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Letters to the Editor

EXCESSIVE CHEMOTHERAPY-RELATEDMYELOTOXICITY IN CHILDREN WITH DOWNSYNDROME AND ACUTE LYMPHOBLASTIC

LEUKAEMIA

SIR,-Children with Down syndrome have at least 18 times therisk of acute leukaemia of the general population.’ A survey from theChildren’s Cancer Study Group found that for children with Downsyndrome and acute lymphoblastic leukaemia (ALL), the outlookfor disease-free survival was no different from that of other childrenwith ALL once an initial remissiori had been achieved.2 Sinceoutcome in ALL is in part related to doses of chemotherapydelivered,3 it might be assumed that children with Down syndrometolerate maintenance drugs as well as other children do. However, achild with Down syndrome and ALL, seen at this hospital, whorequired frequent dose modification because of neutropeniaprompted us to examine records on our other Down syndromepatients.Between 1970 and 1985, seven children with Down syndrome

and ALL (ages 2 to 14 years, median 4 years 8 months) were treatedat our institution with one of the Children’s Cancer Study Groupprotocols, which included daily oral 6-mercaptopurine and eitherweekly oral methotrexate or 24 hour infusions of moderate dosemethotrexate every 6 weeks. Patients received pulses of vincristineand prednisone every 4-6 weeks with or without intrathecalmethotrexate; four patients received cranial irradiation and onecraniospinal irradiation.

Complete and differential blood cell counts and platelet counts atthe outset of maintenance therapy and every 4-6 weeks for theensuing 6 months were noted, together with reasons for dosemodification and results of tests of liver function (serumaminotransferases and bilirubin) and renal function (blood ureanitrogen, serum creatinine).

Cumulative doses per m2 of methotrexate during the first 6months of maintenance in regimens corresponding to those withwhich the Down syndrome children had been treated were 500 mg,500 mg, and 2-5 g. However, because of anecdotal experiencesuggesting increased susceptibility to granulocytopenia, all the

patients had been given maintenance chemotherapy at one-half tothree-quarters the prescribed dose. The dosage was also modified inaccordance with protocol guidelines, when the neutrophil count fellbelow 1000/pl. During the first 6 months of maintenance the Downsyndrome patients received 25-61% (median 40%) of the

anticipated full dose of methotrexate, and 38-67 % (median 60 %) offull doses of 6-mercaptopurine.

In several cases, reduced neutrophil-counts were associated with,or appeared to follow, an acute febrile illness. Three patientsreceived co-trimoxazole as prophylaxis against Pneumocystis cariniipneumonia, but the drug was stopped within 2 months because ofgastrointestinal symptoms or, in two cases, neutropenia. Withdosage modification, neutrophil counts 6 months into maintenanceranged from 874 to 4264/ nl (median 2500). Haemoglobin andplatelet counts remained relatively unaffected by chemotherapy.Liver and renal function studies showed minimal toxicity.

Although the number of patients is small, the modifications seemto have been greater than those required by larger groups ofpredominantly non-Down syndrome children treated comparably,who have been said usually to tolerate full doses of maintenancedrugs.4,5 Our results seem similar to preliminary data from thePediatric Oncology Group6 which found pancytopenia,mucositis, and serious infections even after two-thirds dosereduction in Down syndrome patients receiving intravenousmethotrexate.Down syndrome patients have several defects of the immune

system and they seem to be unusually susceptible to infection.’These may be a cause rather than simply a result of

myelosuppression. However, clinically apparent infection did notappear to be a major feature in our patients before neutropenia wasdetected. Similarly, although co-trimoxazole may have contributed

to neutropenia, it did not appear to be the reason for excessivemyelosuppression. Only two of four patients with neutropeniaduring maintenance therapy had received this drug for

Pneumocystis prophylaxis. In each case, it was terminated within 2months and neutropenia continued to be a problem.The metabolism of chemotherapeutic agents, especially

methotrexate, may be abnormal in Down syndrome. A serummethotrexate level 24 hours after the start of an infusion ofmethotrexate (150 mg/m2) in one of our patients was 2-8 umol/1, alevel comparable with what one might expect after a full dose of 500mg/m. Children with Down syndrome who do not have acuteleukaemia have been noted to have megaloblastic red blood cellprecursors.8 Although serum folic acid and vitamin B12 levels werenormal,8 the metabolism of folate analogues such as methotrexatemay be abnormal.The ability of children with Down syndrome and acute

leukaemia to tolerate chemotherapy, particularly intravenousinfusions of methotrexate, needs to be assessed in a larger group. Inthe meantime, we would recommend that these children be treatedcautiously.This work was supported in part by a grant from the Pittsburgh Chapter of

the March of Dimes. ’

Division of Hematology-Oncology,Children’s Hospital of Pittsburgh,Pittsburgh, Pennsylvania 15213, USA

JULIE BLATTVINCENT ALBOWILLIAM PRINSALVATORE ORLANDOMICHAEL WOLLMAN

1. Miller RW. Neoplasia and Down’s syndrome. Ann NY Acad Sci 1970; 171: 637-44.2. Robison LL, Nesbit ME, Sather HN, et al. Down’s syndrome and acute leukemia in

children: a 10 year retrospective survey from Children’s Cancer Study Group. JPediatr 1984; 105: 235-42.

3. Pinkel D, Hernandez K, Borella L, et al. Drug dosage and remission duration inchildhood lymphocytic leukemia. Cancer 1971; 27: 247-56.

4. Coccia PF, Bleyer WA, Siegel SE, et al. Development and preliminary findings ofChildren’s Cancer Study Group protocols (161, 162, 163) for low, average and highrisk acute lymphoblastic leukemia in children. In: Murphy SB, Gilbert JR, eds.Leukemia research: Advances in cell biology and treatment. New York: ElsevierScience, 1983: 241-50.

5. Freeman AI, Wemberg V, Brecher ML, et al. Comparison of intermediate dosemethotrexate with cranial irradiation for the post induction treatment of acute

lymphocytic leukemia in children. N Engl J Med 1983; 308: 477-84.6. Frankel LS, Pullen J, Boyett J, et al. Excessive drug toxicity in children with Down’s

syndrome treated for acute lymphocytic leukemia despite similarity of clinical andbiological features to other patients. Proc Am Soc Clin Oncol (in press).

7. Gregory L, Williams R, Thompson E. Leucocyte function in Down’s syndrome andacute leukaemia. Lancet 1972; i: 1359-61.

8. Gericke GS, Hesseling PB, Brink S, Tiedt FC. Leucocyte ultrastructure and folatemetabolism in Down syndrome. SAC Med J 1977; 51: 369-74.

BROWN-SÉQUARD SYNDROME DUE TO SPINALCORD INFARCTION AFTER SUBCLAVIAN VEIN

CATHETERISATION

SIR,--Complications of subclavian vein catheterisation (SVC)are usually reversible and do not cause permanent damage. Wereport a patient in whom spinal cord infarction during thisprocedure led to Brown-Sequard and Homer’s syndromes.A 70-year-old woman was admitted to hospital because of

persistent cough, haemoptysis, mild fever, and decreasing urineproduction. Physical examination indicated pulmonary infiltrationon the right side and she had an atherosclerotic murmur. Erythemanodosum was noted on her right leg. Wegener’s syndrome wasconsidered but could not be substantiated. Haemodialysis becamenecessary and SVC was attempted on the left side. The puncturewas done, via the infraclavicular route in an upward direction, by anexperienced anaesthesist, but contact with the lumen of thesubclavian vein or artery was not established. The patientimmediately experienced a lancinating pain in her left arm and leg,lasting for about 5 min. She could not move her left hand or leg andneurological examination revealed partial Homer’s syndrome withmiosis and ptosis on the left but no dysarthria or problems withswallowing. The left arm was paretic, severely in the hand, and theleft leg was paralysed. Hyperreflexia was found on the left side andpositive Babinski signs were present bilaterally. There washypoalgesia on the right side, the upper level lying between C8 andT4. Vibration and position sense were normal. Computerised

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tomography scan of the spine, lumbar myelography, and

cerebrospinal fluid examination were normal.The diagnosis was Brown-Sequard-plus syndrome and partial

Homer’s syndrome, caused by an infarction of the left

cervicothoracic spinal cord. During the next 3 months only slightimprovement was observed. The Homer’s syndrome remainedunchanged. Paresis of the left hand and leg persisted and the thenarand hypothenar muscles of the left hand showed atrophy. TheHoffman-Tromner sign was positive on the left hand and bilateralpositive Babinski signs were found. There was still hypoalgesia onthe right leg. The renal insufficiency and pulmonary infiltrationresponded to corticosteroids and cyclophosphamide.Lobar pneumonia developed after 3 months and the patient died

from septicaemia. Necropsy and histological examinationconfirmed spinal cord infarction on the left side at thecervicothoracic level.To recorded complications of SVCl (including pneumothorax,

laceration of the subclavian vein or artery, haemothorax,hydromediastinum, perforation of the myocardium, catheterembolism, misplaced catheter, sepsis, hydrothorax, and subclavianvein thrombosis) should be added spinal cord infarction, in this casecausing Brown-Sequard-pIus and Homer’s syndromes. In Brown-Sequard-plus syndromes, physical signs indicate involvement ofthe other half of the spinal cord as well. 2

Spinal cord infarction after injection of contrast medium forvertebral angiography via the subclavian artery3 is ascribed to theinjection of contrast into the costocervical trunk, leading to

ischaemic infarction of the cervical spinal cord. The inferiortwo-thirds of the cervical cord is supplied by arteries, arising frombranches of the subclavian, which differ in their arrangement fromone person to another. 4,5 In the days before the Seldinger techniquemechanical irritation of an artery (eg, during direct vertebral arterycatheterisation) used to cause severe spasm at angiography evenwhen the needle had not entered the artery. We think that in our

patient spasm or embolisation in one of the arteries of thecostocervical plexus caused ischaemia in the left anterior part of thelower cervical cord, leaving the posterior columns intact.Brown-Sequard syndrome is rarely caused by spinal cord

infarction.2 Suchenwirth refers to a sulcocommissural syndrome inthe pathogenesis of such cases.6 We do not know why only one sideof the cord was damaged in our patient although the bilateralBabinski signs point to slight extension to the other side. A collateralartery supply might have spared the right side of the spinal cord.

Department of Neurology,Municipal Hospital2504 LN The Hague, Netherlands

P. J. KOEHLERP. R. A. WIJNGAARD

1 De Jong PCM, Von Meyenfeldt MR, Rouflart M, Wesdorp RIC, Soeters PB.Complications of central venous catheterization of the subclavian vein: theinfluence of a parenteral nutrition team. Acta Anaest Scand 1985; suppl 81: 48-52.

2. Koehler PJ, Endtz LJ. The Brown-Séquard syndrome: True or false. Arch Neurol1986; 43: 921-24.

3. Ederli A, Sassaroli S, Spaccarelli G. Vertebral angiography as a cause of necrosis of thecervical spinal cord. Br J Radiol 1962; 35: 261-64.

4. Djindjian R. Normal angiography of the spinal cord. In: Djindjian R, ed. Angiographyof the spinal cord. Paris: Masson, 1970.

5. Lazorthes G, Gouaze A, Zadeh JO, Santini JJ, Lazorthes Y, Burdin P. Arterialvascularization of the spinal cord. Recent studies of the anastomotic substitutionpathways. J Neurosurg 1971; 35: 253-62.

6 Suchenwirth R. Gibt es ein Syndrom der Arteria sulcocommissuralis? Nervenarzt1973; 44: 604-05.

CYCLOSPORIN, HLA MATCHING, ANDTRANSFUSIONS IN KIDNEY TRANSPLANTS

SiR,—The conclusions of Dr Lundgren and colleagues (July 12,p 66), that there is no beneficial effect of HLA-matching andpretransplant blood transfusions on renal allograft survival, are notsupported by the observations of other investigators.1-3 Lundgren etal found no difference in graft survival whether HLA-DRmismatches or sharing of HLA-DR antigens are taken into account.Their table i shows that 113 patients shared two DR antigens withtheir donors and so belong to the zero mismatch group. Thatimplies that the remaining 132 patients in the zero mismatchedgroup share only one DR antigen, which is a very high proportion

HLA-DR MATCHING AND CADAVERIC KIDNEY GRAFT SURVIVAL

*All donors and recipients have two detectable HLA-DR antigens. Consequently, thenumber of antigens in common is precise.

(53%) of the zero mismatch category. Furthermore, the very lowfrequency of DRw-6 in their donors and recipients (0-09 and 0 04,respectively) and the high frequency of "HLA-DR blanks" (0-12and 0 17) creates considerable uncertainty as to the reliability oftheir DR typing and, consequently, their estimates of match grades.Such material is unsuitable for studies on the effect of HLA-

matching on renal allograft survival.Eurotransplant data for 1981-85 for first cadaveric transplants

have been analysed in the way described by Lundgren et al. Allpatients have been treated with cyclosporin alone or in combinationwith other immunosuppressive drugs. The table reveals a

significant beneficial effect of DR matching on renal allograftsurvival. The group of 1548 patients belonging to the zeromismatch category can be divided into two groups-namely, 1106full-house donor-recipient combinations (sharing two DR-

antigens) and 442 non-full-house pairs (so-called identical and/orcompatible combinations which share one DR antigen). Theproportion (442/1548 or 29%) of patients who share only one DRantigen in our series differs highly significantly from the 132/245(53%) in the Scandinavian multicentre study.

In the Eurotransplant material 70% (2056 out of 2926 donor-recipient combinations) have two identifiable HLA-DR antigens,which fits very well with what one would expect on the basis ofcalculations of DR gene frequencies in Western Europe (81 %).4

In another reports the Scandinavian group demonstrated a slightbeneficial effect of HLA-DR matching on graft survival betweenliving related individuals at 2 years. This might be the result ofmuch more reliable tissue typing results in donors and recipients ofa living related kidney.The conclusions drawn by Lundgren et al seem to be based on

incomplete DR-typings and are therefore misleading. As long as theHLA-DR gene frequencies of the population are not in Hardy-Weinberg equilibrium one should be very cautious in drawingconclusions about the effect of HLA-DR matching on renalallograft survival.

Blood Bank,Eurotransplant Foundation,University Hospital,2300 RC Leiden, Netherlands

G. G. PERSIJNG. M. TH. SCHREUDERG. F. H. HENDRIKSB. COHEN

J. D’AMAROJ. J. VAN ROOD

1. Opelz G, for the Collaborative Transplant Study Group. Effect of HLA matching,blood transfusions and presensitization in cyclosporine-treated kidney transplantrecipients. Transplant Proc 1985; 17: 2179-83.

2. Terasaki PI, Toyotome A, Mickey MR, et al. In: Terasaki PI, ed. Clinical kidneytransplants. Los Angeles- UCLA, 1985: 1-26.

3. Persijn GG, D’Amaro J. Cyclosporin-A: experience m Eurotransplant, preliminarydata. Scand J Urol Nephrol 1985; suppl 92: 91-93.

4. Schreuder GMTh, van Leeuwen A, Termijtelen A, Parlevliet A, D’Amaro J, vanRood JJ. Cell membrane polymorphisms coded for in the HLA-D/DR region I:Relation between D and DR. Hum Immunol 1982; 4: 301-02.

5. Lundgren G, for the Swedish-Norwegian multicentre study. Role of blood

transfusions and HLA-matching m cyclosporin treated renal transplant recipients.In: Scandiatransplant annual report 1985. 1986: 29-40.