Evidence of sensory peripheral neuropathy was The electron microscopic findings in the present found in 87-5 %. cases are of particular interest, as they provide Sural nerve biopsies from eight patients were additional evidence that occlusion of the more distal obtained immediately before amputation. Isolated vessels of the occurs in severe peripheral nerve fibres were examined in five of the biopsies, arteriosclerotic disease. Hitherto it has been generally and these showed evidence of segmental demyelina- believed that the smaller vessels in arteriosclerosis tion and remyelination and of Wallerian-type escape occlusive changes (Martin, Lynn, Dible, and degeneration and regeneration. Transverse sections Aird, 1956), in contrast to the situation in Buerger's revealed loss of myelinated fibres. disease, where the small vessels are affected first. The eight nerve biopsies were examined with the Strandness, Nothstein, Alexander, and Bell (1960), electron microscope. Degenerative changes were however, reported intimal proliferation and thicken- found in the nerves, and the small arterial vessels of ing of the vessel wall, with occasional hyalinization, the epineurium showed marked occlusive changes in arterioles in peripheral arteriosclerosis, and with intimal thickening and medial degeneration Cottrell (1940) found medial fibrosis and hyalin- and fibrosis. Perivascular connective tissue was ization in the vasa nervorum of the aged. increased on all vessels, and the basement membranes

Hyalinization of the media and necrosis of smooth were proliferated and thickened. Protected by copyright. muscle cells in arterioles occurs particularly in The nature and implications of these changes, and hypertension, but none of our patients was hyper- their relation to old age and to other neuropathies, tensive and none showed clinical evidence of renal particularly diabetic, are discussed. disease. Banson and Lacy (1964) found thickening of capillary basement membranes in diabetic and in We wish to thank Professor W. T. Irvine for permission some non-diabetic patients with peripheral arterio- to examine and biopsy his patients, and to publish our sclerosis. Evidence has been produced to show that findings, and Mr. A. E. Thompson and Mr. J. T. Hobbs basement proliferation and thickening may precede for their cooperation and help during the amputations. We would also like to express our gratitude to hyalinization, and that hyaline material may in Professor F. Goldby for the use of the electron micro- fact arise from basement membranes (Smith, 1955; scope, for the facilities of the Anatomy Department in Wiener, Spiro, and Lattes, 1965). Smooth muscle which most of the work was done, and for useful cells are well known to occur in the intima of discussion; to the Wellcome Trust for providing the arteries under various pathological conditions, electron microscope; and to the Dowager Countess especially in large arteriosclerotic vessels. The Eleanor Peel Trust for the ultramicrotome. changes in the vasa nervorum found in our patients Finally we are grateful to Professor R. W. Gilliatt and may be indicative of primary vascular disease, or to Dr. P. K. Thomas for much helpful criticism and http://jnnp.bmj.com/ may be secondary to ischaemia, or to thrombosis advice, and to Mr. R. J. Fant for the photographs. more proximally. Further studies are needed on this point. REFERENCES The presence of these changes in the vessels Adams, W. E. (1942). The blood supply of nerves: I. Historical review. indicates that local ischaemia due to occlusion of the J. Anat. (Lond.), 76, 323-341. (1943). Th- blood supply of nerves: II. The effects of exclusion of vasa nervorum may play an important part in its regional sources of supply on the sciatic nerve of the rabbit. determining the nerve damage. Our electron Ibid., 77, 243-250. are Banson, B. B., and Lacy, P. E. (1964). Diabetic microangiopathy in on September 29, 2021 by guest. microscopic findings in the nerve fibres probably human toes; with emphasis on the ultrastructural change in non-specific, the presence of myelin figures in the dermal capillaries. Amer. J. Path., 45, 41-58. Schwann cells and macrophages merely indicating Bentley, F. H., and Schlapp, W. (1943). Experiments on the blood supply of nerves. J. Physiol. (Lond.), 102, 62-71. that myelin has been broken down; the loss of large Blackwood, W. (1944). A pathologist looks at ischaemia. Edinb. med. myelinated fibres is additional evidence for this. It J., 51, 131-143. Buerger, L. (1908). Thrombo-angiitis obliterans: a study of the is perhaps rather surprising that the specific changes vascular lesions leading to presenile spontaneous gangrene. of segmental demyelination were not seen in these Amer. J. med. Sci., 136, 567-580. electron but is no Cottrell, L. (1940). Histologic variations with age in apparently micrographs, there doubt that in normal peripheral nerve trunks. Arch. Neurol. Psychiat. (Chic.), these cases axons completely denuded of myelin 43, 1138-1150. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.30.3.215 on 1 June 1967. Downloaded from

226 Rosemary A. Eames and L. S. Lange

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