Randomised study of antiepileptic drug withdrawal in patients in remission

Saturday

18

May

1991

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ORIGINAL ARTICLES

Randomised study of antiepileptic drug withdrawal in patients in remission MEDICAL RESEARCH COUNCIL ANTIEPILEPTIC DRUG WITHDRAWAL STUDY GROUP

prospective multicentre continued antiepileptic A

randomised

study of

treatment vs slow in conducted 1013 withdrawal patients who had been free of seizures for at least 2 years. Comparison of randomised and eligible, but nonrandomised, patients suggests the results should be applicable to a wider patient population. By 2 years after randomisation, 78% of patients in whom treatment was continued and 59% of those in whom it was withdrawn remained seizure free, but thereafter the differences between the two groups diminished. Non-compliance with continued treatment accounted for only a small proportion of the risk to the group continuing with treatment. The most important factors determining outcome were longer seizure-free periods (reducing the risk) and more than one antiepileptic drug and a history of tonic-clonic seizures (increasing the risk). Other factors (eg, history of neonatal seizures, specific electroencephalographic features) seemed to have smaller effects, but even in such a large study the confidence intervals for these observations were wide. was

and behaviour. Adult neurologists are more cautious, being worried about the effects of further seizures on driving and employment. Moreover, in the UK, most patients who attain long-term remission are unlikely to receive any advice from a neurologist or other physician with an interest in 4

epilepsy. In 1984 the Medical Research Council (MRC) set up the AED withdrawal study, a pragmatic, multicentre, randomised clinical trial to compare seizure control under policies of slow withdrawal vs routine maintenance of drug therapy. A parallel group design was adopted. The aim was to identify important prognostic factors in seizure recurrence. Results of earlier studies had not been consistent enough to permit identification of groups of patients at especially high or especially low risk of relapse with the two policies.2 Placebo substitution was not used during the withdrawal of AEDs because placebos would have greatly complicated the conduct of the study, would have reduced patient recruitment, and would not have contributed to the practical aspects of management since placebo substitution is not a clinical option in the management of patients in remission. To reduce reporting bias associated with the treatment policies we collected details of recurrences, continued follow-up beyond recurrence, and conducted an analysisof tonic-clonic seizure recurrence.

Lancet 1991; 337: 1175-80.

Methods Introduction In most patients with epilepsy seizures remit promptly with antiepileptic drug (AED) therapy; subsequent drug withdrawal and the associated risks of seizure recurrence have important social and medical consequences. There is no general agreement about the success of drug withdrawal policies, nor about the possibilty of identifying patients who are most likely to remain free of seizures .2 Advice given to patients therefore varies considerably. Paediatricians and paediatric neurologists tend to recommend a trial of AED withdrawal in most children because they are impressed by the apparently high success rate and are worried about the adverse effects of drugs on cognitive function, learning,

125 clinicians from forty centres in the UK and five elsewhere in Europe participated. The aim was to recruit and randomise 1000 patients within 4-5 years, this sample size being sufficient to provide an

estimate of the relative risks of recurrence and

to

examine the

Trial Office: Mrs P Bessant (Trial secretary), Dr D. Chadwick (Clinical

coordinator), Mrs B Eaton (Trial secretary), Mrs J. Taylor (Trial administrator) Statistical centre: Ms A. Holland, Mr J. Joannou, Dr A. L Johnson, Ms L Oldfield, Mr N P Reader, Electroencephalography coordinator: Dr E J W. Gumpert, Institute for Social Studies in Medical Care: Mrs A. Jacoby, Steering committee members: Dr H Cuckle, Prof C. Warlow. Correspondence to Dr D Chadwick, University Department of Neurosciences, Walton Hospital, Rice Lane, Liverpool L9 1AE, UK.

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prognostic importance of possible risk factors. Patients were eligible provided they had a history of two or more definite seizures, had been free of all seizures for at least 2 years, and were taking AEDs. Those who had a progressive neurological disorder or other condition likely to reduce follow-up below 2 years were excluded. Demographic and clinical data on all eligible patients were recorded on standard forms-(a) presence of developmental delay, neurological handicap, neurological disorder; (b) psychiatric history; (c) results of most abnormal electroencephalogram (EEG) based on review of historical reports when available; (d) dates of first, second, and most recent seizures, and their classification5 from clinician’s review of historical data; (e) details of AED therapy including starting date, drug and dose at remission of seizures and at entry, diurnal pattern of seizures, and family history of epilepsy; (f) previous unsuccessful attempts at AED withdrawal. We attempted retrospectively to identify patients with specific epilepsy syndromes, according to a classification that was agreed after the study had been initiated.b That the numbers of patients who could be so classified was small indicates the difficulty of applying this classification to patients with few seizures that occurred some time ago. For

patients who did not give informed consent and for those whom the clinician felt should not be randomised, reasons for non-entry were documented and they took no further part in the study. Demographic and clinical characteristics of this group were compared with those of patients who agreed to randomisation Randomisation procedure Patients

consenting

to

randomisation

were

registered by

telephone with the statistical centre and randomised to continued treatment or to slow withdrawal of AEDs by use of the method of minimisation; absolute difference between treatment allocations was used as a measure of imbalance and a prepared list of random allocations was used to break tiesAllocation to the two treatment policies was balanced by centre and by the seizure-free period before registration (at least 2 but not more than 3 years; at least 3 but not more than 5 years; greater than 5 years). At entry, blood was taken for central estimation of serum AED concentrations. A routine EEG was recorded for central analysis by a single observer (Dr E. J. W. Gumpert), who was unaware of the clinical features. Adults randomised to continue AED therapy were maintained on existing doses unless there were clinical indications (eg, adverse events, planned pregnancy) that necessitated a change; patients aged 15 years or less could elect to withdraw treatment 1 year or more after randomisation to continued treatment.

Drug withdrawal Patients randomised to slow withdrawal had therapy withdrawn according to guidelines suggested by the steering committee, with decrements every 4 weeks

as

TABLE I-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS

*Neurological deficit, birth traumatic amnesia > 24

disorder tMedlan

m

trauma, intracranial surgery, head injury with postor other specified neurological

h, meningitis, encephalitis,

years, 25th and 75th centres

in

parentheses

general practitioner was contacted. At each follow-up appointment information was collected about AEDs including dose, number of days in the previous month when drugs had been omitted, adverse reactions to drugs, and dates of any seizures together with a clinical description and whether or not AEDs were restarted. A recurrence was judged to have occurred when the clincian was convinced that the patient had had a further seizure and when an adequate description had been provided to the clinical coordinator. Patients with seizures during follow-up could have their AED regimen modified by their clinician. All randomised patients were followed from randomisation to death, loss to follow-up, or to within the first 6 months of 1989,

new

whichever was earliest. Intervals from randomisation to the first seizure post-randomisation, or to the last date of follow-up in patients who remained seizure-free, were calculated to the nearest week and summarised by use of actuarial life-tables. Importance of prognostic factors was assessed with the Cox proportional hazards regression model, stratified by treatment policy to take account of non-proportional hazards. Deaths were regarded as recurrences if they were associated with seizures, and as censored observations otherwise (a censored observation is one in which the event in question has not occurred before the last follow-up). A second analysis of time to recurrence of tonic-clonic seizures was undertaken-ie, partial seizures that were not generalised and other

minor seizures

were

ignored.

follows:

Results

Physicians were encouraged to make smaller decrements in patients receiving small doses of drugs, the aim being to extend withdrawal to a minimum of 6 months. Patients taking more than one AED had the drugs withdrawn sequentially, in an order determined by the clinician.

Follow-up was at 3 months, 6 months, 1 year, and yearly thereafter from the date of randomisation, and was undertaken by the clinician randomising the patient. When patients did not keep a follow-up appointment information was obtained from general practitioners. Patients who moved within the UK were traced through the Office of Population, Censuses and Surveys and their

Recruitment began in February, 1984, and was completed in June, 1988. 1021 patients agreed to randomisation and 776 were eligible but not randomised. 8 randomised patients were withdrawn and excluded from analysis: 3 had a history of only a single seizure, 1 had stopped taking drugs before randomisation, 1 handicapped patient had not been seizure-free for any extended period before entry, 1 withdrew consent, 1 was subsequently thought to have a history of migraine rather than epilepsy, and 1 was untraceable. Analysis of randomised patients is therefore based on a total of 1013, Demographic and clinical characteristics of the nonrandomised patients and of those randomised to the two treatment policies are summarised in table 1. The groups were similar except that randomised patients were younger than non-randomised and had a slightly longer duration of epilepsy and AED treatment. Delayed development (OR 1-8, 95% CI 3-6, 9-4), special schooling (OR 54, 95% CI

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TABLE 11-SEIZURE TYPES

(%)

I

35, 9-4), and psychiatric history (defined by referral to a psychiatrist, OR 1-8, 95% CI 1-2, 2-6), were also more

frequent in the randomised group. Patients with a history of attempted AED withdrawal (OR 06, 95% CI 0’5, 0’8) and those with a driving licence (OR 0-13, 95% CI 0-1, 0-18) were less likely to be randomised. Classification of seizures is shown in table II. 573 randomised patients had tonic-clonic seizures unassociated with partial seizures. Of these, 223 had at least one EEG showing generalised spike-wave abnormality, 88 had a focal slow-wave or epileptiform EEG abnormality but no generalised abnormality, and 234 had never had an EEG showing anything other than normal features or a nonspecific abnormality. In 28 no EEGs were available. Median number of tonic-clonic seizures in both randomised and non-randomised groups was 4. 83% of patients in each group were receiving monotherapy. Blood levels of AEDs were below the optimum range in 30%, 76%, 67%, and 51% of randomised patients receiving carbamazepine, phenobarbitone, phenytoin, and valproate, respectively. Among patients who did not consent to randomisation, 30% did not wish to participate because they were unwilling to continue AEDs whereas 74% were unwilling to stop drug therapy. An important factor with respect to the desire to continue drugs was possession of a driving licence. Of EEGs at entry to the study (less than 1 year before randomisation and at most 3 months after), 67% of patients had a normal or non-specific abnormality. 11% of randomised patients had a focal (slow or spike wave) abnormality and 17% had generalised spike wave. 5% had both focal and generalised paroxysmal abnormalities.

Follow-up Follow-up of the 10

13 randomised patients was complete to death or to the first 6 months of 1989 for all except 3 (1 in the armed forces,1 an itinerant, and 1 moved and could not be traced). 15 patients died. In 2 patients (M, 27 years and 32 years) who were randomised to continue therapy, the cause of death was probably a seizure. Another patient (F, 58), was believed to have committed suicide and 1 patient (F, 31) was a homicide victim. 1 patient (M, 70) died from a cerebral astrocytoma diagnosed after randomisation and in the remaining 10 the cause of death seemed unrelated either to epilepsy or to AED treatment.

Actuarial percentages of patients surviving seizure free under the two treatment policies are presented in the figure, along with differences, hazard rates, and ratios (and 95% CI) at selected intervals of follow-up. Difference between the two curves is greatest between 1 and 2 years, at which time 78% randomised to no withdrawal continue seizure free vs 59 % randomised to slow withdrawal. Thereafter the difference between the curves decreases. The hazard ratio peaks about 9 months after entry and then declines, so by 2-4 years patients still seizure free may have a higher risk of relapse if randomised to continued AED therapy than if randomised to withdrawal. This result may reflect withdrawal of AEDs after 1 or 2 years in patients randomised to continue (see below). 354 (35%) of the 1013 randomised patients had seizures during follow-up; 138 (39% of recurrences) had a single seizure episode (one or more seizures in one 24-hour period) and were thereafter seizure-free, the remainder had more than one seizure episode. In the slow withdrawal group, 107 (48%) seizures occurred in patients during AED reduction and 114 (52%) after drug withdrawal. Most recurrences were tonic-clonic seizures-98 (74% recurrences) patients with seizures in the no withdrawal group and 183 (83% recurrences) in the slow withdrawal group. Differences between actuarial percentages of patients free of tonic-clonic seizures (primary or secondarily generalised) with the two treatment policies were similar to those obtained from analysis of seizures of all types.

Actuarial percentage seizure-free among randomised groups

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TABLE III-COMPLIANCE WITH RANDOMISATION POLICY BEFORE FIRST SEIZURE (OR DEATH) FOLLOWING RANDOMISATION

with the two randomised policies is summarised in table ill. In the slow withdrawal group, 95% complied with the policy of slow drug reduction; 4 patients elected to stop AEDs abruptly and 10 decided not to reduce AEDs after randomisation (another had a seizure before AED reduction). 8 patients elected to resume treatment having achieved withdrawal without seizure recurrence. In the continued therapy group, 176 (35%) reduced or withdrew treatment during follow-up before a seizure recurred. 67 of these were children who stopped AEDs and for whom the protocol allowed withdrawal after 1 year or more of continued treatment (in practice, 38 were withdrawn by 2 years and 64 by 3 years after randomisation) and 30 were adults who stopped under supervision. 5 adults were withdrawn in error and 15 stopped of their own accord. The remaining 59 either had dosage or drug changes for medical reasons or reduced or stopped treatment after further medical consultation. Actuarial analysis of the continued therapy group, with follow-up censored at the time of initial dose reduction in all patients who decided to withdraw AEDs or withdrew in error, gave 89%, 81%, 77%, and 74% seizure free 12, 24, 36, and 48 months after randomisation. The influence of several prognostic factors on seizure recurrence in randomised patients is shown in table IV. The first column shows a univariate analysis-patients with the characteristic shown in the first column were compared with those without it. Continuous variables were transformed to categorical scales with the lowest category as the reference level, this form of presentation was chosen in preference to regression coefficients both to aid interpretation and to avoid complications introduced by curvilinear effects. To take account of correlations between the factors, all except age at randomisation were entered into a single multivariate model; the estimated effects are therefore "adjusted" for all the others. Several factors influenced recurrence, including taking two or more AEDs at randomisation, history of either primary or secondarily generalised tonic-clonic seizures, and period free of seizures at randomisation. Factors such as a history of neonatal seizures, of myoclonic seizures, and of "never-generalised" partial seizures, as well as occurrence of seizures after initiation of AED treatment and duration of AED treatment itself (at randomisation) might also be important. However, the CIs for those effects, as well as for those of other factors in table iv, are wide and therefore merit further investigation. The prognostic importance of EEG features was studied

TABLE IV-INFLUENCE OF PATIENT CHARACTERISTICS AND HISTORY OF EPILEPSY ON SEIZURE RECURRENCE*

Compliance

*1013 patients mcluded m all analyses tNeurologlcal deficit, birth trauma, intracranial surgery, head injury with posttraumatic amnesia 24 h, meningitis, encephalitis, or any other identified neurological disorder or deficit Factors achieving significance at 95% CI for multivariate model

in the reduced

sample of patients with "historical" or "entry" EEGs, by use of a univariate "survival" model with no adjustment for other factors except treatment policy. The sample was insufficient to reach specific conclusions about the importance of any abnormality (generalised spike wave or focal slow wave, or focal spike or spike wave) in the entry

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patients; relative risk 1-22 [097, 1-55]) or about generalised epileptiform abnormalities (1-25 [093, 1-67]), focal abnormalities (1-08 [075, 1-54]), or their interaction (1 16 [061, 2’22]) in the entry EEG. Patients with a history of only tonic-clonic seizures, associated with generalised spike wave abnormalities in either historical or entry EEG, had higher recurrence rates than other patients in whom either a historical or an entry EEG was available (965 patients; 137 [1 04, 1-80]). Patients with a history of tonic-clonic seizures and focal (but not generalised) abnormalities on either EEG (0-79 [051, 1-23]), and those with no more than non-specific abnormalities (0-99 [075, 1,30 were not at increased risk by comparison with the EEG (873

same

reference group.

Discussion The patients in this study were a self-selected population; to assess the extent of selection bias we collected information on those who were eligible for entry but were not

randomised. Patients who entered the study were similar to those who did not for most clinical factors, but the prevailing UK and European driving licence regulations were an important influence on whether those in remission would entertain withdrawal of AEDs. With this exception, we believe that the results may be generalised to less selected

populations. The risk of seizure recurrence under a policy of slow AED withdrawal is substantial when compared with a policy of continued treatment, especially during the first year. This risk was also high-about 0-12 per year-throughout the first 2 years of follow-up in patients who were randomised to continue therapy. Part of the explanation may be that some patients in the slow-withdrawal group elected to stop AEDs, or that children were included, for whom drug withdrawal after 1 year free of seizures was allowed by the trial protocol. Nonetheless, censoring follow-up times at the start of elective AED withdrawal still indicated substantial residual risk of seizure recurrence-about 0-10 per year. If patients remain seizure free after withdrawal of AEDs for 2 or more years, their risk of recurrence may be reduced and fall below that of patients randomised to continue treatment. Why should this be? First, compliance may become increasingly poor in

patients advised to continue therapy, because their history of seizures becomes more remote. Secondly, it is possible that the major effect of withdrawal of AEDs is to bring forward the recurrence of seizures into the period immediately following the start of dosage reduction and eventual withdrawal of treatment in a group of patients at risk of seizures at some time under either policy. In many published studies it is unclear whether risk of seizure recurrence is estimated from the start of AED withdrawal or from its completion .2 In our study the risk was assessed from the time of randomisation and before the initiation of withdrawal. It was recommended that in the slow-withdrawal group no less than 6 months should elapse before AEDs were stopped. We cannot provide an estimate of the effect of different withdrawal rates, but we note that the recurrence rate in the slow-withdrawal group was similar to that reported by other researchers who used more rapid withdrawal (2-3 months) in adults.2 Although some relapses in the continued treatment group were associated with non-compliance (eg, running out of tablets, stopping drugs when going out for a drink), slower rates of drug withdrawal may not be effective in reducing recurrence rates.

important factors determining outcome were longer periods free of seizures at randomisation (reducing the risk), and number of AEDs at randomisation and history of tonic-clonic seizures (increasing the risk). Earlier studies in which prognostic factors were examined have indicated that children are less likely to relapse on withdrawal of AEDs than adultsan observation supported by our results in an analysis not adjusted for other effects. J anz8 suggested that the classification of seizures and epilepsy has no major prognostic importance,8 the exception being juvenile myoclonic epilepsy. This syndrome, characterised by tonic-clonic seizures and myoclonus on awakening, is poorly recognised in the UK and was almost certainly present in more patients than it was possible for us to identify on the basis of documented myoclonus. However, it is striking that the presence of myoclonus and seizures on awakening may be important in determining The

most

outcome, and this observation accords with the view that the outlook for juvenile myoclonic epilepsy is especially adverse on withdrawal of therapy. A history of tonic-clonic seizures affected outcome adversely, as it did in the study of Shafer et awl. A history of partial seizures never secondarily generalised might also affect recurrence adversely but the confidence intervals for this factor do not exclude minor

effects.

Severity of epilepsy affects outcome. Other studies have shown that the longer the duration of epilepsy before remission the greater the likelihood of relapse.8,10 In our study, duration of treatment, which is related in turn to duration of epilepsy, had an important influence on outcome. Another measure of severity that affected outcome was whether patients were receiving more than one drug; this factor has been identified previously.ll,12 Perhaps the most controversial topic is whether the EEG can predict the recurrence of seizures; this may well be so in children. 1211 Although an abnormal EEG at entry to our study had an adverse prognostic influence, such abnormalities are related to important clinical factors that affect outcome, so an EEG may not be of great value in predicting recurrence in adults. Analysis of prognostic features in previous studies was hampered by small sample size and reliance on p values. Our results, presented as hazard ratios and 95% CI, show that even with sample sizes of over 1000 patients, judgments about prognostic importance of specific factors cannot be made easily. The most important feature of this study is the determination of relative risks of seizure recurrence for patients who elect to withdraw AEDs rather than to continue them after a period of remission. The stratified proportional hazards model used allows the development of a statistical model for prediction of relapse with the two policies in this trial. Validation in this patient population may help in counselling patients who will ultimately have to decide whether they wish to continue with AED treatment. We thank the Medical Research Council for funding this study, and and Wellcome for supporting study

Ciba-Geigy, Parke-Davis, Sanofi, meetings.

Study participants U K: Dr G. Barton (Aylesbury); Dr E. Hicks, Dr V. H. Patterson, Dr M. W. Swallow (Belfast); Dr A. Bush, Dr J. A. Finnegean, Dr A. Gupta, Dr A. Sharma (Birmingham); Dr K. T. Thomas (Blackburn); Dr I. T. Ferguson, Dr C. B. Karki, Dr R. M. Walters (Bristol); Dr J. Morrow, Prof A. Richens, Dr S. Wallace, Dr S. J. Wroe (Cardiff); Dr R. Godwin-Austen (Derby); Dr A. Davidson, Dr D. L. W. Davidson, Dr R. Roberts (Dundee); Dr J. K. Brown, Dr R. E. Cull, Dr A. McInnes, Dr P.

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Sandercock (Edinburgh); Dr C. Gardner-Thorpe (Exeter); Dr W. F. Durward, Dr I. Melville, Dr M. Thomas (Glasgow); Dr M. A. Barrie (Harlow); Dr J. E. Rees, Dr M. Rice-Oxley (Haywards Heath): Dr A. M. Butterfill, Dr N. Fraser (Hereford); Dr M. D. Rawson (Hull); Dr C. H. Hawkes (Ipswich); Dr A. I. Mukhtar (Kettering); Dr E. G. S. Spokes (Leeds); Dr B. Kendall, Dr P. Millac, Dr J. R. Moore, Dr I. F. Pye (Leicester); Dr J. W. Garry (Lincoln); Dr J. Andrews, Dr L. D. Blumhardt, Dr M. Hand, Prof F. Harris, Dr M. Hayward, Dr D. P. Heaf, Dr S. J. Howell, Dr P. R. D. Humphrey, Dr A. D. Kindley, Dr I. Lewis, Dr P. MacFarlane, Dr T. McKendrick, Dr N. Marlow, Dr P. Minchom, Dr I. Morgan, Dr J. R. Roberts, Dr L. Rosenbloom, Dr S. R. Sadik, Dr J. Sills, Dr W. B. Spry, Dr P. Stutchfield, Dr A. P. Thomson, Dr A. J. Williams, Dr E. H. Yousif, Dr T. D. Yuille (Liverpool); Dr P. Chesterman, Dr C. R. A. Clarke, Dr F. Clifford Rose, Dr P. Crawford, Dr C. Dellaportas, Dr R. Elwes, Dr T. D. C. Fox, Dr D. Hall, Dr A. Hellier, Dr N. Legg, Dr P. Monro, Dr G. D. Perkin, Dr E. H. Reynolds, Dr de Silva, Dr T. Steiner, Dr S. Wilson (London); Dr W. J. K. Gumming, Dr R. W. Newton, Dr M. Noronha, Dr D. I. Shepherd (Manchester); Dr P. Newman, Dr M. Saunders (Middlesbrough); Dr D. Bates, Dr N. E. F. Cartlidge, Dr D. GardnerMedwin, Dr D. W. A. Milligan (Newcastle upon Tyne); Dr D. R. Knight (Northampton); Dr R. Greenhall, Dr N. M. Hyman, Dr E. Spalding (Oxford); Dr P. I. Tomlin (Preston); Dr G. Venables (Sheffield); Dr A. W. Pantlin (South Ockendon); Dr B. Crossley, Dr C. Tyrie (Southampton); Dr H. G. Boddie, Dr R. A. Cooper, Dr S. L. Manawadu, Dr R. P. Murphy (Stoke-on-Trent); Dr A. C. Butler (Stourbridge); Dr P. Cleland (Sunderland); Dr C. A. R. Bainton (Torquay); Dr L. Loizou (Wakefield); Dr G. P. McMullin (Warrington); Dr J. Platt (Whitehaven); Dr R. Corston (Wolverhampton); Study participants Europe: Dr B. Pedersen (Denmark); Dr O. Dulac (France); Dr M. Conran (Ireland); Dr P. Zagnoni (Cuneo); Dr G. Zaccara (Florence); Dr A. van Lierde and Prof F. Viani (Milan, Italy); Dr J. Overweg (the Netherlands). REFERENCES

JF, Hauser WA, Elverbalk LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979; 20: 729-37. 2. Chadwick D. The discontinuation of antiepileptic therapy. In: Meldrum BS, Pedley TA, eds. Recent advances in epilepsy 2. Edinburgh: 1. Annegers

3.

Churchill Livingstone, 1985: 111-24. Pedley TA. Discontinuing antiepileptic drugs. N Engl J Med 1988; 318: 982-84.

Goodridge DMG, Shorvon SD. Epilepsy in a population of 6000. II: treatment and prognosis. Br Med J 1983; 287: 645-47. 5. Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 4.

1981; 22: 489-501. on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389-98. 7. White SJ, Freedman LS. Allocation of patients to treatment groups in a controlled clinical trial. Br J Cancer 1978; 37: 849-57. 8. Janz D. When should antiepileptic drug treatment be terminated? In: Wolf P, Dam M, Janz D, Dreifuss FE, eds. Advances in epileptology, vol 16. New York: Raven, 1987: 365-72. 9. Shafer SQ, Hauser WA, Annegers JF, Klass DW. EEG and other early predictors of epilepsy remission: a community study. Epilepsia 1988;

6. Commission

29: 590-600. 10. Oller-Daurella

L, Pamies R, Oller L. Reduction or discontinuance of antiepileptic drugs in patients seizure-free for more than 5 years. In. Janz D, ed. Epileptology. Stuttgart: Thieme-Verlag, 1976: 218-27. 11. Arts WFM, Visser LH, Loonen MCB, et al. Follow-up of 146 children with epilepsy after withdrawal of antiepileptic therapy. Epilepsia 1988; 29: 244-50.

12. Overweg J, Rowan AJ, Binnie CD, Oosting J, Nagelkerke NJD. Prediction of seizure recurrence after withdrawal of antiepileptic drugs. In: Dam M, Gram L, Penry JK, eds. Advances in epileptology: XII Epilepsy International Symposium. New York: Raven, 1987: 503-08. 13. Shinnar S, Vining EPG, Mellits ED, et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. N Engl J Med 1985; 313: 976-80. 14. Emerson R, D’Souza BJ, Vining EP, Holden KR, Mellits ED, Freeman JM. Stopping medication in children with epilepsy: predictors of outcome. N Engl J Med 1981; 304: 1125-29. 15. Todt H. The late prognosis of epilepsy in childhood: results of a prospective follow-up study. Epilepsia 1984 25: 137-44.

Scheduling of revaccination against hepatitis B virus

Studies have shown that to maintain protection against infection after a primary course of hepatitis B immunisation, revaccination can be scheduled on the basis of an anti-hepatitis B virus surface antigen (anti-HBs) titre obtained 1 month after the booster dose. However, schemes which require post-booster testing may present practical difficulties. We applied a random-effects regression model to data from 118 Senegalese infants given three injections of hepatitis B vaccine about 6 weeks apart and a booster injection at 13 months, and show that revaccination can be scheduled on the basis of an anti-HBs titre recorded at the time of the booster dose. We also show that titre-at-booster is no less accurate in predicting future titre than 1-month post-booster titre. In several other studies the post-booster decline in anti-HBs conforms to the same mathematical description, indicating the generality of our findings. Lancet 1991; 337: 1180-83.

Introduction The duration of protection from hepatitis B virus (HBV) infection afforded by a primary course of immunisation depends on the titre of antibody against HBV surface

antigen (anti-HBs) attained shortly after the booster dose.1-5 To maintain protection whilst conserving vaccine, it has been proposed that revaccination should be scheduled on the basis of an anti-HBs titre obtained 1 month after boosting,1-4 and this strategy has been endorsed for adults from non-endemic areas.After finding evidence of. substantial random variation amongst vaccinees in the rate of loss of antibody, Nommensen et al’ proposed that revaccination should be scheduled on the basis of anti-HBs titres obtained on two separate occasions after

boosting. Revaccination strategies which involve post-booster testing may be criticised on logistic and financial grounds. We have shown previously that anti-HBs titre at vaccination has a strong effect on the subsequent antibody response.8 Here we use a formal statistical model to investigate the possibility of scheduling revaccination on the basis of an ADDRESSES Institut de Virologie de Tours and Laboratoire de Microbiologie, Faculte de Pharmacie, Tours, France (P. Coursaget, PhD, B. Yvonnet, PhD, Prof J-P Chiron, PhD); Medical Research Council Biostatistics Unit, Fair View Lodge, 5 Shaftesbury Road, Cambridge CB2 2BW, UK (W. R. Gilks, PhD, Prof N E Day, PhD); Institute of Statistics, Academia Sinica,

Taipei, Taiwan (C. C. Wang, PhD); and Faculte de Medecine et de Pharmacie, Dakar, Senegal (Profl Diop-mar, MD) Correspondence to Dr W R. Gilks

,