101

"ANTIGENIC" DISPARITY BETWEEN

LYMPHOCYTES AND AUTOLOGOUS

PHYTOHÆMAGGLUTININ-INDUCEDLYMPHOBLASTS

L. WOODS.G. E. MOORE.

Public Health Research Group,Roswell Park Memorial Institute,Buffalo, New York 14203, U.S.A.

SIR,-May we comment on a letter from our colleagueDr. Han (Oct. 30, p. 977) ? The wording of his note maybe misleading. We 1 do not claim that new isoantigenswere found in cultured lymphoblasts in the sense that theseadditional detectable antigens were generated de novo.In all probability the " new antigens " represent the

uncovering or expression of existing antigens or a quantita-tive increase in the antigen reactivity. This conclusion isbased on the following observations:

(1) Almost all cytotoxicity reactions of the cultured cellsare two or threefold greater than those of fresh lymphocyteseven when the antigen patterns are identical. This quanti-tative increase in antigenic expression may merely reflectthe greater cell surface of the lymphoblastoid cells.

(2) The additional detectable antigens are rarely majorones. In a comparative study of the isoantigen patterns offresh lymphocytes and the cell lines derived from the sameperson in only seven instances were " new " major antigensdetected, whereas " new " minor ones were recorded in21 of the 46 instances reviewed.

(3) The HL-A patterns of the human lymphoblast linesremain stable (up to 38 months in our study); despitechanges in chromosome constitution in several cell lines,the antigen patterns were not altered.

Perhaps the increase of antigenicity of the cultured cellsis a function of the relative insensitivity of fresh lympho-cytes to the cytotoxicity assay incorporating multispecificor cross-reacting antisera. The histoincompatibility be-tween fresh lymphocytes and autologous cultured lympho-blasts cannot be explained by the present cytotoxicitytesting methods.

" LOCKED-IN SYNDROME " FROM DIAZEPAMTOXICITY IN A PATIENT WITH TETANUS

LARRY E. DAVIS.

Department of Neurology,Johns Hopkins University School

of Medicine,Baltimore, Maryland.

RICHARD B. WESLEYDAVID JUANCHARLES C. J. CARPENTER.

Department of Medicine,Baltimore City Hospitals,

Baltimore, Maryland 21205, U.S.A.

SIR,-Diazepam, in increasingly high doses, is beingused to modify abnormal states such as status epilepticus,delirium tremens, and tetanus. Enormous doses of this

drug 2 have been given to patients with tetanus. In spiteof these high doses, few serious complications have beenreported. However, when side-effects do occur, theyfrequently are of a neurological nature and may complicatethe accurate assessment of the original neurological con-dition.

Case-reportA 77-year-old healthy labourer without previous tetanus-

toxoid immunisations developed tetanus 8 days after

lacerating his knee. Penicillin and human tetanus antitoxinwere begun on admission, but diazepam, up to 280 mg. aday intramuscularly, and chlorpromazine, up to 300 mg.a day intramuscularly, were required to control the severemuscle spasms. On hospital day 7 the patient’s musclespasms were controlled, but he became somnolent andlapsed into semicoma the following day. The chlorpro-mazine was stopped and the diazepam reduced to 30 mg. aday, but the semicoma persisted. No significant liver,renal, electrolvte, blood-pressure, or arterial-blood-gasabnormalities were present. On day 11, 4 days after thehigh doses of diazepam were stopped, the patient wasfound to have a blood diazepam and metabolite level of

1. Moore, G. E., Woods, L. Transplantation (in the press).2. Stoebner, R. C., Kiser, R. W., Decherd, J. F., Perry, J. E. Sth. med.

J. 1970, 63, 445.

610 tg. pcr 100 ml. but no detectable chlorpromazine level.The patient remained semicomatcse until day 17, when hebecame alert enough to blink his eyes in response to

simple verbal commands, but was otherwise mute andtetraplegic. The muscles were generally hypotonic exceptin the paraspinous musculature, which was rigid. Brisk

deep tendon reflexes were present, and plantar responseswere flexor. The patient appeared to have a decreasedappreciation of pain for pin-pricks bilaterally. He remainedin this unusual state for 9 days before he began to move hisfingers and toes. It was not until day 30 that he was ableto sit and swallow. He then slowly made a full recovery.Comment

Unique in this case was the development of prolongedsemicoma followed by transient mutism and tetraplegia.This state resembles the " locked-in syndrome " (alertwakefulness accompanied by mute tetraplegia) described byPlum and Posner. 3 They felt the syndrome representedbrainstem damage with a sparing of the pontine-midbrainreticular formation. However, their example was secondaryto vascular damage and not reversible, as was our case.Femi-Pearse reported a case similar to ours in which ayoung lady with tetanus became mute, paralysed, and didnot respond to any commands while receiving diazepam180 mg. daily. -1 However, she rapidly improved 2 daysafter the diazepam was stopped. We are unaware of anytoxicity lasting as long as in our case.

Therapeutic blood-levels have not been determined fordiazepam in the treatment of tetanus. Although thechemical analysis in our case was done 4 days after thehigh doses of diazepam were stopped, and in an independentlaboratory, the blood-diazepam level was extremely high,and equal to the highest on official record with the manu-facturer. 5

In summary, diazepam, in high doses, can be a usefuladjunct in the treatment of severe tetanus. In spite of theprolonged semicoma, our patient never developed signifi-cant respiratory depression and fully recovered. Neverthe-less, awareness of potential neurological side-effects is

necessary when using diazepam, and tetraplegic mutismmust be added to this list. In the treatment of tetanus,we advise that no standard dosage be used and that thedrug dosage be titrated every two to four hours to achievethe minimum dose necessary to control severe muscle

spasms while maintaining maximum alertness.

ALBINOS IN BORNEO

SIR,—I am at present doing my " elective period "from the Middlesex Hospital, London, at this hospitalon the River Rejang. Our patients are mostly Ibans, theromantic " wild men of Borneo ", and former head-hunters. This is my third visit here, and on each occasionI have noticed many albinos around the bazaars and

longhouses. Further investigations suggested that thisgenetic trait is far commoner here than in Europe. Thetotal population of Sarawak is well under 1 million, andyet I have seen a dozen albinos in the space of a few

3. Plum, F., Posner, J. B. Diagnosis of Stupor and Coma; p. 92.Philadelphia, 1966.

4. Femi-Pearse, D. Br. med. J. 1966, ii, 862.5. deSilva, J. A. F., Koechlin, B. A., Bader, G. J. pharm. Sci. 1966,

55, 692; Pepper, J. J. Director, Department of Medical Services,Hoffman LaRoche, Inc., personal communication.

102

months. In one particular family on the River MujongI traced six albinos, of whom four are still living in thearea.

The only explanation I can offer is that the communallife in a longhouse tends towards close-relative marriages-it is not unknown for a niece and uncle to marry-andthis, of course, would increase the incidence of an auto-somal recessive trait. I would make a rough estimate thatalbinos are seen from 1/5000 to 1/10,000 of the Ibanpopulation. I would be grateful to hear from anyone whocan explain this high incidence or who knows of any othernative population where albinism is so common.

PETER H. ABRAHAMS.

Christ Hospitalof the Methodist Church,Kapit, Sarawak, Malaysia.

RESPIRATORY-DISTRESS SYNDROME ANDDISSEMINATED INTRAVASCULARCOAGULATION IN TWO SIBLINGS

SiR,—We wish to report the occurrence of idiopathicrespiratory-distress syndrome (LR.D.S.) and disseminatedintravascular coagulation (D.i.c.) with fatal outcome intwo infants born to the same parents.The first infant was born on May 17, 1969, to a healthy

23-year-old woman. Her one previous pregnancy hadresulted in delivery at 36 weeks’ gestation of a normal girlweighing 2300 g. The present pregnancy had been un-eventful until the 34th week, when occasional uterinecontractions began. Bed rest and oral isoxsuprine (’Vaso-dilan’) were prescribed; this was the only drug takenduring pregnancy. At 36 weeks she went into labour anda 2600 g. male infant was delivered by low forceps underspinal anaesthesia (tetracaine). The infant’s conditionwas good; Apgar score was 9 at one minute and 10 atfive minutes. Three hours after delivery, grunting andsubcostal retraction with slight cyanosis were noted. Sixhours after birth there was an apnceic spell, and a chestX-ray showed opacification of the left lung field with airbronchogram. His condition deteriorated rapidly andrespiration could only be maintained by positive pressurevia endotracheal tube. The umbilical artery was catheter-ised and blood in the catheter was observed to clot imme-diately. At the same time there was oozing from the mouthand umbilicus. A coagulation study at this time revealeddisseminated intravascular coagulation (see table). Heparin,4 mg. every four hours, was given by continuous intravenousinfusion. He also received 15 ml. of platelet concentrate,10 ml. of packed red cells, and fresh frozen plasma. Bloodcultures drawn at this time were negative. Despite all

supportive therapy the child died approximately 36 hoursafter birth. Necropsy showed hyaline-membrane diseaseof the lungs and thrombi in vessels of the lungs, spleen,

pancreas, and kidneys. In addition, there were subarach-noid and subdural hxmorrhages and massive bleeding intothe gastrointestinal tract.A year later, on June 30, 1970, the second infant was

born. The only drug taken was isoxsuprine, prescribeibecause of contractions during the last trimester. Labourbegan at 36 weeks, and a 2300 g. boy was delivered by lowforceps under epidural anxsthesia (lidocaine). The baby’scondition was satisfactory (Apgar 9 at one minute and atfive minutes). Eight hours after delivery there was slightsubcostal retraction; X-ray and blood-gases were normal.Platelet-count at this time was 160,000 per c.mm. andhxmatocrit 52%. There was no substantial change untilsixteen hours after birth, when the baby had a respiratoryarrest. An endotracheal tube was passed, oxygen wasadministered, and after five minutes spontaneous respira-tions returned. The baby was now in poor condition,and required almost constant assisted respiration. ChestX-ray showed some parenchymatous changes and airbronchogram. A coagulation study at this time revealed aprofound defect interpreted as being due to D.LC. (seetable). Hasmatocrit had fallen to 30%. Intravenousheparin, 4 mg. every four hours, was started, and 10 ml.of platelet concentrate and 37 ml. of packed red cells weregiven. A coagulation study of the mother approximately24 hours after delivery was within normal limits. Bothmother and baby were A rhesus-positive, and the cord-blood Coombs test was negative. The patient improvedslowly during the next five days, although his bilirubin(indirect) rose to 20-2 mg. per 100 ml. on July 6. He wasplaced under fluorescent lights and the bilirubin fell to

14 mg. per 100 ml. by the following day. Heparin wasdiscontinued on July 6, at which time he was breathingspontaneously for long periods and was quite active.Four hours after heparin was discontinued a coagulationstudy (table) showed a near normal picture. His conditionremained stable for two days, until July 8, when he againrequired assisted respiration. His hsematocrit fell to 300and haematuria started. Coagulation studies revealedrecurrence of D.I.c.; heparin therapy was reinstitutedand platelets and packed red cells given. Nevertheless, hecontinued to deteriorate and died on July 10, aged 10 days,Blood-cultures drawn on 4 occasions during the clinicalcourse were all negative. Necropsy revealed hyaline-membrane disease in resolving phase, and moderate focalpulmonary haemorrhages bilaterally. No intravascularthrombi were detected. In retrospect, we wonder whetherthis infant would have gone on doing well if the heparinhad been continued.The first unusual feature in these two cases is that

I.R.D.S. occurred in the absence of any of the recognisedassociated conditions. It is commonest in premature in-

1. Karpatkin, M. Pediat. Clins N. Am. 1971, 18, 23.

COAGULATION STUDIES ON THE TWO INFANTS

* Patient receiving heparin.