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established, however, and there are probably over 2500 patientseffectively blinded by the condition in this country. Injectiontreatment should be available at all major neurological andophthalmological centres. The possibility of extending its use toother muscles affected by spasmodic dystonia (eg, the sternomastoidin torticollis) or by contracture, as in cerebral palsy, needs moreactive investigation.

Department of Clinical Ophthalmology,Institute of Ophthalmology,Moorfields Eye Hospital,London EC1V 2PD JOHN S. ELSTON

1. Dolly JO, Black J, Williams RS, Melling J. Acceptors for botulinum neurotoxin resideon motor nerve terminals and mediate its internalization. Nature 1984; 307:457-60.

2. Tonge DA. Chronic effects of botulinum toxin on neuromuscular transmission andsensitivity to acetylcholine in slow and fast skeletal muscles of the mouse. J Physiol(Lond) 1974; 241: 127-39.

3. Duchen LW, Strich SJ. Changes in the pattern of motor innervation of skeletal musclein the mouse after local injection of Clostridium botulinum toxin. J Physiol (Lond)1967; 189: 2-4.

4. Elston JS, Lee JP, Powell CM, Hogg C, Clark P. The treatment of strabismus in adultswith botulinum toxin A. Br J Ophthalmol 1985; 69: 718-24.

5. Scott AB. Botulinum toxin injection into extra-ocular muscles as an alternative tostrabismus surgery. Ophthalmology 1980; 87: 1044-49.

6. Elston JS, Lee JP. Paralytic strabismus: the role of botulinum toxin. Br J Ophthalmol1985; 69: 891-96.

7. Scott AB. Injection treatment of endocrine orbital myopathy. Doc Ophthalmol 1984;58: 141-45.

8. Jankovic J, Havins WE, Wilkins RB. Blinking and blepharospasm: mechanismsdiagnosis and management. JAMA 1982; 248: 3160-64.

9. Berardelli A, Rothwell JC, Day BL, Marsden CD. Pathophysiology of blepharospasmand oromandibular dystonia. Brain 1985; 108: 593-608.

10. Loeser JP, Chen J. Hemi-facial spasm treatment by microsurgical decompression,Neurosurgery 1983; 13: 141-46.

11. Elston JS. Botulinum toxin treatment of hemi-facial spasm. J Neurol NeurosurgPsychiatry (in press).

12. Magoon EH. Botulinum toxin chemo-denervation in infants and children. J PediatrOphthalmol Strabismus 1984; 21: 110-12.

CHILDHOOD LEUKAEMIA IN NORTHERN SCOTLAND

SiR,-In preparation for the public inquiry to be held later thisyear on the planning application for a nuclear reprocessing plant atDounreay on the north coast of the Scottish mainland we were askedto examine cancer registration and other data from that area. Ourprimary concern here is to report findings for lymphatic andhaematopoietic neoplasms (ICD-9: 200-208) in people aged 0-24years during the period 1968-84. The places of residence of thepatients at the time of registration have all been postcoded andgrouped into five groups: mainland enumeration districts whosecentroids fall within 12 - 5 km or within 25 km of the existingDounreay installation, the remaining mainland districts fallingwithin the KW postal area(KW relates also to Kirkwall, Orkney) andwithin 25-75 km of Dounreay, and places of residence on theislands of Orkney (range 35-120 km) and Shetland (range 160-300km). Expected figures are based upon all-Scotland cancer

registration rates. Population data were extracted from the 1971 and1981 censuses.The table shows the observed and expected registrations for the

periods 1968-73, 1974-78, and 1979-84. The cell in this tablewhich gives cause for concern is that for leukaemia (ICD-9:204-208) between 1979 and 1984, less than 12-5 5 km from

Dounreay (p<0-001, one-tailed test). In this group 4 of the 5patients with leukaemia lived in Thurso, the only significant centreof population within 12-5 5 km of Dounreay, and the fifth lived about3 km from Dounreay. 4 patients were aged under 15 at registration. 4were originally registered as acute lymphoid, and 1 as acute myeloidleukaemia but subsequent validation has changed the diagnosis of 1lymphoid case to myeloid.The importance of this finding is difficult to evaluate. The choice

of radii and time-periods is arbitrary and, although there is an excessof cases over the whole period 1968-84, no cases at all were

registered within 25 km in the period 1968-78. On the other hand,the facts that all reported cases within 25 km occurred within a5-year period, 5 were in children under 15, and 5 occurred within12 - 5 km of Dounreay, may increase its potential importance.Similar findings have been reported from near other UK nuclear

REGISTRATIONS FOR LYMPHATIC AND HAEMATOPOIETIC NEOPLASMS

IN DEFINED AREAS IN NORTHERN SCOTLAND: AGE GROUP 0-24

*Remamder ofKW postcode area on mainland.

installations (eg, Sellafie1d,1 Hunterston,z and Aldermaston andWest Burghfield3).

Preliminary examination of all other cancers in childhood and ofleukaemia and selected sites of cancer in adults, and of theoccurrence of congenital malformations, showed no significantlyraised figures in the area around Dounreay.These findings will be reported to the Committee on Medical

Aspects of Radiation in the Environment. A further report will dealwith the validation of all cases of leukaemia in people aged 0-24 inScotland for the period 1968-81. It is hoped also to report on anyother clusters throughout Scotland and to update findings to 1983.

Information Services Division,Scottish Health ServiceCommon Services Agency,

Trinity Park House,South Trinity Road,Edinburgh EH5 3SQ

M. A. HEASMANI. W. KEMP

J. D. URQUHARTR. BLACK

1. Investigation of the possible increased incidence of cancer in West Cumbria 1984Report of the Independent Advisory Group (chairman, Sir Douglas Black). LondonHMSO, 1984.

2. Heasman MA, Kemp IW, MacLaren Anne-Marie, Trotter P, Gillis CR, Hole DJIncidence of leukaemia in young persons in west of Scotland. Lancet 1984; i1188-89.

3. Barton CJ, Roman E, Ryder HM, Watson A. Childhood leukaemia in West BerkshireLancet 1985; ii: 1248-49.

RECURRENCE OF NEPHROTIC SYNDROME DURINGCYCLOSPORIN TREATMENT AFTER RENAL

TRANSPLANTATION

SIR,-Preliminary studies suggest that treatment with

cyclosporin can induce remission of nephrotic syndrome in patientswith focal glomerulosclerosis (FGS) and membranoproliferativeglomerulonephritis (MPGN). 1- We describe here six patients withend-stage renal disease due to FGS (three males, two females)or MPGN type II (one male) in whom the original disease recurredafter renal transplantation despite immunosuppression with

cyclosporin. All patients received a cadaveric donor kidney. At thetime of transplantation, ages ranged from 16 to 51 years and theintervals between onset of disease and transplantation ranged from 3to 17 years. All patients received cyclosporin orally in a dose of 17’ 5mg/kg body weight, and this dose was decreased every fortnight by 2mg/kg. The prednisone dose was 10 mg daily.Despite the cyclosporin proteinuria developed within 3 months of

transplantation, and in all cases recurrence of the original disease

267

was histologically confirmed. Two patients had had recurrence ofFGS in a previous graft 2 years earlier, while being treated withazathioprine. One patient lost his graft within 5 months aftertransplantation, while the other five still have a normal serumcreatinine 1-2 - 5 years after transplantation.Recurrence of glomerulonephritis in kidney allografts during

conventional immunosuppression by azathioprine is well known.4 4Our results demonstrate that this occurs also duringimmunosuppression with cyclosporin. Claims that this drug holdspromise for the treatment of several forms of glomerulonephritisshould therefore be viewed with scepticism until formal proof isprovided by controlled trials.Division of Nephrology,St Radboud Hospital,University of Nijmegen,6500HB Nijmegen, Netherlands

A. J. VOETSA. J. HOITSMAR.A.P. KOENE

1. Cattran DC, Dossetor J, Halloran PF, et al. Ciclosporin in glomerulonephritis: a pilotstudy. In: Schindler R, ed. Ciclosporin in auto-immune disease. Heidelberg:Springer, 1985: 311-15.

2. Meyrier A, Simon P, Perret G, Condamin-Meyrier MC. Use of ciclosporin inidiopathic corticoresistant or corticodependent nephrotic syndrome (minimalchange glomerulopathy and focal-segmental hyalinosis). In: Schindler R, ed.

Ciclosporin in autoimmune disease. Heidelberg: Springer, 1985: 316-22.3. Brodehl J, Hoyer PF. Ciclosporin treatment of idiopathic nephrotic syndrome in

children (minimal change disease and focal segmental glomerulonephritis). In:Schindler R, ed. Ciclosporin in autoimmune disease. Heidelberg: Springer, 1985:329-33.

4. Morzycka M, Croker BP Jr, Seigler HF, et al. Evaluation of recurrent

glomerulonephritis in kidney allografts. Am J Med 1982; 72: 588-98.

HLA MATCHING AND CYCLOSPORINIMMUNOSUPPRESSION: A STRONG CORRELATION

SIR,-The inverse effect of HLA matching in cyclosporin-treatedpatients reported from the UK by the Wessex transplantationcentre! is likely to be an unusual finding at a single unit. Studiesbased on data from several centres reveal a clear beneficial effect ofHLA matching in cyclosporin-treated patients. 2-5 From data kindlyprovided to us by more than a hundred transplant centres in the USand Canada, we have re-examined the interrelation. The relativeeffect of HLA matching and cyclosporin can be separated, as shownin the figure. The improvement in one-year graft survival rangedfrom 6% to 17% for zero to five HLA A,B,DR mismatched antigens.This means that graft survival was already high without cyclosporinfor well-matched transplants whereas with poorly matched grafts,cyclosporin produced a much greater degree of improvement.Cyclosporin-treated patients can be seen to have a 12% higher one-year graft survival rate. The same data for patients treated with

Effects of cyclosporin and HLA matching on one-year graft survival.

Cross-hatched area on left represents difference in cyclosporin and non-cyclosporin between specific mismatching categories. Stippled area on rightshows difference in cyclosporin-treated patients with 1, 2, 3, 4, 5, and 6mismatched antigen categories as compared with zero mismatch ideal; cross-hatched area is same comparison in non-cyclosporin-treated patients.

cyclosporin showed that there was a 26% difference in one-yeargraft survival for transplants with the best (zero) A,B,DR mismatchas compared with the worst (six) mismatches. Thus, the HLAmatching effect was larger than the cyclosporin effect amongpatients treated with cyclosporin. Even among patients who did notreceive cyclosporin, the difference in the best A,B,DR mismatchand the worst mismatch was 30% at one year.Most of the previous studies on HLA matching have been based

on the effect of the A,B locus alone or, more recently, the DR locus.It now seems that if all these loci are combined, a much higherdegree of correlation between matching and graft survival isobtained.6 Mickey et als have calculated that, with a recipient poolof 10 000, as many as 28% of the transplants can be done with zeroA,B,DR mismatches. Hence, despite the difficulty in matching forthree highly polymorphic HLA loci, with sufficient cooperationamong transplant centres high degrees of compatibility can beachieved. The often expressed notion that, with the advent ofcyclosporin, HLA matching can be ignored, has not beensubstantiated.Data from the multicentre European trial6 of cyclosporin shows

that there is a loss of grafts even after 3 years. This late loss isprobably attributable to underlying incompatibility. With

improving one-year success rates, long-lasting transplants can nowbe sought by utilising zero mismatched HLA A,B,DR grafts.

UCLA Tissue Typing Laboratory,UCLA School of Medicine,Los Angeles, California 90024, USA

JAMES CICCIARELLIPAUL I. TERASAKIM. RAY MICKEY

1. Harris K, Gosling DC, Campbell MJ, et al. Azathioprine and cyclosporin: differenttissue matching criteria needed? Lancet 1985; ii: 802-04.

2. Opelz G. Ninth International Histocompatibility Workshop renal transplant study. In:Albert E, Baur MP, Mayr WR, eds. Histocompatibility 1984. Heidelberg:Springer, 1984: 342-47.

3. Cats S, Terasaki P, Perdue S, Mickey MR. Effect of HLA typing and transfusions oncyclosporin-treated renal allograft recipients. N Engl J Med 1984; 311: 675-76.

4. Opelz G. Effect of HLA matching, blood transfusion and presentation in cyclosporin-treated kidney transplant recipients. Transplant Proc 1985; 17: 2179-83

5. Mickey MR, Carnahan B, Terasaki P. Effectiveness of zero A,B,DR mismatch forcadaver kidneys. Transplant Proc 1985; 17: 2222-24.

6. Calne R, Wood AM. Cyclosporin in cadaveric renal transplantation: 3 year follow-up ofa European multicentre trial. Lancet 1985; ii: 549.

ALTERNATE-DAY IMMUNOSUPPRESSION

SiR,&mdash;Professor Salaman and Mr Griffin (Nov 9, p 1066) reportthat immunosuppression with a combination of cyclosporin,azathioprine, and prednisolone may be unsafe. We haverecommended alternate-day cyclosporin and azathioprine plussteroids, describing our experience in five patients,’ and have sinceinvestigated this regimen in dogs. Kidneys were transplanted to theiliac vessels between unrelated mongrel dogs of either sex and theopposite kidney was removed. Serum creatinine measurements andblood cell counts were made at least weekly. Full post-mortemexaminations were done on animals that died or were killed because

they appeared ill, and an open biopsy was done on day 84 on allsurviving animals.Group 1 (alternate day) animals received either cyclosporin

25 mg/kg or azathioprine 5 mg/kg on alternate days. Group 2 (half-dose daily) animals received cyclosporin 12 - 5 mg/kg and

azathioprine 2’5 5 mg/kg every day. Drugs were administeredparenterally and then orally after day 3.The results are shown in the table and figure. Survival at 84 days

in group 1 was 67%, and biopsy of the 8 survivors revealed noevidence of rejection or cyclosporin nephrotoxicity in 6, rejection in1, and proximal tubular vacuolation indicating cyclosporin toxicityin 1. In group 2 survival at 84 days was 36%, in the 5 survivors therewas no evidence of rejection or cyclosporin toxicity in 3 but in 1rejection was seen and another had cyclosporin toxicity (proximaltubular vacuolation) and severe thrombocytopenia and leucopenia.The serum creatinine of the survivors in group 1 was higher thanthat of survivors in group 2, but remained within the normal rangeexcept in 1 animal with biopsy evidence of rejection.