Seizure
1992;
1: 57-59
CLINICAL CONTROVERSY: CONVERSATION WITH CLINICIANS*
What to do when the first anticonvulsant work It is an accepted fact that the majority of people who start to have epilepsy will nowadays respond swiftly and successfully to a single anticonvulsant drug and have no more seizures. Currently, sodium valproate for primary generalized epilepsy and carbamazepine for partial seizures, or partial seizures which become secondarily generalized, are the drugs of first choice. Most of my colleagues will probably agree with the above, although some might choose phenytoin instead of carbamazepine: indeed, some might choose sodium valproate for all new patients whatever type of seizure they have and only use a second agent if the sodium valproate is ineffective. There is no evidence to suggest that sodium valproate is any less effective than carbamazepine or phenytoin for partial seizures: carbamazepine is certainly contra-indicated in some forms of primary generalized epilepsy. It may make absences worse, for instance. All three drugs have unwanted side effects and often the choice of drug is dictated by the kind of patient for whom the drug is being prescribed and the particular risk that the unwanted side effect may pose for them. Sadly, no drug nowadays looks as though it is without risk for women who are pregnant, so choosing a first line drug for a woman of child bearing age has become difficult. I presume, however, most of us would, because of the known spina bifida risk, avoid valproate in a woman who was likely to want to become pregnant at some time in the near future, unless it was the only drug likely to help her become seizure free. There would, therefore, be little disagreement about the choice of the first drug to try in a new patient. But what happens if the patient has taken the drug to the limits of This section of the journal will contain a personal account of a particular clinician’s practice related to some controversial area of epilepsy management. The clinician can remain anonymous if he/she wishes to. We hope that this section will develop a lively correspondence column.
l
1059-1311/92/010057+03
$03.00/O
does not
tolerance (or the top end of the normal dose range for that particular drug) and the seizures, after an appropriate time of observation, have not resolved. What should be done next? Here there is likely to be a difference of opinion. The first thing that I would do is to check that I have got the diagnosis right. Has the patient actually got epilepsy and if it is epilepsy have I made the right decision about what kind of seizure the patient has? This may involve re-investigation and retaking the history. I would also check compliance, look for evidence of reflex epilepsy and look to see if the patient’s seizures were particularly stress-related. If I have made a mistake in my classification then I would obviously start the correct drug for the patient’s seizures (either sodium valproate or carbamazepine) whilst slowly withdrawing the original one. I normally increase the new drug to the full dosage before withdrawing the first drug slowly. The problem with this method is that sometimes after the second drug is added the patient’s seizures stop, and the patient is then reluctant to withdraw the first drug because of anxiety about seizures re-starting. Most of us would probably try to withdraw the first drug but pressure from the patient or relatives often prevents us from following a completely rational plan with medication. If the second drug is as ineffective as the first then it should be withdrawn before anything else is tried. If the original diagnosis was right and the classification of the seizures is right and the drug of first choice for the patient’s particular kind of seizures has not worked, what do I do then? If the patient has primary generalized epilepsy, the choice of a second drug lies between clonazepam, ethosuximide or the new agent, lamotrigine. Patients with primary generalized epilepsy who do not respond to sodium valproate are not common, but do occur and can be a problem. Ethosuximide is @ 1992
Bailliere
Tindall
58
only effective for absences and does not mix well with sodium valproate. Clonazepam may be effective but often at the price of excessive fatigue and drowsiness for the patient. I would add lamotrigine to sodium valproate in a small dose and build up very slowly to the limits of tolerance (loo-200mg), and then withdraw the valproate very slowly. Although valproate increases the half-life of lamotrigine and elevates its serum levels, the two drugs seem to work well together. If this combination failed to work I would then withdraw the lamotrigine and try clonazepam. Many patients with primary generalized epilepsy who do not respond to sodium valproate have atypical absences which do respond well to lamotrigine and complicated multifocal generalized epilepsy, such as the Lennox-Gastaut syndrome, also responds well to it. If the patient had simple partial or complex partial seizures without secondary generalization and they failed to respond to carbamazepine, I would immediately initiate investigation of the possibility of surgical treatment. The reason for this is that this will take many months: surgery would be at least a year away, and in that year full experimentation with drug treatment could be tried. I would not want the patient hanging around for surgery too long, becoming increasingly demoralized, when it has become patently clear that medication is not going to help. In the mean time I would add vigabatrin to the carbamazepine. I would do this in preference to either phenytoin or sodium valproate because I think vigabatrin is more likely to be effective against partial seizures without secondary generalization than either of the other two drugs. I would add it extremely slowly, starting with 500mg at night for at least a fortnight and then 500mg twice daily for at least a month followed by a cautious increase to no more than 3 g a day over the next 3 months. In my experience quite small doses of vigabatrin work as well as large doses: introduced slowly in this way the common problem of drowsiness and the rare problem of psychosis are minimized. If it did work then after a while I would slowly withdraw the carbamazepine, and leave the patient on vigabatrin monotherapy. If there was a clear history of previous psychosis in the patient I would use phenytoin as my second drug. If there was some improvement with viga-
Clinical controversy
batrin, but not complete seizure control, I would slowly withdraw the carbamazepine then add phenytoin. Phenytoin seems to work well with vigabatrin, in my experience. If that was ineffective I would withdraw either the phenytoin or the vigabatrin and try lamotrigine. By that time I would know whether the patient was likely to be a suitable candidate for surgery or not. In all patients, but particularly in those with simple partial or complex partial seizures with an ‘awake’ aura I would be assessing for behavioural treatment. If the patient had partial seizures (either simple or complex) with secondary generalization, then I would add valproate to the carbamazepine and assess the effect of that combination before deciding whether to withdraw carbamazepine or leave the patient on the two drugs. Some patients with partial and secondary generalized seizures do seem to need a combination of the two. If that failed to work, I would slowly withdraw the valproate and try vigabatrin: if that failed I would try lamotrigine and, lastly, phenytoin and clonazepam (I don’t like the combination of carbamazepine and phenytoin). By this time the patient will have been assessed for surgery and behavioural treatment. If the patient with partial seizures with or without secondary generalization had clusters of attacks, I would consider using intermittent clobazam (particularly if they were pre-menstrual). Some intractable pre-menstrual seizures respond well to an oral contraceptive such as intermittent progesterone or danazol. This is how I would personally manage the kind of patients I have described. I am sufficiently impressed with the benefits of vigabatrin and lamotrigine, to feel that we should not wait until three or four other drugs have been given before trying these new agents. Both can be very effective in some patients and I suspect that they will be even more effective when used as second choice drugs in patients who are only taking one anticonvulsant. Their use in this way will give us an idea of whether or not they will ever become drugs of first choice. I suspect both will do so. At the moment 70% of people who start to have epileptic seizures will respond swiftly to the first drug they are given and it probably does not matter what it is. Between 54% will respond to a second drug and about 3-5% to a third, leaving 20% who do not respond. If vigabatrin or lamotrigine are tried in this resistent 20%, then 20% of them are likely to
What to do when the first anticonvulsant
does not work
59
become seizure free, and perhaps 50% achieve a useful reduction in seizure frequency. This suggests to me that it might be worth trying these drugs sooner than we do since they may
be more effective second choices than the ones we currently use. What do my colleagues think?
The Correspondence Columns are open for comment on this anonymous contribution versy section. The Editor
to our clinical contro-
1992;
1: 57-59
CLINICAL CONTROVERSY: CONVERSATION WITH CLINICIANS*
What to do when the first anticonvulsant work It is an accepted fact that the majority of people who start to have epilepsy will nowadays respond swiftly and successfully to a single anticonvulsant drug and have no more seizures. Currently, sodium valproate for primary generalized epilepsy and carbamazepine for partial seizures, or partial seizures which become secondarily generalized, are the drugs of first choice. Most of my colleagues will probably agree with the above, although some might choose phenytoin instead of carbamazepine: indeed, some might choose sodium valproate for all new patients whatever type of seizure they have and only use a second agent if the sodium valproate is ineffective. There is no evidence to suggest that sodium valproate is any less effective than carbamazepine or phenytoin for partial seizures: carbamazepine is certainly contra-indicated in some forms of primary generalized epilepsy. It may make absences worse, for instance. All three drugs have unwanted side effects and often the choice of drug is dictated by the kind of patient for whom the drug is being prescribed and the particular risk that the unwanted side effect may pose for them. Sadly, no drug nowadays looks as though it is without risk for women who are pregnant, so choosing a first line drug for a woman of child bearing age has become difficult. I presume, however, most of us would, because of the known spina bifida risk, avoid valproate in a woman who was likely to want to become pregnant at some time in the near future, unless it was the only drug likely to help her become seizure free. There would, therefore, be little disagreement about the choice of the first drug to try in a new patient. But what happens if the patient has taken the drug to the limits of This section of the journal will contain a personal account of a particular clinician’s practice related to some controversial area of epilepsy management. The clinician can remain anonymous if he/she wishes to. We hope that this section will develop a lively correspondence column.
l
1059-1311/92/010057+03
$03.00/O
does not
tolerance (or the top end of the normal dose range for that particular drug) and the seizures, after an appropriate time of observation, have not resolved. What should be done next? Here there is likely to be a difference of opinion. The first thing that I would do is to check that I have got the diagnosis right. Has the patient actually got epilepsy and if it is epilepsy have I made the right decision about what kind of seizure the patient has? This may involve re-investigation and retaking the history. I would also check compliance, look for evidence of reflex epilepsy and look to see if the patient’s seizures were particularly stress-related. If I have made a mistake in my classification then I would obviously start the correct drug for the patient’s seizures (either sodium valproate or carbamazepine) whilst slowly withdrawing the original one. I normally increase the new drug to the full dosage before withdrawing the first drug slowly. The problem with this method is that sometimes after the second drug is added the patient’s seizures stop, and the patient is then reluctant to withdraw the first drug because of anxiety about seizures re-starting. Most of us would probably try to withdraw the first drug but pressure from the patient or relatives often prevents us from following a completely rational plan with medication. If the second drug is as ineffective as the first then it should be withdrawn before anything else is tried. If the original diagnosis was right and the classification of the seizures is right and the drug of first choice for the patient’s particular kind of seizures has not worked, what do I do then? If the patient has primary generalized epilepsy, the choice of a second drug lies between clonazepam, ethosuximide or the new agent, lamotrigine. Patients with primary generalized epilepsy who do not respond to sodium valproate are not common, but do occur and can be a problem. Ethosuximide is @ 1992
Bailliere
Tindall
58
only effective for absences and does not mix well with sodium valproate. Clonazepam may be effective but often at the price of excessive fatigue and drowsiness for the patient. I would add lamotrigine to sodium valproate in a small dose and build up very slowly to the limits of tolerance (loo-200mg), and then withdraw the valproate very slowly. Although valproate increases the half-life of lamotrigine and elevates its serum levels, the two drugs seem to work well together. If this combination failed to work I would then withdraw the lamotrigine and try clonazepam. Many patients with primary generalized epilepsy who do not respond to sodium valproate have atypical absences which do respond well to lamotrigine and complicated multifocal generalized epilepsy, such as the Lennox-Gastaut syndrome, also responds well to it. If the patient had simple partial or complex partial seizures without secondary generalization and they failed to respond to carbamazepine, I would immediately initiate investigation of the possibility of surgical treatment. The reason for this is that this will take many months: surgery would be at least a year away, and in that year full experimentation with drug treatment could be tried. I would not want the patient hanging around for surgery too long, becoming increasingly demoralized, when it has become patently clear that medication is not going to help. In the mean time I would add vigabatrin to the carbamazepine. I would do this in preference to either phenytoin or sodium valproate because I think vigabatrin is more likely to be effective against partial seizures without secondary generalization than either of the other two drugs. I would add it extremely slowly, starting with 500mg at night for at least a fortnight and then 500mg twice daily for at least a month followed by a cautious increase to no more than 3 g a day over the next 3 months. In my experience quite small doses of vigabatrin work as well as large doses: introduced slowly in this way the common problem of drowsiness and the rare problem of psychosis are minimized. If it did work then after a while I would slowly withdraw the carbamazepine, and leave the patient on vigabatrin monotherapy. If there was a clear history of previous psychosis in the patient I would use phenytoin as my second drug. If there was some improvement with viga-
Clinical controversy
batrin, but not complete seizure control, I would slowly withdraw the carbamazepine then add phenytoin. Phenytoin seems to work well with vigabatrin, in my experience. If that was ineffective I would withdraw either the phenytoin or the vigabatrin and try lamotrigine. By that time I would know whether the patient was likely to be a suitable candidate for surgery or not. In all patients, but particularly in those with simple partial or complex partial seizures with an ‘awake’ aura I would be assessing for behavioural treatment. If the patient had partial seizures (either simple or complex) with secondary generalization, then I would add valproate to the carbamazepine and assess the effect of that combination before deciding whether to withdraw carbamazepine or leave the patient on the two drugs. Some patients with partial and secondary generalized seizures do seem to need a combination of the two. If that failed to work, I would slowly withdraw the valproate and try vigabatrin: if that failed I would try lamotrigine and, lastly, phenytoin and clonazepam (I don’t like the combination of carbamazepine and phenytoin). By this time the patient will have been assessed for surgery and behavioural treatment. If the patient with partial seizures with or without secondary generalization had clusters of attacks, I would consider using intermittent clobazam (particularly if they were pre-menstrual). Some intractable pre-menstrual seizures respond well to an oral contraceptive such as intermittent progesterone or danazol. This is how I would personally manage the kind of patients I have described. I am sufficiently impressed with the benefits of vigabatrin and lamotrigine, to feel that we should not wait until three or four other drugs have been given before trying these new agents. Both can be very effective in some patients and I suspect that they will be even more effective when used as second choice drugs in patients who are only taking one anticonvulsant. Their use in this way will give us an idea of whether or not they will ever become drugs of first choice. I suspect both will do so. At the moment 70% of people who start to have epileptic seizures will respond swiftly to the first drug they are given and it probably does not matter what it is. Between 54% will respond to a second drug and about 3-5% to a third, leaving 20% who do not respond. If vigabatrin or lamotrigine are tried in this resistent 20%, then 20% of them are likely to
What to do when the first anticonvulsant
does not work
59
become seizure free, and perhaps 50% achieve a useful reduction in seizure frequency. This suggests to me that it might be worth trying these drugs sooner than we do since they may
be more effective second choices than the ones we currently use. What do my colleagues think?
The Correspondence Columns are open for comment on this anonymous contribution versy section. The Editor
to our clinical contro-
