53

CLINICAL SECTIONCLINICO-PATHOLOGICAL CONFERENCE-No. 16*

Non-Diabetic Coma in Diabetes

Case History (Dr. Russell Fraser)We are considering the case of Mrs. B.B., aged

72 in 1951. She was first admitted in 1940 withsix months' typical diabetic symptoms; loss ofweight from 9 st. to 7 st., hunger, thirst, vulvalpruritus and tiredness. This had been partiallyrelieved by her doctor's diet prescription. Shehad had good health hitherto.

The family history included no diabetes; hermother was an epileptic and her one child haddied at birth.On examination she showed some wasting,

blood pressure o08/70, and an egg-shaped thyroidlump known to have been present for five years.Urine: S.G., 1021, albumen negative (as through-out her illness), sugar yellow to Benedicts,Rothera acetone test positive. Glucose tolerancetest: Fasting blood sugar, 251 mg. per cent.;1 hour, 294 mg. per cent.; i hour, 318 rig.per cent.; i4 hours, 408 mg. per cent., and2 hours, 343 mg. per cent.; all urines positivefor sugar.

Out-Patient Supervision, 1940 to 1946. Herweight remained at 8 st. with little variation, andapart from a few hypoglycaemic attacks she wassymptom-free, receiving 20 units of soluble in-sulin twice a day, sometimes exchanging part ofthe insulin for P.Z.I. During 1945 the insulinwas changed to globin and increased to 60 units,and the glycosuria decreased (from yellow tousually green with Benedict's solution). From1946, though the insulin remained unchanged, herurinary Benedict was usually orange. In October1948 her blood pressure was first noted to beraised (196/o00).Her second admission, in I949, was for thyroid

reassessment. She had been more worried and

*Held at the Postgraduate Medical School of London..The report was assembled by Dr. Bernard Lennox, towhom the Editor would once more like to expresshis appreciation. The sections are by Mr. J. G.Griffin andi the photomicrographs by Mr. E. V.Willmott.

increasingly dyspnoeic on effort for six months.On examination her blooc pressure was i8o/20o,her heart enlarged and the apex beat in the fifthspace I in. outside the mid clavicular line; herjugular venous pressure was raised 5 cm., butthere was neither oedema nor signs of lung con-gestion. Her left eye showed a cataract and herright some small retinal haemorrhages. Hererythrocyte sedimentation rate was found to be10 mm./I hour (Westergren), haemoglobin 84 percent., her fasting blood sugar 450 mg. percent., serum cholesterol 220 mg. per cent., andurea 44 mg. per cent. Her B.M.R. was -45 percent., and her urinary excretion of radio-activeiodine was normal, 44.9 per cent. of the ad-ministered dose in o to 8 hours, 20.8 per cent. in8 to 24 hours, 7.5 per cent. in 24 to 48 hours, and73.2 per cent. in o to 48 hours. It was concludedthat her thyroid function was normal and that thedeterioration in her condition was due to hyper-tension and recent worries.

Supervision Until the Next Admission. For fourmonths from December 1950 she was given methylthiouracil, 0.2 g. t.d.s., as a therapeutic trial.She became myxoedematous but no improvementin her symptoms or diabetes occurred, furtherexcluding the suspicion of thyrotoxicosis. Shewas admitted in November in hypoglycaemic comadue to missing her breakfast, and in December indiabetic coma precipitated by a digestive upset;she also had other minor insulin reactions. Her.insulin remained equivalent (P.Z.I. 36 and S.I. 24),her weight steady and her urine generally onlygreen to Benedicts.Her third admission, in September 1950, was on

account of one month's intermittent vaginal bleed-ing. An ulcer was felt on the cervix uteri;biopsy revealed a cancer, which was found to bein Stage 2. Three radium insertions as well asdeep X-ray therapy to the pelvis were given.This was complicated by attacks of acidosis andby urinary infection.Her fourth admission, in February 1951, was on

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54 POSTGRADUATE MEDICAL JOURNAL January 1952

account of pain in the right thigh of three months'duration. On investigation there was a fracture ofthe neck of the right femur and she had lost j st.in weight. Her blood pressure was I8o0/oo, therewere no signs of heart failure and nothing ab-normal was felt per rectum except some fixation ofthe uterus. X-rays confirmed the fracture of thefemur and showed a generalized osteoporosis .ofthe spine. Her erythrocyte sedimentation ratewas 3 mm./i hour (Westergren), her serum cal-cium II.0 mgm. per cent., phosphate 2.4 mgm.per cent., and phosphatase 16.5 King-Armstrongunits per cent. Her leg was put up in a caliperand stilboestrol and testosterone were given, atfirst by injection, later by implantation (two25 mgm. estriadol and three I50 mgm. tes-tosterone). From April 4 to 8 tromexan was givenfor tender calves but was stopped because of twoattacks of vomiting.On the morning of April 2I an attack of vomiting

progressed to semi-coma. Her urine gave noreduction and was negative for acetone; her bloodsugar was ioo mgm. per cent. On examinationshe had a pulse of IIo, blood pressure of I80/90,jugular venous pressure of 3 cm., but no oedemaor abnormal chest signs. There were no localizingsigns in the central nervous system; her pupilswere dilated but reacted, her tendon jerks werebrisk and equal and her plantar reflexes flexor.Her fundi showed no new abnormality (onlyarterial changes). Intravenous administration of50 cc. of 50 per cent. glucose produced no change.Vomiting continued at intervals throughout theday until a nasal drip of glucose, together withinsulin injections, was instituted. Thereaftercoma fluctuated but steadily deepened; fromabout the tenth hour her blood pressure remainedunder ioo systolic and steadily fell. A lumbarpuncture on the second day revealed a low pressurebut no other abnormality. Coma deepened with-out localizing signs and she died on April 23.

Diagnosis. Diabetes mellitus. Non-toxic thyroidadenoma. Hypertensive heart disease. Cancerof cervix (? healed). Coma of uncertain origin(? cerebral thrombosis).Autopsy Findings (Dr. C. V. Harrison)A thin elderly woman (5 ft. 8 in. and 7 st. 2 lb.)

with a visible thyroid nodule and an old ap-pendicectomy scar.The heart (395 gm.) showed left ventricular

hypertrophy but was otherwise healthy. Thelungs showed congestion and oedema but nomacroscopic pulmonary emboli. The alimentarysystem was normal. The thyroid contained acalcified nodule 30 mm. diameter in the isthmus.The other endocrines appeared normal. Thekidneys weighed 280 gm. together and showed a

trace of granularity and some thinning of thecortex. The cervix uteri showed some scarringbut no apparent tumour and there was scarringand narrowing of the vagina. The lymph nodesalong the right iliac artery showed macroscopicmetastases. The right femur showed a fracturedneck with some callus but no union. The brainshowed vaguely-defined areas in the right occiputand the right corpus striatum where the tissueswere congested and a little soft, but withoutdefinite thrombosis or infarction.

HistologyThe right lung contained a microscopic pul-

monary embolus. All organs showed widespreadand severe arteriolosclerosis (Fig. 3) with hyalinechange. This was particularly severe in thekidneys which also showed marked fibrous thicken-ing of the capillary basement membrane (Fig. i)like that seen in the Kimmelstiel-Wilson kidney.The thyroid nodule was inactive. The cervixuteri was free from tumour but there were de-posits in the iliac glands. The femur showedosteoporosis but no tumour or bony necrosis andno apparent activity of osteoblasts or osteoclasts.There was a zone of callus along the line of thefracture (Fig. 2).The brain showed an unusually severe degree of

arteriolosclerosis with many hyaline arterioles(Fig. 4). Some of these were associated withhaemorrhage, others with thrombosis (Fig. 5).The brain in these areas showed cell destructionand the formation of fat-filled compound granularcorpuscles (Fig. 6). We found no localized area ofsoftening.The final pathological diagnosis was: Hyper-

tension and diabetes with widespread arteriolo-sclerosis and diffuse cerebral ischaemia. Coinci-dental carcinoma of cervix with post-irradiationosteoporosis of femur causing fracture.

DiscussionDR. FRASER: This is an instance where the

pathologist has had no trouble in producingpathology. Dealing with some of this pathology,perhaps we might take the brain first of all. Wewere puzzled in life as to the cause of the coma andI think perhaps we are a little puzzled still.Firstly, we wonder how possible it is that thearterial changes shown to us could be secondary tothe prolonged low blood pressure in the laterphases of her coma (systolic pressure below60 mm. for two to three days). Secondly, on thatsame point, how are we to envisage the pathologyoccurring? Why did the thrombosis occur in somany areas?With regard to the diabetic complications, this

case had appeared to be an instance of aiterial

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January 1952 Clinical Section 55

ii

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

FIG. i.-Kidney. Glomerulus showing thickening of the interstitial tissuebut no fully-form!d nodular lesions. (Mallory stain x 460.)

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mmQ. pa.m.. i.. . 44.~~4..

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-.4..Wa. .a. ....fFt.:*WIa

FIG. 2.-Head of femur, showing callus formation. The two big trabeculae to the right areoriginal bone, the rest is new-formed bone, cartilage and fibrous tissue. (H. & E. X 54.)

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6POSTGRADUATE MEDICAL JOURNAL January 1952

FIG. 3.-Liver showing hyaline arterioles in a portaltract. (H. & E. x 256.)

disease without the other degenerative complica-tions of diabetes, and I would like to suggest thatperhaps Dr. Harrison has not demonstrated realKimmelstiel-Wilson lesions in the kidney. Per-haps Dr. Gilliland would take that up with him.In life we never found any evidence of diabeticneuropathy, we never found any albuminuria andwe never found any really convincing retinitis. Ather first admission in 1948 some retinal haemor-rhages were noted and there was a cataract, butshe was old and hypertensive-adequate causes forthis eye pathology without incriminating thediabetes. As regards the other points, thethyroid did seem to fit our expectation that this wasan adenoma which was ancient and had led to noabnormal thyroid function. The instability of herdiabetes was unusual. She, after all, was anelderly woman who started having diabetes in the6o's and yet I think it would be proper to call herdiabetes insulin-sensitive as well as extremelyunstable under control. She wa. not obese likethe typical elderly insulin resistant diabetic. Thisis an unusual type of diabetes in the elderly but,as she instances, this variety does occur at thisage.

FIG. 4.--Brain, occipital region showing two arterieswith hyaline fibrosis of their walls. (H. & E.X o05.)

Two other small points not particularly relatedto the diabetes; first, the pathological fracture.The osteoporosis seemed clearly evident in theX-ray, even if not histologically very marked. Ialways understood that radiation osteoporosis was

primarily ischaemic; 1 suppose it is quite likelythat the vessels had been reduced in number by theX-rays without histological evidence still beingpresent. The cancei of the cervix is another in-teresting point; if early diagnosis leads to the cure

of cancer, this case should have been cured. Ithad one month's symptoms and immediate treat-ment, but there are cancer cells in the lymphnodes.

DR. GILLILAND: I would like to comment onthe kidney pathology here. I think we have seena very remarkable degree of arteriosclerosis. Thatis, I think, common in the diabetic-Bell hasshown that it is five times more common in a

diabetic, especially a diabetic woman, than in thesame age range of ordinary people. But 1 thinkit is confusing the issue to call this type of lesiona Kimmelstiel-Wilson lesion. After all, Kimmel-stiel and Wilson described in their paper a pictureof nodules inside the gomerulus, a relatively un-

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January I952 Clinical Section 57

FIG. 5.-Brain, occipital region showing a thrombosedvessel with an inflammatory reaction. (H. & E.X I73.)

changed glomerulus apart from the nodules, andthey did show also the caps occurring on Bowman'scapsule, caps of hyaline material (which are notpresent here), and also quite considerable fattychange in the tubules, which also we have not seentoday. I think it is wrong to call today's picture aKimmelstiel-Wilson lesion. The argument hasbeen made in the past that this is the early grade ofit, but there has been no evidence produced on thatpoint, and I think the picture we saw rather con-tradicts it. The glomerulus has been shot throughwith fibrous tissue, it is not a normal-lookingglomerulus, so that even if it developed hyalinelumps the picture would still not be that of thetypical lesion. So 1 think that as Kimmelstiel andPorter said in their last review there are two typesof lesion, and that these have been confused inmany people's minds. If you stick to the nodularform as the Kimmelstiel-Wilson lesion you cancorrelate it with a clear clinical picture. But thesort of thing seen in this case, as Dr. Fraser haspointed out, did not give any clinical signs at all,not even albuminuria.

FIG. 6.-Brain, occipital region showing an arterysurrounded by compound granular corpuscles.(Frozen section. Sudan stain x 256.)

PROFESSOR MCMICHAEL: 1 would like to askwhat the blood pressure in fact was on the lastday. We have been given a variety of accounts,with I80/90 as the only recorded figure, and nowwe are told it was below 50.

DR. FRASER: As is evident, I had to abbreviatethis a lot. The blood pressure when the attacksstarted on April 2I, 1951, was I80/90, that is,within three hours of the onset of the first attack.I recorded that in our summary to indicate thatshe had neither rise nor fall in blood pressure withthe onset of the attack. Eight hours later herB.P. was 40/? and that has been abbreviated in oursummary, I am sorry to say, merely to ' B.P. fell.'Thereafter, that is, from i hours after the onsetof coma on the 2Ist to midday on the 24th, herblood pressure was never above 60 systolic.

DR. LENNOX: Dr. Harrison has given me per-mission to comment on the Kimmelstiel-Wilsonlesion for him as I have been somewhat interestedin the subject. I agree very much with what Dr.Gilliland has said on this point. I do not thinkthere is any doubt that if you see a kidney with the

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58 POSTGRADUATE MEDICAL JOURNAL January I952

kind of lesion seen in this case, with the basementmembranes unusually thickened in a tree-likemanner, you can begin to suspect diabetes. Youdo see such lesions in cases of simple arterio-sclerosis but it is relatively much more frequent incases of diabetes. But this is not associated withthe clinical picture of the Kimmelstiel-Wilson type,and it is probably a mistake to use the termKimmelstiel-Wilson for anything short of the fullhistological picture of big balls of aniline blue-staining material in the centre of capillary loops,and usually also red fuchsinophile material(probabiy lipoid) in several different sites. Thefull-blown Kimmelstiel-Wilson lesion is pathogno-monic of diabetes; this lesser, possibly quite un-related lesion is only a pointer.There are two other points I would like to raise:

I am not sure that Dr. Harrison has demonstratedany changes very clearly in the femur whichsuggest a cause for the fracture. He did demon-strate osteoporosis, but Dr. Fraser's X-raysshowed that the osteoporosis was generalized in thewhole spine, as far as I could gather, well out ofthe range of radiation, and I would like to suggestthat the patient in fact had a generalized osteo-porosis. From the point of view of the irradiationhaving seriously affected the femur at all, 1 wouldlike to recall a case, of which I have just seen thehistology, of Hodgkin's disease which had beenirradiated about three months before, in which themarrow of the femur showed the same kind ofchanges which have been described in atom bombcasualties after about the same interval, that is,overgrowth of reticulum cells and various primitiveforms of marrow cells. I think if this femur hadsuffered from irradiation there would be character-istic changes in the marrow cells. I do not knowwhether Dr. Harrison did in fact notice the pre-sence of any such changes. What I am trying tosuggest is that all we have seen are the changes ofan ordinary osteoporotic senile fracture of thefemur and that the association with the carcinomaand its irradiation might be purely coincidental.The third thing I would like to say is that the

inflammatory and thrombotic changes in thevessels of the brain were extremely unusual ones.They are so unlike the changes in the vesselselsewhere in the body that they almost suggestthey are not part of the ordinary arteriosclerosis.I am sure this is not a case of arsenic poisoning,but as an indication of the fact that I think it is anextremely odd arterial disease I would like tosuggest that in some respects it recalls an arsenicalhaemorrhagic encephalitis as much as a primaryvascular lesion.DR. COPE: Just one point about this coma. Is

it not rather unlikely that we can attribute thiscomplete and deep coma (as it ultimately was) to

the widespread blocking of small arterioles, inview of the fact that there was never an extensorresponse, as far as I can see, right to the end.DR. FRASER: Not right to the end.DR. COPE: You say 'no change in the C.N.S.

signs until the end.'DR. FRASER: Till she was very deep in coma,

by which time we felt it had no localizing value.We said ' no localizing C.N.S. signs.'

DR. HOWELL: As regards this 'diffuse'change throughout the brain, from your macro-scopic appearances the main instance was at thelevel of the trigone, that is in the parietal lobes,was it not?

DR. HARRISON: And further back. It was acoronal section at the level you state, but I merelyshowed that because it was the best preservedpiece. Sections were in fact also taken posterior tothat, further into the occipital lobe.

DR. HOWELL: My point was that it has beenpostulated (though no such case has yet been pro-duced) that if you got a sudden bilateral destruc-tion of function in the parietal lobes you wouldsuddenly remove the neurological mechanismunderlying the body image, and that would, so tospeak, produce a disembodied spirit who must bein coma. That is Dr. Purdon Martin's idea asexpressed in his lecture on Consciousness, and wehave been looking for a case ever since and we arejust wondering whether we can possibly manoeuvrethis one into it!

DR. DONIACH: To add another to Dr. Lennox'ssuggestions about the brain changes; is it possiblethat your frozen section stain for fat might re-present the end result of fat embolism following afracture?

PROF. MCMTCHAEL: Dr. Harrison!DR. HARRISON: 1 will try to take these points.

The Kimmelstiel-Wilson lesion has already beendealt with by Dr. Lennox. With regard to cerebralchange and its relation to coma. First of all, theextensive arteriolar hyaline change must have beenpresent before the terminal coma; it is an olddisease. The fact that there is an inflammatorycellular infiltration 1 think dates the cerebralvascular changes as being a good many hoursbefore decease. I do not recall how long thepatient was in coma.

DR. FRASER: Three days.DR. IIARRISON: I should have said certainly 24

hours and probably appreciably longer. Whetherin the first place the coma and the fall of bloodpressure caused the thrombus or the thrombuscaused the fall of blood pressure and coma Ifrankly do not know. To come to Dr. Howell'spoint; we have not taken sections from enoughplaces to be able to state where the lesion ispresent and where it is not. We were concerned

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January 1952 Clinical Section 59

with finding a lesion and we went for the areaswhere morbid anatomy gave hints. I cannot helpfurther. With regard to the failure of cure in anearly carcinoma, may 1 delete the word 'early'because according to the notes it was Stage 2 andnot a Stage i carcinoma, so it is not really an' early' tumour in clinical practice though it wasearly on a time scale of symptoms.

Lastly, with regard to the bone; 1 must confesspersonal ignorance over this. I have merely donethe obvious thing and taken advice from theorthopaedic surgeons and turned up a few papers.They say it is an absolutely cast-iron case and Iam not going to cross swords with them. Withregard to published papers, there is an admirableone by McCrorie (Brit. J. Radiol., I950, 23, 587).He observed ten cases of spontaneous fracture ofthe neck of the femur amongst approximately I,oooirradiated pelves, roughly one in Ioo. They alloccurred from a few months to about a couple ofyears after treatment; they all showed osteo-porosis. He denies the occurrence of necrosis andhe offers two suggestions; one is that unduevascularity of the bone following irradiation isassociated with porosis; the other, based on ex-perimental evidence, is that irradiation depressesthe osteoblasts without depressing to the sameextent the osteoclasts.- You therefore have a re-lease of activity on the part of the osteoclasts andthe bone goes into a sort of negative state. Theseare hypotheses, and I think the truth is that we areextremely ignorant about this particular changeand it will be necessary to collect much more databefore we can say anything definite.

DR. GILLILAND: What change would thetestosterone and oestradiol for two months pro-duce in the bone?

DR. HARRISON: I have no idea.DR. McLEMORE: I would like to ask Dr.

Harrison about the pituitary in view of the pre-sence of thyroid and diabetic symptoms as well asosteoporosis.

DR. HARRISON: It was examined. Dr. Pearsecould find nothing significant of either disease.DR. PEARSE: It was a pretty active gland. The

acidophils were the most interesting cells, theywere considerably degranulated and there werelarge forms resembling the Erdheim cells of preg-nancy. But in view of the therapy 1 could notattribute it to anything else.

DR. FRASER: Can you attribute it to the oestro-gen and testosterone?

DR. PEARSE: Yes, 1 think we can.DR. FRASER: Could I comment on the osteo-

porosis and the fracture? I think it is a little odd toattribute this solely to irradiation in that it isunusual for the standard irradiation of the cervixto produce this effect. As pointed out by Dr.Lennox, this patient's X-rays showed generalizedosteoporosis throughout the spine which could notbe attributed to the irradiation of her pelvis.Possibly the osteoporosis was increased by weightloss due to the cancer. I wonder whether theanswer really is not that elderly women are ratheroften irradiated in that region and they very oftenalready have post-menopausal or senile osteo-porosis, and if you irradiate anyone with primaryosteoporosis anyhow you will exacerbate this orany similar atrophic condition. I think thedifficulty in attributing the whole thing to osteo-porosis is that it is extremely rare to get a fractureof the femur as the presenting feature of osteo-porosis, so perhaps radiation fractures have twocauses-both radiation and osteoporosis.

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