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s THE Lq.r:CET, SEI'TEr1BER 16, 1989 antibodies in SCLC patients withounLES has to be further investigated in a larger population to better define their possible pathogenetic role. None of the myasthenic patients tested'had anti-VOCC antibodies,,whereas 11 LES patientt had also antinicotinic receptor antibodies, which suggests the possibility of a combined myastherlic syndrome,' atileasr at the immunochemical ln'el! Use of this new immunoassav to screen a larger number of mya: thenia gravis patients will allow the detection'of cases in~which LES occurs together with rrtyasthetlia gravis. Antigenic modulation is a common mechanism by which anti-receptor antibodies down-regulate the number of receptors expressed at the cell I surface, and this effect is importanr for explaining the biological and clinical activity of the autoantibodies.10 LES antibodies clearly recognise antigenie detemzinants on the VOCC which are "epaernal"' to the site where wCTx binds, since, for the purpose of the immunoassac, this site was alteadv occupied by the toxin. Furthermore, LES autoaraibodies were not able to directly ' inhibit 1351-fuCtx binding to Ih'1R32 membranes. However,. LES antibodies were able to down-regulate the expression of VOCCs' in: This effect was highly specific with respeLZ~ to other~ membrane molecules such as the el-Bgtx receptor. However, we cannot exclude the possibilirv that different patients syrlthesise different antibodies with different specifieities and mechanismsof action, as in the case of anttbodles against nicotinic receptors in myasthenia gravis. We thamkDr V. A.. Latnon for aldowirsgg usto.perform the blind acperunent;..for the pemussionto use these resulu, and4arhelp with the manuumpr;,Dr L. Rosenthal for helping to improve the paper; Prof G. FtsrrugzEli for his criod'suggestions; DrT: Baggi for help with anfuucoaitvc receptor antibods usays; and JNr P: Tinetli for technicJ callabornion... This woric' was panh•funded br.the C~R Special Proiea '".tieurobrolog`'" All torresp,otsdence shouldbed addressed to ~ E. S., C~R. Crnter of Cytoptiamu.rologs, Vu Y'am-iteJ1:32;:'01?9.Nilan, ]rari,. REFEREKCES I. O'Xr&JM, Mum~ N.v.F, I:-Dnx .. r Tbr. Lmsbm-Earon m.asthcue z,nd- . A ~ ~ of 50 osea. BrmnI986,111: 2.:Lamber. EM, RoekrED, Eao- LM;, Hodgsun: CH, . M.astlierne syrsdromr oensanally aooaud rith Drvrseluil neoplium . neurophysiolopc smdras. In: H L Vrtn, ed. .Nmrhmu pans. SpmnafiddCC Thomas, 196.,1. 362-110. 3: Cull-Cs:dy 5G, SLled R. Tnuunan A, Udiirel OD On therelease of mrsmrina an nenru:.myasrlsasn pv.v and ml}stherur synddome aHenedbum.n asdplaces.. J Pm-! .1980; 299: 621-38. . 4. M-dusi. MBi R'alsli,Rl:, Rutirno FA,.BnnrsMan RT, H~e Wi. Avronomu dsfuncvm andEaren,Lambcrt sYrsdrome. J Aurm Nrr..- Sysn 1985, 12: 315-20'. 9~Lmnon VA', Lamberr Eli, Qluraadium S;,Fu-bvrks V. Aumirsununiay:m the tLmberr,Earon myurtrc:uesyndrvme: M-4 h'm,r 1982; S: 821-25. 6: t.ars` B, tie.s®n-Ds.v 1, tt'ny D8, Vmceni A, Muuray; N. Aurovrmsune.euoIop - for-thasic'Earmn,Lamberr,qesd'- . L- 198'1; ii:224-26. 7. Kun tY Pass"ive asnsfer of rhe.L.mEen-Faron m}aatheuc s3ndlomc: neurwnuscu}v. v.nsrsvsswn m msec mlecred wdapuume. Mwc4lvm. 1985; 8. 162-i2. 8.J~ B. \rwsotn-Dnu ); Pnnr C,.~'by Da'.. Mdtiodus m rnotor nme.uerrnusd~.n dacoophyuobp¢sl krudy of.huerm myuttiauc syndrome.oansferred w nq,ac. ],PMym!,1983; 1a4: 335-45: 9. Knn IY- PaasrveJy.v ansfecred. l~ben-Eason syndrome mms¢ remvsrst pun5ed. I{G. Mur Jr' .Vrnr.1986; f: 52}30. 10. 1-Dert EH, I.auson VA. Seleard.leCr eapidlysMUm t-bvr-Faeon myndbauc eyndrome m mrte: c-piensmt ihdepasdenoc and;EMG,abnonmahea. Mmc4 Krrvr 198&, Ia: 11.33-45. 11. Fukunap H, FilRel AV, tAV B, New.orn-Daws J, Vuscesl A.,Pasuvettansfer.of Lmbm-Earoo mysnhetie .vndrnme with IyG fromman ro mouse deplern rhe. praynapuc manbnnc.arnvc nu!se. lbor Irar! vtcnd Sn USJ1:1983;1tr. 7636-80. IP. Fukirok. T„Etsgel AG, Lanj B, N~Dsss:J, Pnos C, Q'nyDW. tLmbm-. Eaaon myasNasc syndrnmc. 1.. Firy'.. morphologrnl effecss ofi IgG on the prenynapoc manbnnc .cvve mnes Ain Narro! 198- , 22: 193-99. 13. Fukurup H, EneeliAG, Osrrn CN, Lmben M...Pauananddiwryuuanon of pra}supIDC n~rs6rane .cove m die Lambm-Earon myschervc syndroma- Masc4 A'nu 1982; S: 686-97. 14. Rooeru A, Pexn S, lun[ B, Vareer,c A, Ne.r~orn-Deviv )'. Parweoplasac mlueheruu. synCtame la('imluErx •'G"' Cu m a hurwr,small lorcss,oma lunc h'ansr..1985'. 317: 73 7-39 Refhmcrs rontirwrd otfoor.oJ nezr colsnm: SMOKD~G AS A R1SF4 FACTOR FOR CEREBRAL ISCHAEMiA, GEoFFREY A. Doh'NANs-I JoH:: J. M,GNEILS MJCHAEL A. ADENA' AL'Sr1': E. Do11.E' HF1a773ER IW1. O'MALLEY' GEpRGINA C. hiEILLs'' Deparrmerau of hreurologl,''aw' Medianc,? A'usasn Flospifal, (imz+rroiiti~ of Melooirrne Department of Socia1 and Preventive Medieine, Monruh' Crrmursiry, Melbourne,' and'lnlseaf Ascstralta Pry Ltd; Cmtb'erra,` Australia Summary To assess whether a rigorous clinical classification, based on aomputeriscd tomogsaphy, of patients with cerebral ischaemia would identify' subgroups at higher or lower risk with, respeca to cigarette smoking habits„a ease-control study was carried out on 422 cases of first-episode cerebral ischaemia matched for age and sex with 422 community-based neighbourhood controls. Patients with ischaemic stroke due to extracranial or intracranial vascular disease were at higher risk from smoking than has previously been reponed' for stroke (relative risk 5 7, 95 °io confidence inter\'al 2 8, 12 0) whereas those with stroke due to cardiac enboh hadino excess risk associated with smoking (relative risk 0 4 [0 1, 1 8];. After cessation of smoking. the relative risk declined gradually over l O vears, at the end of which time a significant risk was still evident, This fihding,may imply that the risk incurred by smoking is d'ue mainly to ather'oma formatDon„ rather than transient haematological effects. Exposure to smoking by a spouse was an independent risk factor for the whole group of cerebrral isehaemia patients (telative tisk 1 7 [1 1, 2,61),,but this wasnot sofor smoking by'eitherparent' (relative E. SHER A.\D OTHERS'.REFERENCES-r.ont7mccd 15. De. Aupwma H7, Ismben EH, Grxsnunn GE, Ouwen B\l. Le.non \A' AntaBausm of salusgr-pred aloum diarsnrl> v~ arrull dl a~nnorrsi of pammu.nh oo rnhouu Ly flen-Earon m.asdimnc. slndrome o.auroenubnGn. wmnorown.andadc,osmc C.vur Ru 19b6:4&: i711a 16.Kun IY, Nehc E. 1CG 6:vm p.IDmrs.wtb I-bm-Firoe nrdrvrm., blocks .vltla{edcpmdencoalaumrLrvxh Sanc..198b',239:a[,s-0E. I7:CruxLJlOlireecBS4 C~Imumdururdcsaaerxsua-amep- G\'tAd'efvnesa ne- h*i a.sou) vrc. J,Hu1C6i.e 1986, 2YI162Y133 I B.: Feldmaa DH I Ob.m B.N, Yoslirkarni D. Omep C- ta+t.; •^. .roun . a pepcdr thae bl.ds osFoum dsarmeh. FEBS'Len lofi', 214:'95-30P 19: R,wtt 1, Gahrm. R, G- 37t. Aamu.7cnaox. A', .Nclhman JM. Cru: LI, Oh. mBS4. Neurvr.al alchum. char:nd Ivilab:rors J e.a CA_- :1967, 26:': I 1-+-% 20; Bstirarun J, Sd=dA, tuziumskr ~M Properoei of struccure v.d mrescvon of rlie te.m, ror for omer -mnorom:,. a po.lyprpode.cn•ron Ca=" dunneu Brof,.h,.a Rr, i C- 198',15P1051-62~ 21. Ye.eer RE, Yoshikana D, Rrvw.J, C+ur.L); Mslurudr GP Tevsurunrr rcl/asc from , praynapec- vmsuWh ofdeeasc orpn srJubimor.: b, Ihee olourn ehannell v,ta9onssr.. omeQc Camus roan J.l:mosn 1987, 7:.39ia46' 22. rboln -. DJ! Lupp A, Hemm,t G. I+JUbsoon of amvaJ ineu,vwwwner.relesu b% omep-otui, e pepode rnod.ulatorr of the T:-e)yc wlorr-smuns<- oltium , durmaLl A'a. yn-Sc/w.rde6r7s A.rA'. P6erwsorol 1987; 336:.46'-70. 23-McOakey.ECr, Fm AP; Feldesus DH, n.1 as-L-.orsaomn , duenand pennrmr. blat.da of speciBc nres ef olourn rhwse4 m neurons bw non musde P+crr .\'-!' . Arad So C"SA.198", 54; 4327-311 ?A.. CeuzL JoM.us DS. Obva B.N' Cbannersaoon of tbe.amp- uree. E~sdc,oc fer oa.ue-ryec5c Aerero8asory'-doum dunncl ryye 6-A-r3 . 198 7:7[:.820-24 25:. Sher E, Pmdsdla A, Llarsasti F Omep~w bmduu vrd effrcn onn olnumdvmrl fumeaan m human neun>blardrs. and rar phroCUOnne~- ¢Ui Imes FEBSLrrr 1988, 235: 17H$'. 26'Gato C,: Mamessua R. Clbnotu F N- mnt-. lot .nmbodv.. desecmn m rnyasNerua p-.ns l.'ixoiq, I CL. 198-1, 34: 37i-' 27. Oonarnu F, Cabrsru ~ D, Goro C, Sher E Pfs.mvmlopd' dunnma~ of dsohneryrc.re.tpron mu human nrueobianom- re4'.bnr J.\.v.nsM.~.f9h6., a: 291-07 28Clensena F, Sli- E Motwdl.mduced5 mrersabamom of a¢nICholme rucvu-~c r epror hmcoo mecharusm. md s<kev- - Ero J,C.!!' R.n! 9oE5, 37, 29 . M,lia Rl-.Nuloplt alnum rlsannrls aM neurmul fvn<vmn S-la6:. ] 35: 4s 5:30 CJernmuF, :Shn. E. AnoMh -mduceddown eetulouon of ine:noramr rca-epr,.n u.i humar:drra.es In Koerir: TM, a al., ad,~tolnvh• mechamsm,of doenumrauonm-vlpul,nohnileh Berlm Sprm,er\'rrlat, 19E7 30'1-1-

64-.1'~ risk 1 2'[p-8, lr8]p. These findings suggest that smoking is a more potent risk factor, for the most~ common fotan of ischaemirst7oke than has previously been appreciated. The persistent nature of the risk even after cessation of smoking and the possible risk associated with passive exposure strengthens public health arguments against smoking: Introduction TriE clinical ipimzre of stroke can be produced'by several pathophpsiological mechanisms,, the most importartt of which are atherothrombotic brain infarc[ion,,intracerebral haenorrhage, and subarachnoid haernorrhage. Before the development of rntnputerised tomography (CT), the diagnosis of tutdiSereatnated "srroke" was often tontaminated~ bv other causes of acute, focal neurological deficits, such as cerebral neopl9sm, subdural haematoma, and cerebral abscess. Furthermore, the discrimination between pathophysiological subrypes was difficult. CT sca*+n+*+g; now established as a routine diagnostic procedure in musz deveioped countries, provides an accurate and non-invasive means of subgrouping stroke n•pes. Risk factors for stroke have been identified in c•arious epiderniological studies. Most were carried out before CT becarrte available and attributed'hypertension and ageing ass the primary antecedctts.t-1 Cigarette smoking, which~ is associated'With atheroma generation elsewhere in the body,, has been less consistatth• implicated as a major risk factor for stroke, although the latest studies have shown a more convincing association.y' Our aim, was to examine the risk relation between cigarette smoking and subnpes of cerebral ischaemia whose pathogenesis is related to atherosclerotic change in major cranial and ea-[recranial! blood vessels. The hypothesis examined was that, without the possible diluting efiect of crrebral haemorrhage and other non-th.romboembolic causes of stroke„ the stroke risk associated: w•ith cigarene smoking would be greater than that reponed'previousl}• and that there may be subgroups t<ith ver}' high risk. We also took the oppornutin' to examine the effects of' stopping, smoking on any obsen•ed' risk for cerebral ischacmia„ together w-ith any independent risk which may be attributablt to smoking among other famil}', members. Patients and Methods 1:urse-intervieus ide:nti5ed cases of acute cerebral lisciiaettia in four major hospitals serving the nonh-eactem region of Melbourne betu•ern 1985 and 1986: These hospitals manage mostsuch cases in this area, the exception being the very old, who maybe managed at home, in smaller private hospitalsy or in nursing homes. , Patients wcre enrolled in the study if the clinicrl'evcnt was thei.r first episode of cerebral ischaemia. Patients who died were included in the study by interview of elosest relatives. The duration of cerebral ischaania was defined to rartge from 24 h or, less (tnnsient isehaemic anaek [T1A]) to a permanent defioi (cerebral irtfarcrion): There was no age restricoon for study entry. CT scans were carried out on 98% of ases Kithin 10 days of hospital admission:,'Phose who did not receive CT scans were elderly, in a moribund state on admission, had cerebral isehaemia diagnosed on clinical grounds by the srunering runue of the progressive deficit, and died shortl}• afterwards. Patirnts in whom cerebral haemorrhagc v.as shown on CT were excluded from the study: Patients were asked to take pan in a study of previous diet and lifestyle factors. A sauctnred questionnaire was used to record i.nfot•mation about personal characteristics, habits such as agarene smoking, alcohol consumption, past dietary and ncerasc pracvices, and medical history (including that of treated hypenension). A TtHE L4NCET;,SERTEXtBER 16,,1989. detailed' list of current and past drugs was used to validate information about medical histon. The section of the questionnaire about smoking sought information on current mnsumpuon, prnious consumption in decades, npe of cigarcnc, dgar„or, pipe smoked, anddegree of inhalation. The time since stopping smok:ng was recorded in periods,of'' years and then 5 years from the 19sr ogarene to increase the rctiabiliin of rerrll. For the effects of passive smoking among other family members, patients were asked whether mother, father, or spouse smoked as many as I cigaren e per day for z long as 1.xar and, if sa4 what was the highest number smoked regularl}•, for as long as I'. ynr. The laner was recorded as agaretta per dav in amounts of 10:. Controls were matched indnidualli•y b.•y age (:t 5 ycars) and scx and were identified by knocking on doors in the same sveet (according to a strict protocol) until a household with a matching inditidual frec of prnious cerebrovascular disease was found. When an identified control was absent from the household„the intenie.a•er returned on at least two fizrther occasions to anempu contact. About 10% of identified eontrold refused to paniapate or could not be contacted and in these cases the next suitable ncighbourhood control was choset: Each case and matehing control were inteniewed'by the same nurse-interntiewer. Otth 1°Sb of cases refused interview. In approairnateh 20°.0 of cases eomtnunication was restriczed and the closest available relative was intrnieu•ed;, the closest available relative ofl the matdied control w•as, inteniew•ed' to avoid information btas. Most patients were inten-iewed while in hosptal, but about 5% were imerviewed at home because of rapid discharge from hospital. The relative risk of cerebral ischacnua was estimated for subjem in various categories of smoking histor}., with the group who had never smoked as the reference eategon. Ittitiall};, unadjusted relative risks were nlcvlated with paired data and'then potcttiall}- confounding variables were oontrolled for by means of a eondioonal logisnc trgression model.' Estimates of'the relativ.e risk associated with smoking were then made for the tarious categories of'cerebral iscliaemia with con-ecvon for hfpertension and the small'residual effect of age. Dcfinizirnu Snurkm; carcgnrics.-Vre d'eftned an ever smoker as a person who smoked at least I cigarene, dgar„or, pipe pcr da) for at Itast 3 months at some period during his or her life. a current smoker as a person smoking at least I cigarene, cigar, , or pipe per da\ for the preceding 3 months. and'an ex-smoker as a person who met the mieria for an ever smoker, but had not smoked for the preceding 3 months. The ategor~ never smoked'included people who µ ere not current smokers and'who did'not mee; the m-iteroa for er-smoker or ever smoker. Ce+ebral ischacnna was defined as acute onset of a fi Eal neurological deficit in which CT snn excluded causes other than cQebral isehaania; the duration of ischaemia could be 24 h or less (TIA), or longer than 24 h (cerebral infarcuon). Lacvnar nwdra.nr was acute onset of one of the five recognised lacunar syndromes' (pure motor hemiplegia, ataxio hemiparesis, dysarthna clumsy hand s}ztdrome„sensorimotor suokc, and puroe sensory'stioke) in whieh CT had excluded und'crlying ouobral hae7norrhage: ln many cases the site of infarction was idennfied on CT scan, but this w•as not an absolute req µiiement for classification as a lacunar s.mdi•ome. , Tlrronllwmbnliu mfarction was defined as acute onset of focal neurological defiat with documentation of the site of utfarcvon on CT scan in either cerebral hemispheres or hind brain, in which the mechanism of infarction was attributed to large vessel exmaanial onintncrrtval vascular disease. Ca>diac embnlic cerebral infarczirn, was the acute oncet~of a focal neurologica) deficit in which the site of infarnion, had been docvmented' on CT scan in the pre~ence of atnal fibrillation, myocardial i infarction within the preeedi.ng 3 weeks, or, eirdiomyopatliy. In some cases cerebral angiognph}° or non- invasive studies of the octr2rnttial arculation were done to help exclude carotid occlusive disnse as a causal meehanism„but this %t15 not an.absolule requlremenL

Tt-M LANCET, SEr'T'EMBER 16, 1989 TABLE 1-AGE DtSTAtBl7101-0F 423CASES AND CON'TROLS Age~ ., , I Cues~. 1 Convols ~ <40. 17 40-Yi 11 14 45--}9' 15 T% 5(~-54 22 21 55-59 35 37 60-6a 70 66 65-69 75 87 70-74 98 8- 75-79 61 51 asa, 19 25 Cereb'ra1 infarr] siie or mecharriem uncerrain;-Ttus group had acute onset of a focal neurolo®cal deficit in which the site of infarcvon or the mechanism of its genesis was unelear but causes other than vascular causes were excluded by CT scan. H~•pertennim was defined as a histon of h}~ettension documented' by ' a meditsl practitioner or currnit use of antih}pertensive drugs recorded at interview. High cholestrral was defined as a plasma coneentration of 5 5 nunol I or greater. Results The 422 consecutive patients and their matched controls were of mean age 65 years (range 25-85 in patients, 20-8 i in controls; table 1). There were 256 men and 166 women in each group: The relative risk (rnsde) of cerebral isctiaemia for all faciors which migllt have a confounding effect on srno7<ing as a nsk facZor ae shown in table 11. These factors were controlled for by means of multiple logistic regression atlalysis.' Smoking, hypenension, and a history of' myocardial infarcvon were signifieanrand independent risk factors, whereas alcohol consumption seemed to have a modest but significant protective effeet. Since adjusttnent for all risk factors made little additional difference to the overall relative risks, adjustment for hypertension and age only was made for the rest ofthe analysis. Hence, rhe relative risk of cerebral ischaemia was 3 7(95°/a confidence interval'. [CI] 23, 519) for current smokers and 2•0 (1i3, 3-1) for ex-smokers„ both compared with those who had never smoked (adjusted for age and hyperteasion only). Both risks were significann (XI = 30•0 and 1'1 •0; respectis'ely, each for 1 degree oflfreedom [df]l p<0'001 and p<0•01). In1 women the risk for current, compared with never smoking was 3 2 (1 6, 6 6)l whereas in men:the risk was slightly higher (3 8 [2 1, 7-0]; ',this difference was non significant (X' = 0 1 for I df, A: S): Similarly, there was no difference between the sexes for ex-smoking risk (relative risk for men 1B [1 1; 3 1] and women 3-0 [ 1 3, 7' 1]; X==1 •O for I df, 2` S). The stroke risk was greatest in the group aged 55-64 years and the risk of stroke was significantly higher for current smokers under the age of 65 yearsthan for those of 65 years or older (relative risk 6-813 1,15 0] vs 2-4 [12;,43]; X' =4-8 for I df, p<0 05). However, when the two groups in which smoking was not a risk factor (cardiac embolic and cerebral infarct with site or mechanism uncertain) were excluded from the analysis the difference was no longer apparent (X' = 3 3 for I df, h S). The mean ages of the cardiac embolic group (69 years) and'zhe cerebral infarcZ, site or mechanism unknown group (68 years) were greater than that of the other groups (64'years). There was a positive dose-response effect in that the risk of stroke among current smokers rose with the amount smoked. Two current smokers of the same age and hypertension status and whose dail j' consumption differed by one pack (20 cigarettes per day):were estimated to have a 645 TABLE II-aiL'DE AND ADJUSTED RISKS OF C'EREBRAL ISOiAE.M1A FOR ALL FACTORS' ExA+dIXFD BY A4LITIPLE LOGISTIC REGRESSION 1 1:a ~ %~ I Esnnuicdnik Cases~. Conaols Crudr!Adlusied'95°%o~Cl r: i Curresrsrnoker 135 32". 78 '18'"...,.~ 3" 3'6'2 2, 59., Ex-Imoker 145'~34„ 13 '32° ~,~ 1~9. 20.,13,329 Never smokcd ~ 14- ~ 34 % 207 49° . 1.0~ 10 Hypenension J 281',67.0 145 -91°0: 4 _ 47(32,68' H'gh cholesurol I 45 14„ 3, 11.1°.~ ~ 1-6 1 3(01i,25) . Mvoardiol mfarcnon~. &i '20 50 1129..; ~ 1-9. 1.6(10,25; Aloohol mnsumpnonY'52. 168 °b a 274~ ( 7S"%. ,~ 0~6. 06(04,1 ~.0;. Otaloonnaoepnvesr I 31I~19%., i 39~(23%~~.) ~1 1-0 09.(0.4; 26). •Of subiees whose nsk faetor surus was known. fl'es or~nor iln¢ludess past as well as pnsent use- §Adius=ed for all othcrnsk'r facton~~. risk differing bv 2-1 (1 -1, 3 8; X' for linear trend = 6 7 for, 1 df, p < 0-01 C. The distribution of' patients within each categon of cerebral ischaemia with reference to smoking status is shown in table nt. For attzenrsmokers, the greatest effect on stroke risk was for thromboembolic and lacunar stroke combined: the relative risk in this group w2s 5, 7'(2 8, 12 0; y' = 25 0 for I df, p<0-001): Patients with laeunar, stroke albne had the higliest relative risk associated with current smoking of all subgroups (infinite [3 0, infirtin']); this risk was signifieantl% higher than that for all otherigroups combined (X' = 7-7 for 2 df, p<0-05)„but only 10 matched'pairs were available for, analysis (the analysis method ignores pairs in which smoking status of case and contro) arc the same) and this result should therefore be interpreted with mution. There was no risk associated with either curTent smoking or ex-smoking in the patients with cerebral infarcvon presumed to be due to cardiac emboli and patients in whom the site or, mechanism of infarction was uncertain (table 1Il), However, aslTent, smoking was a significant risk factor for TIAs (52 [2 1, 1i3-0]i, X' =13`0 for 1 df„p < 0 001). TABLE Ill-A1'1.4$ERS'OF PATIENTS AL'D .tiL1TCH5D CO\TROLSIN " EACH CLI\ICAll SL73GROLP OF CEREBRAL ISQdA'E.NIA R'In-I RESPECT TO S.MOKI\G STATUS AND RELiTIVE RISi:S No ~(%). ' Rcliovr nsk ~ I of~.cerebrsl Currrnt ~ t:n•cr isducua• Subgroup smokers ~ E~-smokers smok'ed'~ i, (95 io~ Cl y. T1i1 rn-120, ~ Cases 35:.19%~) ~ 53~eI4',:~,, 32~~27"i- 5~-'(27{13-0)~. Controls 21 r18%;~ 42r33%~i, 57~f7:a; Th.w+o6Kmbotic (n- 1631. Ctsa 59 r36%, 54 ~335;,, 50.31%, 5,0(2'3, 1) -0; Coneois 36~ 122> ) ' 49 ~y0°:7~ 78~~r87.,. ' (d~ ln-S6/' Cases. 25' ~4'tq;, 1&1235:a, IB'~32%) . Infi3~0, Inf.~. Connols 7r13B.; 1900°.6.;, 30~.~S1.'~.:. Ca.d~ anboticn (-46) Cases 7~r15D.r 14r30S:~ , 25,151"~;, 0'~4(011,1~8;'. Consrols 8~ i175:, 15 l335..;. 23 Suu-dsmeiwr ~. vur+smn iw-37.;. Gaus. 9.r2R°o, 11 r30t.~,~ 1p,46%:~, . 019.(0^_,3~~5)~. Canaols. 6~~16°b., 12132'::-~ 19~~51,9e~.,. Toacl i Cases 135 ~32°..~, 145 r34;e~. 1 142 ~34~°,6.,. Conaola. 78 ~ 18'b, 13' ~3:"b,~1 207 ,W6~. 'Current cv nevcr smoked_ 1nf - u,fwsy . I%

8. 6' ~ a ~ tz 3 7, 3_2 3 11 21' r Np. R,SK, - - - - - - - - - r - - - aj Cunrent <2 2'5 5-10 >10 Years since stopping EtTect of sioppiag. smok'mg on relativc risk ofaerebra] ischacmiL Relaavc nskk for,e+cli iniMal unth 95':0CI. R'hen the period since stopping smoking was divided into five interti•als up to 10 years after stopping, a trend towards reduction in relative risk was seen (see acc•ompamingg figure;. However, this trend was not significant (x? = 0 5 for 1 df, \S; and'an appreciable risk A•as,still apparent after 10 vears. The effect of passive smoking as a risk factor for cerebral ischaemia was assessed for each parent and for spouse. After control for the subjects' oWn smoking, hypertension, andhhe residual eftea for age, smoking by the spouse increased the risk of stroke 1 7-fold{]12, 2•6;,r2=7•8:for 1 df, p<0•01),. whereas smoking by a parent increased the risk 1 2-fold (0-8, 1 8; x== 1!2 for 1 df,NS), The effect of a smoking spouse was sligtitly higher after exclusion of the two groups im wn,;di mmmt smoking was not a risk factor (cardiac embolic and sne or meclianisn unknov.v;. The relative risk for the remainder was 1-9 (112, 3 0;: However, because we thought the observed effect of smoking by the spouse could be explained by current smokers with a smoking spouse tending to smoke more than those without, a further control for daily , cigarette consumption of current smokets, was introduced; this control did not change the estimates of' relative risk for either parent or spouse. There appeared to be a positive dose-response effect in that the risk was increased by, 1.3 per pack smoked by ttie spouse per day (x' for trcnd=4-8 for 1 df, p<005). However, for never smokers only among the cases and matched controls, the relative risk associated with a smoking spouse was slightly lower (1-6 [0 6, 3-9j; X'=1 1 for I df, T:S); perhaps because only 88'matched pairs ramained4or analysis, and smoking ln•, either parcrtt was nora risk factor (relative risk 1' •0, (0,5; Z' 1']). Discussion The large number of cases and the high diagnostic precision by use of CT scanning in 98% of our cases has allowed us to extend the findings of previous studies in several important ways. First, in this "pure" sample of patients uith ctrebrali ischaemia, not contaminated with other forms of "suoke", the relative risk associated with smoking was somewhat higher than thav in other oohorrt" and case-control" studies. Itt four of those studies`b the use of CT scan was infrequent or not stated'and the possibilityy thatnon-strokes as well as cerebral laemorrhages may have contaminated the sample is therefoFe higher. In the only J tl T1;iE L.ANGET, SErTE.ti1EER 16„1989. case-control study in which the clinical and CT entry criteria were similar to our: own, outpatient medical clinic rather than comm unirv -based controls wereused.' h5edicall outpatienvcontiol groups are likel.to be contaminated wtith i smoking-related diseases, which may party account for the lower relative risk foundin that study. Second, in the two most common forms ofl stroke due to exaacranial or intracranial vasculiir disease (laautar and thromboembolic infarction), the relative risk associated with smoking was even higher, at five to six times that of those who had never smoked, and was of the same order of magniivde as treated hypertension as a risk factor. Third, the large number of cases in our study has enabled us to examine the nature of the relation between smoking and cerebral ischaernia in more detail than has been~ possible previously, particularly the effects of age and stopping smoking. There are various mechanisms by which smoking may increase the risk of cerebral ischaenva. Smoking is Imouet to increase platelet adhesiveness" and fibrinogen levels and therefore blood',nscosita•."'Cerebral blood flow is reduced in chronic ssrtokers," perhaps because of the higher~ blood viscosity, but also vascular: resistance may be greater because of the atherogenie properoesof smoking." Our finding of an overall three to four times greater risk of cerebral ischaemia for smokers compared with non-smokers is siinilar to that reported for myocardial infarcoon," and higher than the two to three times greater risk previously reported for "stroke"." The five to six fold increase in risk for lacunar and t}iromboembolic infgrction is closer to thar reported for peripheral vascular discase, in which one study reported an eight to nine fold increase in risk." In both mvocardia] infarction and peripheral vascular disease, the pathogenesis relates predorninandy to atheromatouss changes, so the similarly sized risks with pure forms of cerebral ischaetnia would be expectedi Examination of other subgroups in our study showed that smoking is alt;o a potent risk factor for T1As. This finding, confirms the general belief tliat cerebral ischaemia of brief or prolonged duration has,a common underlying mechanism and hence similar risk factors. The reason for the lack of risk associated with~ smoking in the cardiac embolic group is uncertain, but a large proportion of this group:had strokess secondary to atrial fibrillation, a cardiac disorder which is nonassociated with smoking as a risk factor.'d Ih the site and mechanism uncertain group the risk associated Kith smoking was also negligible. This finding emphasises, the importance of' a precise classification of stroke subtypes, since the group would otherwise contaminate the more dearly defined lacunar and tlvombocnbolic groups. Althou$It numbers were small'{56 patients)', the finding of a highly significant risk associated with smoki.ng in the lacunar group compared with 211 other groups combined'suggests that further study of the effects of smoking on small cerebral ~ vessel disease may be useful. In the only , other study to eatamine smoking as a risk factor for lacunar infarction," the relative risk was 2.3, but that study used hospital-based control9 and current smokers were not analysed separately: Given the positive dose-response effect of smoking on risk of cerebral isehaemia and the likelihood that attierogenesis may be at least pardy the reason for this, it was someWhat surprising to find that patients younger than 65 years were at greater risk than those over 65 years. However, when the two groups in whom smoking was not a risk factor (cardiac embolic and site or mechanism uncertain groups) were excluded from the analysis, this differential in risk with age was lost, This finding is mosvlikelv due to the greater age of'

THE LA.NCET, SEt`rEJ+iBER' 16, 1989 patients in ~v.•hom stroke was due to atriallfibrillation in our studyl6o'years, compared with'64 }+ears for the remainder), and the fact tlian smoking is not a risk factor for this rhythm disturbance." A signi5cant risk differential with age for smoking and stroke has not beea shown in previous studies, although, in a meta-anah•sis of all known' published studies on smoking and stroke, a signifirantl}• reduced risk with increasing agc w'as showrt." In view ofotu findings, and''the fact that pathophpsiologica] subgroups of stroke were not' classified in most of'the published studies, this effcet in the meta-analysis may well be due to the unrecognised presence of elderly, paoents: with' atrial fibntllazion~ as a saoke mechanism. In other, words, there may nonbe an age effect in patients with cerebral infarction due to exvacraniali or intracTanialluascular disease. The persistence of' the risk of cerebral ischaemia for at least.l0 years after stopping smoking was surprising; since in the two cohort studies that addressed this question,66 the risk was found to return to that of never smokers within 2-5 years. However, in both those studies the number of patients who actually stopped smoking was much smaller and no' distincoon was made between cerebral haemorrhage and infarction in this parnof the ana]ysis Since the knowTt effeets of smoking on plktelet adhesiveness. fibrinogen levels, and blood viscosin• are reversible within a short period„it seems likely that atherogenesis causes tlte petsistence of risk as well ac the maj,rr par, of nsk as'sociated with current smoking. Trie presence of' a smoking spouse appeared to be an independ'ent risk factor for cerebral ischaemia when all patients (smokers and non-smokers) were included in the analvsis. A positive dose-response effect was observed~ for this tisk with the number of cigarenes smoked by the spouse and the risk was more evident when cerebral ischaemia'due onlv to exnaeTanial or intracranial vascular disease was anal}•sed. However, for non-smokers alone, there was a similar but non-signifrcant increase in tisk perhaps because of the restriction to fewer matched pairs in the analysis. Considering these two anal}tioal methods together, it appears likely that passive smoking has a small effect. Since passive smoisrtg is novw such an important social!issue, and has been shown to be a risk factor for non-smokers for other diseases19 our, preliminary findings on this subject cerrairtly warrant further studS'. ThisseudJ.vissupponed by agant:.6om the TobaccoResorch Foundaoon of AusQalia. Corrapondrnrr should be addressed~ to G. A. D., Deparvriclt of t+ieurolog.%-, Austin Hospi~talJ Hadelberg, Vinoria )084; Ausmlia.: REFEREI:CES. 1, WtusnamJP, Fissvbbons JP, Kialvd LT4 S.yrr GP Natssral'IslsxaryW of koote inRorhenserMumesosa, 19M5.Ouou0 1954. Snoke 1971;2: 11-2-1 . 2: Kacsne1 R'B; D-ber TR,. Soorlie P, Q'ol( PA. Cmipasmrs of blood bressure arsd nsaaf astserosbromtiooc ,rsfanaa;: tlsc Fr.rnvs{riam -dy. Sna4e 19 -,6, 7: 327-31 3.: Boruo R, Scraay R, S~A, Jadsm R, Besydwk R. Cprenr smoCr4and nsk of psvrsaner.e saote m snm and'+.vsssa, B.. M.d) 1986; 2f3. 64'. l. Abbon RD, Ym Y, Reed DM, Kanutiito Y: Rak ofaookem mak aprene.nsdse:. N,Eart J ,Md 198tr:315: 717-20. 5. Colditx GA, tlaw R, Sompfe MJ, et d..Gpreetr.amksK and :ruk ofavute in m.ddrr-,a.e ..on>m: N sWr)<M.d 19ea; 31c 937-a1 6. S`o1f PA, D'lyw9no RB, KarundWB, Banso R, Belaastier AJ. Gprenesrrokcst as a nsfc fanot.for.evke. The Frmnrspnm, Seudy, JAMA:1988, 259: 1025-'-'9. 7. G-enck PB, Rod. MB, 1-W-brrt P. H;Q De, CasuPn J. ¢ xly .16oboi aasesanpuon, eprenr smokusland the rnk of udsonic mole~ sauloof a numnovl sssdy .r tlwa suti.n e,edsd im,ress oe Quo{0. 11Ltsoss : A•aso/cd.1989, 39: 339-d3 . 8Heeslb.•.fi•E,Da.,\'E Staosuolme[ISOUta sna>Q,on reaearU;,.al1'.Theanalyusof mrmnvvlsnd,eLycxi~ Insenvoanal Ataseyfor.R-arch on Can¢r, 1980. 24F79: 9. Fn6er Cl-i.lacvsar. snota od ,rJarns~ a mve... h•.voLty.1982; 32: B i 1 -76. Referrnats tontwaed cf Juot of isess tohonn 647 PERCLTA,ti'EOUS CORONARY EXCIMER LASER ANGIOPLASTY: LNTTLAL CLL'`'ICAL RESULTS K. R. KARsaa K. K. HAASE M. MAUSER 0. ICJCR4TH' VZ'. VOELICERS. DUDA, L. SEIPEL Medua! Chmc, Department of Cardia/M, Eberiiard-Kvrls.Umzarrsiry, Tficfngen, Fedcrad Republic of Gmna>r.) Sumsnary A novel 1 3 mrn diameter laser catheter, consisting of 20ieoncentric 100 µtn quartz fibres around''a central lumen for a 0 35 mm flexible guide wire, was used to ablate atherosclerotic tissue in thirty patients with coronary artery disease. The laser catheter was coupled to an excimer laser delivering eaergy al a wavelength of 308 nm and a pulsew-idtli of 60' ns. The primarv , success rate was 90P7o (27 of 30 lesions): The mean (SD; percentage stenosis fell from 85 (15)% to 41 (19;°.0' afier.laser ablation, In ten'paDents the lumen diameter after laser, angioplastv'w•as considered sufficlenty but subsequent balloon angioplast}• was earried' out for the other t.venrc patients. Failure to pass the lesion was caused by vessel kinking in two patients and a total occlusion in one patient. No complications directly attz•ibutable to laser ablation, such as vessel wall perforation; occurred; one disseevon occurred but had no clinical sequel9e. There was one earli• reocclusion and death in'a patient with triple vessel'disease and unstable angina, probably as a result of plaque rupture after balloon angiopl9sty. These results are encouraging and' justif<<'funher clinical investigations. Introduction PERCLTA.`.'EOtS transluminal coronarti• angioplastv has been widely accepted as treatment for coronary anen- disease." Resrenosis, however,, greatlv limits the clinical effime}• of balloon angioplasty:''' The use of laser energy transmitted through' flexible fibreoptic fibres may be a possible adjuna or alternative to:eonventional angioplasn•; because it removes atherosclerotic tissue or thrombus bs- vaporisation tather than by stretching and'fracturing of the stenosis as in balloon angioplasry.6" In-vivo studies have shown not only greater efficacy of laser-heated probes but G. & Don?:A>; A.~,'D o7HFJts REFERF1:cES-conrint.ed 11),.Nehu P, Meho J. Elfecn of snsokvs`.m ptaoeka and on pluns. Nsombo>:ane-pronacvdsn baLnae m man. Pruuqflmas5wr L+sJa.nenv Med I981. f. 1il -50 . 11. Dsnrefass L. Eknnnn of'b4nud'wsman) , sgiti-epnon of trsdaUs; haenuinmi val,re and fsbrusqen kvels m cyareese snnim . Mrd J A,u+. 19^. S, ,61:-:0 , 12. Raws RL, MryeJS•,Sto..TG„Mond. KF, Hardenbera JP, Zud;RR. Cip+enr msoksn` d- mebral.blood tlk- wairaevyune.med hsY for aaukc.. JAAf.t 1983: 25D. 2796,800 13.McGJIHC Posessoslsnediausrn for, theaupnmooon of'aNerosdneass.avsdadseaoscknaocdunse E.' espsenr snsnkulQ An.m .M.d1979, a: W-~403 11. KanndWB, MeGs DL, Cissdfi WP' Lanesc.penpeev.e on oprenevssolorrt vsd ordsovscWardueasr sfrc Frasnsny}sarn 5nsd5, 7 Ca^d.u- RihoMl 1984. a. 26:--, 15.. HugtnanC'G. Musn JI, Ganod A Jnsemunem ctaudsaoon, pmalena.and nsY 4nura. Br M.dy 1976,1 1379-A:1 16.:Kavuset WB,.Abbem RD, S..Ke DD. Mt!tiansva PM'. Epdmuokpe femsrn of mronuacW, Gbrill.nar., tre Frvsws/tumStudl A'N tlr(J Mrd.198=. 30n: 301&22 1' Gvsdofpfio: C, Caponneno. C, t><J Senr M, Sanm,lon D, CUrt C Rnr fanon, u:YcvnarfpndforMSw a su mnnol snud). Ar4: A'rmd Stmd 1988, 77: =-26. 18 SbsrnonR,Ber.enG M~-whsisofrt4oorsbesreoinearenrsnroWavsdsaok'r B+ Md J 1989, 278: 7N9-W ', 19Fwldirii; JE, Pfsaw.K1 , HdN eltecv of n.oiununssrsulisr,a.'.• EKt7 Mrd 19N6, 319-.145'--59'