1243

TABLE II-PREGNANCY OUTCOME-

I I

* HCG figures relate to 82 patients only. 19 samples were not assayed undercentral quality control, 17 were not properly stored, and 10 were not clearlyidentifiable; the remaining 17 samples had plasma HCG values below normal,(normal range defined by mean ±2SD).t Outcome not specified in medical records.

drug assessment, it would be interesting to check the yield of trialswith an explicit educational role, aimed at "old" concepts and atdoctors likely to be outside the mainstream of information. Suchtrials might not seem very creative scientifically. Nevertheless, they’could well be part of "what doctors should be doing" . 11The following clinicians took part in the trial: A. Tomassini, C. De Nigris, A.

Vecchione, M. Vignali, M. Luerti, G. Fontana, E. Manenti, A. Valsecchi, G.Mattioli, A. Teatini, E. Tucci, G. Variati, D. Gentile, F. Revelli, A. Patnarca,E. Imparato, R. Durola, C. Radaelli, A. Mazzoleni, and F. Balacco. The workwas supported by a C.N.R. contract on biology and reproduction and by theLombardy Regional Centre for Drug Information.

Lombardy Regional Centre forDrug Information,

Istituto di Ricerche Farmacologiche"Mario Negri",

20157 Milan, Italy

IV Department of Obstetrics andGynaecology,

University of Milan

G. TOGNONIL. FERRARIOM. INZALACO

P. G. CROSIGNANI

FANSIDAR-RESISTANT FALCIPARUM MALARIA INPAPUA NEW GUINEA

SIR,-Chloroquine-resistant falciparum malaria was first

reported from Papua New Guinea in 1976., By 1980, in in vivochloroquine sensitivity tests in schoolchildren with asymptomaticparasitaemia, type I resistance (RI) was found in approximately 60%of children and cases of RII and RIII resistance were also noted. 3In areas of the world where there is a high prevalence of

chloroquine-resistant falciparum malaria, a short course of quininefollowed by a single dose of’Fansidar’ (pyrimethamine 25 mg plussulfadoxine 500 mg) has been recommended for the treatment ofacute falciparum malaria.4 The exigencies of treatment in tropicalcountries mean that a single dose drug is desirable, and fansidar isone of the few commercially available preparations. However, treat-ment failures with the pyrimethamine-sulfadoxine combinationhave been reported from a number of areas in South East Asia 5,6 andelsewhere and recently from Irian Jaya. 7We report here four cases of Plasmodium falciparum malaria

clinically resistant to fansidar observed in the Madang Province ofPapua New Guinea during a clinical and field trial offansidar for the

11. Black D. What should doctors be doing? Lancet 1980; ii: 304-06.1. Grimmond TR, Riley I, Donovon KO. Chloroquine resistant malaria in Papua New

Guinea. Papua New Guinea Med J 1976; 19: 184-85.2. Han CM. Studies on the occurrence of a strain of chloroquine-resistant Plasmodium

falciparum in Papua New Guinea. Papua New Guinea Med J. 1978; 21: 306-16.3. Gibson FD. Chloroquine resistance studies in Papua New Guinea. In: Eighth South-

West Pacific Malaria Conference. (Port Moresby, Papua New Guinea, Aug. 4-8,1980).

4. Hall AP. The treatment of malaria. Br Med J 1976; i: 323-28.5. Doberstyn EB, Phintuyothin P, Noeypatimanondh S, Teerakiartkamjorn C. Single-

dose therapy offalciparum malaria with mefloquine or pyrimethamine-sulfadoxine.Bull WHO 1979; 57: 275-79.

6. Schmidt LH, Harnson J, Rossan RN, Vaughan D, Crosby R. Quantitative aspects ofpyrimethamine-sulphonamide synergism. Am J Trop Med Hyg 1977; 26: 837-49.

7. Rumens LW, Dennis DT, Atmosoedjono S. Fansidar resistant falciparum malaria inIndonesia. Lancet 1979; ii. 580-81

treatment of acute malaria in children. In one case fansidar failed toclear the parasitaemia and in three cases parasitaemia reappeared afew days after initial clearance.

Case-reportMale, aged 15 months, weight 7 - 4 kg. Presenting symptoms were

fever and cough for 3 days. On examination, temperature was38-2°C, spleen grade 4. Initial blood film (day 0) showedP. falciparum: 50 00011. He was treated with half a tablet fansidargiven under observation. The fever subsided by 60 h. On day 2 theparasite count (per JlI) was 4080 and gametocytes were noted. Theparasite count was 10 400/1 on day 3, 8000 on day 4, and 67 000 onday 5 when fever returned. On day 6 he was given 7 ml of chloro-quine elixir (50 mg chloroquine base per 5 ml) and this was repeatedon day 7 and day 8, when the parasite count was 320 with plentifulgametocytes. On day 9 no asexual forms were noted in 200 highpower fields in a thick blood film, and no further asexual

parasitaemia occurred in the next 28 days.Three other patients aged between 3 years 6 months and 5 years,

all male, with initial parasite counts between 1760 and 44 400 weretreated with fansidar on a dose/kg basis. Asexual parasites disap-peared from the peripheral blood on day 3 or 4 and reappeared onday 7 or 8. All three were treated with chloroquine, in two cases suc-cessfuly, there being no asexual parasites noted in the subsequent 28days. The third case showed RII chloroquine resistance and wassubsequently successfully treated within 7 days of quinine togetherwith fansidar on the fifth day.

Comment ’

In the first patient the parasitaemia persisted for 8 days. We aresatisfied that the patient was observed to have taken the prescribedtreatment (and parasitaemia did initially fall with the subsidence offever) and the evidence for parasite resistance to the drug combina-tion in this case is firm. In the other three patients the parasitaemiadisappeared only to reappear a few days later and the time course ofevents makes it likely that these were cases of recrudescence ratherthan second infections (although this cannot be entirely excluded).

In the face of the increased prevalence of chloroquine-resistantfalciparum malaria in Papua New Guinea, there is obviously a needfor an alternative to chloroquine for the treatment of presumptivecases. Unfortunately fansidar would not appear to be that alter-native, at least in the Madang area of Papua New Guinea, althoughit is undoubtedly a useful drug with which to treat inpatients who donot respond to standard therapy. It seems on preliminary evidence(P. Chen, G. Lamont, T. Elliott, C. Kidson, G. Brown, G. Mit-chell, J. S., and M. A., unpublished) that pyrimethamine resistancein Papua New Guinean strains of P. falciparum may be severalorders higher than that in African strains, and it is likely thatwidespread use of fansidar would rapidly lead to increased numbersof resistant strains to the pyrimethamine-sulfadoxine combination. 6This letter draws attention to this danger and to the need for carefulevaluation of the drug wherever it is being used.We thank Roche Products Pty Ltd, Australia, for supplies offansidar tablets.

Papua New Guinea Instituteof Medical Research,

P.O. Box 378, Madang;and

Department of Public Health,Madang Hospital,Papua New Guinea

BRIAN DARLOWHELENA VRBOVA

JOHN STACEPETER HEYWOODMICHAEL AALPERS

FEBRILE CONVULSIONS

SiR,-Your Sept. 27 editorial supports the prevailing concept thatfebrile seizures, which are usually benign, are due entirely to theheight of the fever. However, these seizures usually occur at thevery onset of the febrile illness, often before the extent of thetemperature rise is known; they do not recur if, during the illness,the temperature again rises.

Livingston states: "... we have never observed a simple febrileseizure as the initial convulsive reaction to an elevation of

temperature later than 24 hours after the onset of an acute febrile-

1244

illness." Rather than, in the words of your editorial, "... there isno need for treatment other than advice about reducingtemperature", it might be better to expect to proceed with ap-propriate treatment for the infection. The exact origin of theseseizures is uncertain-they may be due to toxic or metabolic changesat the onset of the illness-but it seems unlikely that fever alone isresponsible. Perhaps these convulsions are similar to the shakingchills seen in adults at the onset of pneumonia.Some change in terminology and our concept ot aetiology might

reassure those who become so very anxious about a secondary rise intemperature and resort to aspirin and other antipyrexial methods toreduce fever and prevent a convulsion. A seizure at the very onset ofa febrile illness is not necessarily dangerous but later in the course ofan illness a convulsion should alert one to the possibility of centralnervous system involvement by the infection.

University of California Medical Center,San Franciso, California 94143, U.S.A. EDWARD B. SHAW

SIR,-Professor Lorber and Dr Sunderland have followed up alarge number of children, but perhaps they have fallen into the trapswhich beset those who try to find an easy answer to the difficultquestion of long-term anticonvulsant protection for childrenvulnerable to damaging febrile convulsions. One cannot assumeanything about these children, particularly those lost to follow-up.The painstaking work of Lennox-Buchthal and her colleagues inCopenhagen2 involved follow-up of almost all the susceptiblechildren in that city and showed the value of anticonvulsants inthose at risk; they confirmed the superiority of phenobarbitone tophenytoin as the drug of choice.3 Recent work suggests thatphenobarbitone may also be more acceptable to parents andchildren than sodium valproate. The dose is 3-5 mg/kg every 24 hwhich may be given in a single dose at night. Blood levels, althoughuseful to confirm that the child is taking the drug, need not be part ofthe routine outpatient visit:4 careful discussion with both parentsand a good explanation of the risks and the reasons for anticonvul-sant cover certainly are.My indications for recommending treatment are much in accord

with those of Ounsted and other authorities: a first convulsionunder one year (especially where there is a family history), repeatedepisodes, and convulsions lasting more than five minutes or increas-

, ing in severity. Those with birth injury, developmental delay, orany other adverse factor should also be protected. Child and paren-tal acceptance is good; irritability is slight and transient, lastingperhaps ten days until equilibrium is reached. Follow-up must pro-vide encouragement, and the help and cooperation of the generalpractitioner is essential.

Queen Mary’s Hospital for Children,Carshalton Beeches, Surrey SERENA DAVIDSON

CELLS T, B, AND NULL

SIR,-Though lymphocyte surface markers have been known fornearly a decade, several of them have been modified as the interrela-tionships between them have been reappraised. As Haegert andCoombs5 and Dr Robertson and colleagues (Oct. 4, p. 743) point outsuch developments can be exemplified by the SmIg test for B cells.However, Robertson et al. go on to argue that the E-rosette test,even under ideal conditions, still has an inherent weakness-name-

1. Livingston S. Comprehensive management of epilepsy in infancy, childhood andadolescence. Springfield, Illinois. Charles C Thomas, 1972: 29.

2. Lennox-Buchthal M. Febrile convulsions: a reappraisal. Amsterdam: Associated Scien-tific Publishers, 1973.

3. Melchior JC, Buchthal F, Lennox-Buchthal M. Epilepsia 1971; 12: 55.

4. Vajda F, Williams FM, Davidson S, Falconer MA, Breckenridge A. Brain,cerebrospinal fluid and plasma concentration of phenytoin and phenobarbitone inman. Clin Pharmacol Ther 1974; 15: 597-603.

5. Haegert DG, Coombs RRA. Do human B and null lymphocytes form a single im-munoglobulin bearing population? Lancet 1979, ii: 1051-52.

ly, the significant number of cells binding only one or two

erythrocytes (sub-rosettes). The figure shows E-rosette results fromten normal donors tested with untreated and AET-treated sheep redblood cells;b treatment with 2-amino-ethylisothio-uronium bromide

Distribution of numbers of sheep red blood cells bound to lym.phocytes.

hydrobromide (AET) increases the avidity of the lymphocytes form-ing rosettes with one to seven SRBC so that the vast majority ofrosette forming cells now bind more than seven erythrocytes.Similar data have been presented by Stein. We feel, unlike Robert-son et al., that the expression of SRBC receptors can be regarded asan all-or-none phenomenon, provided the E-rosette assay is doneunder ideal conditions.We agree with Robertson and with your editorial (Oct. 11, p. 781)

that monoclonal anti-T antisera probably will provide new insightinto the definition of normal and malignant T-cell subsets. Further-more, the finding from Schlossman’s group that some E-rosette for-ming cells react with a monoclonal anti-monocyte antibody make usrephrase the question posed by Robertson et al. and ask: "Are someT-cells really T-cells?".

University Department of Medicineand Haematology,

Aarhus Amtssygehus,8000 Aarhus, Denmark

PETER HOKLAND

J. ELLEGAARD

SIR,-The concept of a "null" cell-negatively defined as a celllacking conventional T or B surface markers-remains popular,although recently subject to cogent challenges. Haegert andCoombs, in a critical review of the conflicting claims of functionalproperties of so-called null cells, have argued that most of them canbe shown to have stable membrane-incorporated immunoglobulinand are therefore B-cells.l Dr Robertson and colleagues point outthat an arbitrary definition of what constitutes an E-rosette mayrelegate some T-cells to the "null" compartment. Whilst awaitingthe contribution of monoclonal antibodies to the identification of

lymphocyte populations, we will argue that the null cell concept nolonger serves a useful purpose.From twenty-two healthy adults, monocyte-depleted peripheral

blood lymphocytes were obtained after incubation of whole bloodwith carbonyl iron and centrifugation over ’Ficoll-Hypaque’. Cells

6. Hokland P, Hokland M, Heron I. An improved method for obtaining E-rosettes withhuman lymphocytes and its use for B cell purification. J Immunol Meth 1976, 13:175-82.

7. Stein G. Evaluation of rosette formation on smears. J Immunol Meth 1977; 14: 371-80.1. Haegert DG, Coombs RRA. Human B and null lymphocytes form a single

immunoglobulin-bearing population. Lancet 1979; ii: 1051-2.