535PLASMOQUINE IN MALARIA.

months, or only vague and indefinite symptoms beforesigns of cerebral compression made their appearance.Sometimes the extravasated blood did not clot, butappeared to suffer defibrination.

Dr. J. G. GREENFIELD considered only that formof cerebral aneurysm which had been called " berryaneurysms." In his experience these aneurysms hadbeen found most frequently in the arteries of youngor middle-aged subjects who had shown either no traceof atheroma or only small isolated plaques. Anabnormal arrangement of the cerebral or systemicarterial system had been commonly described in

patients dying from ruptured intracranial aneurysm,a fact which constituted one of the grounds for

considering a congenital malformation of vesselsas the cause of these aneurysms. In an importantpaper published in November, 1930, Wiley Forbushad given a clear description of the true defect.He had shown that it was primarily a defect in themuscular coat of the artery rather than in the elasticcoat, and had demonstrated its presence not only atthe point where the aneurysm formed, but at practicallyevery bifurcation of the cerebral vessels in thesesubjects. He had demonstrated such a defect also inthe mesenteric vessels. Dr. Greenfield had examinedthe cerebral arteries in five non-atheromatous casesof cerebral aneurysm, and had found this defectpresent in all, whereas it was not present in two casesof intracerebral haemorrhage of the atheromatoustype. As regards treatment, the value of drainageof cerebro-spinal fluid in cases of subarachnoid

haemorrhage had been stressed by Dr. Collier, but there, were some who were still opposed to this procedure on

theoretical grounds, holding that reduction of intra-cranial pressure removed some support from theouter surface of the aneurysms. This theory hadbeen proved to be fallacious by new knowledge on therelationship between the intracranial arterial pressureand the general intracranial pressure. Baillard and

Magidot had demonstrated the fact that the pressure inthe intracranial arteries rose and fell with raisingand lowering of the general intracranial pressure.It had been known since the work of Cushing thatrises in the general intracranial pressure up to thenormal diastolic blood pressure did not cause anyrise in the latter as measured in the brachial artery.But such rises automatically caused correspondingrises in the cerebral arteries, so that, whereas thepressure in the retinal artery was normally 50 per cent.of that in the brachial artery it rose to 60 or 90 percent. of it with increase of intracranial pressure.Berens had also shown that, in even so small a branchas the retinal artery, the systolic pressure is from

eight to ten times the general intracranial pressureas measured by the lumbar puncture manometer. Itwas therefore evident that: (1) the rise of intracranialpressure which was caused by rupture of a basal

aneurysm automatically raised the blood pressurewithin that aneurysm, and was therefore likely tocause further bleeding; (2) that reduction of thegeneral intracranial pressure by drainage of cerebro-spinal fluid would automatically reduce the pressureinside the aneurysm to a far greater extent than itwould remove support from outside it.

Mr. A. A. MCCONNELL described a case of subduralhsematoma in a man aged 70, in whom headacheappeared two days after jerking the head. In thecourse of a week focal symptoms-paresis of the leftarm and leg-made their appearance. At no timewas consciousness impaired, although cerebrationwas slow. Operation revealed a definite subduralhsematoma, and the patient made a good recovery.

Mr. ASTLEY CLARKE mentioned hilarity as an early,and almost only, symptom in a male case, aged 24,of aneurysm of the basilar artery, which rupturedand caused death. He had also seen two other casesin females, in whom laughing of an unusual characterwas observed as an early symptom in similarintracranial haemorrhage.

Dr. HINDS HowELL emphasised the frequency withwhich subdural haemorrhages were bilateral, and citedan instance in a man aged 60. Following what atfirst appeared to be a mild head injury, left hemi-plegia developed after six weeks. Operation wasperformed on the right side, and a large subduralhaematoma was found and evacuated. The patientimproved for 24 hours, after which he relapsed into asemi-comatose condition. The operation area wasre-explored, as it was thought that further

haemorrhage might have occurred. Nothing was found,and it was hoped that the compressed brain still

remained unexpanded. The patient died on the

following day, and autopsy showed another subduralhsematoma on the opposite side. The speaker had seencases of subarachnoid haemorrhage with massive albu-minuria similar to those described by Prof. Hall, andthere was an obvious danger of making a preliminarydiagnosis of uraemia. In association with the albu-minuria, glycosuria and acetonuria might also occur.

PLASMOQUINE IN MALARIA.A REVIEW OF RECENT EXPERIENCES.

PLASMOQUINE, the trade name for N-diethylamino-isopentyl-8-amino-6-methoxy-quinoline, was intro-

duced into the therapeutics of human malaria in 1926,and for five years workers in various parts of theworld have been testing its uses and limitations.

The Army in India.There is no organised body of men whose efficiency

has been more handicapped by malaria than theBritish Army serving in India. Accurate statisticsof the morbidity from this cause have been keptover a long period, so that it has become possibleto estimate the value of any form of antimalarialtreatment with greater degree of accuracy amongstsoldiers under continuous and disciplined observationthan amongst a similar body of civilians. Anexhaustive trial in India of plasmoquine and quininehas recently been reported 1 by Major J. A. Manifoldin the treatment of benign tertian malaria, the formof malaria most prevalent amongst serving units andmost detrimental to service. In this paper MajorManifold has drawn on the accumulated experienceof 325 publications on this subject which haveappeared lately. From a study of these it has beenrealised that many of the untoward symptomshitherto described were due to the slender marginbetween the therapeutic and toxic doses of plasmo-quine. Sinton, Smith, and Pottinger having in 1930reported unfavourably on a daily dose of 0-06 g.,it was resolved to try 0-04 g. plasmoquine plus1.25 g. (grs. 20) of quinine taken for 21 consecutivedays. The troops concerned in mass treatmentincluded both British and Indians, the latter varyinggreatly in physique. The experiment being spreadover such a huge area of country with varying degreesof humidity and temperature, the conditions variedenormously. In most stations it was quite impossibleduring the malaria season to discriminate between fresh

1 Jour. R.A.M.C., May-June, 1931.

536 PLASMOQUINE IN MALARIA.

cases of malaria and relapses. Any attempt to takeinto account different factors by varying the dosage ofplasmoquine was obviously impracticable ; no differ-ence was made in the dosage used for individual casesand any fresh attack within six months of completionof treatment was considered as a relapse. By entrustingthe treatment however to a large number of medicalofficers in different parts of India many individualresults and opinions could be obtained. Sufficientplasmoquine was available to treat 4000 cases,and in each command certain officers were selectedto undertake the treatment and to keep recordsof the cases treated. In stations in which a laboratorywas situated the medical officer carrying out thetreatment worked in close cooperation with theofficer in charge of the laboratory.The treatment of all cases of benign tertian malaria

consisted of one tablet containing 0-02 g. plasmoquinecombined with grs. 10 of quinine in the morning anda similar amount in the evening, the total course oftreatment being 21 days. In all, 3187 cases (1286British, 1901 Indian) of benign tertian malaria

completed this course and are included in the analysis.Cases treated after Dec. 31st, 1929, and subtertiancases treated partially with quinine and subsequentlywith plasmoquine were not included. A specialwatch was maintained for toxic symptoms and

precise instructions having been issued regardingtheir nature. In the great majority of instancesthese symptoms were never severe and frequentlywere not mentioned in the hospital register after thefirst 20-30 cases had been treated. The effects ofsuggestion, particularly as regards " colic," couldnot be neglected for it was noticed that once patientand medical officers had gained confidence in the drug,complaints became fewer and eventually ceased

altogether. As a corollary to this the larger thenumber of cases treated in a hospital, the morefavourable the opinions expressed on the value ofthe treatment and the fewer were the toxic symptomsof real importance noted-a statement which tallieswith the experience of other workers both here andin the tropics.

TOXIC SYMPTOM.TOXIC SYMPTOMS.

The percentage of toxic symptoms recorded,such as abdominal pain, cyanosis, and digestivedisturbance was less amongst Indian than amongstBritish patients, owing no doubt to the greaterattention paid to mild symptoms. In view of thefact that 99 per cent. of all the cases ultimatelycompleted their course of treatment, toxic symptomscannot have been severe. Abdominal pain constitutedthe one constant complaint; it was found to occurwith less frequency when the drug was taken on a I,full stomach -or with a large draught of water. Theincidence of this pain definitely increased with theduration of the treatment indicating, as had alreadybeen realised, that plasmoquine is a cumulativedrug showing its maximum effects on about thesixth day of treatment. Epigastric pain oceurredas a rule within a few days of beginning the courseand disappeared quickly on temporary cessation ofplasmoquine administration. In this series of casescyanosis is recorded as having been noted in 4-3 percent. of British and 0-67 per cent. of Indians. Thelower proportion amongst the latter group is probablyaccounted for by the difficulty of recognising it indark-skinned races. As previously noted by Fischerand Weise the cyanosis becomes evident clinicallyabout the seventh day and it appears also to occurwith greater frequency in anaemic cases and is

accompanied usually by epigastric pain. Manycases appeared to lose their pink complexion during

treatment, but yet could not be called actuallycyanosed. It seems then that in a small percentageof cases there does exist a definite individualidiosyncrasy to the action of the drug with referenceto epigastric pain and cyanosis. In the averagecase of cyanosis a continuance of the treatment doesno harm and the methæmoglobinæmia does not,increase.

,

Opinions were much divided as to the effect of the,treatment in the reduction of chronic enlargementof the spleen ; only in acute enlargements is iteffective in reducing the organ to normal size. Asregards the pyrexia it was found that on the wholepatients responded more rapidly to treatment withplasmoquine and quinine than to quinine alone, andin no case was it necessary to give intravenous orintramuscular quinine. Relapse is the crux ofefficient treatment and out of this trial the testhas emerged triumphant. The relapse-rate was

surprisingly small, the average for all classes andstations being 5-2 per cent. If cases relapsing afterwhat may be roughly called the end of the malariaseason in the various stations only were acceptedas relapses, then the relapse-rate would be as lowas 2-4 per cent. The figures for the relapse-rate aredefinitely favourable as compared with the usualquinine treatment. In the quinine-treated controlseries of Sinton, Smith, and Pottinger at Kasaulithe relapse-rate was as high as 42 per cent.There were two deaths amongst the Indian cases.

The first occurred after vomiting and was notconsidered to be due to plasmoquine treatment;the second appears to have been due to blackwaterfever (methæmoglobinæmia) and it is possible that

B

it was a case of mixed injection with benign and sub-tertian malaria. There were two other cases of mildmethæmoglobinæmia which recovered ; they mayhave been mild cases of blackwater fever more

likely than instances of toxic plasmoquine methæmo-globinæmia.The report closes with quotations from various

medical officers in the 1.M.S. and R.A.M.C. On thewhole the opinions were favourable and encouraging.The efficacy of this treatment combined with

simplicity of administration and shortness of courseappealed to both medical officers and troops. Most

questions on this important subject having been

satisfactorily answered it remains to be ascertainedwhether plasmoquine can be safely issued to patientsnot under medical supervision. The answer would

appear to be definitely in the negative, but if the

margin of safety can be made greater and good resultsobtained by utilising 0-03 g. plasmoquine as a dailydose plus quinine (grs. 20) for 21 days, a definiteadvance would be made. Investigations on theselines are being carried out at the malaria treatmentcentre, Kasauli. There 57 cases have been treated up todate. Toxic symptoms have been non-existent andthe patients have been able to play an occasionalgame of hockey or football.

Central America.

Three other reports of importance are before us.The staff of the United Fruit Company have beenassiduous in recent years in investigating plasmoquinetreatment. In the nineteenth annual report of thecompany’s medical department, Dr. N. P. Macphailwrites on plasmoquine as an aid in malaria preventionin Guatemala. The conclusions arrived at as the resultof the administration of 1,388,000 tablets of plasmo-quine were as follows : Plasmoquine effectively destroysthe gametocytes of all forms of malaria when given indoses of 0.03-0-.04 g. daily for one week. Combined

537REVIEWS AND NOTICES OF BOOKS.

with quinine, plasmoquine is a safe and sure way ofpreventing the formation of gametocytes duringan attack of malaria ; and the combination destroysall types of parasites. Toxic symptoms need not befeared when the dosage is limited to 0-03 g. dailyfor a week or more. It is considered that there is

ample clinical proof to justify the hypothesis thatplasmoquine is of importance as a curative factorin chronic cases which have resisted extendedefforts at eradication with quinine and arsenical

preparations.Dr. Vincente Bustillo, at Banes, Cuba, has come to

much the same conclusions. The doses of plasmo-quine in his practice are much smaller and consistof one plasmoquine tablet (0-01 g.) for four days andgrs. 20 of quinine. Children under 5 years of agereceived 0-005 g. for eight days and no untowardeffects with the dosage above mentioned have been Inoted. Since 31 out of 34 cases showing crescents in i,the blood became negative within nine days subsequentto the initiation of plasmoquine treatment, it can beconcluded that the doses used were sufficient to causea disappearance of gametocytes from the peripheralcirculation from one to eight days in 91 per cent. ofthe cases and within nine to twelve days in theremaining 9 per cent. The easy disappearance of

gametocytes leads to the belief that plasmoquinehas a direct action upon them ; but it is probable thatthey are devitalised to be afterwards destroyed byphagocytoses.

In assessing the role of plasmoquine in the sanita-tion of Panama, 0. T. Brosius exercises due care inthe field of its application. Working with a forceof employees totalling some 4800 the difficulty ofgauging the value of " blanket treatment " with

plasmoquine and quinine may be imagined. Theconclusions arrived at are that plasmoquine hasprobably played a more active role in effecting a

reduction in malaria infections than was given creditfor in earlier attempts to determine its exact valuein tropical sanitation. It is emphasised that with adistinct reduction in malaria, there was a simultaneousdecrease in the hospital admissions, which was moreor less in direct ratio to the malaria decline. Ina community such as Panama with a comparativelylimited turnover in the labour force by sufficientlyfrequent plasmoquine and quinine blanket treatmentsthe sterilisation of the gametocytes to malariacarriers can be repeated at given intervals.

The Present Position.

It is evident from the information summarisedabove and the publication 2 of the prophylacticexperiments of S. P. James and his co-workersthat the whole question of plasmoquine has entereda new phase. The progress so far achieved has beensatisfactory, but a less poisonous compound thanplasmoquine would undoubtedly lead to greaterconfidence in its extended usage away from medical

supervision, and it is much to be hoped that in thefuture less toxic oompounds will be found. Moreinformation is needed about the effect of administeringplasmoquine under all sorts of conditions. Recentwork has confirmed in a striking manner the accuracyof the pioneer observations made with a limited seriesof cases at the Tropical School in Hamburg, andsubsequently at the Hospital for Tropical Diseases,London.

2 THE LANCET, August 15th, p. 341.

REVIEWS AND NOTICES OF BOOKS

Heart Disease.

By PAUL DUDLEY WHITE, M.D., Instructor inMedicine, Harvard Medical School; Physician,Massachusetts General Hospital, Boston. London :Macmillan and Co., Ltd. 1931. Pp. 931. 42s.

Dr. Paul White’s book is the most comprehensivetreatise on cardiology which has appeared in the

English language in recent years. It touches on

every aspect of the subject, from the most importantto the most trivial, and therein lies its chief defect-namely, a lack of perspective. There is too muchdetail, too little emphasis on some of the main points.To deal adequately with all the subjects to whichthe author refers would require a book of at leasttwice this size, and it is doubtful whether any onecardiologist would be competent to write such a book.Possibly this criticism will be less pertinent for theAmerican than the English reader, for there is a

wide difference in the outlook on medicine in the twocountries. In America the investigation of clinicalcases follows a more universal plan than in Britain ;every fact is carefully recorded in the case-notes, withthe result that sometimes it appears to us difficultto sort out the capital matter. With us the investiga-tion of cases is less systematic. Our idea of a

great clinician is a man who can pick out theessential points of a case and give his undividedattention to them alone, discarding everythingwhich is irrelevant. The great teachers ofmedicine in this country have impressed on the mindsof their students vivid pictures of individualcases in the wards. This difference of viewpoint

is strikingly illustrated by Dr. White’s book. Herefers occasionally, it is true, to the occurrence ofparticular symptoms in patients in his own practice,but from beginning to end his treatment of the subjectis strictly systematic.The book is divided into four parts, which deal

respectively with the methods of investigationincluding symptoms and physical signs, the ætio-

logical types of heart disease, structural lesions, andlastly, disorders of function. Part I. includes anexcellent account of cardiovascular radiology, anaspect of diagnosis which has hitherto been scantilytreated in most English text-books. In other parts ofthis section the author is apt to over-classify. Thestatement that such and such a condition may be dueto 1, 2, 3, or 4 is a joy to students, but is too water-tight for the more advanced reader. In the chapterdealing with sphygmomanometry (p. 127) the authorrefers to the disappearance of the Korotkow soundsas the diastolic end-point. With this neither physio-logists nor clinicians will agree.

Part II. opens with some extremely interestinggraphs comparing deaths from heart disease in theUnited States with those from cancer and tuberculosis,and the age-incidence in fatal cases. But influenzaand focal infections, which we regard as importantcauses of cardiac invalidism, are allotted onlyhalf a page each, while gout is dismissed in two lines.Sense of proportion is similarly lacking in thereference to Raynaud’s disease and chilblain (Part IV.),and to angina pectoris, to the consideration of whichthe author devotes only 20 pages. Part III. dealswith structural lesions. This inevitably leads to