INVOLVEMENT OF AUTONOMIC NERVE-FIBRES IN DIABETIC NEUROPATHY

560 And secondly I dislike any anastomosis in front of the colon. A posterior anastomosis runs in a straight line from oesophagus to jejunum without distortion and without interference (fig. 1). An anterior anastomosis displaces the stoma upwards and to the left and subjects it to the vagaries of the colon, and the colon is an uncertain neighbour (fig. 2). Some anterior anastomoses work, but others are only kept working by constant tribute paid to the manufacturers of salts and liquid

paraffin. We hear a great deal today about the problem of afferent loop stasis." A recent paper on the subject 2 states that " among the unpleasant symptoms following subtotal gastrectomy, bilious regurgitation is one of the most common." I believe that, far from being " one of the most common," this complication should be exceedingly rare, and of the many factors tending to produce it an antecolic anastomosis is the most potent. Antecolic anastomosis is not the only cause of proximal loop dysfunction, but it is the commonest. Too short a loop is one. The Finsterer type of postcolic anastomosis is another, because in it the transverse mesocolon is sewn to the stomach above the anastomosis, forming a tent that drags down and strangulates the proximal loop ; the hole in the mesocolon should be small and its edges should be stitched round the stoma only, but the jejunum where it is applied to the stomach proximal to the stoma should lie free in the lesser sac above the mesocolon. But the antecolic anastomosis is always The faulty. proximal loop, however long it may appear to be, can be no longer than the length of the arteries in the mesentery, and when it is placed in front of the colon, it is pulled upon where it joins the lesser curve. The higher the gastrectomy and the bulkier the colon, the bigger the pull. The combination of a very high gastrectomy with an anterior anastomosis will produce kinking of the afferent loop with all the regularity of a scientific experiment. And lastly I regard the Polya operation-i.e., anastomosis of the full width of the stomach to the jejunumas wrong. The large stoma opens impartially into the proximal and distal jejunal loops, but that is the least of its disadvantages. The real stoma is not the large opening in the stomach but the lumen of the jejunum at its lower end. The part of jejunum in between is simply a pedicled transplant to the stomach wall, and it is distended whenever the stomach distends, but much more easily because its walls are thinner, stretching its mesentery and producing those symptoms of faintness and nausea which are part of the " dumping " syndrome.

Experiment and Advance All books dealing with the construction of medical articles advise us to end with a summary. This article might be summarised as a plea for orthodoxy, but it is not quite as bad as that. Heterodoxy and the spirit of inquiry are the essence of progress ; but the heterodox by inclination are apt to regard movement and advance as synonymous terms, to think that running round in circles is really getting them somewhere. The history of gastric surgery is one of perpetual circumambulation, of constant re-arrival after a long and tortuous journey at the same point. Let us experiment by all means, but let us learn by experiment. If the experiment is successful let us study it with a view to discovering the road to still greater success. If it is unsuccessful, let us record that fact and ensure that a fresh set of human guineapigs shall not be subjected to it in order to give some enthusiast the information he could have obtained in the library. Let there .be no more rediscoveries of failed methods as the answer to troubles that-should not have

M. MERCER MARTIN M.D. Durh., M.R.C.P. MEDICAL

Ibid, ii, 1189.

REGISTRAR,

OF DIABETES, HOSPITAL, LONDON

DEPARTMENT

COLLEGE

KING’S

As long ago as 1890 Buzzard, Pryce, and other’described vasomotor and trophic disturbances in case: of diabetic neuropathy : they recorded dependent oedema, smooth and shining skin, malformation and loss of nails, and changes in sweating. They related these findings to involvement of the autonomic filire, of the peripheral nerves. More recently abnormalities in bowel and bladder function-e.g., nocturnal diarrhoea, neuropathic bladder, and impotence-have also been ascribed to autonomic nerve damage in diabetes’mellitns (Rundles 1945, Treusch 1945, Foster and Bassett 1947, Swarts and Stine 1948, and others). Karsner and Hamman (1943) and Runules (1945) described disturbed regulation of body-temperature in patients with diabetic neuropathy, with intolerance to extreme temperature and drenching night-sweats, in the absence of infection or other common cause. As temperature regulation depends on the balance between heat lost from the body and that produced in the body by katabolism and is mediated largely by vasomotor adjustment of cutaneous blood-flow and perspiration, which are under sympathetic control, Rundles suggested that a disturbance of the autonomic system was responsible for the faulty adjustment of temperature. Orthostatic hypotension due to faulty control of blood-pressure, with fainting on assumption of the upright posture, was also described (Karsner and Hamman 1943, Swarts and Stine 1948). Rundles (1945) reported 5 patients with this syndrome, which had previously been recorded in association with tabes dorsalis, encephalitis, and other neurological and endo. crine conditions, and was attributed to a disturbed function of the sympathetic nervous system (Bradbury and Eggleston 1925, Spingarn and Hitzig 1942, and others). Rundles thought that orthostatic hypotension associated with diabetic neuropathy was of a similar nature and due to dysfunction of the sympathetic

system. Objective

tests confirming a disturbance of function of the autonomic nerve-fibres in diabetic neuropathy, as in other types of peripheral neuritis (Guttmann 1940. have been reported Wilkins and Kolb 1941, and in a few cases :

others),

Shumacker (1942) tested the integrity of the sympathetic to the legs and feet in patients with peripheral neuritis. including 2 with diabetic peripheral neuropathy. In both diabetic cases he could not elicit reflex vasodilatation or vasoconstriction, although there was no evidence of ocelusive vascular disease. Rundles (1945) studied the skin-temperature in 8 patients with oedema and deficient sweating and found vasomotor function diminished or lost. De Takats (1945 also mentioned inability to elicit reflexly either vasoconstric tion or vasodilatation in diabetic neuropathy with clinua. evidence of damage to sympathetic nerves. Foster and Bassett (1947) found lesions of sympathetic nerves in their 2 patients with diabetic neuropathic joint lesions. Single cases have been reported by Treusch (1945), Montuschi and Melton (1948), Speckmann (1950), and others.

nerves

Thus considerable evidence has accumulated ill ih ten years that autonomic nerve-fibres may be involved in far more cases of diabetic neuropathy than the clinical findings of autonomic dysfunction suggest Nevertheless the manifestations of involvement of

past

*

happened. 2. Wells, C. A., MacPhee, I. W.

OF AUTONOMIC NERVEFIBRES IN DIABETIC NEUROPATHY*

INVOLVEMENT

Based on a paper read to the first congress of the International Diabetes Federation on July 11, 1952, at Leyden. Holland.

561 the least commonly of diabetic peripheral neurorecognised component to autonomic of incidence the and damage pathy, nerves in diabetes is quite unknown. It was therefore decided to test the functional integrity of the sympathetic nervous system in unselected consecutive cases of diabetes with or without diabetic

autonomic

nerves

are

probably

TABLE I-AGE-DISTRIB-UTION OF CASES IN WHICH

SUDOMOTOR,

VASOMOTOR,

AND VASCULAR STUDIES WERE MADE

peripheral neuropathy. MEANS OF INVESTIGATION

Reflex vasoconstriction, vasodilatation, and sudomotor activity in the legs in response to cooling and heating of the trunk were held to indicate efficiently the state of the sympathetic nervous system. Reflex vasoconstriction and

vasodilatation

are

due

to

cooling and heating of the blood respectively. Lowering and raising the temperature of the blood was said to influence a centre in the hypothalamus (Fulton 1950), whereupon

vasoconstriction and vasodilatation in the extremities takes place as a result of influences mediated by the sympathetic nerves (Lewis and Pickering 1931, Gibbon and Landis 1932, Pickering and Hess 1933, Prinzmetal and Wilson 1936, Fatheree and Allen 1938, Brattgard et al. 1951). As the temperature of the skin depends mainly on the heat brought to it by the blood-stream, measurements of skin-temperature are most reliable for gauging the state of the blood-flow to a resting limb (Lewis 1946).

measured with thermocouples index of vasomotor activity.

Skin-temperature used as

an

was

Before failure of the skin-temperature to rise in response heating of, the trunk could be ascribed to impairment of vasomotor activity, the ability of the blood-vessels to dilate had to be proved, particularly as coexisting vascular disease was to be expected at least in some of the elderly patients with diabetic neuropathy. For this purpose I usedPriscol’ (2-benzyl-2-imidazoline hydrochloride), which is known to be a powerful vasodilating agent with direct action on the blood-vessels, particularly of the legs (Frank 1950, Wakim et al. 1950, Douthwaite and Finnegan 1950, and others). Grimson et al. (1948) and Lynn (1950) showed further that priscol produced peripheral vasodilatation in cases in which preganglionic and postganglionic sympathectomy had been carried out, as well as in a transplanted skin tube devoid of any nerve-supply. These findings suggested that priscol had a peripheral effect independent of intact innervation, and was therefore the drug of choice in the to

present investigation. The sudomotor fibres concerned in thermoregulatory sweating have been shown to follow the peripheral course of sensory nerves. Secretion of sweat depends on an intact nerve-supply, but may take place in the absence of normal circulation (Kendall and Luchsinger 1876, Dieden 1918). Nevertheless local perspiration usually takes place under the same conditions that cause peripheral vasodilatation (List and Peet 1938). The functional activity of the sudomotor system in diabetic neuropathy was tested by dusting the patients’/ legs with quinizarin powder (quinizarin 2 : 6-disulphonic acid 28%). which is used to detect sweat. Jl aterial The cases studied were in patients attending the diabetic clinic under Dr. R. D. Lawrence and Dr. W. G. Oakley at King’s College Hospital. Only patients with indisputable evidence of involvement of the peripheral nervous system were regarded of diabetic as cases neuropathy, and the diagnostic criteria were subjective neuritic symptoms complained of by the patients and objective signs of disorder of nervous function, such as Io--. of tendon-reflexes, disturbances of sensibility, and weakness, paralysis, and atrophy of muscles (Martin

*No. of patients with clinical evidence of occlusive vascular disease, judged by presence or history of intermittent claudication or by absence of pedal pulses.

(table i). In addition 2 diabetics with neuritic pains without neurological signs and 2 patients with diabetic diarrhoea without other evidence of neuropathy were also tested. Method The temperatures of the skin of the pads of both big toes, the calves, and the pad of one thumb were measured with copper-constantan thermocouples lightly applied with adhesive tape, and a Cambridge skin-temperature measuring outfit. The mouth-temperature was recorded with an ordinary clinical thermometer. The roomtemperature was measured with a thermal junction suspended in the air of the room. The room in which the experiments were made was protected against draughts and maintained as constantly as possible at a temperature of 18-20°C. Changes in humidity could, for practical purposes, be ignored at the temperature at which the experiments were conducted

-

(DuBois and Hardy,1938). The investigations were divided into

injected intravenously, and and

the room

peratures

skin temwere

recorded at 10-min. intervals until maximal vasodilatation had taken

again

place, judged by the fact that the

skin-temperature had become

stable.

’

RESULTS

Normal

People

In the 5 normal people vasoconstriction took place soon after exposure to

sudomotor, and vascular responses

investigated in 5 normal, 5 new diabetics without evidence of peripheral nerve involvement, and 20 patients with diabetic -neuropathy. In all three groups the ages ranged from 20 to 70 years, and were therefore comparable

parts :

was

1953). The vasomotor,

three

Part I.—The patient lay undressed at room-temperature until either his toes had cooled to nearly the same level, or else it had become -obvious, after about three hours with the patient shivering, that vasoconstriction was not to be expected. During this phase of the investigation the skin, mouth, and room temperatures were recorded at 15-minute intervals. Part II.-The trunk was then heated with a radiant-heat cradle. To overcome the objection of Uprus et al. (1937) to this method, a cradle was used which was powerful enough to raise the temperature within it to above 70°C. The skin, mouth, and room temperatures were recorded at 10-min. intervals. Sweating was detected with quinizarin powder dusted on to the skin. Part I I I.Priscol 50 mg.

were

Fig. 1—Vasomotor

response (mean normal people.

curves)

room-temperaf ture. When the trunk

was

562 Kolb

heated the toe-;

temperature began after

-to -rise-

and this sug-

latent of 20-

gests damage to

a

the sympathetic vasoconstrictor fibres,

period 30 min, and

reached a maximum above 32°C within 20-40 min. (fig. 1), except in a-

patient,

presumably the result of the diabetic neuropathy. This

type of response is illustrated iri fig. 3. -

aged

(2) In 10 pat-

66, in whom

ients the and toes

occlusive vas-

cular disease of the right leg prevented the

always and

present already at the start of

the

nor-

2

it rose to 99°F. Profuse sweat2-Vasomotor response in non-diabetic aged ing of the Fig. 66 normal in left hallux ; impaired in right whole body, hallux ;indicating occlusive vascular disease. including the feet, was noted in all the cases. The findings were within the range for normal people established by Brattgard et

al. (1951). Diabetic Patients without Neuropathy In the 5 newly discovered diabetic patients without a history of nerve involvement and without clinical evidence of peripheral nerve disease, reflex vasoconstriction, vasodilatation, and sweating took place normally. Diabetic Patients with Peripheral Neuropathy In all 20 patients with diabetic neuropathy conclusive evidence of impairment of the function of the vasomotor and sudomotor nerves was obtained. Three types of response were shown :

patients peripheral

temperature above 30°C

was

Time allowed for

the

tempera-

ture of the thumb to fall, to gain evi-

perature

In 9

experi-

ments.

In 3 cases the mouth-temremained

cold

vasocon-

striction apto be

toe-tem-

mal, and in

feet were

peared

perature from rising -above 28°C (filg. - 2).

(1)

1941,

.Lewis 1946),

was

Fig. 4-Vasomotor response in patient, aged 84, dence that with diabetic neuropathy : absence of reflex intravenous priscol SO mg. vasoconstricvasodilatation ; caused maximal peripheral vasodilatation, tion was occurindicating absence of occlusive vascular disease ring in the arm. The trunk of each patient was then heated. Reflex vasodilatation invariably took place in the thumb, the skin-temperature of which rapidly rose to 35°C or more. The mouth-temperature rose to above normal and usually reached 100°F before the end of the investigation. In no instance did the toe-temperature rise ; in fact, in many cases it continued to fall. After the trunk had been heated for about 30 min., most patients began to perspire, sweating usually starting on the trunk. In some cases sweating was noticed in the legs, but the feet remained dry in every case. Heating of the body was continued for 80-90 min., by which time it was certain that reflex vasodilatation was not going to occur. Moreover by that time most patients complained of discomfort, and some even of distress.

Complete absence of vasodilatation

might have been

vasodilatation with the toepresent at the beginning of the experiments and persisted throughout the three hours’ observation. Vasoconstriction did not come on in the toes in response to cooling of the body, in spite of shivering and of vasoconstriction in the thumb.

Normally,

cular disease,

were

cases.

Therefore the patients showing this type of response were

given

intravenous priscol 50 mg. and further

temperature

changes

vaso-

were

recorded. In all the cases there

fingers (Pickering and Hess 1933, Doupe et

response, and within 20-30 min. the toe-

1937).

haved

:

present in

most

constrictor tone is greater in the toes than in the

al.

diabetic neuropathy vasoconstriction in toes.

to vas-

although the pedal pulses

The belike who

was a prompt

temperature

began to ri.reaching a

patients

36, Fig. 3-Vasomotor response in patient, aged absence of reflex with

due

occlusive

patients have undergone sn-mpathectoi-ny ( S c o tand Morton 1931, W i 1k i nand

5—Vasomotor response in patient, aged 60, with diabetic neuropathy and occlusive vascular disease in left leg : absence of reflex vasodilatation ; intravenous priscol 50 mg. caused maximal vasodilatation in right hallux, but response in left hallux was impaired.

Fig.

level above

30=C inai; but two pan ents, in whom occlusive vascular disease

j

563 prevented a rise above 26° and 27 °C. The response of this irroup of patients is shown in fig. 4. The response of 1 of the patients with peripheral vascular disease is shown in fig. 5. (3) The 1 remaining patient gave the response shown in 6. On cooling, the right big toe behaved abnormally, though its temperature eventually fell below that of the thumb. Reflex vasodilatation on heating. took place normally. The tests of autonomic function were made when his neuropathy was recovering except for residual loss of his knee-jerks and ankle-jerks, and it is believed that the test indicated normal function of the vasodilator nerves with partial recovery of the vasoconstrictor fibres.

TABLE

II—PARTICULARS

OF PATIENTS FROM SPECIMENS WERE OBTAINED

WHOM

BIOPSY

ng.

Diabetic Patients with Neuritic

but

Manifestations

no

’Vetirological Signs A patient, aged 33, with twenty-three years’ diabetes, it diabetic retinopathy, occasional ankle cedema in the

past, and impotence, complained of neuritic pains in hi,, legs, worse at night. On examination no abnormal neurological signs were found. Tests of sympathetic function showed persistent vasodilatation and lack of vasoconstriction on cooling (fig. 7). The same response was obtained in another patient with symptoms only. A similar result was recorded in a patient with diabetic nocturnal diarrhoea, faecal incontinence, and impotence. Another patient with diarrhoea showed a normal response ‘ in his legs. INTER-

PRETATION

OF RESULTS

All

patients

the with

diabetic neuroshowed evidence of impaired autonomic function when tested as described above. In half the patients the response

pathy

suggested paralysis of the sympathetic vasoconstrictor and sudomotor

fibres,

as

seen

+ Some degeneration. + + Moderate degeneration.

+ + + + + + +

Severe degeneration. Very severe degeneration.

Lewis and Pickering (1931) and Fatheree and Allen (1938), but Uprus et al. (1935) questioned the conclusions of other workers. Evidence has also been obtained of autonomic dysfunction in patients with neuritic pains in the legs without signs and in 1 of 2 cases with diabetic nocturnal diarrhoea, but no symptoms or signs in the legs.

previously by

PATHOLOGY

Further evidence of involvement of autonomic nerva, fibres in diabetes was obtained from the histological examination of biopsy specimens. Very few studies have been made on nervous tissue in diabetic neuropathy : Woltman and Wilder (1929) collected the published reports the pathology of diabetic neuropathy and reported 10 cases of their own. Their material showed extensive degeneration of peripheral nerves in 8 cases and less severe degeneration in 2. Jordan et al. (1935) emphasised the susceptibility of the myelin sheaths to degeneration in diabetic neuropathy. Foster and Bassett (1947) found, in 1 case after on

in the amputation, a striking reduction in increase an sheaths and axis-cylinders,

number of myelin Schwann cells, and advanced endoneural and perineural fibrosis. Muri (1949)

reported demy-

after

fig. 6-Vasomotor response in patient, aged 39, with diabetic neuropathy : absence of reflex vasoconstriction in right hallux; presence of re3ex vasodilatation in both toes.

sympathectomy. In the

elinisation of

peripheral

other half the

but found no evidence of fibrosis. nerves

legs remained persistently

the the of in dia-

Thus

cold and did observed after

reports on pathology

respond to heating of the body, as complete denervation (Lewis and Pickering 1936). Lewis (1946) ascribed this to degeneration of the nerves of the posterior root system, in addition to degeneration of the sympathetic vasoconstrictor fibres. That this was not the case in the patients with diabetic neuropathy was shown by their response to the intradermal injection of 0-1% histamine into the skin of the feet. Neither in the patients in whom the legs were cold and did uot respond to heating of the body nor in the patients with persistent peripheral vasodilatation was the flare f the triple response present (Lewis 1927). This indicates that the posterior root system was involved in both types of cases, as was to be expected in view of the

this due to the fact that this complication of diabetes is reversible and not fatal, and they

damage

biopsies of nerves feasible,

not

nerves

betic

pathy

very

scanty. Joslin et al. (1947),

thought

was

lot. uf pain perception in both groups, and was not the explanation for the different vasomotor changes observed. The findings therefore suggest not only the presence of to autonomic vasomotor fibres in all the cases f diabetic neuropathy examined but also the separate ’xi-tenee of vasodilator and vasoconstrictor fibres. The existence of vasodilator fibres had been demonstrated

neuroare

did not consider

diabetic, legs: aged

in Fig. 7-Vasomotor response in 33, with neuritic pains, but no signs, absence of reflex vasoconstriction indicates loss of function of vasoconstrictor fibres.

because of the

danger paralysis.

of

564 DISCUSSION

Involvement of the nervous system in diabetes appears to be much more common than the published reports suggest. Severe diabetic neuropathy with muscle weakness and extensive loss of sensory perception, such as used to be called tabes diabetica, may not be a common finding in smaller diabetic clinics, but every physician treating diabetic patients must be familiar with the common complaints of pains and paræsthesiæ, particularly in the legs and often associated with calf tenderness and vasomotor disturbances. Although neuritic symp. toms in the absence of physical signs have been regarded as separate from diabetic neuropathy with its more permanent findings of peripheral nerve involvement (Rundles 1945), there is little doubt that both have a common of sural nerve in diabetic neuropathy, reduction in number of axis-cylinders (Holmes) (x 320) cf.

Fig. 8--Biopsy specimen In the

present investigation biopsy specimens

showing fig. 9.

neuropathy

seems

to, be characterised by

a

diffuse and

of the

obtained from 10 cases of diabetic The age and sex distribution, duration of diabetes and of the diabetic nerve complication, the clinical evidence of occlusive vascular disease, and the pathological findings are set out in table 11. The preparations were stained with osmic acid,- hsemalum, and eosin, and by the methods of Van Gieson, Holmes, and Bielschowsky. The sections of nerves from cases of diabetic neuropathy showed conspicuous degenerative changes in all the specimens. There was considerable reduction in axis-cylinders (figs. 8 and 9) and in myelin sheaths (figs. 10 and 11) as reported previously, without, however, any evidence either of endoneural or perineural fibrosis or of cellular infiltration. The degree of degeneration met with in the different cases varied and seemed to correspond to the clinical severity of the neuropathy. Actual counts, however, have not yet been made. In the most affected

aetiology.

The earliest phase in the development of diabetic

nerves were

neuropathy.

Fig. 9-Normal

nerve

showing numerous closely packed axis-cylinders (Holmes) (x 320) cf. fig. 8.

severe cases the degenerative change was diffuse, but in the milder cases it was more patchy and appeared to involve isolated bundles of fibres surrounded by more normal-looking ones. Close scrutiny of the silverstained sections suggested that there was a greater reduction in the number of non-mvelinated nervefibres, compared with the myelinated ones (figs. 12 and " 13). That the closely packed clumps of naked " axiscylinders adjacent to, and in between, the large myelinated fibres were in fact non-myelinated autonomic nerve-fibres was suggested by Nevin (1930). This under is still investigation. question Diabetic neuropathy thus appears to be a degenerative condition of nerves in which the non-myelinated smallcalibre fibres degenerate more extensively than the larger myelinated ones. Further, the primary lesion seems to be a degeneration of axis-cylinders, with a reduction in the myelin sheaths as a secondary phenomenon.

Fig. 10-Biopsy specimen of sural nerve in diabetic neuropathy, showin, reduction in number of myelin sheaths (osmic) (×230) cf. fig. 11.

pain, vasomotor disturbances, thermal parsesthesiae, changes in tendon-reflexes, and often an alteration in pain sensibility in the feet without much impairment of perception of touch or pressure. If the disease progresses, shooting pains develop, vibration sense is lost, and, lastly, sense of touch and position as well as motor power becomes involved (Martin 1953). The modalities of pain and temperature sensation as well as the vasomotor responses are conveyed by non-myelinated or thinly myelinated nerve-fibres (Gasser and Erlanger 1929, Ranson 1931, Ranson et al. 1935, ill-localised

Clark et al. 1935, Lewis and Pochin 1937, Woollard et al. 1940), which tend to be affected by noxious influences long before the myelinated sensory and motor fibres. It is now generally accepted that this susceptibility is due to the difference in the size of the nerve-fibre (Gasser and Erlanger 1929). The finding that autonomic fibres seem to be involved early in the development of diabetic neuropathy, and

Fig.

11—Normal

nerve

showing fairly numerous myelin sheaths (osmic) (x 230) cr. fig. 10.

565 appear also to be non-myelinated fibres. This is suggested by the finding that caudal analgesia by a method affecting only the smallest fibres produces loss of reflexes and pain without loss of other types of sensation or motor power

(Martin 1953). Whereas, in the past, neuritic symptoms without in diabetics were not regarded as indicating nerve now appears on the evidence presented that Jordan’s (1936) " hyperglycaemic neuritis " and Treusch’s (1945) " diabetes with pain " are early manifestations of diabetic neuropathy due to involvement of the nonmyelinated pain fibres. The concept of a degenerative lesion of small-calibre non-myelinated nerve-fibres subserving pain perception and the vasomotor and visceral responses as well as the tendon-reflexes, occurring in diabetes without necessarily being either followed or associated with involvement of larger fibres required for the clinical recognition of diabetic neuropathy, would explain many of the abnormalities at times met with in diabetics. The recognition of such a lesion is of great importance as a sign of nerve injury readily amenable to treatment.

signs

disease, it

Fig. 12—Transverse

section of sural nerve in diabetic neuropathy, showing striking absence of non-myelinated nerve-fibres (Holmes) ( 1000) cf. fig. 13.

affected in all the cases of diabetic neuropathy investigated, suggests that non-myelinated nerve-fibres may be the first to suffer damage from the pathological process responsible for the nervous complication of diabetes. This would explain such diverse manifestations in diabetes as impotence, bladder paralysis, and diabetic nocturnal diarrhoea, often in the absence of neurological symptoms or signs elsewhere (Martin 1953). The studies with priscol have shown a good functional response of the blood-vessels in the great majority of Diabetics with patients with diabetic neuropathy. intermittent claudication and evidence of occlusive were

I wish to thank Dr. R. D. Lawrence for his great kindness, advice, and encouragement ; Dr. W. G. Oakley for much help and criticism ; Dr. L. G Kiloh for his help with the histological sections ; Mr. G. Harwood for technical assistance ; and Mr. W. Smith and Mr. A. J. Poole for the photographs ; my thanks are also due to the patients for their tolerance and ready cooperation ; and to the nurses of King’s College Hospital for their assistance. REFERENCES

Bradbury, S., Eggleston, C. (1925) Amer. Heart J. i, 73. Brattgård, S. O., Lindquist, T., Sigroth, K. (1951) Acta med. scand. 140, 220. Buzzard, T. (1890) Brit. med. J. i, 1419. Clark, D., Hughes, J., Gasser, H. S. (1935) Amer. J. Physiol. 114, 69. De Takats, G. (1945) Proc. Amer. Diabetes Ass. 5, 181. Dieden, H. (1918) Dtsch. med. Wschr. 44, 1048. Doupe, J., Robertson, J. S. M., Carmichael, A. E. (1937) Brain, 60, 281. Douthwaite, A. H., Finnegan, T. R. L. (1950) Brit. med. J. i, 869. DuBois, E. F., Hardy, J. D. (1938) Science, 87, 430. Fatheree, T. J., Allen, E. V. (1938) Arch. intern. Med. 62, 1015. Foster, D. B., Bassett, R. C. (1947) Arch. Neurol. Psychiat., Chicago, 57, 173. Frank, N. (1950) J. med. Soc. N.J. 47, 9. Fulton, J. F. (1950) Physiology of the Nervous System. London. Gasser, H. S., Erlanger, J. (1929) Amer. J. Physiol. 88, 581. Gibbon, J. H. jun., Landis, E. M. (1932) J. clin. Invest. 11, 1019. Grimson, K. S., Reardon, M. J., Marzoni, F. A., Hendrix, J. P. (1948) Ann. Surg. 127, 968. Grundfest, H. (1940) Annu. Rev. Physiol. 2, 213. Guttmann, L. (1940) J. Neurol. Psychiat., Chicago, 3, 197. Jordan, W. R. (1936) Arch. intern. Med. 57, 307. Randall, L. O., Bloor, W. R. (1935) Ibid, 55, 26. Joslin, E. P., Root, H. F., Marble, A. F., White, P., Bailey, C. C. (1947) Treatment of Diabetes Mellitus. Philadelphia. Karsner, H. T., Hamman, L. (1943) N. Orleans med. surg. J. 96, 50. Kendall, A. J., Luchsinger, B. (1876) Pflug. Arch. ges. Physiol. 13, 212. Lewis, T. (1927) Blood Vessels of the Human Skin and Their —

_.

section of normal nerve, showing closely packed clumps of non-myelinated nerve-fibres in between large myelinated ones (Holmes) (x 1000) cf. fig. 12.

Fig. 13-Transverse

Responses.

peripheral vascular

disease

invariably showed a poor response to reflex heating and priscol, although there was no indication of involvement of the nervous system ill these patients. This is rather against the contention that Mclimmia plays an important part in the setiology of diabetic neuropathy. Further support for this helief is given by the fact that non-myelinated nervefibres, which seem to be involved early in diabetic neuropathy. are known to be more resistant to impairment uf blood-supply than are the larger myelinated fibres Gasser and Erlanger 1929, Lewis and Pochin 1938, -

Grundfest 1940). The evidence

presented supports the belief that the non-myelinated subserving the autonomic vasomotor and visceral responses as well as the perception of pain and extremes of temperature are involved early in diabetic neuropathy and may be damaged in nerve-fibres

diabetes with

no other evidence of a nerve disorder on routine clinical examination. The frequent loss of the tendon-reflexes in diabetics without other neuritic

symptoms or signs is explained on the the afferent pathways subserving

same

the

basis, because

tendon-jerks

London.

(1946) Vascular Disorders of the Limbs. London. Pickering, G. W. (1931) Heart, 16, 33. (1936) Clin. Sci. 2, 149. Pochin, E. E. (1937) Ibid, 3, 67. (1938) Ibid, p. 141. List, C. F., Peet, M. M. (1938) Arch. Neurol. Psychiat., Chicago, 39, 1228. —

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—

—

—

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