S61 Clinicat Neurology and Neuroswgety, 94 (Suppl.) (1992) S61S63
0 1992 Elsevier Science Publishers B.V. All rights reserved 0303~8467/92/$05.00 CNN 00110
First seizure in adults: to treat or not to treat Benjamin Chandra
Key words: Epilepsy; Valproate; First fit Summary A double-blind trial was done in 22.8patients with one single seizure 2 weeks before coming to the author. One group was given sodium valproatc, the other group placebo. The duration of therapy was 12 months. The results of this trial show that a person with a single seizure has epilepsy and should be treated with sodium valproate. Introduction Indonesia, a country of 180 million people is stretched out over an area roughly the size of Europe (the distance between Sabang in the West and Merauke in the East of Indonesia is similar to the distance between London and Ankara). However, while Europe is a continent, Indonesia consists of islands, a fact which makes communication much more difficult. In this big country the government has organized that a district with 10 ~0 people has one general practitioner with a small district hospital (D hospital). Every city with 100 000 inhabitants has a regional hospital (C hospital) with a hundred beds, where an internist, pediatrician, gynecologist and surgeon are working. There are 11 state medical schools, which have a B hospital, comprising a neurological department and a CT scanner. In Jakarta and Surabaya the top A hospitals are situated, in which modern equipment, such as CT and MRI scanners, aids the neurologist. As a neurologist I realized that one of our main problems was epilepsy. With a prevalence of 2-5% (according to the WHO) this means that there are between 3.6 and 9 million people in Indonesia who have experienced at least one non-febrile seizure. According to other epileptologists this figure is rather conservative: they mentioned a total prevalence of 59% [l-4]. In 1984 after having given a lecture in Graz, Austria, on epilepsy in developing countries, I went into this problem more deeply: 1. Did people with one seizure reafly have epilepsy ? -__..-Co~e~~o~dc~cero~ Prof. Benjamin Chandra, MD, PhD, Dr. Sutomo
HospitaI, Airlangga University, Surabaya, Indonesia.
Until now many experts believed that to make the diagnosis of epilepsy one has to have more than one seizure (non-febrile) [4,5]. 2. Should people with single seizures be treated with anticonvulsant drugs? Until then the policy in our department at Airlangga University was that only patients who had had more than one convulsion (non-febrile) were treated with anticonvulsants. 3. What was the risk of recurrence in untreated patients. 4. After searching the literature, I found no report of treatment of a single seizure, probably because it was not considered to be epilepsy. 5. If these people with single seizures were treated, what wcrc the results and how long should they be given anticonvulsants. This question is very important in Indonesia as many patients have only a small income and paying for anticonvulsants can be a heavy burden. While I was in San Francisco in 1962-1963, I heard about the work of Professor Morel1 concerning secondary epileptogcncsis in rats. Giving anticon~lsants in an early stage probably wouId prevent the development of secondary foci. What anticonvulsants should be given to patients with a single seizure? According to Goldensohn, kindling was rctardcd by sodium valproate, phenobarbital and benzodiazepine. We chose valproate because it does not induce somnolcncc and because it is effective against gencralizcd scizurcs [6]. Methods All patients who came to the author either in the department of neurology of Airlangga University teaching
S62
hospital or to one of the private hospitals whcrc the author is a consultant, who had one seizure (first scizurc) and were adult (over the age of 16 years) wcrc asked by the author to participate in this study. If the patient had the first seizure as a result of a neurological disease like meningitis or intracranial tumor he was excluded. All patients underwent the usual general and neurological examinations. In each patient a routine blood examination was done, which included electrolyte estimation (calcium, potassium and sodium), liver and kidney function tests and glucose. In every patient an EEG was made. If the patient was over 40 years, had a partial seizure or focal neurological sigs, a CT scan was made. Only patients who had a seizure within 2 weeks before coming to the author were included. The author also asked colleagues in the eastern part of Indonesia to refer patients if they met the above mentioned criteria. From July 1, 1984 until July 1, 1990, 234 patients were admitted. They were asked to come to the author for a follow-up examination every 3 months if no seizure occurred, or earlier if there was a recurrence. Six patients declined or did not return for follow-up. A double-blind valproate versus placebo trial was performed. One group of patients received 4 times a day 1200 mg sodium valproate, the other group received placebo in identical capsules. If a patient had a second seizure the code was broken and the patient received sodium valproate if he was on placebo. During the trial, sodium valproate was given for 12 months after which the code was broken, and in patients receiving sodium valproate the dose was tapered. The follow-up period was at least 9 months, but many of the patients were followed for 5 years.
‘I‘AI3I.li
I
SEX DISI’I~IBUTION IN 228 PATIENI‘S WIT1 I FIRST SEIZURI! Group
Male
Female
Sodium valproate Placebo
59 56
56 57
TABLE2 DISllUBUTIONOF AGES IN 228PATIENIX Age in years
Valproate
Placebo
16-19 20-29 30-39 40-49 So-59 60-69 70-79 Total
17 43 13 12 13 11 6 115
16 44 14 10 12 12 5 113
Valproate
Placebo
TABLE 3 TYPE OF INITIALSEIZURE TVpe Tonic-clonic no evidence of partial onset clinical evidence of partial onset Partial complex simple Total
8.5
87
14
15
9 5 113
9 4 115
Results After breaking the code 115 patients appeared to have received sodium valproate and 113 placebo. Distribution of sex and age is shown in Tables 1 and 2. The age group between 70 and 79 is scarcely represented. This may be due to the fact that the average age in Indonesia is lower than in Europe or the U.S.A. The type of the initial seizure is given in Table 3. What were the results of giving sodium valproate to patients with an initial seizure within 2 weeks before consulting a doctor. 9 The results and the side-effects are given in Tables 4 and 5.
TABLE
Discussion
Side-effect
Valproate
The two groups were similar. The results in Table 4 clearly show that administration of sodium valproate dur-
Gastro-intestinal Weight gain Loss of hair
5 (4.3%)
4
RESULTS
OF TIIERAPY
Group
RCCUrrCllCC
Sodium valproate Placebo __-
5 ( 4.3%) 63 (55.7%)
TABLE
_
-
5
SIDE EFFECTS
IN BOTH TREATMENI.
3 (2.6%) 2 (1.7%)
GROUPS Placebo 1 (0.9%) 1 (0.9%) ~___._
S63 ing 12 months within 2 weeks after the initial seizure prevents recurrence in most of the patients. How can we explain these results? 1. Morrell’s theory [7]. Morrell, who has been working on secondary epileptogenesis since a long time, divides the process into 3 stages: (i) In the first stage, the primary lesion drives the distant epileptic abnormalities. If we remove the primary focus the distant epileptic abnormalities will disappear immediately. This stage is therefore called the dependent stage. (ii) In the second stage, if the primary focus is removed, the secondary discharges will occur for a period of time but will gradually disappear. This stage is therefore called the intermediate stage. (iii) In the third or independent stage, removal of the primary focus will have no effect on the secondary focus. Morrell showed that the whole process can be aborted by giving phenobarbital. 2. Goldensohn’s theory of kindling. The repeated stimulation of animals with subthreshold irritative electrical stimuli will produce EEG responses and seizures. If this application of subthreshold irritative stimuli is continued, eventually spontaneous seizures will occur. This process of kindling can also be retarded by phenobarbital, benzodiazepine and valproate. 3. In human beings, we sometimes see that focal cercbra1 tumors may slowly stimulate the occurrence of mirror foci and eventually independent epileptic seizures [7].
The three theories mentioned above probably may explain why the use of sodium valproate in the first 2 weeks after an initial seizure may prevent further seizures [911]. This trial confirms the findings of others, such as Shorvon and Hopkins: a person with one single seizure has epilepsy and should be treated [4,9,12-B]. Side effects of sodium valproate therapy were minimal (Table 5). References 1 Shorvon SD. Lancet 1990; 336: 93-96. 2 Hauser WA et al. In Ward AA, Penry JK, Purpura DP (eds.), Epilepsy; New York: Raven Press, 1983. 3 Goodridge DMG et al. Br Med J 1983; 287: 641-644. 4 Ilopkins A et al. Iancet 1988; 1: 721-726. 5 IIart YM et al. Lancet 1990; 336: 1271-1274. 6 Scheuer ML, Pedley TA. N Engl J Med 1990; 323: 1468-1474. 7 Morrell P. Arch Neural 198.5; 42: 318-334. 8 Goldensohn ES. In Porter RJ, Morsel1 PL (eds.), The Epilepsies; London: Butterworth, 1985. 9 Shorvon SD. In Warlow C, Garfield J (eds.), More Dilemmas in the Management of the Neurological Patient; Edinburgh: Churchill Livingstone, 1987: 8-13. 10 Reynolds EII, Elwes RDC, Shorvon SD. Lancet 1985; 2: 952-954. 11 Reynolds EH, Ekes RDC. Lancet 1991; 324: 1214-1215. 12 Hopkins A, Garman A, Clarke C. Iancet 1988; 1: 721-726. 13 IIart YM, Sander JWAS, Johnson AL, Showon SD. Lancet 1990; 336: 1271-1274. 14 Reynolds EII. Br Med J 1990; 301: 1112-1114. 15 Reynolds CII. Br Med J 1988; 297: 1422-1423.
0 1992 Elsevier Science Publishers B.V. All rights reserved 0303~8467/92/$05.00 CNN 00110
First seizure in adults: to treat or not to treat Benjamin Chandra
Key words: Epilepsy; Valproate; First fit Summary A double-blind trial was done in 22.8patients with one single seizure 2 weeks before coming to the author. One group was given sodium valproatc, the other group placebo. The duration of therapy was 12 months. The results of this trial show that a person with a single seizure has epilepsy and should be treated with sodium valproate. Introduction Indonesia, a country of 180 million people is stretched out over an area roughly the size of Europe (the distance between Sabang in the West and Merauke in the East of Indonesia is similar to the distance between London and Ankara). However, while Europe is a continent, Indonesia consists of islands, a fact which makes communication much more difficult. In this big country the government has organized that a district with 10 ~0 people has one general practitioner with a small district hospital (D hospital). Every city with 100 000 inhabitants has a regional hospital (C hospital) with a hundred beds, where an internist, pediatrician, gynecologist and surgeon are working. There are 11 state medical schools, which have a B hospital, comprising a neurological department and a CT scanner. In Jakarta and Surabaya the top A hospitals are situated, in which modern equipment, such as CT and MRI scanners, aids the neurologist. As a neurologist I realized that one of our main problems was epilepsy. With a prevalence of 2-5% (according to the WHO) this means that there are between 3.6 and 9 million people in Indonesia who have experienced at least one non-febrile seizure. According to other epileptologists this figure is rather conservative: they mentioned a total prevalence of 59% [l-4]. In 1984 after having given a lecture in Graz, Austria, on epilepsy in developing countries, I went into this problem more deeply: 1. Did people with one seizure reafly have epilepsy ? -__..-Co~e~~o~dc~cero~ Prof. Benjamin Chandra, MD, PhD, Dr. Sutomo
HospitaI, Airlangga University, Surabaya, Indonesia.
Until now many experts believed that to make the diagnosis of epilepsy one has to have more than one seizure (non-febrile) [4,5]. 2. Should people with single seizures be treated with anticonvulsant drugs? Until then the policy in our department at Airlangga University was that only patients who had had more than one convulsion (non-febrile) were treated with anticonvulsants. 3. What was the risk of recurrence in untreated patients. 4. After searching the literature, I found no report of treatment of a single seizure, probably because it was not considered to be epilepsy. 5. If these people with single seizures were treated, what wcrc the results and how long should they be given anticonvulsants. This question is very important in Indonesia as many patients have only a small income and paying for anticonvulsants can be a heavy burden. While I was in San Francisco in 1962-1963, I heard about the work of Professor Morel1 concerning secondary epileptogcncsis in rats. Giving anticon~lsants in an early stage probably wouId prevent the development of secondary foci. What anticonvulsants should be given to patients with a single seizure? According to Goldensohn, kindling was rctardcd by sodium valproate, phenobarbital and benzodiazepine. We chose valproate because it does not induce somnolcncc and because it is effective against gencralizcd scizurcs [6]. Methods All patients who came to the author either in the department of neurology of Airlangga University teaching
S62
hospital or to one of the private hospitals whcrc the author is a consultant, who had one seizure (first scizurc) and were adult (over the age of 16 years) wcrc asked by the author to participate in this study. If the patient had the first seizure as a result of a neurological disease like meningitis or intracranial tumor he was excluded. All patients underwent the usual general and neurological examinations. In each patient a routine blood examination was done, which included electrolyte estimation (calcium, potassium and sodium), liver and kidney function tests and glucose. In every patient an EEG was made. If the patient was over 40 years, had a partial seizure or focal neurological sigs, a CT scan was made. Only patients who had a seizure within 2 weeks before coming to the author were included. The author also asked colleagues in the eastern part of Indonesia to refer patients if they met the above mentioned criteria. From July 1, 1984 until July 1, 1990, 234 patients were admitted. They were asked to come to the author for a follow-up examination every 3 months if no seizure occurred, or earlier if there was a recurrence. Six patients declined or did not return for follow-up. A double-blind valproate versus placebo trial was performed. One group of patients received 4 times a day 1200 mg sodium valproate, the other group received placebo in identical capsules. If a patient had a second seizure the code was broken and the patient received sodium valproate if he was on placebo. During the trial, sodium valproate was given for 12 months after which the code was broken, and in patients receiving sodium valproate the dose was tapered. The follow-up period was at least 9 months, but many of the patients were followed for 5 years.
‘I‘AI3I.li
I
SEX DISI’I~IBUTION IN 228 PATIENI‘S WIT1 I FIRST SEIZURI! Group
Male
Female
Sodium valproate Placebo
59 56
56 57
TABLE2 DISllUBUTIONOF AGES IN 228PATIENIX Age in years
Valproate
Placebo
16-19 20-29 30-39 40-49 So-59 60-69 70-79 Total
17 43 13 12 13 11 6 115
16 44 14 10 12 12 5 113
Valproate
Placebo
TABLE 3 TYPE OF INITIALSEIZURE TVpe Tonic-clonic no evidence of partial onset clinical evidence of partial onset Partial complex simple Total
8.5
87
14
15
9 5 113
9 4 115
Results After breaking the code 115 patients appeared to have received sodium valproate and 113 placebo. Distribution of sex and age is shown in Tables 1 and 2. The age group between 70 and 79 is scarcely represented. This may be due to the fact that the average age in Indonesia is lower than in Europe or the U.S.A. The type of the initial seizure is given in Table 3. What were the results of giving sodium valproate to patients with an initial seizure within 2 weeks before consulting a doctor. 9 The results and the side-effects are given in Tables 4 and 5.
TABLE
Discussion
Side-effect
Valproate
The two groups were similar. The results in Table 4 clearly show that administration of sodium valproate dur-
Gastro-intestinal Weight gain Loss of hair
5 (4.3%)
4
RESULTS
OF TIIERAPY
Group
RCCUrrCllCC
Sodium valproate Placebo __-
5 ( 4.3%) 63 (55.7%)
TABLE
_
-
5
SIDE EFFECTS
IN BOTH TREATMENI.
3 (2.6%) 2 (1.7%)
GROUPS Placebo 1 (0.9%) 1 (0.9%) ~___._
S63 ing 12 months within 2 weeks after the initial seizure prevents recurrence in most of the patients. How can we explain these results? 1. Morrell’s theory [7]. Morrell, who has been working on secondary epileptogenesis since a long time, divides the process into 3 stages: (i) In the first stage, the primary lesion drives the distant epileptic abnormalities. If we remove the primary focus the distant epileptic abnormalities will disappear immediately. This stage is therefore called the dependent stage. (ii) In the second stage, if the primary focus is removed, the secondary discharges will occur for a period of time but will gradually disappear. This stage is therefore called the intermediate stage. (iii) In the third or independent stage, removal of the primary focus will have no effect on the secondary focus. Morrell showed that the whole process can be aborted by giving phenobarbital. 2. Goldensohn’s theory of kindling. The repeated stimulation of animals with subthreshold irritative electrical stimuli will produce EEG responses and seizures. If this application of subthreshold irritative stimuli is continued, eventually spontaneous seizures will occur. This process of kindling can also be retarded by phenobarbital, benzodiazepine and valproate. 3. In human beings, we sometimes see that focal cercbra1 tumors may slowly stimulate the occurrence of mirror foci and eventually independent epileptic seizures [7].
The three theories mentioned above probably may explain why the use of sodium valproate in the first 2 weeks after an initial seizure may prevent further seizures [911]. This trial confirms the findings of others, such as Shorvon and Hopkins: a person with one single seizure has epilepsy and should be treated [4,9,12-B]. Side effects of sodium valproate therapy were minimal (Table 5). References 1 Shorvon SD. Lancet 1990; 336: 93-96. 2 Hauser WA et al. In Ward AA, Penry JK, Purpura DP (eds.), Epilepsy; New York: Raven Press, 1983. 3 Goodridge DMG et al. Br Med J 1983; 287: 641-644. 4 Ilopkins A et al. Iancet 1988; 1: 721-726. 5 IIart YM et al. Lancet 1990; 336: 1271-1274. 6 Scheuer ML, Pedley TA. N Engl J Med 1990; 323: 1468-1474. 7 Morrell P. Arch Neural 198.5; 42: 318-334. 8 Goldensohn ES. In Porter RJ, Morsel1 PL (eds.), The Epilepsies; London: Butterworth, 1985. 9 Shorvon SD. In Warlow C, Garfield J (eds.), More Dilemmas in the Management of the Neurological Patient; Edinburgh: Churchill Livingstone, 1987: 8-13. 10 Reynolds EII, Elwes RDC, Shorvon SD. Lancet 1985; 2: 952-954. 11 Reynolds EH, Ekes RDC. Lancet 1991; 324: 1214-1215. 12 Hopkins A, Garman A, Clarke C. Iancet 1988; 1: 721-726. 13 IIart YM, Sander JWAS, Johnson AL, Showon SD. Lancet 1990; 336: 1271-1274. 14 Reynolds EII. Br Med J 1990; 301: 1112-1114. 15 Reynolds CII. Br Med J 1988; 297: 1422-1423.
