1954] MANIFESTATIONS OF MELLITUS : VAISHNAVA 463

is the commonest lesion in diabetic neuropathy inal Articles but nerve trunks, spinal ganglia, posterior nerve Orig roots, posterior and lateral columns and ante- rior horn cells of the or the motor nuclei of the brain stem, the autonomic ner- Neurological manifestations of vous system and the brain may also be affected. DIABETES MELLITUS The lower extremities appear to bear the greatest brunt of the disease. % HARI P. VAISHNAVA, m.b., b.s. (Lucknow), exact mechanism of these M.R.C.P. (Ed.) The neurological manifestations is not known. As this condi- Medical Registrar and Resident Medical Officer, tion is more common in elderly people, arterio- Victoria Hospital, Blackpool, England sclerosis is considered the most likely cause Neurological complications of diabetes though this theory does not account for its ^ellitug have baffled many physicians. There occurrence in younger people without signs of ]s an extensive American literature on this sub- arterio-sclerosis; moreover, so many elderly ject which is being increasingly recognised in subjects with arterio-sclerosis do not suffer ?ther countries. The incidence of diabetic neu- from neuropathy. r?Pathy varies with different authors, Jordan Martin (1953).states that the condition is a (1936) mentioning 67 per cent; Collens at al degenerative one in which non-myelinated (1952) 93 per cent ; Bonkalo (1950) 49.3 per small calibre fibres degenerate more extensively contrasting with Rundles (1945) 5 per cent. ^eilt, than the larger myelinated ones. The primary *he difference in these figures is mainly due to lesion, according to Martin, is a degeneration lriterpretation of the symptoms; if objective of axis cylinders and sheaths are re- ^gns must be taken into account with the duced as a secondary effect. These parts of Objective symptoms, only low figures are the nervous system containing the most non- ?btained. The presence of subjective symptoms myelinated fibres are most affected. Lewis and a^?ne according to some authors does not Pochin (1938) hold the view that non-myeli- institute diabetic neuropathy. Jordan (1936) nated and thinly myelinated nerve fibres are neuropathies into hyperglycaemic, cjassifies more resistant to loss of their blood supply than Clrculatory, degenerative and neurotic types, the larger myelinated fibres but that the former ^binowitch (1952) adds the achlorohydric tend to be affected by noxious influences ^Pe in which diarrhoea and other intestinal long before the myelinated sensory and motor fibres. symptoms improve with the administration of Other authors consider that patchy de-myelina- hydrochloric acid. Hirson et al (1953) have tion is early and is mostly confined to the divided them into hyperglycaemic, active and. peripheral nerves but that it can be widespread Symptomatic neuropathies. Roots and Jordan and become continuous and that also, it can be ^aVe tried to separate them into degenerative reversed control of the diabetes. and vascular. by adequate The neuropathy may be permanent once the The writer has found the following anatomi- involvement of axis cylinder takes place. Cal classification of value : Autonomic disturbances and an.early difficulty in the perception of pain and of extremes of 1. including cranial temperature can be explained as due to early nerve palsies. involvement of non-myelinated nerve fibres. 2. Autonomic neuropathy. Ischaemic neuropathy,. which is due to defi- ciency of vascular supply, is progressive and 3. Involvement of , shows itself as nocturnal and brain cord and paroxysmal pain including stem, spinal sometimes cerebellum. hyperaesthesia, anaesthesia, change in colour and gangrene which is extremely pain- 4. Combination of two or more. ful and it is mostly confined to the lower extremities. Symptoms in hyperglycaemic (or functional) **eUropathy improve with the treatment of hy- Post-treatment neuropathy has also been Psrglycaemia and restoration of electrolytes and mentioned for Rundles noticed in a few of his ^ater. Involvement of the peripheral nerves cases that pain and parasthesiae had sometimes 464 THE INDIAN MEDICAL GAZETTE [Aug., 1954 been brought about by Insulin treatment and extremities. The objective sensory signs include this condition has sometimes been termed anaesthesia, loss of vibration and position sense, "Insulin neuritis" and has reverted back on hypersensitivity of the skin to the extent of stopping the Insulin treatment or by administra- having difficulty in dressing and tolerating the tion of Aneurine. Vitamin B. Complex plays bedclothes. These sensory manifestations are an important role in the intermediate metabo- mostly marked in the lower extremities arH* lism of carbohydrate, deficiency of Vitamin Ba sometimes along the distribution of the femoral, causing excessive formation of pyruvic and sciatic, anterior tibial, ulnar and other main lactic acid. Insulin therapy, by utilising car- nerves. Tabes dorsalis may be simulated when bohydrate, necessary for the full operation and lightening pains occur particularly when these existence of Vitamin B, may make a latent are accompanied by sensory ataxia, hypotonia Vitamin B deficiency quite apparent. Even and pupillary changes. This condition is some- pellagra has been precipitated in this way. times called pseudotabes or tabes diabetica. Besides arterio-sclerosis of the vasovasorum Sensory symptoms have also been complained and Vitamin B deficiency, other factors which of on the face. Nocturnal pains are sometimes so severe that the cannot and have been said to play a part in some way or patient sleep other in the pathogenesis of diabetic neuropathy prefers walking to get relief; this condition include toxic effects of , ketone bodies, has been mistaken for osteo-arthritis of the hips- infections, local deprivation of carbohydrates, Pains in the chest, may also simulate angina- lipoid disturbances and mal-nutrition. Collens All these symptoms may be mild, moderate or severe in et al and Rabinowitch have claimed great suc- and may disappear with treatment cess in the treatment of diabetic neuropathy by weeks, months or years respectively. mammalian liver extract. Cases giving pregnant Martin (1953) believes that the earliest of "diabetic cord bladder" and diabetic gross manifestations of diabetic neuropathy are have shown in a few neuropathies improvement diffuse pain, thermal pallesthesia, vaso-motor instead of the months and days years which disturbances, changes in the tendon reflexes these cases used to take with Vitamin Bx, B12, and alteration in pain sensibility in the distal Liver Extract and even B.A.L. (Dimercaprol). part of the lower extremities. Touch and also believe that such as They complications pressure sensibility are also altered. If the and sexual in retinopathy importance diabetes, disease progresses shooting pains develop and in future be treated may successfully. Though vibration sense is lost together with a sense of it is to other mechanisms involved early say, position and touch. Lastly motor power be- in these be found neuropathies may and, per- comes affected. Sometimes the only physical new fields in the metabolism of diabetes haps, sign may be the loss of reflexes, ankle jerks will be opened. being earliest to go. Bailey and Root (1942 and 1947) described Motor changes.?Certain groups of muscles neuropathies occurring between the age group of tend to be wasted. These are the 29 and 69. The duration of diabetes in these quadriceps; the anterior tibial group giving foot uni- cases had been from several weeks to several drop lateral or bilateral; scapulo-humeral muscles years but recently Hirson et al (1953) published causing resemblance to the myopathies. Weak- cases in which the neuropathy had preceded the ness of the pelvic muscles and even of diabetes mellitus. wasting the small muscles of the hand, with or without Peripheral NeuropcCthy sensory symptoms, have been mentioned. Sensory changes.?Subjective sensory symp- Cranial nerve changes.?Involvement of all toms are very common and more often occur the cranial nerves has been described but the without objective signs. Moreover, the patients 6th and 3rd are the most frequently affected. do not always volunteer their symptoms. Some Irregular pupils which react, sluggishly to light consider them to be part of their creeping old are quite common. Partial 6th and 3rd nerve age, especially when symptoms are slight. They palsy may be of fairly rapid onset and, as in may complain of tingling, numbness, nocturnal the writer's three cases, may revert completely cramps, formication, "pins and needles", diffuse to normal after treatment. There may be optic pains in the extremities, burning sensations in or retrobulbar neuritis?unilateral or bilateral- the toes and feet and sometimes stiffness in the Sensory changes on the face have been men- Kxjg., 1954] MANIFESTATIONS OF DIABETES MELLITUS : VAISHNAVA 465

tioned above. These cranial nerve lesions are afferent pain and proprioceptive impulses and c?nsidered to be due to small nuclear haemorr- with intact motor power, repeated minor trauma hages in the brain stem or in some way to peri- lead to destructive and proliferative lesions of pheral neuropathy. Arteriosclerosis in the the bone. Other joints of the body have also retina is a common feature in the old diabetics been involved. Charcot spine in this condition hut the writer has noticed it also in young has been described by Zucker and Marder Patients who have .suffered from this disease for (1952). Signs and symptoms of neuropathy ^any years. The youngest one in his series are usually severe. Bailey and Root collected Was a boy of 23 who suffered from diabetes for 17 cases (in their 2,000 diabetics) with joint ^ years. Discrete waxy exudates with red dots changes which were observed mostly in the scattered all over the retina due to micro- tarsus and matatarsal bones, unilateral or ai*eurisms or haemorrhages, are frequently seen bilateral, earliest changes being thickening of 111 elderly diabetics but it is well known that the trasal bones without any fluid, pain or signs they occur in younger diabetics with long- of inflammation. Pathological fractures have standing disease. Papilloedema and woolly also occurred. Diabetic gangrene due to neuro- exudates with flame-shaped haemorrhages have pathy as opposed to ischaemic gangrene is been seen when diabetes is complicated with usually painless and in most cases limited. renal changes as in the Kimmelsteil-Wilson Painless distention of the bladder due to re- syndrome. Retinitis was seen in proliferans tention of urine has been mentioned by Jordan two of the writer's one 20 patients, being years and Crabtree (1935). They described 7 cases age and the other 43. Strands of connective with large residual urine in the age group of tissue radiated and in the from the retina 42 to 62 showing arterio-sclerosis which varied of the two cicatrisation had y?unger patients in degree. They believe this to be a factor in ?aused detachment of the retina. producing such a distention. Autonomic changes are most marked in the distal parts of the limbs Autonomic neuropathy because their small vessels receive vasoconstric- tor branches from mixed nerves while Among many autonomic manifestations which proxi- fibres come from have been described are orthostatic hypoten- mally these sympathetic s*?n, tachycardia, abnormalities of sweating and plexuses in the adventitia of the aorta and its |etnperature regulation, Argyll Robertson pupils, main branches. lritermittent noctural diarrhoea, constipation, Involvement of central nervous system anorexia, gastric and intestinal atonv, distor- Signs and symptoms within the central tion of the small bowels, ("puddling"), sexual nerves system, which mimic subacute combined sterility, loss of libido, atrophy of ^potence, degeneration, have been seen with the involve- ^stes and ovaries, a tendency towards mis- ment of the posterior and lateral columns, carriage, dependent oedema, (which is some- (sometimes only the posterior column). Ante- *Ws mistaken for congestive heart failure or rior horn cells may also be affected alone with ^0r renal oedema), loss of sphincteric control resultant muscle wasting and diminution of urgency at without Blis- night polyuria. tendon reflexes. ters on the toes, shining skin and loss of nails, Painless aseptic necrosis of the phalanges resem- Clear cut features which occur are weakness, bling osteo-myelitis radiologically, with or wasting, areflexia, loss of sensation, extensor ^vi'hout skin lesions, have all been described. plantar responses and involvement of sphinc- Indies (1945) described drenching sweats at ters. Bonkalo (1950) described cases of cere- night in the absence of other known causes. bellar ataxia showing hypotonia and nystagmus and Sophie changes in the skin may precede pain- scanning speech. Crying spells, depression, less perforating ulcers, most of which heal easily vertigo and agitation have all been attributed to ^Ith adequate treatment. Though the com- lesions of the brain due to the diabetes. Cranial monest causes of Charcot joints are tabes dor- nerve lesions have been described above. been Salis and syringomyelia, they have also Illustrative Cases Ascribed in peripheral nerve and spinal cord Diabetic Issions, congenital sensory neuropathy, leprosy, Peripheral Neuropathy arid diabetes mellitus. In diabetics of long Case 1.?Mrs. S. S. aged 61, complained of landing, due to impairment of conduction of weakness in the legs which improved slightly 466 THE INDIAN MEDICAL GAZETTE [Aug., 1954 after a month and then recurred. At that time tered blind persons. The father and mother she had no symptoms of diabetes mellitus but 2 were cousins but there was no history of dia- years later this was discovered. Tingling and betes in the distant relatives. The patient was paras .hesiae in the legs was followed shortly having Insulin but had never been satisfacto- after by numbness and some impairment of rily stabilised. Retinopathy had been re- power. She showed well-marked signs of peri- ported by the Ophthalmic Surgeon, some pheral neuropathy with general wasting in both months previously. The patient had early legs and total analgesia with sensory impairment bilateral cataracts, and his pupils were irregular of several grades below the knees. The protein and did not react to light. His general growth content of the C. S. F. was 105 mg. per 100 ml. was that of a boy of 15 and he was underweight, but there was no other abnormality and the and mentally somewhat backward. There were was on diet diabetes easily controlled and no changes in sensation, motor power or the Soluble Insulin 14 units in the morning and 6 reflexes. His bladder was distended to just in the evening. She was given Vitamin B com- below the umbilicus. There was no overflow plex and physiotherapy. While she was in hos- incontinence and he had a normal desire to pass pital she became incontinent of faeces with water but there was always residual urine recurring attacks of diarrhoea and did not res- amounting to 20 ozs. and there was no tender- pond to any measures. Fractional Gastric ness in the supra-public region. C.S.F. protein Analysis and radiological examination of the was 100 mg. per 100 ml. with an excess of alimentary tract and spine revealed no abnor- globulin. The blood Khan test was negative. mality. The pulse had alweys been in the region of 110- 120. The patient was stabilised and was Motor Neuropathy sent home but within a few days was re-admitted with marked agitation. He died soon after Case '2.?Mrs. M. S. aged 71, was obese and and the cause of death was not determined. had had diabetes for over 10 years wi h inade- His bladder was large and showed fine trabe- quate control by diet. For over 12 months she culation. There was a slight dilatation of had noticed difficulty in walking, especially ureters but the kidneys were normal. There when going upstairs, and she was geting gra- were no causes of obstruction in the urethra. dually worse. Examination showed wasting The brain and spinal cord showed areas of of the quadriceps and muscles round the hip softening. joints. Sensation- and reflexes were normal and Case 5.?Mrs. G. R. had been dia- there was no wa&ting of subcutaneous tissue. aged 62, betic for over 5 but did not attend a dia- There was no arthritis of the hips. years ' ; ??? ' l ; ?: | ::.Vi ij< I ?-;! |T" !~"| 1 H betic clinic regularly. Her liver was 4 fingers and was soft. She had in "Functional" or "hyperglycaemic" type enlarged difficulty walking on account of ataxia. Examination Case 3.?Mrs. L, aged 43, was noted to have revealed loss of reflexes, vibration, pain, touch polyuria, increased thirst and hunger, and loss and postural sense in the lower extremities. The of weight from 15 to 12 stones. When \chilles tendons were quite tender and a pain- seen the diabetes was unsatisfactorily control- less perforating ulcer was present on the bnll of led with only slight improvement in her symp- fhe right toe. The right metatarsophalangeal toms. She was admitted in severe diabetic ;oint was lax and could be moved in any direc- ketosis and was then stabilised on Insulin. ion without discomfort to the patient. X-ray After the institution of Insulin therapy the -howed thickening of the adjacent bones with patient lost the severe cramps and "pins and diminution of bone space. The patient gra- needles" in the legs which had been worse a+ dually improved on adequate treatment with night. She had no other signs of diabetic diet, Insulin and Vitamin B complex. neuropathy. Case 6.?Mr. S. H. aged 66, attended the Eye Clinic on account of diminution of vision in the Autonomic Neuropathy right eye. The left eye had been blinded by Case 4-?Mr. E. R. was aged 23, and had an injury many years previously. Diabetic been diabetic since the age of 5. His brother retinopathy was observed with small haemorr- was 20 years of age and has also suffered from hages and several micro-aneursyms and exudates diabetes since the age of 5, Both were regis- at the macula. Except for the loss of a fe^v Plate XLII NEUROLOGICAL MANIFESTATIONS OF DIABETES MELLITUS PAGE 463

?

1111

HH II: 1 -I

!? , . . Fiff- 1. . . , , e.,. VvsSl*H?s c u ?ig. Sth5tn |JJetatgr c.harcotarc?t jointjoint withwith necrosisnecrosis ofof thethe leftleft Fig.Fig. 2.2. ^one.bone. ^It also also showsshows calcificationcalcification of of one one of of AfterAfter fivefive monthsmonths adequateadequate controlcontrol ofof diabetesdiabetes mellitusmellitus dij>vgItal(jjr.Sa' ?'tal arteriesarteries butbut pulsationpulsation inin thethe quitequite normal.normal. withwith insulininsulin andand dietdiet butbut withoutwithout anyany chemotherapy.-chemotherapy. Aug., 1054] MANIFESTATIONS OF DIABETES MELLITUS : VAISHNAVA 467

Pounds in weight he had no symptoms of dia- ence in the literature to bladder involvement betes mellitus. He had a chronic painless ulcer in such a young patient, only 23 years of age. ?n the lateral margin of the left foot which Cases 5 & 6 illustrate Charcot joint, perfora- '?ealed when his diabetes was controlled by diet ting ulcer and aseptic necrosis. Both improved anfl Insulin Zinc Suspension (Lente) 12 units with adequate control of the diabetes. daily. Tendon reflexes were absent in the lower e*tremities and all forms of sensation were di- Case 3 was a good example of hyperglycae- minished. X-ray showed necrosis of the 5th mic or functional peripheral neuropathy. All Medial side of the tarsal bones (See Plate XLII). her symptoms improved after hyperglycaemia was controlled. Diabetic Myelopathy All these cases presented poorly controlled Case 7.?Mrs. B. L. aged 73, was admitted diabetics. Garland and Tavener (1953) repor- ?n account of weakness of the legs of 10 months' ted cases of myeloparhy which have shown duration. She had been diabetic for the last improvement and reversibility of extensor plan- ?ne year. There was a family history of dia- tars though Case 7 actually deteriorated. In betes. The patient started with tingling and Case 1, neurological signs and symptoms Numbness and then the legs "gave way" while actually preceded the discovery of diabetes diking. Her general condition was satisfac- mellitus and such cases are not unknown. One tory. The pupils were unequal and reacted is also familiar with cases where, on routine ^Uggishly to light. The fundi showed arterio- examination, diabetes is discovered though the sclerotic changes with micro-aneurysms and patient may not complain at all of any main ^vaxv exudates. The lower abdominal muscles symptoms of this disease. It is analogous to ^'ere weak and there was general wasting of 'he appearance of signs of subacute combined both lower extremities and gluteal muscles with degeneration preceding Addisonian anaemia. bilateral foot drop. All the reflexes were absent Some authors have noticed disturbed carbohy- aNd the left plantar was extensor. There was drate metabolism without glycosuria in cases of diminution of all sensations. The skin of the unfamiliar neuropathy and advocate Glucose legs and feet was dry and rough and the nails Tolerence Testing. Though in a patient with Xvere broken. She became incontinent of faeces. glycosuria and increased protein in the C.S.F. C.S.F. was within normal limits and X-ray the writer made a diagnosis of diabetic neuro- the chest, spine and colon were all normal, pathy for a few days he had to change it to ^he patient was given intensive treatment metastases in the hypothalamus. This increa- without any benefit. sed protein is thought to be due to involvement of posterior roots as in Guillain-Barre polyneu- ritis. In spite of uncertain prognosis in severe Discussion neuropathy, perseverance in treatment with adeauate diabetic control, vitamins and phy- The writer has described above only the most siotherapy, is well worth a trial. Noteworthy cases. He has observed objective sensory symptoms quite commonly in his dia- Summary and Conclusion betic patients. The first case was diagnosed as a Guillain-Barre polyneuritis as there was The neurological manifestations of diabetes lr>crea?ed protein without an increase in the cell- mellitus are classified anatomically as follows : count, but the of diabetes and the sub- presence (i) Peripheral neuropathy. sequent course of the illness led one to believe that it was a case of diabetic neuropathy. (u) Autonomic neuropathy.

Case No. 4 was also provisionally diagnosed (m) Involvement of C.N.S. as congenital obstruction of the neck of the (iv) Combination of two or more of these. bladder (and was actually put on the list for cystoscopy), but his tachycardia and increased Several noteworthy cases are described illus- C.S.F. protein were in favour of autonomic trating this concept. Adequate confrol of the Neuropathy involving the bladder. Thus the diabetes with Insulin and diet, and of the neuro- diagnosis was proved subsequently at post pathy wMi the Vitamins, especially of the B Mortem. So far the writer has not found refer- group, and physiotherapy, is advocated. 468 THE INDIAN MEDICAL GAZETTE [Aug., 1954

Acknowledgement

The writer is indebted to Dr. P. R. Duncan for his constant encouragement and helpful sug- gestions and his thanks are due to Dr. R. E. Horsfall, Dr. I. McD. G. Stewart, for allowing him to quote their cases, and also to Dr. D. M. L. Doran and Dr. M. Deane of the West Middle- sex Hospital under whom be worked as Registrar.

He wishes to thank Mrs. M. Barnett for typing.

REFERENCES

Bailey. C. C.. and Root, J. Clin. Invest., 21, 629. H. F. (1942). Idem (1947). New England J. Med., 233, 397.

Bonkalo, A. (1950) .. Arch. Intern. Med., 85, 944. Collens, W. S., Zinlin- Amer. J. Med., 12, 53. " ' ' ; sky, J. D., and Green- } I 7< | : I I | i "VVALD, J. J. (1952). Garland, H., and Brit. Med. Ji, 1405. Tavener, D. (1953). Hirson, C., Fienman, Ibid., i, 14CS. E. L., and Wade, H. J. (1953).

Jordan, W. R. (1936) .. Arch. Intern. Med., 57, 307. Jokdan, W. R., and Ibid., 55, 17. Crabtree, H. H. (1935).

Lewis, T., and Pochin, Clin. Sci., 3, 141. E. E. (1938).

Martin, M. M. (1953) .. Lancet, i, 560.

Rabinowitch, I. M. Amer. J. Med., 12, 59. (1952).

Rundles, R. W. (1945). Medicine, 24, 111. Zucker, G.. and Mardei?, Amer. J. Med., 12, 118. M. J. (1952).

SELECTED BIBLOGRAPHY

Beidleman, B., and Amer. J. Med., 12, 43. Duncan, G. G. (1952)

Jordan, W. R. (1943) .. South Med. J., 36, 45. Jordan, W. R., Randall, Arch. Intern. Med., 55, 26. L. 0., and Bloor, W. R. (1935).

Joslin, E. P., et al. Treatment of Diabetes Melli- (1946). tus. Lea & Febiger, Phila- delphia.

Rarinowitch, I. M. Amer. J. Digest. Dis., 16, 322. (1949).