Scot. med, J., 1976, 21: 11

THE MANAGEMENT OF EPILEPSY R. H. E. Grant The David Lewis Centre for Epilepsy, Alderley Edge, Cheshire

Guainerius was a physician and lecturer in medicine at the University A of Pavia in the early fifteenth century. In the N TON IUS

course of 8 chapters in his work Opera Medica published in 1488 he gave some very specific instructions for the care of the patient during an epileptic seizure. 'If a paroxysm comes to an epileptic, let it be your aim to prevent the ascent of vapors, and as far as possible to draw the matter downwards. Therefore perform vigorous rubbings or painful ligatures on the extremities, on the buttocks; under the knee make a slight incision with a cupping glass; and call the patient in a loud voice by his own name-Place a wooden peg between his teeth-Also when an epileptic falls, at once kill a dog, and give the gall to the patient in any way that you can. If the one who first sees the attack urinates in his own shoe and then stirs it around as if to wash it, then gives the urine to the patient to drink, afterwards, the patient will be entirely delivered.'

He may well be but one wonders precisely where. Guainerius may perhaps have been slightly less unpopular in his recommendations for the inter-seizure management of epilespy when he instructed that the unfortunate sufferer should, ... avoid fear, sadness, anger and all disturbances of soul; also coitus, unless he be a robust youth accustomed to it; he may have intercourse lest his semen be turned into poison by being too long retained.'

Amongst over 100 remedies which he states will root out all curable epilepsy Guainerius includes pills made , ... from the rib of the left side of a man who has been hanged, or beheaded, and give it with water to the patient every morning for a month.'

These chapters on epilepsy contain nothing not found in writings which antedated them by hundreds of years. They are quoted mainly to illustrate the mythology which has surrounded the falling sickness for at least 4000 years of recorded history, and which may still be responsible for some of the wide misconceptions held today. As Owsei Temkin says in the opening paragraph of his book (Temkin 1971)'In the struggle between the magic and the scientific conception, the latter had gradually emerged victorious in the western world. The fight has been long and eventful, and in it epilepsy held one of the key positions. '

The management of epilepsy has advanced considerably since the days of Guainerius but there is still much that is not satisfactory and perhaps in 200 years time physicians will look back on our feeble efforts with the same degree of amusement with which we may feel inclined to regard Guainerius. Diagnosis

The management of epilepsy cannot be started until the diagnosis is established and it is difficult to over-emphasise this point. Once a patient is told that he is suffering from epilepsy the effects on his daily life may be profound and all sorts of restrictions for employment, leisure activities, insurances etc., in addition to the ugly spectre of prejudice may arise. Diagnosis depends very largely on a detailed history both from the patient aad from a reliable person who has witnessed the alleged siezures. This can take a great deal of time and is an argument in favour of special epilepsy clinics. It is not uncommon to see patients who have been treated with anti-epileptic drugs for some years, with all the attendant restrictions, on quite inadequate evidence. The following case history may serve to illustrate the point. Case report. Janice aged 26 years was referred to the Assessment Unit at the David Lewis Centre. She had a long history of depressive illness and disturbed behaviour and had been diagnosed at a London teaching hospital as a psychopathic personality. At the age of 18 years she took an overdose of phenobarbitone, sustained cardiac arrest and at that time had a series of grand mal seizures. She was told about this and treatment with anti-epileptic drugs was commenced. From then onwards she continued to have recurrent attacks of loss of consciousness with a variety of so called convulsive movements and 'automatisms', Numerous changes of anti-epileptic drugs were made in many different hospitals in various parts of the country none of which made the slightest, difference to the frequency of her attacks. On admission to the Unit she was taking primidone 1.5 g. phenobarbitone 90 mg., and diazepam 30 mg. daily. Clinical examination was entirely negative, but she exhibited many attention seeking symptoms. She was employed in an industrial therapy workshop and observed closely for 4 weeks. She had frequent 'attacks' but they were universally suspect. I personally witnessed a 'grand mal' seizure during the clonic

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phase of which there was a strongly positive corneal reflex. Repeated electro-encephalograms were normal. Treatment was gradually withdrawn and elementary psychotherapy given. The result was a dramatic reduction in the frequency of seizures over the next 4 weeks and an im.provement in her person.ality. She was told that she did not suffer from epilepsy and asked to co-operate in total abolition of treatment to which she agreed. She was discharged after 6 months without treatment and remains free of 'attacks' 6 months later but will be followed up for several years.

This patient is typical of many who are treated quite unnecessarily. Jeavons (1972) reported that 19 per cent of 276 adults and 21 per cent of 195 children attending his clinic with a diagnosis of epilepsy did not in fact have the condition. If the experience of Jeavons is nationwide, a large number of people are taking a large number of unnecessary and potentially harmful tablets. Clonic movements of the limbs and incontinence of urine do not invariably mean that the attack is epileptic; they can occur in simple vaso-vagal attacks when there will be a history of a sensation of faintness beforehand and usually very rapid recovery, without confusion and sleep. There are frequently precipitant factors. Hysterical attacks usually occur in relation to an emotional upset, almost always in the company of other people and may show a bizarre seizure pattern. There is usually no change in the patients colour, incontinence is rare, the plantar responses are flexor and most important of all the corneal reflex is present. A previous history of febrile convulsions in infancy does not mean that attacks developing several years later are epileptic and neither does an abnormal electro-encephalogram. The important factor is what is happening to the patient now during the attack and only time, effort, and patience will reveal the true nature of the condition. Psychomotor seizures often provide difficulty in diagnosis because the manifestations may be so widespread. The commonest features are epigastric sensations often described as an unpleasant feeling of fear rising from the epigastrium to the throat, involuntary swallowing movements, hallucinations of smell, taste, hearing and vision, a wide variety of automatisms, and alteration of

consciousness. If very brief in duration they may be confused with simple absences (petit mal), with obvious implications in treatment. Ounsted, Lindsay and Norman (1966) give a graphic account of the confusion which may arise. It is abundantly clear that epilepsy is not one disease but a group of disorders more correctly called the epilepsies although for convenience the singular term is usually used. Many attempts have been made to classify the epilepsies. The most generally acceptable is that proposed by The International League Against Epilepsy (Gastaut, 1969) which divides epileptic seizures (not patients with epilepsy) into four major groups, a simplified version of which is shown in Table 1. Table I. International classification seizures.

of epileptic

------------

I. Partial seizures (local onset).

A. With elementary symptomatology-generally without impaired consciousness. (I) With motor symptoms-includes Jacksonian seizures. (2) With special sensory or somatosensory symptoms. (3) With autonomic symptoms. (4) Compound forms. H. Partial seizures with complex symptomatology

-generally with impaired consciousness. (Temporal lobe or psychomotor seizures). (I) Impaired consciousness only. (2) Cognitive symptomatology. (3) Affective symptomatology. (4) Psychosensory symptomatology. (5) Psychomotor symptomatology (automatisms). (6) Compound forms. C. Partial seizures secondarily generalised. 2. Generalised seizures (bilaterally symmetrical without local onset). (I) Absences-Petit Mal. (2) Bilateral massive epileptic myoclonus. (3) Infantile spasms. (4) Clonic seizures. (5) Tonic seizures. (6) Tonic-clonic seizures (Grand Mal). (7) Atonic seizures. (8) Akinetic seizures. 3. Unilateral seizures. 4. Unclassified seizures-due to incomplete data.

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Treatment Once the diagnosis of an epileptic seizure has been established by a careful history, electroencephalogram, and other investigations when appropriate, a decision has to be made about the future management of the patient. The treatment of epilepsy is, and for some time is likely to remain primarily medical but before considering various anti-epileptic drugs I should like to pose 2 questions. (1) Should the patient be treated at all? (2) When should treatment start? Certain categories of patient may not require medical treatment at all the most important being those already discussed who do not suffer from the condition. However, even in these patients existing treatment must be withdrawn slowly because sudden withdrawal may actually precipitate a genuine epileptic seizure which can be somewhat disconcerting. There is also a group of patients who are able to control their own seizures by various means. They are usually motor seizures with a focal onset and sufficient warning to enable the patient to hold the offending part of the body, commonly an arm or leg. Some patients with temporal lobe seizures can ward off an attack by mental exercise. If the seizures are persistently of this type anti-epileptic drugs are probably not required. Finally, a few patients have seizures only when watching television and this phenomenon has been studied particularly by Jeavons and his colleagues (Jeavons et al., 1966; Jeavons & Harding, 1970); 50 per cent of these patients have normal electro-encephalograms except when exposed to intermittent photic stimulation usually between 15 and 25 flashes per second, and a large proportion only respond with binocular vision. The simplest treatment is to sell the box, but this may be considered heresy in the 1970's and more acceptable methods are to view the television from 10 feet or more, have plenty of other light in the room and cover one eye if for any reason the television set must be approached. Drugs are quite unnecessary in these cases. Assuming that the patient has a spontaneous seizure not fulfilling the criteria outlined above when should medical treatment begin? Most neurologists would probably state that

treatment should commence once the diagnosis of epilepsy is accepted but the point at which this diagnosis is made in an individual case is sometimes debatable. Epilepsy is the tendency to recurrent seizures and therefore one epileptic seizure does not make a diagnosis of epilepsy. It is not uncommon to see a patient in the third or fourth decade of life who suddenly presents with a classical grand mal seizure. In many cases there are features in the history which suggest that treatment need not be started immediately. These include a period of 'hectic living', excessive alcohol consumption, low food intake, and lack of sleep in the 24 hours prior to the seizure. In such a case I never start antiepileptic drugs and very seldom do even in the absence of such a history. If treatment is started and no further seizures occur how are we to judge whether the treatment is required at all? This is in disagreement with Eadie and Tyrer (1974) who state that anti-epileptic therapy should begin at the time of the first recognized epileptic manifestation. In the case of absences (petit mal) in children, and temporal lobe seizures in children and adults, the decision is very much easier because there is usually a history of recurrent episodes at the first consultation. Drug treatment The main anti-epileptic drugs available today are summarised below with the main indications for use. Notice my avoidance of the word anti-convulsant-the child with simple absence attacks (petit mal) does not convulse and neither do patients with many other types of epilepsy. (1) Barbiturates (a) phenobarbitone-neonatal and febrile convulsions, grand mal, focal motor or sensory seizures. (b) primidone (Mysoline)-grand mal and psychomotor seizures.

(2) Hydantoinates (a) phenytoin (DPH, Epanutin) (b) methoin (Mesantoin) (c) ethotoin (Peganone) (neonatal and febrile convulsions, grand mal, focal motor and sensory seizures). 13

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(3) Oxazolidinidiones (a) trimethadione, troxidone (Tridione) (b) paramethadione (Paradione) (absences (petit mal) (4) Succinimides (a) ethosuximide (Zarontin) (b) phensuximide (Milontin) (c) methsuximide (Celontin) (absences (petit mal) with 3 c.p.sec. spike/ wave activity) (5) Benzodiazepines (a) diazepam (Valium) myoclonic epilepsies, status epilepticus: (b) nitrazepam (Mogadon) infantile spasms, akinetic seizures: (c) clonazepam (Rivortil) infantile spasms, absences, myoclonic epilepsies. (6) Miscellaneous drugs (i) carbamazepine (Tegretol) - psychomotor seizures and grand mal; (ii) sodium valproate (Epilim)-absences (petit mal), grand mal, myoclonic epilepsies; (iii) sulthiame (Ospolot) psychomotor seizures; (iv) pheneturide (Benuride)- psychomotor seizures: (v) acetazolamide (Diamox)-all types, especially absences (petit mal): (vi) ACTH-infantile spasms, minor epileptic status: (vii) pyridoxine-rare forms of infantile epilepsy. It is not my intention to examine all these drugs in detail. Such information is readily available in the literature and particularly in a recent publication by Eadie and Tyrer (1974). Before considering some of the more important drugs there are certain basic principles in the use of drugs in epilepsy which are worth emphasizing: (1) Having established the type or types of epilepsy the safest and most appropriate drug should be selected. In the case of a patient with two distinct types of epilepsy for example simple absences (petit mal) and tonic-clonic seizures (grand mal) it may be necessary to use two separate drugs at the outset of treatment.

(2) Always introduce anti-epileptic medication gradually with increases in dosage at weekly intervals. This is particularly important with certain drugs especially primidone which can produce severe side effects if started in a 'full' dose. (3) If seizures are only partially controlled the dose of the drug selected should be raised to the limit of tolerance. (4) If this fails a second drug may be added in the same way by gradual incremental increases. (5) Maintenance treatment should be continued in full dosage for at least 2 years after the occurrence of the last seizures. In many cases it may be desirable to continue for much longer than this. (6) As a general principle every attempt should be made to control the condition with one or two drugs in correct doses, monitored if necessary by regular estimation of the serum drug level. There is an undesirable tendency to add 'a little bit of this drug' to see if it will help. The danger is that the unfortunate patient may end up by taking 4, 5 or even 6 different kinds of drug, all of them in sub-optimal doses. On the other hand it is equally true that about 20 per cent of patients are not satisfactorily controlled on two drugs and it may be necessary to add a third and very occasionally a fourth. Phenobarbitone has been available for over 60 years and is probably the most commonly used anti-epileptic drug for neonatal and febrile convulsions, grand mal, and focal motor or sensory seizures. Because of its long history, low cost and apparent lack of toxicity there is a tendency to use unnecessarily high doses. The therapeutic serum level varies quite widely with different authors. Van Meter et al. (1970) quote a range of 20 to 24 ug. per mI., but Buchtal and Lennox-Buchtal (1972) suggest a lower range of 10 to 25 ug. per mI. The latter is more acceptable in my experience and is usually achieved with a dose of 1 to 2 mg. per kg. daily. Initial drowsiness is common but this disappears in a few days. However, I find that many patients are undoubtedly slower on long term phenobarbitone therapy and this is only noticeable in retrospect when the drug is withdrawn. In general the total daily dose of

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phenobarbitone should not exceed 90 mg., although 120 to 150 mg. may be needed in some patients. A further point to stress is that phenobarbitone may be an extremely bad drug to use in brain damaged children with epilepsy and overactive behaviour because the latter can be greatly accentuated. My tendency is to avoid the drug altogether in children with epilepsy. Primidone (Mysoline) was synthesised by Bogue and Carrington (1953) and was put to clinical trial by my predecessor Dr Richard Handley at the David Lewis Colony (Handley & Stewart, 1952). It is especially effective against grand mal and psychomotor epilepsy but may be useful in other types of seizure as well, except typical petit mal absences. It is very liable to cause sedation and treatment should always be introduced gradually, taking two to three weeks to achieve an average total daily dose of 750 mg. Other side effects include vertigo, ataxia, confusion, rashes and occasionally megaloblastic anaemia. Since primidone is partially converted to phenobarbitone there is still considerable argument that the drug is merely an expensive method of giving phenobarbitone. The estimates of the extent of conversion to phenobarbitone vary from 15 per cent (Butler & Waddell, 1956) to 25 per cent or more (Olesen & Dann, 1967) the latter authors particularly doubting that primidone has independent anti-epileptic activity. Nevertheless primidone is considered by most authorities to be a useful drug. However, it is quite illogical to use it in combination with phenobarbitone and this should be avoided. Phenytoin (diphenylhydantoin, 'Epanutin') is the most extensively studied anti-epileptic drug available and many would consider it to be the drug of choice in all forms of epilepsy except simple petit mal absences and myoclonic epilepsy. The usually accepted therapeutic serum level is 10 to 20 ug. per ml. produced by a dose of 4 to 5 mg. per kg. daily for adults and a somewhat higher dose in children. The side effects of phenytoin are extensive and will only be summarised briefly as follows: (i) Local effects: Gastric disturbance may be experienced in the first few days of treatment and can often be relieved by taking the drug with meals or a glass of milk.

(ii) Dose-related effects: (a) Neurotoxicity. The first sign of this is usually horizontal nystagmus followed later by ataxia, double vision, nausea, vomiting and drowsiness as the serum level of phenytoin rises. Nystagmus is common when the level is above 20 ug. per mI., the other symptoms usually not occurring until a level of 30 ug. per ml. is reached. The side effects are accompanied by a deterioration in seizure control in some cases (Levy & Fenichel, 1965) and I can confirm this from personal experience. I have also seen patients who exhibit behaviour and personality disturbances in the absence of other clinical signs of phenytoin intoxication, which improve on reducing the dose of phenytoin. A preliminary report on this problem has been presented by Reynolds and Travers (1974). (b) Folic Acid deficiency. This problem has been particulary studied by Reynolds (1967, 1968). Megaloblastic anaemia may occur but more prominent symptoms include impairment of mental function and personality changes. Reynolds (1967) found that treatment with folic acid improved the mental state in 22 out of 26 epileptic patients but that the control of epilepsy deteriorated in 50 per cent. I was quite unable to confirm these findings (Grant & Stores, 1970). (c) Hypocalcaemia and osteomalacia can be produced by phenytoin, phenobarbitone and primidone. (d) Gum hypertrophy is common, probably a very high percentage of patients taking phenytoin showing some degree. In some cases the swelling will be reduced on lowering the dose but it may not disappear and indeed Merritt (1958)and Kutt and McDowell (1968) state that the hypertrophy is unrelated to serum phenytoin level. (iii) Idiosyncrasy (a) Dermatitis occasionally occurs, sometimes with pyrexia and eosinophilia. (b) Hirsuitism may develop in about 5 per cent of patients. (c) Occasional cases of leucopenia, agranulocytosis, thrombocytopenia and aplastic anaemia have been reported. (d) Lymphadenopathy is a rare complication. 15

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An important factor in the clinical use of phenytoin is that in the individual patient the relationship between dose and serum level may not be linear (Bochner et al., 1972). This means that small alterations in dosage may produce either toxic or sub-therapeutic serum levels. In some patients this phenomenon is very marked and frequent alterations of dosage may be required. A tablet of 25 mg. or less would be useful in these cases. There is now considerable evidence that phenytoin may be given as a single daily dose preferably in the evening. Buchanan et al. (1973) treated 28 institutionalized children with seizure disorders, excluding petit mal absences, in a cross-over design trial each patient acting as his own control between divided daily dose and single daily dose. They found no clinically significant difference in seizure control or drug related toxicity. Strandjord and Johannessen (1974) studied 8 healthy volunteers and 11 male patients with epilepsy. In the volunteers peak values of phenytoin in the serum after a single oral dose of 500 mg. was reached in 4 to 8 hours. Similar findings were obtained in the 11 patients, who had a mean evening dose of 4.9 mg. per kg. In a further 19 adult inpatients studied over a period of 2 months there was no significant variation in serum phenytoin during 24 hour periods and absolutely no difference in the frequency, severity or type of seizure. The implications of these findings are important especially in terms of patient convenience and therefore the possibility of better seizure control. It is now my practice to prescribe phenytoin in a single daily dose for out-patients. The other hydantoinates ethotoin (Peganone) and methoin (Mesantoin) have little to offer as an alternative and I do not recommend them. Carbamazepine (Tegretol) which is chemically related to imipramine, was first shown to be of clinical value in the treatment of trigeminal neuralgia (Blom, 1962). Early reports of anti-epileptic activity came from Professor Bonbduelle and his colleagues in Paris (Bonduelle et al., 1964 a, b, c). Subsequently Bird et al. (1966) in England carried out a controlled double blind trial for 18 months in 45 mentally defective patients with

epilepsy, They reported that carbamazepine had equivalent anti-epileptic action to phenobarbitone, phenytoin and primidone and that side effects were uncommon. On the other hand Arieff and Mier (1966) claimed that although carbamazepine was shown to have anti-epileptic and psychotropic properties in over 4000 patients reported in the literature, it was a very dangerous drug and should not be used routinely to replace any of the standard drugs but only as an additional therapy. Partly as a result of the latter findings carbamazepine was used very much as a 'second line' anti-epileptic drug, usually for the treatment of psychomotor epilepsy. However, at an International Clinical Symposium (Wink, 1972) many authors claimed that carbamazepine is an effective and safe drug. I now use carbamazepine as the drug of first choice in grand mal and psychomotor epilepsy (Grant, 1972, 1975) because of its remarkable freedom from serious toxicity and excellent clinical results if the dose is raised to limits of tolerance. This usually means at least 1200 mg. daily and more. Local side effects such as anorexia, nausea and vomiting are avoided by gradual introduction of the drug, and dose related side effects such as diplopia, nystagmus, drowsiness and fatigue can usually be relieved by reduction in dose by 200 mg. daily. My overall experience with this drug is very much in accord with that of Cereghino et al. (1974) namely: (1) Carbamazepine would appear to be a major anti-epileptic drug and not merely a supplemental medication. (2) Carbamazepine does not help all patients. (3) Results would appear to be best with tonic-clonic (grand mal) and partial seizures with complex symptomatology (temporal lobe or psychomotor). (4) Absence seizures (petit mal) do not appear to be influenced by carbamazepine. (5) Initial fears about toxicity, particularly bone marrow depression, seem exaggerated in view of subsequent experience with the drug. (6) A psychotropic effect has been noted but not definitely proven. Sodium valproate (sodium dipropylacetate, 'Epilim'). This drug has only been introduced to this country very recently but has been

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available in France and other European countries since 1964. Although it is perhaps still a little early to assess its fun potential, sodium valproate seems to me to be the most interesting and useful anti-epileptic drug to appear for a very long time. Its chemical structure is completely different from alI previously known anti-epileptic compounds but although the structure was first described in 1881 its anti-epileptic activity was only demonstrated in 1963. It appears to act by increasing the level of intracerebral gammaamino butyric acid (GABA) which is a major inhibitory transmittor in the CNS. This is brought about by inhibition of the enzyme systems responsible for the degradation of GABA. The drug thus in effect stimulates inhibitory neurones, rather than directly reducing discharge in excitatory cells. Sodium va1proate can now be considered as the first drug of choice in simple absence epilepsy (petit mal) with 3 c.p.sec. spike/wave activity in the electro-encephalogram, and in myoclonic epilepsy. It is also highly effective in grand mal but conflicting results have been reported so far in temporal lobe epilepsy. Jeavons and Clarke (1974) reported a high success rate in previously intractable cases of grand mal, simple absences and myoclonic epilepsy, 43 per cent having complete cessation of seizures and 22 per cent showing a reduction of more than half. Barnes and Bower (1975) treated 24 children with a variety of the epilepsies alI of whom 'were remarkably resistant to conventional therapy'. Six of these children had their seizures reduced by more than 90 per cent and a further six by more than 50 per cent with an improvement in alertness and school performance in the majority of cases. In a double blind cross-over trial in 20 patients with severe epilepsy in a residential centre Ahmad et al. (1975) found that sodium valproate significantly reduced the frequency of grand mal and other, mainly focal, types of seizures. My own experience with this drug is quite similar to the results quoted and I now have some 100 patients who have been treated for periods ranging from 3 months to 2t years. The results will be published later this year. The best results have been seen in grand mal. All these patients have severe epilepsy

and associated problems and have previously been treated with a variety ofdrugs in different combinations and different doses. A particularly striking success was illustrated by the following case. Case report. David, aged 8 years at the time of admission to the David Lewis School in 1971, had a generalised grand mal seizure at the age of 22 months. They continued regularly but not frequently from that time onwards but they were often prolonged and severe, sometimes being followed by left sided Todd's paralysis. Hospital investigations showed dilatation of the right lateral ventricle and widespread electroencephalogram abnormalities. After his admission to the School he made very little academic progress. He had no overt seizures but electro-encephalogram revealed almost continuous atypical spike/wave activity at 3-4 c.p.sec. He was quite incapable of anything but the simplest of activities due to repeated minor epileptic status. Numerous changes of drug treatment made no significant difference. In September 1973 sodium valproate was started and slowly raised to a total daily dose of 1200 mg. The effect was quite dramatic and there was a complete change in the whole child. He became more alert with increased conversation, better concentration and generally improved performance. Coincident with this was a striking reduction in the spike/wave activity in the electro-encephalogram. He was discharged to a day E.S.N. school in April 1975 having been free of seizures for 2 years.

Sodium valproate should be introduced gradually starting with 200 mg. twice daily for about one week, followed by 400 mg. twice daily for a further week and then 400 mg. 3 times daily. Thereafter the dose may be increased slowly until the optimum effect has been achieved, and in some of my patients this has been at a total daily dose of 3 g., but this dose level requires careful monitoring. The side effects of the drug are relatively few but temporary nausea and vomiting is the most common. This can be reduced by more gradual introduction of the drug. Another interesting side effect is temporary loss of hair which has been reported by Jeavons and Clark (1974), Barnes and Bower (1975) and others. There have been three patients in my series and in all the hair loss is temporary. A further feature of sodium valproate is that the serum level of phenobarbitone may be raised producing drowsiness, and this also applies to the phenobarbitone component of primidone. In these cases the dose of phenobarbitone or primidone should be reduced. No constant interaction with phenytoin has yet been reported. The great advantage of sodium valproate is that )1

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many patients feel more alert, sometimes because it is possible to reduce the dose of other sedative anti-epileptic drugs but the increase in alertness can occur even in the absence of such reduction. Other anti-epileptic drugs As I stated in the introduction to this section it is not my intention to review all antiepileptic drugs in detail and the following have been well reported in the literature. Ethosuximide (Zarontin) was the drug of first choice in simple absences (petit mal) and is the most effective of the succinimide group. It is liable to increase the frequency of grand mal and should only be given in absences (petit mal) associated with 3 c.p.sec. spike/ wave activity in the electro-encephalogram. It has largely replaced the oxazolidinediones of which trimethadione (Tridione) was the most widely used. Sulthiame (Ospolot) was particularly recommended for temporal lobe epilepsy but it may act largely by elevating the serum level of phenytoin (Green et al., 1974)and it should be avoided with the latter. It has also been reported to improve behaviour disturbances but I have found remarkably little evidence for this except in highly selected patients (Grant, 1974). The incidence of side effects is high. Pheneturide (Benuride) has a place in the treatment of temporal lobe epilepsy but there are other more effective and less toxic drugs available. Diazepam (Valium) may be useful by reducing anxiety in those patients whose seizures are precipitated by stress. The major use of diazepam is in the treatment of status epilepticus, given by intravenous infusion and in this situation it is the first drug of choice. The recent benzodiazepine clonazepam (Rivotril) has been reported to be effective in a wide variety of epilepsies (Lund, 1973) but I have experienced considerable difficulty with over-sedation when using this drug. Surgical treatment Surgery is obviously indicated in a partial or symptomatic epilepsy due to a local lesion such as a neoplasm; in these cases seizures will often be abolished or substantially reduced. At the present time there is no

acceptable surgical procedure for the treatment of the primary generalized epilepsies. The most interesting aspect of surgical treatment is in the management of selected cases of temporal lobe epilepsy. The pioneer work in this field was carried out by Professor Wilder Penfield and his team and in 1950 a report was made on 68 patients with temporal lobe epilepsy treated by surgical removal of part of a temporal lobe (Penfield & Flanigan, 1950). Subsequently in Britain, Falconer has been a strong advocate of the operation in carefully selected patients, both adults and children (Falconer, 1970, 1972 a, b). Operation should not be undertaken without a full and adequate attempt to control seizures with drugs, together with detailed investigation of the source of seizure discharge. The latter will include repeated electroencephalogram, air encephalography, which may show an abnormal dilatation of one temporal horn, and angiography to exclude a space-occupying lesion. The operation usually consists of the excision of the anterior and medial part of the affected temporal lobe including the uncus, amygdala and hippocampus and can only be performed on one side. The commonest lesion found at operation is mesial temporal sclerosis and in these cases about 50 per cent can be completely freed of seizures. In a suitable case operation should not be delayed, even in quite young children. Much less commonly performed is the operation of hemispherectomy which is a formidable undertaking. It is suitable in only a very small proportion of children with cerebral palsy, especially hemiparesis associated with epilepsy and severe behaviour disturbances, but in properly selected cases can control seizures and improve behaviour. Biological feedback I can not resist the temptation to mention this fascinating development which is in the early stages of investigation. Most of the pioneer work on this subject has been carried out by Sterman (e.g. Sterman, 1973; Sterman et al., 1974). Briefly, it has been discovered, using sophisticated electronic filtering systems, that there is a discrete 12 to 14 c.p.sec. electroencephalogram rhythm in the sensorimotor cortex of mammals including man. By

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The Management of Epilepsy

arranging a suitable system of biological sensory feedback to the patient he can be 'trained' (in some inexplicable way) to augment this sensorimotor rhythm (SMR) which is inhibitory to seizure production. Although at present experimental this represents an entirely different approach to the conventional control of epilepsy and a research programme at the David Lewis Centre is currently being organised in association with research workers at Keele University. Social aspects The diagnosis of epilepsy is almost always associated with profound social implications. Although often concealed, there are feelings on the part of the patient of shock, revulsion and despair. In the case of a child, the parents, especially the mother, feel a great sense of guilt, and in this field the assistance of a medical social worker can be invaluable. There are certain aspects which may require particular attention: Employment. People with epilepsy are often refused employment merely on the grounds of the possibility of a seizure leading to injury. With the increasing safety precautions in industry epilepsy need not be a bar to working with machinery and it may be necessary to make a direct approach to prospective employers or seek the assistance of a Disablement Resettlement Officer. The person with epilepsy who is unemployed is far more likely to have seizures than those who are placed in satisfactory jobs. Apart from the obvious restrictions of working at great heights, or with totally unguarded machinery most people with epilepsy can be found satisfactory jobs. Marriage. Epilepsy in itself is no bar to marriage although it is not uncommon even in the mid 1970's for patients to be told categorically that they should not marry. The advisability of children is very much dependent on the cause of the epilepsy, and whether both parents suffer from the condition or not. In general terms the incidence of epilepsy in the children of a marriage where one parent suffers from the condition is 2.5 per cent, but when both parents have epilepsy the incidence quoted is between 15 and 25 per cent. One particular danger from the child's point of view is that in severe uncontrolled seizures

in the mother the baby may be liable to injury. Driving licences. For many years the restrictions on people with epilepsy were severe but the regulations were modified in 1969 and it is now possible for a person with epilepsy who has been free of seizures for 3 years, or whose seizures have exclusively occurred during sleep for 3 years, to obtain a driving licence, subject to annual review. It is no longer required that the patient should be off anti-epileptic drugs. Recreation. Perhaps the most common prohibition in this field is that of swimming, but I consider this to be completely permissible provided that the patient is accompanied by an experienced swimmer and who will be personally responsible. Horse riding in the absence of an aura could be dangerous, and rock climbing by those wishing to emulate Don Whillans should not be undertaken, The main point is that in considering recreational activities global prohibitions should be avoided. The patient's individual circumstances must be taken into accountthe type of seizure, frequency, existence of an aura, the seizure pattern etc. For example those patients who have seizures only while asleep present no problem, and women whose seizures only occur in association with menstruation can avoid potentially dangerous recreations at the appropriate time. Prejudice. Threaded through all the social problems encountered at some time or other by the majority of people with epilepsy there runs the spectre of prejudice. Bagley (1972) has shown that this prejudice still exists in 'advanced' as well as non-advanced societies. It occurs at all levels-employment, education, and even in medical care. People with epilepsy are often regarded with greater hostility than for example the mentally ill and people with cerebral palsy, and using reliable social attitude rating scales Bagley has shown that prejudice against epilepsy in this country exceeds that of race and colour. This may be because the falling sickness is truly an invisible handicap-that it conceals itself until the seizure occurs. Physical deformity, mental defect and racial colour are there all the time and one can come to terms with them. When a seizure occurs it is perhaps the personal 19

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Grant

feeling of inadequacy on the part of the onlooker which leads to resentment and prejudice. Only a hard slog of public education will overcome this almost impenetrable barrier to progress. With thousands of years of history to overcome I fear the problem will be with us for some considerable time but every physician should play his part to the full. Residential treatment The question of residential treatment of epilepsy is practically never described in papers on the management of the condition but since I am responsible for the direction of one of the few residential centres in the United Kingdom I feel it appropriate to mention the subject briefly. Historically the old epileptic colonies evolved to fill a need for places to care for people with epilepsy on a long term basis, and medical treatment was a secondary aim but this, of course, coincided with a period in history when the drug therapy of epilepsy was much less effective than it is today. The most important factor is to avoid the iatrogenic condition of institutional neurosis and this is largely achieved by attitudes within the institutions. The interested reader is referred to Dr Russel Barton's excellent treatise on this subject (Barton, 1966). I think there are three indications for residential treatment which I have reported in greater detail elsewhere. (Grant, 1972) Short term treatment. In people with severely uncontrolled seizures a period of a few months in a residential centre can be very helpful in assessment of treatment. Continuous observation by trained staff of the frequency of seizures together with regular examination, serum drug level estimations, repeated electro-encephalograms and supervised alteration of drug therapy can be most helpful. The patient may also derive benefit by coming to terms with his condition and discovering that others can be more handicapped than himself. It is not infrequently found that many of the so called seizures are of emotional rather than organic origin. Employment possibilities can also be assessed and recommendations made direct to the Department of Employment and Productivity.

Long term care. In spite of improvements in treatment there is still a very small proportion of people with epilepsy who require long term residential treatment. These are usually people with additional handicaps such as a mild degree of mental sub-normality, behaviour disorders, etc. and cannot at the present time be adequately managed in the community. They are small in number but their need is great and this need I believe will exist for quite a long time to come. Residential schooling. Although it is general policy to keep all children with epilepsy in normal schools it is likely that many have potential which is under-utilised. The child with frequent seizures, emotional problems and maladjustment, and social rejection by his peers can often obtain considerable benefit from a period of residential treatment in a school for children with epilepsy. In this situation the seizure is but a passing incident which causes the minimum of disturbance and allows the child time to come to terms with his disability. A particularly difficult period is the transition from primary to secondary education and temporary residential schooling can often prevent the development of serious emotional and social complications. Prognosis In a review article of this kind it is not possible to deal with all the aspects of epilepsy in detail but it is widely quoted in the literature that 80 per cent of all patients with epilepsy can have their seizures satisfactorily controlled by anti-epileptic drugs, although the definition of the word 'satisfactorily' is often omitted. In a thoughtful and stimulating review of the problem Rodin (1972) challenged this statement. Taking the criterion of complete cessation of seizures for a 2-year period Rodin directed attention to the fact that in 12 studies from various parts of the world published between 1901 and 1968 the 2-year remission rate for complete freedom from seizures was virtually the same at about 34 per cent. It is difficult to assess the chances of success in anyone patient. William Gordon Lennox who spent a professional lifetime devoted to the study of epilepsy in all its forms came to the following conclusion (Lennox. 1960).

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The Management of Epilepsy

'Often if all the factors are in the patient's favour, attacks may persist. On the other hand, if chances of relief seem against him, seizures may greatly diminish or even vanish. This unpredictability is a part of the interest in the puzzle of epilepsy.' Rodin in his excellent book on the prognosis of patients with epilepsy (Rodin, 1968) commented on Lennox's conclusion as follows: 'With all the experience that Lennox had accumulated in a lifelong effort to understand the nature of epilepsy, the last sentences strike one as particularly sad. They had to be written because they correspond to the facts, but they are also testimony to our abysmal ignorance of the true nature of the disorder.' Such is the fascination of the Falling Sickness. REFERENCES

Ahmad, S., Richens, A., Leighton, M. (1975). Controlled trial of sodium valproate in severe epilepsy. British Medical Journal, (in press) ArietT, A. J., Mier, M. (1966). An.ticonvulsant and psychotropic action of Tegretol, Neurology, 16, 107

Bonduelle, M., Bouygues, P., Sallou, c., Grobius, S. (I 964c). Experimentation clinique de l'anti-epileptique 0.32883 (Tegretol). Revue Neurologique (Paris), 110, 209 Bonduelle, M., Sallou, c., Guillard, J., Gaussel, M. J. (1964b). L'etat de mal psycho-moteur. Ses rapports avec les autormtismes et les psychosis aigues epileptiques. Revue Neurologiques (Paris), 110, 365 Buchanan, R. A., Turner, J. L., Moyer, C. E., HetTelfinger, J. C. (1973). Single daily dose of diphenylhydantoin in children. Paediatric Pharmacology and Therapeutics, 83, 479 Buchtal, F., Lennox-Buchtal, M. A. (1972). Phenoba.bitol. Relation of serum concentration to control of seizures. In Antiepileptic Drugs, p.p, 335343. Edited by D. M. Woodbury, J. K. Penry, and R. P. Schimdt. New York: Raven Press Butler, T. C., Waddell, W. J. (1956). Metabolic conversion of primidone (Mysoline) to phenobarbitol. Proceedings of the Society of Experimental Biology (N~w York), 93, 544 Cereghino, J. J., Brock, J. T., Van Meter, J. C., Penry, J. K., Smith, L. D., White, B. G. (1974). Carbamazepine for epilepsy. A controlled prospective evaluation. Neurology, 24, 401 Eadie, M. J., Tyrer, J. H. (1974). Anticonvulsant Therapy, p. 5. Edinburgh and London: Churchill Livingstone

Bagley, C. (1972). Social prejudice and the adjustment of people with epilepsy. Epilepsia, 13, 33

Falconer, M. (1970). Significance of surgery for temporal lobe epilepsy in childhood and adolescence. Journal of Neurosurgery, 33, 233

Barnes, S. E., Bower, B. D. (1975). Sodium valproate in the treatment of intractable childhood epilepsy. Developmental Medicine and Child Neurology, 17, 175

Falconer, M. (1972a). Temporal lobe epilepsy in children and its surgical management. The Medical Journal of Australia, 1, 1117

Barton, R. (1966). Institutional Neurosis. Bristol: John Wright and Sons Limited

Falconer, M. (1972b). Place of surgery for temporal lobe epilepsy during childhood. British Medical Journal, 2, 631

Bird, C. A. K., Griffin, B. P., Miklaszewska, J. M., Galbraith, A. W. (1966). Tegretol (carbamazepine). A controlled trial of a new anti-convulsant. British Journal of Psychiatry, 112, 737

Gastaut, H. (1969). Clinical anu EEO classification of epileptic seizures. Epilepsia, 10, Supplement 2

Blom, S. (1962). Trigeminal neuralgia; its treatment with a new anticonvulsant drug (0-32883). Lancet, 1, 839

Grant, R. H. E. (1972). Assessment and training of a young person with epilepsy at the David Lewis Centre. The Candle. London: British Epilepsy Association

Bochner, F., Hooper, W. D., Tyrer, J. H., Eadie, M. J. (1972). The effect of dosage increments on blood phenytoin concentrations. Journal of Neurology, Neurosurgery, and Psychiatry, 35, 873 Bogue, J. Y., Carrington, H. C. (1953). The evaluation of Mysoline-A new anticonvulsant drug. British Journal of Pharmacology, 8, 230 Bonduelle, M., Bouygues, P., Sallou, C., Chemaly, R. (1964a). A review of clinical trials conducted with the anti-epileptic 0-32883. Results obtained with 89 cases. III Congress of the International College of Neuropsychopharmacy, Munich, 1962. Amsterdam: Elsevier, 1964, p. 312

Grant, R. H. E. (1972). The use of carbamazepine (Tegretol) in patients with epilepsy and multiple handicaps. In Tegretol in Epilepsy, edited by C. A. S. Wink, p. 16-24. Manchester: C. Nicholls and Company Limited Grant, R. H. E. (1974). Sulthiame and behaviour. Developmental Medicine and Child Neurology, 16, 821 Grant, R. H. E. (1975). Carbamazepine in the treatment of severe epilepsy. In Epileptic SeizuresBehaviour-Pain. An International Symposium, St. Moritz. In press

21 Downloaded from scm.sagepub.com at SAGE Publications on June 21, 2016

Grant Grant, R. H. E., Stores, O. P. R. (1970). Folic acid in folate deficient patients with epilepsy. British Medical Journal, 4, 644

Ounsted, C., Lindsay, J., Norman, R. (1966). Biological Factors in Temporal Lobe Epilepsy. London: W. Heinemann Medical Books

Green, J. R., Troupin, A. S., Halpern, L. M., Friel, P., Kanarek, P. (1974). Sulthiame: evaluation as an anticonvulsant. Epilepsia, IS, 329

Penfield, W., Flanigin, H. (1950). Surgical therapy of temporal lobe seizures. Archives of Neurology and Psychiatry, 64, 491

Guainerius Antonius. Opera Medica, Pavia, Carchavo 1488, quoted in Antonius Guainerius on Epilepsy by William G. Lennox. Annals of Medical History (1940) Third Series, 2, 482

Reynolds, E. H. (1967). Effects of folic acid on the mental state and fit frequency of drug treated epileptic patients. Lancet, 1, 1086

Handley, R., Stewart, A. S. R. (1952). Mysoline: A new drug in the treatment of epilepsy. Lancet, 1, 742 Jeavons, P. M. (1972). Clinics for the treatment of epilepsy and convulsions. Lancet, 1, 904 (April 23rd) Jeavons, P. M., Clarke, J. E. (1974). Sodium valproate in treatment of epilepsy. British Medical Journal, 2, 584 Jeavons, P. M., Harding, G. F. A. (1970). Television epilepsy. Lancet, 2, 926 Jeavons, P. M., Harding, G., Bower, B. D. (1966). Intermittent photic stimulation in photosensitive epilepsy. Electroencephalography and Clinical Neurophysiology, 21, 308 Kutt, H., McDowell, F. (1968). Management of epilepsy with diphenylhydantoin sodium. Journal 0/ American Medical Association, 203, 969 Lennox, W. G. (1960). Epilepsy and related disorders, Volume 2, p. 1009. Boston: Little, Brown and Company Levy, L. L. Fenichel, G. M. (1965). Diphenylhydantoin activated seizures. Neurology (Minneapolis), IS, 716 Lund, M. (1973). Symposium on the Therapeutic Use of the Anticonvulsant R05-4023 (Clonazepam) in Different Forms of Epilepsy. Acta Neurologica Scandinavica, 49, Supplement 53 Merritt, H. H. (1958). Medical treatment in epilepsy. British Medical Journal, 1, 666 Olesen, O. V., Dam, M. (1967). The metabolic conversion of primidone (Mysoline) to phenobarbitone in patients under long-term treatment. Acta Neurologica Scandinavica, 43, 348

Reynolds, E. H. (1968). Mental effects of anticonvulsants and folic acid metabolism. Brain, 91, 197 Reynolds, E. H., Travers, R. D. (1974). Serum anticonvulsant concentrations in epileptic patients with mental symptoms. British Journal 0/ Psychiatry 124,440 Rodin, E. A. (1968). Prognosis of patients with epilepsy, p. 28. Springfield, Illinois: Charles C. Thomas Rodin, E. A. (1972). Medical and social prognosis in epilepsy. Epilepsia, 13, 121 Sterman, M. B. (1973). Neurophysiologic and clinical studies of sensorimotor EEG biofeedback training: some effects on epilepsy. In Biofeedback: Behavioural Medicine, edited by L. Birk, p. 147-165. Boston: Grune and Stratton Sterman, M. B., Macdonald, L. R., Stone, R. K. (1974). Biofeedback training of the sensorimotor electroencephalogram rhythm in man: effects on epilepsy Epilepsia, IS, 395 Strandjord, R. E., Johannessen, S. I. (1974). One daily dose of diphenylhydantoin for patients with epilepsy. Epilepsia, IS, 317 Temkin, Owsei (1971). The Falling Sickness. A History of Epilepsy from the Greeks to the Beginnings of Modern Neurology. Second Edition 1971. Baltimore and London: Johns Hopkins Press Van Meter, J. C., Buckmaster, H. S., Shelley, L. L. (1970). Concurrent assay of phenobarbital and diphenylhydantoin in plasma by vapour-phase chromatography. Clinical Chemistry, 16, 135 Win::, C. A. S. (1972). Tegretol in Epilepsy: Report of an International Clinical Symposium. Manchester: C. Nicholls and Company Limited

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