422

diagnosis.18-20 Of particular benefit is the stronglinkage disequilibrium that exists between the Z alleleand a unique haplotype identified by means of AvaIldigests and a 6-5 kilobase &agr;1-AT probe extendingfrom exon II to the 3’ flanking region of the gene. Forthe uninitiated this means that, for reasons unknownbut almost certainly of intriguing evolutionarysignificance, a unique Southern blot band pattern,designated 371, is seen consistently and exclusivelywhen DNA from PiZZ individuals is hybridised withthe 6-5 kilobase probe after digestion by the AvaIlrestriction enzyme.Cox and Mansfield20 in Toronto have now

reaffirmed that all 32 PiZZ patients studied showedthis unique 371 haplotype, which was not present inany of the 32 controls. This being so, it should now bepossible to offer direct prenatal diagnosis of PiZZ&agr;1-AT deficiency by analysis of fetal DNA withoutrecourse to DNA from parents or siblings. Wisely, theCanadian authors urge caution since it may emergethat the 371 haplotype can occur with non-Z alleles orthat the Z allele may be associated with other

haplotypes. At present, therefore, parents and/orsiblings should always be studied. Other DNA

polymorphisims have been identified, including onewith the MaeIII enzyme,21 which promises to be ofparticular value in chorionic villus biopsy diagnosis, inwhich meticulous attention must be paid to separationof the fragments. Other extremely rare deficiencyalleles such as Mmalton and a null allele have been

described,22 so that accurate Pi typing of parentalsamples is essential before prenatal diagnosis is

attempted. The situation is further complicated by theexistence of an S allele which could be misinterpretedif only the M and Z oligonucleotide probes were used.Thus thorough clinical, biochemical, and molecularevaluation is essential for every family presenting forprenatal diagnosis.Many may ponder on the ethics of prenatal

diagnosis of &agr;1-AT deficiency, since only a smallproportion of deficient individuals encounters serioushealth problems in early life, and the pulmonarydisease of middle age can be modified byenvironmental factors, chiefly avoidance of cigarettesmoking. Furthermore, treatment with synthetic orblood-derived &agr;1-AT is on the horizon.23 A largeprospective population survey conducted in Sweden,where the PiZZ incidence of approximately 1 in 1500is at its highest, indicated that 14 of 120 PiZZ infants

18. Cox DW, Mansfield T Prenatal diagnosis for alpha1-antitrypsin deficiency. Lancet1985; i. 230

19. Hejtmancik JF, Sifers RN, Ward PA, Hams S, Mansfield T, Cox DW. Prenataldiagnosis of &agr;1-antitrypsin deficiency by restriction fragment lengthpolymorphisms, and comparison with oligonucleotide probe analysis. Lancet 1986;ii: 767-70.

20. Cox DW, Mansfield T. Prenatal diagnosis of &agr;1-antitrypsin deficiency and estimates offetal nsk for disease. J Med Genet 1987, 24: 52-59.

21. Cox DW, Billingsley GD. Restriction enzyme MaeIII for prenatal diagnosis of&agr;1-antitrypsin deficiency Lancet 1986; ii: 741

22. Garver RI, Momex JF, Nukiwa T, et al. Alpha1-antitrypsin deficiency andemphysema caused by homozygous inheritance of non-expressing alpha1-antitrypsin genes. N Engl J Med 1986, 314: 762-66.

23. Editorial. Treatment for &agr;1-antitrypsin deficiency Lancet 1985; ii: 812-13.

had prolonged neonatal jaundice,24 but by the age offour years only 4 of these children had clinicalevidence of liver disease.25 This low risk of severe

hepatic involvement in early childhood would scarcelyjustify termination of pregnancy. However liverdisease in PiZZ children shows a strongly positiveintrafamilial corelation, so that if one sibling isseverely affected the risk to subsequent PiZZ siblingsmay be as high as 78 %,26 although the Canadiansurvey suggests that a figure of 40 % is more

appropriate.20 Prenatal diagnosis for these familieswould seem entirely justifiable.There is still much to learn about &agr;1-AT deficiency,

Why, for example, do only a few PiZZ homozygotesget serious hepatic problems and why do these tend torecur in siblings? Did the Z allele originate in a singlenorthern European individual and spread throughoutthe Caucasian population as the result of heterozygoteadvantage (or Viking marauders)? The answers tothese and many other equally intriguing questionsare eagerly awaited. Meanwhile, thanks to thecollaborative efforts of molecular scientists in North

America, parents who have had one severely affectedchild now have the option of reliable first trimesterprenatal diagnosis.

Epilepsy—La Belle Indifférence?EPILEPSY is a common condition with a remarkably

uniform prevalence in Western countries of 1 in 200individuals;1 2-5 % of the population have a fit at sometime. It represents the clinical expression of a largenumber of cerebral disorders affecting all age groups,2Specialist investigation is required and diagnosticfacilities include various electroencephalographictechniques and access to an expanding range ofcomplex (and expensive) scanning procedures. Man-agement consists primarily of anticonvulsant drugs,which are often given life-long. The realisation thatanticonvulsant polypharmacy confers no benefit overappropriate monotherapy4 has led to increasingreliance on therapeutic drug monitoring to tailor drugdosage for the individual patient. 5

Whilst the majority of patients can be renderedseizure-free by pharmacological means, chronicintractable epilepsy develops in a sizeable minority(approximately 20%6), particularly in those with an

24. Sveger T. Liver disease m alpha1-antitrypsin deficiency detected by screening of200 000 infants. N Engl J Med 1976; 294: 1316-21.

25. Sveger T, Thelin T. Four-year old children with &agr;1-antitrypsin deficiency Acta

Paediatr Scand 1981; 70: 171-77.26. Psacharopoulos HT, Mowat AP, Cook PJL, Carlile PA, Portmann B, Rodeck CH

Outcome of liver disease associated with &agr;1-antitrypsin deficiency (PiZ) Arch DisChild 1983; 58: 882-87.

1. Zielinsky JJ. Epidemiology. In: Laidlaw J, Richens A, eds. Textbook of epilepsy. Drugs

ed. Edinburgh: Churchill Livmgstone, 1982: 16-33.2. Delgaco-Escueto AV, Treiman DM, Walsh GD. The treatable epilepsies N Engl J

Med 1983; 308: 1508-13.3. Davidson DLW. Anticonvulsant drugs. Br Med J 1983; 286: 2043-45.4. Reynolds EH, Shorvon SD. Single drug or combination therapy for epilepsy. Drugs

1981; 21: 374-82.5. Brodie MJ. Therapeunc drug monitoring. Practitioner. 1986; 230: 1003-096. Reynolds EH, Elwes RDC, Shorvon SD. Why does epilepsy become intractable?

Lancet 1983; ii: 952-54.

423

anatomical basis for their seizure disorder. For a few

patients with intractable epilepsy surgery can beremarkably effective, although meticulous

preoperative assessment is essential to increase thelikelihood of success while ensuring minimal loss ofcerebral function. Identification of patients with"pseudoepileptic" seizures is also important, sincecontinued juggling with their anticonvulsant

regimens would be counterproductive.9The diagnosis of epilepsy carries important social

and psychological implications. The patient’s reactionto his illness may be a disturbing factor, as may theresponse of his family, friends, workmates, andemployer. Both epilepsy and its treatment can

adversely affect psychomotor and cognitive function,resulting in subtle changes in concentration, memory,performance, mood, and will.1O In children, there areproblems with education, and subsequently withrestricted opportunities for training and employment.Marriage can uncover underlying sexual difficulties inaffected men," while the fear of teratogenicity andgenetic transmission of the disorder can make

pregnancy an unwelcome spectre for young epilepticwomen. The persisting stigma attached to the illnessmay persuade the patient to deny or hide the

diagnosis-all the more understandable since theattitude of society towards epilepsy is oftenuncomfortable and unpitying.12A condition as common as epilepsy, which has

major repercussions for the patient and his family, canbe expected to make a substantial call on medical andcommunity resources within the National HealthService. How has the service responded to rneet thisneed? In the UK, epilepsy is usually suspected ingeneral practice, diagnosed by a hospital consultant,and treated under the auspices of an outpatient clinicwithin the main medical, neurological, or paediatricservice. There have been few studies surveying themanagement of epilepsy and these have been mostlysmall and limited in their goals. The picture that hasslowly emerged over the past decade, however, is notat all reassuring.13-19. Compare the facilities available

7 Schmidt D, Tsai J-J, Janz D. Generalised tonic-clonic seizures in patients withcomplex-partial seizures: natural history and prognostic relevance. Epilepsia 1983;24: 43-48.

8 Editorial. Cerebral dominance and epilepsy surgery. Lancet 1986; ii: 1318-19.9 Fenton GW. Epilepsy and hysteria. Br J Psychiatry 1986; 149: 28-37.10 Hirtz DG, Nelson KB. Cognitive effects of antiepileptic drugs In: Pedley TA,

Meldrum BS, eds. Recent advances in epilepsy 2. Edinburgh: Churchill

Livingstone, 1985: 161-81.11 Toone B. Sexual disorders in epilepsy. In: Pedley TA, Meldrum BS, eds. Recent

advances in epilepsy 3. Edinburgh: Churchill Livingstone, 1986: 233-80.12 Canger R, Cornaggia C. Public attitudes towards epilepsy in Italy: results of a survey

and comparison with USA and West German data Epilepsia 1985; 26: 221-26.13 Hopkins A, Scambler G. How doctors deal with epilepsy. Lancet 1977; i: 183-86.14 Zander LI, Graham H, Morrel DC, Fenwick P. Audit of care for epileptics in a general

practice. Br Med J 1979; ii: 1035.15 Lloyd Jones A. Medical audit of the care of patients with epilepsy in one group

practice. J R Coll Gen Pract 1980; 30: 396-400.16 White PT, Buckley EG. The management of epilepsy-an audit of two practices.

Health Bull (Edinburgh) 1981; 39: 82-88.17 Goodman I. Auditing care of epilepsy in a group practice Practitioner 1983; 227:

435-36.18 Goodridge DMG, Shorvon SD. Epileptic seizures in a population of 6000 II:

Treatment and prognosis. Br Med J 1983; 287: 645-4719 Cooper GL, Huitson A. An audit of the management of patients with epilepsy in thirty

general practices J R Coll Gen Pract 1986; 36: 204-08

to the epileptic patient and his family with those fordiabetes, another common disorder affecting all ageswith similar medical, pharmacological, psychosocial,and surgical features. Diabetic clinics are now

commonplace and have undoubtedly improvedpatient care. Most major teaching and district generalhospitals have at least one consultant diabetologistwho has substantial specialist nursing and communityresources at his disposal.

Since the inception of the NHS there has been asuccession of Government-sponsored reports on theprovision of services for patients with epilepsy.20-22Their conclusions have been largely ignored. Thelatest in the series has now been published.23 Aworking group under the chairmanship of MissP. M. C. Winterton reviewed the complete range ofrequirements for care of epileptic patients of all agesand made no fewer than seventy-eight recommenda-tions. Attention was paid to the overall framework ofhealth care. Arrangements for investigation of thedisorder and for assessment of drug therapy,including anticonvulsant assays, were studied. Specialservices for children and for patients with additionalhandicap were discussed, as was the provision ofresidential care. The role of the voluntary bodies wasexplored and the importance of education of thepatient, his family, and society at large was

emphasised. The crux of the report centred on theneed for more specialist epilepsy clinics both forinitiation and withdrawal of treatment in patients withmild ictal disorders and, more importantly, for

investigation and management of intractable epilepsy.Such an approach has gained widespread acceptancein Europe and in North America. The working groupemphasised that this network of hospital clinics shouldbe linked to a number of supraregional assessmentcentres with residential facilities; two of these centresalready exist.

The need for a more coordinated policy iscommanded by the figures. In a health region of 4million people, there will be a pool of 20 000 activecases of epilepsy, more than 20% of whom willcontinue to have fits regularly despite "optimum"therapy. Another factor must also come into theequation. There are now a dozen or more much-needed fledgling anticonvulsants at various stages ofclinical evaluation.24 These drugs have to be assessedin major long-term trials. Where better than in

specialist epilepsy clinics linked to supraregionalcentres? The present service could not possibly cope

20. Ministry of Health. Welfare of handicapped persons: the special needs of epileptics andspastics. London: HM Stationery Office, 1953.

21. Ministry of Health (Cohen Report). Central Health Services Council. Report of thesub-committee on the medical care of epileptics. London, HM Stationery Office,1956.

22. Central Health Services Council (Reid Report) People with epilepsy. London, HMStationery Office, 1969.

23. Report of the Working Group on Services for People with Epilepsy: a report to theDepartment of Health and Social Security, the Department of Education andScience and the Welsh Office. London, HM Stationery Office, 1986.

24. Meldrum BS, Porter RJ, eds. Current problems in epilepsy 4: new anticonvulsantdrugs. London. John Libby, 1986.

424

with proper evaluation of even a handful of these

agents.Epilepsy has a long history. Its dramatic clinical

presentation has ensured that all literate civilisationshave recorded comments on aetiology and treatment.The fear engendered by the disorder over thecenturies led to a medieval association with sorceryand witchcraft which has translated to a modem, more"civilised", indifference. More worrying is the

possibility that this indifference extends to the medicalprofession which does not perceive epilepsy as an areaof diagnostic and therapeutic difficulty. Sadly thereseems to be a low priority for this common condition,which is so demanding of time and effort, yet notusually life-threatening. Nor is there the emotionalelement that attaches to heart disease or cancer tostimulate public interest. The resource implications ofthe latest recommendations are modest, andcoordination of the presently scattered facilities makesexcellent economic sense. Ominous, however, is thedelay of two years in publication of the report and thelack of practical recommendations by the DHSS intheir covering letter to health authorities. A degree ofpolitical will is required. The time to act is now.

DOUBTS ABOUT THE VALUE OFMAINTENANCE LITHIUM

IN the past fifteen years there has been an enormous

expansion in the use of maintenance drug therapy inthe management of functional psychoses. Althoughprophylactic neuroleptics undoubtedly produce a

significant reduction in the relapse rate of schizophrenia,lsuch drugs are perhaps prescribed with rather lessconfidence and optimism now because it has been shownthat even when compliance is assured the relapse rateremains substantial and, moreover, because the

extrapyramidal side-effects are difficult to ignore.3However, the initial enthusiasm for lithium has not waned.The value of this treatment in terms of reduction in the

frequency of relapses of affective illness has been confirmedin many carefully controlled trials." Although lithium is notfree from side-effects, those that occur are not disabling, andirreversible and untreatable conditions do not arise as aresult of its use.

Many psychiatrists believe that prophylactic lithium is atreatment that they can recommend with confidence asbeing likely to provide substantial benefit for appropriate

1. Hirsch S, Gaind R, Rohde PD, Stevens BC, Wing LK Outpatient maintenance ofchronic schizophrenic patients with long acting fluphenazine: double blind placebotrial. Report to the Medical Research Council Committee on Clinical Trials inPsychiatry Br Med J 1973, i: 633-37

2. Hogarty GE, Schooler NR, Ulrich T, Mussare F, Ferro P, Herron E. Fluphenazineand social therapy in the after care of schizophrenic patients Arch Gen Psychiatry1979; 36: 1283-94.

3 Baldessarini RJ, Cole JO, Davis JM, et al Tardive dyskinesia. Summary of an APATask Force Report Am J Psychiatry 1980; 137: 1163-72.

4. Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A Prophylactic lithium.double blind discontinuation in manic-depressive and recurrent-depressivedisorders. Lancet 1970; ii: 326-30.

5. Coppen A, Noguera R, Bailey J, et al. Prophylactic lithium m affective disorders.Controlled trial Lancet 1971; ii: 275-79.

6 Pnen RF, Klett L, Caffey EM. Lithium carbonate and imipramine m the preventionof affective episodes Arch Gen Psychiatry 1973, 29: 420-25.

patients. This confidence may well be shaken by the

findings of a study by Dickson and Kendel,’ who examinedthe number of patients per annum in Edinburgh for whomlithium was prescribed between 1970 and 1971 andadmission rates for mania, schizophrenia, and depressivepsychosis over the same period. The number of patients forwhom lithium was prescribed rose from 65 in 1970 to over700 in 1979 and subsequent years. However, this rise wasnot associated with the fall in admission rates for affectiveillness which would have been expected on the basis of theevidence that lithium is an effective prophylactic agent.There was a three-fold rise in the admission rate for maniabetween 1970 and 1981; the admission rate for depressionalso rose while that for schizophrenia fell. In this carefulpaper, Dickson and KendelF considered the possibilities ofchanging diagnostic criteria, admission of patients withmilder affective illnesses, or poor and deteriorating lithiumsurveillance as causes of the changed rates but found noevidence to support any of these suggestions. Nevertheless,the retrospective methods necessary because of the nature ofthe study are not ideal for the assessment of such issues. It isnot easy to ascertain the severity of mania from case-notes.Whilst the fact that the proportion of patients with theclinical diagnosis of mania who fulfilled the Research

Diagnostic Criteria8 for manic disorder, hypomanicdisorder, or schizo-affective disorder manic type on the basisof case-note scrutiny did not alter between 1970-72 and1979-81 suggests that diagnostic criteria did not change,another interpretation is possible.

Psychiatric symptoms that are sought are more likely to befound, and it may be that manic symptoms were sought withmore enthusiasm in Edinburgh once lithium became widelyused. Studies of prophylactic medication are conducted inpatients who will comply with a trial protocol forconsiderable periods of time, and in such studies themotivation of the investigators to ensure strict adherence todrug regimens is high. The circumstances of routinepractice may be rather different and may partly explain thesubstantial discrepancy between the results of the trials ofprophylactic lithium and the fmdings of Dickson andKendel1.7 Whatever the cause of the discrepancy, the

Edinburgh fmdings, as the authors themselves point out,offer little comfort to those who have believed thatmaintenance lithium provides an effective prophylactictreatment for at least a substantial minority of patients withrecurrent affective disorders.

TOTAL ISCHAEMIC BURDEN

TOTAL ischaemic burden has been called "an excitingnew concept":1 it is a phrase used to describe the totalnumber of ischaemic episodes, both painful and painless.occurring in an individual subject. It is suggested that theconcept helps to "individualise" the treatment of a patientwith ischaemic heart disease by adjusting therapy to takeaccount of both painful and painless ischaemia. But is totalischaemic burden anything more than a potentialmisleading piece of jargon?

7. Dickson WE, Kendell RE. Does maintenance lithium therapy prevent recurrences ofmania under ordinary clinical conditions? Psychol Med 1986; 16: 521-30

8. Spitzer RL, Endicott J, Robins E. Research diagnostic criteria New York: BiometricsResearch Division, New York State Psychiatric Institute, 1975.

1. Cohn PF. Total ischemic burden: definition, mechanisms, and therapeuticimplications. Am J Med 1986: 81 (suppl 4A). 2-6.