73DR. A. H. IMRIE : APLASTIC ANEMIA FOJaeOWTNG NEOKHARSIVAN

prominent in both of them, and pentose nucleotidetherapy was tried in the hope of stimulating the

granulopoietic activity of the bone-marrow, but notthe slightest response was obtained.Evidence is increasing that dramatic success can

be expected of pentose nucleotide therapy only inthose cases of granulocytopenia attributable to a

" maturation arrest " of the granulocytes of thebone-marrow.3 In such cases much hyperplasia ofthe granulopoietic elements of the marrow is found,and this is in contrast to the hypoplasia or aplasia seenin aplastic anaemia. There is usually no associatedanaemia, or only a very slight diminution in red cells.

If this supposition be correct the failure of pentosenucleotide in the above two cases was to be expected,for in both of them there was almost complete aplasiaof the marrow. Failures in the treatment of granu-locytopenia by pentose nucleotide have been recordedby Fairley and Scott,4 Blackie,5 Hall,6 and Fettesand Whitby,’ and it is probable that many of thesecases were of the aplastic variety, not associatedwith hyperplastic changes in the marrow. In thetwo cases reported here the presence of severe anaemiain addition to the granulocytopenia made it neces-sary to give blood transfusions. It may be saidthat transfusion was too infrequent ; but as oftenhappens, the transfused blood was quickly destroyedand gave little benefit apart from a slight improve-ment in the red cell count of the second patient.A larger number of cases is obviously necessary

before any definite conclusions can be reached with

regard to the use of pentose nucleotide in aplasticconditions of the bone-marrow; but in view of theuncertain 2etiology of many of these conditions itseems to be worth a trial.

My thanks are due to Dr. T. W. Griffiths andDr. G. Goodhart for their kind cooperation.

BIBLIOGRAPHY

1. Mills, E. S.: Canad. Med. Assoc. Jour., May, 1931, 628.2. McCarthy, F. P., and Wilson, R.: Jour. Amer. Med. Assoc.,

1932, xcix., 1557.3. Lescher, F. G., and Hubble, D. : Quart. Jour. Med., 1932,

i., 434.4. Fairley, N. H., and Scott, H. H. : THE LANCET, 1933, ii., 75.5. Blackie, W. K.: Ibid., 1934, ii., 335.6. Hall, D. : Ibid., 1934, ii., 1441.7. Fettes, J., and Whitby, L. E. H. : Ibid., 1935, i., 205.

APLASTIC ANEMIA FOLLOWING

NEOKHARSIVAN

BY ALEX. H. IMRIE, M.B. Glasg., M.R.C.P. Lond.ASSISTANT PHYSICIAN TO OUT-PATIENTS, ROYAL

INFIRMARY, GLASGOW

AMONG the untoward results of the treatment of

syphilis by the organic arsenical preparations aplasticanaemia and the other blood dyscrasias seem to havereceived very little attention in this country. Never-theless, although rare, they are well recognised,especially in America, where McCarthy and Wilson 1in 1932 published an analysis of all the availablerecorded cases and added 2 from their own observa-tion. Bickford and Tilghman 2 in 1933 recorded 2non-fatal cases of purpura haemorrhagica occurringduring the treatment of congenital syphilis withneoarsphenamine, and Scarf (1934) a case of aplasticansemia with recovery also following neoarsphen-amine. These conditions are rare and McCarthyand Wilson were able to collect only 79 cases in all.Cole and his co-workers 4 (1931) observed only 2cases in a total of 338 complications arising in thetreatment of 1212 patients over a ten-year period,

Phelps b had 2 cases in 272,354 injections, andCombes 6 1 in 4000 patients.

CLASSIFICATION AND CLINICAL FEATURES

The classification of these conditions of the bloodhas always presented difficulties, for they all appearto be due to greater or less depression of the bone-marrow, but it seems that this depression may affectthe various formative functions in varying degreeand the provisional classification suggested byKennedy is likely to prove as useful as any. The

importance of being able to classify a case is thatthe prognosis and treatment vary in the differenttypes.The suggested groups are : (1) thrombocytopenic,

(2) granulocytopenic and agranulocytic, and (3)aplastic. A few cases are atypical and defy exactclassification. Of the 79 cases referred to above,65 fell into one or other of the three groups in thefollowing proportions :—

(Seven cases were placed in Sub-group i. because theyshowed granulocytopenia; one case, where this was marked,proved fatal.)

In Group I. purpura and external haemorrhageare constant symptoms and occur within a few daysof the last injection. The patients have usuallyreceived a considerable dosage, the average numberof injections in the above series being 23. Anaemia isseldom severe, reduction of platelets being the

striking feature. In Group II., the agranulocyticgroup, fever and necrotic angina of the pharynx arethe commonest signs; they tend to appear after

relatively few injections and within a few days of aninjection. There is only very slight lowering of thered cell count, the damage being apparently confinedto the granulocytes and granulopoietic tissues.

Group III., the aplastic, is the largest. In these casesall the haemopoietic functions of the marrow are

depressed. The early clinical manifestations are

generally purpuric. bleeding from a mucous surfacebeing very common. In a few cases, however, extremepallor and weakness are the only signs. Aplasticanaemia appears as a rule only after a large numberof injections, at an interval varying from two hoursto over one month. A large proportion of the casesare fatal (in McCarthy and Wilson’s series the death-rate was 83 per cent.) but the illness usually lastsa considerable time.

HISTORY OF A CASE

A. B., a motor-bus driver aged 29, was admitted to theRoyal Infirmary, Glasgow, on May 18th, 1933, complainingof increasing weakness and pallor. He stated that duringthe past six weeks he had been easily tired, suffered frombreathlessness on exertion, and had become extremelypale. It was ascertained that the Spirochota pallida hadbeen isolated from a small genital ulcer and that anti-syphilitic treatment had been instituted on Nov. 8th,1932. The treatment consisted of 5-85 g. of Neokharsivanin 13 injections, 2-2 g. of bismuth metal, and Hutchinson’spill (dosage unspecified). On April 21st, 1933, four weeksafter the last injection, he was found to be feverish andunwell and thereafter he became steadily weaker and paler.On admission to hospital, apart from extreme pallor

and a soft systolic apical murmur, physical examinationwas negative ; the Wassermann reaction was negative,

74 DR. E. H. HUDSON : PURPURA H2EMORRHAGICA

there was no sign of purpura and no history of haemorrhage.The blood count was as follows :-

There were no nucleated red cells, no reticulocytes, and infact no evidences of marrow activity. Platelets were veryscanty. Indirect van den Bergh reaction showed 0-25unit of bilirubin.The condition of the blood during the patient’s stay

in hospital is summarised in the accompanying Table.

Table showing Biood Count

Improvement was very slow, but ultimately, on

Sept. 25th, 1933, a blood count showed :-

The patient was dismissed on Oct. 10th, 1933, and hasremained well so far as is known. In the early stages ofthe illness platelets were very scanty in the films butincreased in number as the blood improved. In the courseof treatment, in addition to blood by transfusion, Blaud’spill up to grs. 30 t.i.d., liq. arsenicalis up to 111 5 t.i.d.,Campolon, Hepatex, whole liver and thyroid extractwere administered. It was interesting to note that theappearance of reticulocytes in considerable numberscoincided with the administration of thyroid extract.

During the earlier stages of the illness there was no evidenceof marrow activity and life was maintained mainly byblood transfusions; eventually, however, the bone-marrow apparently resumed its hsemopoietic activities andthe blood improved. It is suggested therefore that thecase is to be regarded as one of aplastic ansemia caused bythe depressing effect of neokharsivan on the bone-marrowand that it belongs to Group III. of the suggested classifi-cation. The volume of the earlier blood transfusions wassmall owing to difficulty in obtaining suitable donors.

MECHANISM OF PRODUCTION

These various blood dyscrasias so far recordedhave occurred most frequently after the administra-tion of neoarsphenamine ; but this is probablybecause the drug is used more extensively than anyother ; in fact many authorities 8 regard sulph-arsphenamine as much more dangerous in thisconnexion. All the organic arsenical preparationscommonly used in the treatment of syphilis containthe double benzene ring and as the aplastic ansemiafollowing these drugs closely resembles that occurringin benzene poisoning, most observers are of theopinion that the anaemia is caused by the action ofthe benzene group. The development of agranulo-cytosis and thrombocytopenia is more difficult to

explain ; the former may perhaps be due to a selectivedepressant action of the drug on the granulopoietictissues. McCarthy and Wilson suggest that thrombo-

cytopenia may be anaphylactoid in nature ; alltheir cases had many injections and they considerthat a sensitivity to the arsphenamines may developgradually, and that the platelets are destroyed inthe peripheral circulation. Support is given to thisview by the rapid regeneration of platelets after the-injections are stopped and also by the fact that in afew cases symptoms recurred whenever treatmentwas recommenced.Whatever the exact mechanism of production may-

be,- it is apparent that the organic arsenical drugsused in the treatment of syphilis can act as powerfulpoisons to the bone-marrow and further that their-toxic action may not become manifest until severalweeks have elapsed after the cessation of treatment..

TREATMENT

In the thrombocytopenic group no special treatment.is required beyond discontinuing injections, for almostall the patients recover spontaneously within a fewdays. Where agranulocytosis or marked granulo-cytopenia is a feature blood transfusion is said to beof doubtful value. There appears to be no record.of treatment by drugs such as pentose nucleotide,.but in view of their value in other cases of agranulo-cytosis they should certainly be given a trial. In the

aplastic cases blood transfusion frequently repeatedis the only remedy with any prospect of success.

Prevention is better than cure, however, and purpuric-symptoms or pallor appearing during the treatmentof syphilis should be regarded with grave suspicionand lead to the arsenical drugs being stopped at once.

I am indebted to Prof. W. K. Hunter for permissionto publish the notes of this case.

REFERENCES1. McCarthy F, P., and Wilson, Robert, Jun.: Jour. Amer.

Med. Assoc., 1932, xcix., 1557.2. Bickford, J. V., and Tilghman, R. C.: Ibid., 1933, c., 1984,3. Scarf, M. : Ibid., 1934, civ., 2159.4. Cole, H. N., de Wolf, Henry, McCuskey, J. M., Miskjian,

H. G., Williamson, G. S., Rauschkolb, J. R., Ruch, R. O.,and Clark, Taliaferro: Ibid., 1931, xcvii., 897.

5. and 6. Cited by Scarf (ref. 3).7. Cited by McCarthy and Wilson (ref. 1).8. Council on Pharmacy and Chemistry : Jour. Amer. Med.

Assoc., 1932, xcix., 1688.The reader is referred to the admirable paper by McCarthy

and Wilson for a full bibliography of the cases recorded up to1932.

PURPURA HÆMORRHAGICA CAUSED BY

GOLD AND ARSENICAL COMPOUNDS

WITH A REPORT OF TWO CASES

BY E. H. HUDSON, M.B. Camb., M.R.C.P. Lond.PHYSICIAN TO OUT-PATIENTS, CITY OF LONDON HOSPITAL FOR

DISEASES OF THE CHEST; LATE HOUSE PHYSICIAN, WESTLONDON HOSPITAL

THE idiosyncrasies shown to the compounds of

gold and arsenic are very similar. Both drugscommonly’ affect the skin and digestive system;. yless often they attack the haemopoietic system, causinga reduction in the number of platelets, prolongationof the bleeding-time, and haemorrhages, particularlyfrom the uterus and nose. Purpura hsemorrhagicaand agranulocytosis are rarer sequels.

GOLD PURPURA

Weil states that’ the first case of gold purpurawas reported in 1919. Since then others have

appeared at intervals, chiefly in France, and examina-tion of accounts of 21 of the recorded cases shows thatthey can be divided into two main groups :

(A) Purpura unassociated with any strong hsemorrhagiotendency. These cases recover spontaneously on stoppingthe injections.2 3