ANNOTATIONS

When Not to Treat Epilepsy with Drugs

Refrain tonight. And that shall lend a kind of easiness To the next abstinence. the next more easy: For use almost can change the .stamp of nature. And either mock the devil or throw. him out. With wondrous potencv:

H A M L ~ T (111, sc.IV)

SPECIALISTS treating children with epilepsy who are hard to manage

d N sometimes find that difficult behaviour and obstinate fits both disappear when,

% under close supervision, the child is weaned from all drug treatment. This z

2 policy might be seen as a dangerous heresy 2 or as a logical extension of the trend 2 towards monotherapy. While mono- 2 therapy'-3 permits a close try at no-drug

treatment, at the same time it uses all the z d

5 * course it allows a variety of manipulable alternatives in the shape of different drugs. These provide experiments which are easy

5 to set into a scientifically acceptable E f r a m e w ~ r k ~ - ~ , whereas not using drugs

might be regarded as something that is 4 9 done only when necessity demands and

courage, ingenuity, therapeutic rapport 822 and occasion permit. Hitherto it has been

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largely a private device of certain epilepsy specialists and open discussion here is intended to raise it as an important issue in epilepsy management. This is not the same issue as how and when to withdraw drug treatment from patients who have been effectively treated'-''. We will touch on that question as we consider the inclination towards the disadvantages of using drugs. Indeed, such is the repertoire of known disadvantages that the fundamental assumption that convulsions should be treated with anticonvulsants deserves to be challenged.

Patients, doctors and society all have expectations about treatment. Even though at times their aims conflict, all their needs are usefully encapsulated in giving a medication. The patient requires, o r relatives require on the patient's behalf, a diagnosis which validates their experience, that it is what it seems to be, both for themselves and for other people. A prescribed medication helps powerfully with that validation. They require an explanation of their symptoms, both aetiologically and mechanically, and anticonvulsants carry a built-in ex- planation. People hope, through total control of epilepsy, to avoid the stigma that follows from having fits, which is greatly feared. Medication sustains that hope. For doctors, diagnosis is the basis of rational practice, but effective treatment

also proves them both right and powerful. Doctors are trained to do something rather than nothing; to recognise the risk of hypoxic brain-damage, sudden death, and death by exhaustion o r by accident. They also might want to relieve stigma and distress from experiencing the condition. The existence of a category of drug called anticonvulsants provides an obvious apparent solution t o the problem of convulsing. Society’s view is most evident in the medicolegal process, in which i t might be argued in court that a person who had acceded to becoming a patient could reasonably expect to be treated by the most appropriate means available as soon as the diagnosis was established. But there are problems about the apparently easy, ready-made solution.

Patients, in accepting a diagnosis of epilepsy, are accepting membership of a stigmatised group. This generates intense ambivalence about treatment, since loss of esteem may follow equally from being treated for fits as from suffering them. Such is the deep fear of epilepsy as an inherent arcane defect that people have confessed publicly their relief when their seizures were found to be due, not to ‘epilepsy’, but ‘only to a brain tumour.’ The Welsh poetess MARCAID EVANS called her epilepsy ‘a ray of darkness’. The experience of epilepsy sets up therapeutic needs which are not necessarily met by anticonvulsants. Considering the dif- ficulties involved, doctors ought to recognise their powerful prejudice towards medication. (How many of the people with epilepsy who die suddenly die because of untreated epilepsy?) Doctors have to contend with the very unclear conceptual standing of epilepsy and with extreme degrees of developmental variation in its expression, which makes its explanation to patients difficult and requires frequent revision of treatment. They also receive powerful intermittent reinforcement not to miss anything serious, or leave undone anything that might be done. Because the fits are distributed over a long period of time, treatment is hard to monitor. Twelve seizures a year, one a month, on a given regimen might be regarded as unacceptably frequent. But to monitor and manipulate that regimen under inpatient supervision may require a more protracted admission

than would be desirable for other reasons. Bringing relief close enough t o treatment to be therapeutically reinforcing is a problem. The lengths of time create difficulties in the therapeutic partnership. Doctors and patients may settle for a standard of management far short of the ideal, time drifts by, appointment intervals lengthen, the prescription is left on the family doctor’s table, chronicity is accepted.

The conditions under which treatment without drugs might be tried will be considered under the following six headings:

Are drugs necessary yet.? The emergent childhood epilepsies are unlikely to survive the doctors’ and parents’ need to start drug treatment. The natural history of these disorders is likely to remain unknown. Perhaps we could be more conservative in our response to two or three seizures, o r at least more sporadic in our drug response t o them. Yet the experience of many follow-up studies over a very large range of years suggests that their associated mortality and morbidity remain a t much the same levels and are crucially dependent on factors other than management by med i~a t ion” - ’~ . Perhaps this is because, once anticonvulsant management is established, broader therapeutic vigilance actually drops. GOWER’S forceful opinion, post hoc observation and the kindling model persuasively suggest a need for prompt treatment, since long-established epilepsy is hard to treat. The retrospective viewpoint creates a formidable artefact in the theory that seizures wear a little footpath through the brain15* 1 6 , each playing Wenceslas to the next, since the explanation is rather seriously caught up in the definition, and duration of epilepsy is tied, through age at onset, to crucial aetiological issues. If it were not regarded as a presumption that we should intervene at once (or very soon), it might be easier to see how therapy actually alters the established pattern of fits. The effective- ness of surgical treatment following on years of repeated seizures and the recurrent experience of spontaneous remission d o not support GOWER’S nostrum. REYNOLDS and colleagues15 note COWER’S obser-

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vation (in 1881) that seizures of less than one year’s duration had a good prognosis, even then, and without any of our current drugs. Retrospectively too, but perhaps less suspect, comes the recurrent experience of obtaining, on careful questioning, a history of seizures which went untreated for years without seriously compromising a child; also the brevity of expression of some seizure disorders, notably infantile spasms, which without treatment may last days or weeks. It is quite uncertain what the effects of treatment might have been. Cautious approaches to drug treatment may make for better chances of detecting both the hysterical’”- I‘ and the fictitiousl’epilepsies. These cannot be regarded as contributing an insignificant proportion of children presenting with symptoms that might be epilepsy and they are powerfully validated by treatment to their disadvantage.

Thoughtlessl-v or as replacement therapy Dr. OUNSTED related, for example, how one of his patients in his long-term follow- up, not seen for the 17 years between ages 1 1 and 28, had continued seizure-free and on medication kindly prescribed ‘as usual’ by his family doctor. Such behaviour is not confined to family practice and is likely to be promoted in clinics where junior staff change frequently and no one feels like tangling with the problem of drug with- drawal. This is regressed thinking, primitive animism, where epilepsy is seen as lying in wait ready to pounce. So it might, of course, during the early stages of experimental drug withdrawal. The tend- ency to require a patient to have no fits on medication” before weaning them off it provides a perfect ‘catch 22’ for those patients whose seizures are perpetuated by medication. Reports about stopping medication seem more concerned with relapses than with successes. It is worth remembering that the patient might have enjoyed some years seizure-free off drugs before the onset of epilepsy, and might possibly d o so again given the chance. I t seems that only in the treatment ofseizures in the newborn is the concept ofultra-brief therapy systematically exploited’”, whereas it might be effective to stop ‘attacks’ of epilepsy on a sporadic basis just as ACTH is used to ‘switch of f infantile spasms.

I f alternatives are possible I t is not our purpose to promote alternative therapies, but the possibility of ( a ) learning seizure control and the avoidance of triggers, ( b ) bio-feedback and relaxation, (c) psychotherapy or ( 6 ) surgical treatment is actually never seriously considered during most epileptic careers. While there is universal agreement that situational factors can make epilepsy worse, there is far less interest in the notion that personal and situational adjustments are powerful therapeutic adjuncts. But AIRD”, in a well-reasoned article, shows that for 17 per cent of 500 people with refractory epilepsy, these factors were of crucial importance in establishing control.

If they do not work Better baselines off all treatment would improve our knowledge of what constitutes therapeutic success. This detailed, caring aspect of management is obviously part of the success of research- monitored monotherapy regimes. Manifest drug success is common and justifies treatment if the side-effects are acceptable and less trouble and danger than the seizures. But many patients are kept in treatment, despite continuing seizures, on the basis of anxieties about what might happen without it and what does happen when changes are made in the regime. These changes, i t has to be said, are not always enthusiastically agreed to, not necessarily accurately undertaken, and not executed under ideal conditions. BUCHANAN”, however, reorganising the treatment of 20 ‘hard core’ epileptics with their enlisted support, reported three patients ceasing treatment entirely without furthcr seizures.

If several different drug regimes d o not differ in their effect, they may also not be any bettcr o r worse than nothing. Drug regimes for the treatment of epilepsy arc often poorly organised in terms of the daily schedule, poorly explained, consequently ill-received, and subsequently not properly adhered to. Compliance was adequate in only 50 per cent of PETt:RSON and colleagues’ sample”. RIDDLE24 has suggested a general formula for manage- ment in chronic disease clinics which requires, first, ‘Acquisition by the health professionals of an adequate base of

information about the disorder’. Which means that the doctor should know what he is doing. And second, ‘Acceptance by the patient of primary responsibility for coping with the disorder and maintaining health’. The patient is not viewed as a passive cypher, or an experimental preparation, or even a parasite on the practitioner. The aim of medicine is to aid their management. RIDDLE adds that patients must be taught about their disorder, agree management goals, and participate in the evaluation of success in achieving those goals. The distance between this and current reality was painfully revealed by HOPKINS and

I f drugs do more harm than good The aim of treatment is to produce the ‘best possible child’. Too high a price can be paid even for complete seizure relief and, short of this, the negative effects upon well-being, behaviour, mental state, education and work need to be weighed in the balance of Even in carefully conducted trials of monotherapy, clinical ~ide-effects~’ and biological changes” are not avoided. The most vulnerable people are those who have poor advocates (including the mentally retarded and neurologically damaged’6q 29), other ostensible ‘reasons’ for deterioration, and those whose epilepsy is in the form of cyclical exacerbation. Reduction of treat- ment in monotherapy trials has led to reduced frequency of seizures’ and can be seen as evidence that drug therapy was previously making patients worse. This was the experience of THEODORE and PORTER’” in removing sedative drugs in particular from the treatment schedule. Few people report pressing this advantage to its obvious conclusion. Theexacerbation of epilepsy by anticonvulsant drugs is reported, however”, especially in the Lennnx-Gastaut syndrome26q 32* 3 3 , which is critically related to cerebral state and the sleep waking cycle but not alone in that. More remote and as yet insufficiently researched is an anxiety that anti- convulsants may affect cerebral develop- ment if given during very early childhood34. ’. When they are no longer necessar.y The established prejudice is that epilepsy is

SCAMBLER”.

an unremitting disorder-a propensity, like a character fault. A similar view hovers over other prejudicial groups; it was once a necessary component of the diagnosis of schizophrenia, for example. The im- plication that recovery is ephemeral or frail and treatment always necessary effectively diminishes people permanently. Many long-term follow-up studies have certainly revealed the solid core of truth within the prejudice”-13, but i t is by no means universally true and outcome is highly predictable on the basis of facts that d o not depend upon drug treatment.

Finally, DEVILLIS et a f . 3 b noted that initial research suggests that the ‘locus of control’ in epileptics is poor, that is ‘external’. They noted ‘the close parallel between the natural history of seizure disorders and laboratory procedures for inducing learned helplessness’. Learned helplessness, like external locus of control, implies a belief that outcomes are not controlled or influenced by personal responses. Patients cannot afford to be the passive victims of their treatment because outcome includes how they view themselves in their own world, both now and in the long term.

Seizures are clinical phenomena which may emerge at any time in development, have a wide diversity of clinical forms, and associated electrical characteristics in the EEG. They may be single, sporadic, ephemeral, transient, or persist with relentless frequency across a lifetime. They may be symptomatic of cerebral abnormalities ranging from the rapidly lethal to the trivial, or merely indicative of a quirk or propensity of that central nervous system. Despite relatively pre- dictable emergent patterns over ontogeny, many idiosyncratic and unknown factors render drug treatment less specific and predictable than it might be, especially in childhood. We have argued that it is necessary to challenge the current presumptions that epilepsy must be treated with anti-epileptics, that this treatment improves safety, that it improves well- being, that responsible treatment with drugs necessarily requires a prolonged or protracted course, particularly over years, and that persistence of epilepsy despite treatment is the surest indication for persisting with treatment. A more

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cautious, thoughtful approach to drug treatment may allow a better under- standing of the natural history, avoid the notion of some form of chronic replacement therapy, provide for alter- native treatments, allow the recognition that treatment has failed o r that harm outweighs benefit, and keeps in constant view the possibility of stopping treatment. We recognise that some of these considerations inform many of the monotherapy trials.

DAVID C. TAYLOR* IAN MCKINI .AYt

*Professor of Child and Adolescent

Jesson House (R.M.C.H.). Manchester Road, Swinton, Manchester M27 IFG. t Consultant Paediatric Neurologisr, Booth Hall Children’s Hospital, Charlestown Road, Manchester M9 2AA.

Psychiatry .

References 1. Beran, R. G., Sutton, C. (1982) ‘Treatment of

epilepsy. Monotherapy versus polytherapy.’ Medical Journal of Ausrralia. 2, 135-138.

2. Reynolds, E. H., Chadwick, D., Galbraith, A. W. (1976) ‘One drug (phenytoin) in the treatment of epilepsy.’ Imicet. 1 , 923-926.

3. Reynolds, E. H., Shorvon, S. D. (1981) ‘Mono- therapy or polytherapy for epilepsy.’ Epilepsia, 22, 1-10,

4. Andersen, E. B., Philbert, A, , Klee, J. G. (1983) ‘Carbamazepine monotherapy in epileptic outpatients.’ Acra Neurologica Scandinavica. 67, Suppl. 94, 29-34.

5. Heranz, J. L., Arteaga, R., Armijo, J. A . (1982) ‘Side effects of sodium valproate in mono- therapy controlled by plasma levels: a study in 88 pediatric patients.’ Epilepsia, 23, 203-214.

6. Schmidt, D. (1983) ‘Reduction of two-drug therapy in intractable epilepsy.’ Epilepsia, 24,

7. Emerson, R., D’Souza, B. J., Vining, E. P., Holden, K. R., Mellits, E. D., Freeman. J . M. (1981) ‘Stopping medication in children with epilepsy.’ New England Journal of Medicine. 304, I 125- I 129.

8. Holowach. J., Thurston, D . L., O’Leary. J. L. (1972) ‘Prognosis in childhood epilepsy. Follow-up study of 148 cases in which therapy had been suspended after prolonged anti- convulsant control.’ New England Journal of Medicine. 286, 169- 174.

9. Holowach, J., Thurston, D. L.. Hixon, B. B., Keller, A. J. (1982) ‘Prognosis in childhood epilepsy. Additional follow-up of 148 children I5 to 23 years after withdrawal of anti- convulsant therapy.’ New England Journal of Medicine. 306, 83 1-836.

10. Yoshioka, M. (1982) ‘The policy for termination of antiepileptics.’ Folio Prychiarrica er Neurologica Japonica. 36. 295.

11. Cavazzuti, G. B., Ferrari, P., Lalla, M. (1984)

368-376.

‘Follow-up study of 482 cases with convulsive disorders in the first year of life.’ Developmental Medicine and Child Neurology. 26, 425-437.

12. Chevrie, J . J., Aicardi, J. (1979) ‘Convulsive disorders in the first year of life. Persistence of epileptic seizurcs.’ Epilepsia. 20, 643-649.

13. Harrison, R. M., Taylor, D. C. (1976)’Childhood scizures: a 25-year follow-up.’ Lancer. 1 , 948-952.

14. Todt, H. (1984) ‘The late prognosis of epilepsy in childhood: results of a prospective follow-up study.’ hpilepsia. 25, 137-144.

15. Reynolds, E. [ I . , Elwes, R. D. C.. Shorvon, S. D. (1983) ‘Why does epilepsy become intractable?’ Lancer. 2. 952-954.

16. Shorvon, S. D., Reynolds, E. H. (1982) ‘Early prognosis of epilepsy.’ Rrirish Medical Journal, 285, 1699- 170 1.

17. Taylor, D. C. (1985) ‘The falling sickness: a reorientation to hysterical epilepsy.’ I n Gordon, N., McKinlay, I . (Eds.) Neurological1.v Handicapped Children: Trearmenr and Manage- menr. Oxford: Blackwell ( in prcss).

18. Wilkus, R. J., Dodrill. C. B . , Thompson. P. M. (1984) ‘Intensive EEG monitoring and psychological studies of patients with pseudocpileptic seizures.’Epilepsia. 25,100-107.

19. Meadow, R. (1984) ‘Fictitious epilepsy.’ Lancer. 2. 25-28.

20. Gillam, G. L. (1982),’Convulsions following birth asphyxia/birth trauma-are long term anticonvulsants necessary?’ Australian Paediarric Journal, 18, 90-9 1.

21. Aird, R. B. (1983) ‘The importance of seizurc- inducing factors in the control of refractory forms of epilepsy.’ Epilepsia. 24, 567-583.

22. Buchanan, N. (1982) ‘Treatment of epilepsy: whose right is it anyway.’ Rrirish Medical Journal, 284, 173-1 74.

23. Petersen, G. M., McLean, S. , Millingen, K. S. (1982) ‘Determinants of patient compliance wi th anticonvulsant therapy.’ Epilepsia, 23.

24. Riddle, M. C. (1980) ‘A strategy for chronic disease.’ Lancer. 2, 734-736.

25. Hopkins, A., Scambler, G. (1977) ‘How doctors dcal with epilepsy.’ Lancer. 1 , 183-186.

26. DeNegri, M., Doria, L., Gaggero, R., Rolando, S. (1981) ‘Ncurological and psychic side effects of antiepileptic drugs in pediatric age.’ Pediarria Medira e Chirurgica. 3, 159- 163.

27. Stores. G. (1975) ‘Behavioural effects of anti- epilcptic drugs.’ Developmenial Medicine and Child Neurology, 17, 647-658.

28. Dellaportas, D. I . , Shorvon, S. D., Galbraith, A. W., Laundy, M., Reynolds, E. H., Marshall. W . J., Chanarin. I . (1982) ‘Chronic toxicity in epileptic patients receiving single-drug treatment.’ British Medical Journal, 285, 409-4 10.

29. Rodin, E., Klutke. G., Chayasirisobohn. S. (1982) ‘Epileptic patients who are refractory to anticonvulsant medications.’ Neurolo,sy. 32. 1382-1384.

30. Theodore. W. H., Porter. R . J. (1983) ‘Removal of sedative-hypnotic antiepileptic drugs from thc regimens of patients with intractable epilepsy.’ Annals uf Neurology. 13, 320-324.

31. Shields, W. D., Saslow, E. (1983) ‘Myoclonic, atonic, and absence seizures following institution of carbamazepinc therapy in children.’ Neurology. 33, 1487-1489.

32. Tassinari, C . A.. Gastaut, H., Dravet. C.. Rogers, .I (1971) ‘A paradoxical effect: status epilepticus induced by benzodiazepines (Valium and mogadon).’ Elecrroenrephalography and Clinical Neurophysio1og.v. 31, 182. (Abstracr.)

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33. Tassinari, C. A,. Dravet, C., Roger. J., Cano. J. T. , Gastaut, H. (1972) ‘Tonic status epilepticus precipitated by intravenous ben7o- diazepine in five patients with I.ennox-Gastaut syndrome.’ Epilepsia, 13, 421-435.

34. Diaz. J . . Shields, W. D. (1981) ‘Effects of dipropylacetate on brain developmcnt.’ Annals of Neurolo,qy. 10. 465-468.

Fetal Neurosurgery-a New Challenge on the Horizon A few years ago it would have been unthinkable to suggest that surgery could be performed on a fetus still in the uterus, yet today operative procedures are being performed not only on laboratory animals but also on humans. The development of surgical procedures likely to benefit the fetal brain and spinal cord affected by hydrocephalus and spina bifida is a challenge that has already been taken up by a number of groups working in a variety of fields’-’. While this work is still a t an early stage of development, it is timely to review its background, the situation a s it stands a t present, and its likely progress in the future.

Fetal surgery could not be developed until a number of problems had been solved. Making an incision in the uterus, and to a lesser extent passing instruments into it, are accompanied by a high risk of causing premature labour. Partial delivery of the fetus through an incision in the fundus of the uterus nearly always causes the uterine muscle to contract, which thus makes it difficult, and frequently im- possible, to replace the fetus in the uterus. However, recent advances in the pharma- cology of tocolysis have gone a long way toward solving this problem, and now it is possible to control uterine contractility much more effectively than in the past. In the laboratory it is now common practice for the uterus to be opened and for procedures to be successfully carried out on the brain, spinal cord, diaphragm or bladder of partially delivered fetuses. At the end of the procedure the fetus is

35. Fishman. R. H. R., Yanai. J . (1983) ‘Long- lasting effects of early barbiturates on central nervous system and behavior.’ Neuroscienceand Biohehavioral Reviews. 7, 19-28.

36. Devillis, R. F., Devillis, B. M.. Wallston, B. S., Wallston, K . A. (1980) ‘Epilepsy and learned helplessness.‘ Basic and Applied Social Psychology. I , 24 1-253.

returned to the uterus, and in a significant number of cases the pregnancy continues to term without the threat of early termination.

Clinically, fetal surgery also had to await developments, particularly in imaging techniques, so that detailed examination of the fetus in utero could be carried out. Ultrasonography has been the majorbreak- through in this field, and it has advanced to the point that the fetal head can be visualized sufficiently well by the 8th o r 10th week of gestation for measurements to be made. The lateral ventricles can be seen by the 12th week, and the 3rd and even the 4th ventricles can be identified after the 17th week’. The spinal cord as such cannot be identified, but details of the anatomy of the spinal column can be seen a s early as the 16th week, provided the fetal position is optimal’.

Laboratory studies are currently being undertaken to investigate the rBle of intrauterine intervention in the manage- ment of lesions of the fetal central nervous system (CNS)’-’, l o . Experimental hydro- cephalus has been induced in fetal subhuman primates and sheep by feeding teratogenic agents to the mother o r by injecting adhesion-producing agents into the subarachnoid space of the posterior fossa of the fetuss-’. In the latter part of gestation, after it has been established that hydrocephalus has been induced, the uterus is opened and cerebrospinal fluid (CSF) diversion is carried out. In one method a metal screw with a built-in one- way flow system is used to divert CSF into the amniotic The device is passed through the fetal skull until its tip lies in the frontal horn of the lateral ventricle; its upper end is left protruding into the amniotic cavity. In another method an implanted shunt is used to divert CSF from the lateral ventricle into the fetus’s own peritoneal cavity’. Both methods require the uterus to be opened and the head or the

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