Carbamazepine as a Sole Anticonvulsant for Partial Seizures Hitomi Sato, MD, Makoto Doi, MD, and Takehiko Okuno, MD
The efficacy, serum concentration and side effects of CBZ for partial seizures in children were evaluated. The study was undertaken on 27 patients with partial seizures ranging from 5 to 17 years of age. Further 15 patients with various types of epilepsy taking CBZ with other anticonvulsants were selected as controls to compare the serum levels ofCBZ. In nineteen of the 27 patients seizures were controlled completely, in whom serum CBZ levels varied from trace to 15.6 mcg/ml, average being 8.18 j; 3.40 mcg/mI, while those of uncontrolled ones ranged from 3.5 to 11.3 mcg/ml, average being 7.50 j; 2.97 mcg/ml. There was no significant difference between both groups of the above. EEG was improved in the seven of 19 seizure-free cases, serum levels of which ranged from 5.9 to 13.2 mcg/ml. With regard to the side effects, transient leucopenia was observed in four patients and serum GOT and GPT slightly elevated in two. Correlation between dose and serum level in the mono therapy group was not significant as well as in the combined therapy group. Serum CBZ levels in the mono therapy group were significantly higher than those in combined therapy group. Sato H, Doi M, Okuno T: Carbamazepine as a sole anticonvulsant for partial seizures, Brain Dev 2:97-102,1979
Carbamazepine (CBZ) was synthesized in the late 1950s. It is a tricyclic compound related to imipramine and thereby represents a departure from the structure of previous anticonvulsants. It was found to be clinically useful as an anticonvulsant by Theobald et al [23], Lorge [15] and Bonduelle et al [2]. In 1962, it was also shown to be useful for the treatment of trigeminal neuralgia by Blom and has been now c~msidered as the drug of choice against epilepsies and trigeminal neuralgia. Since its psychotropic effect was also recognized, CBZ has been preferentially used against psychomotor seizures, but mostly in combination with other From the Department of Child Health, Osaka City University, Osaka (HS), Department of Pediatrics, Kyoto University, Kyoto (MD, TO). Received for publication: December 29, 1978. Accepted for publication: September 12, 1979.
Key words: Carbamazepine, serum level, partial seizure. Correspondence address: Dr. Hitomi Sato, Department of Child Health, Faculty of Science of Living, Osaka City University, Sugimoto-cho, Sumiyoshi-ku, Osaka.
anticonvulsants such as diphenylhydantoin or phenobarbital [4, 6, 7, 9, 20, 21]. However, recent studies showed that it would be proved to be beneficial even if it be administered as a single anticonvulsant in cases with generalized as well as partial seizures, no matter subjects be children [6, 7, 13, 22] or adults [3, 4, 6]. In this paper, we report the result of single CBZ treatment for partial seizures in children. Subjects and Methods CBZ was administered to 27 children with partial seizures. All these patients treated with CBZ orily for at least 12 months, have been followed at the neuropsychiatric clinic of Department of Pediatrics, Kyoto University Hospital. Another 15 patients treated with CBZ in combination with .other anticonvulsants have been followed to compare the serum levels of CBZ. The average dosage of CBZ was 8.1 mg/kg (the range from 2 to 21.0 mg/kg), given daily in two separate doses. Blood samples were taken 4-8 hours after
the morning dose and serum thus obtained was used for the determination of CBZ levels by means of gas chromatography [12] . Extraction schema is shown in Fig 1. Laboratory tests and EEG examinations were carried out prior to treatment and every 6 months after the start of medication. Age, seizure type, seizure frequency and daqy dosage in 27 patients are shown in Table 1. Twenty out of the 27 patients suffered from partial seizures secondarily generalized, three partial seizures with simple symptomatology and four partial seizures with complex symptomatology. EEG recordings at rest prior to medication were obtained from all patients.
EEG in five patients showed slight slowing background activities. The others were within normal limits. Paroxysmal abnormalities were found in 23 cases, the contents of which were summarized in Table 2. Spike or sharp wave focus was present in anterio- or mid- temporal area in most cases and in frontal area in fewer cases. Only four patients demonstrated no paroxysmal abnormality. Results 1. Effects on seizures Nineteen of the 27 patients (70.4%) were ren-
Table 1 Data on 27 patients with partial seizures receiving carbamazepine alone Patient no
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Age
Seizure type
Seizure frequency
6 12 10 5
WSS SG SG SG SG SG WCS WCS WCS SG SG WSS SG SG SG SG SG SG SG WCS SG SG SG SG SG SG WSS
116m 116m 113m
11 10 12 8 10 15 13 15 12 11 14 15 13 17 9 13 11 15 13 11 5 13 8
113m 114m 116m 113m 2/1w 112m 116m 112m 113m 111m 114m 111m 116m 112m 1/2w 111w 112m
111m 111m 113m 111d 113m 113m I11d
Oral dose ofCBZ (mg/kg) 9.0 6.0 6.0 18.2 5.4 6.9 7.3 4.0 14.3 7.2 7.1 4.1 5.3 10.3 4.8 7.7 5.0 4.0 13.8 6.9 5.7 4.0 2.9 21.0 5.0 9.5 16.7
Serum level ofCBZ (meg/ml) 8.3 9.6 4.5 5.9 6.0 4.8 4.9 3.8 13.2 15.6 9.6 7.3 7.6 6.3 13.6 9.6 8.4 6.8 9.6 6.7 10.0 3.0 trace 10.7 3.5 6.5 11.3
WSS: partial seizures with simple symptomatology, SG: partial seizures secondarily generalized, WCS: partial sei7ures with complex symptomatology, m: month, w: week, d: day.
98
Brain & Development, Vol 1, No 2. 1979
Table 2 Paroxysmal EEG abnormalities prior to the medication Paroxysmal EEG abnormalities Focal spikes Focal sharp waves Generalized spike and waves Slow wave focus
Number of cases
15 2 5 1
dered seizure-free. But in eight of the 27 cases the seizures did not improve, their seizure types being secondarily generalized partial seizures in five, partial seizures with simple symptomatology in two and with complex symptomatology in one. With regard to serum levels of CBZ, seizurefree group had levels that ranged from trace to 15.6 mcg/mI, average being 8.18 ± 3.40 mcg/mI, while the levels of the group that failed to respond ranged from 3.5 to 11.3 mcg/mI, average being 7.50 ± 2.97 mcg/mI. The difference in serum levels between both groups is not Significant.
2. Effect on EEG Seven of the 19 whose seizures were controlled completely showed improvement in EEG_ Focal spikes disappeared in five patients. In other two patients spike activities were markedly decreased. None of the subjects studied presented the trend of worsening in their background activities. Illustrative two cases will be described below in whom EEG findings remarkably improved under CBZ monotherapy: Case 1: Male, 12 years old, partial seizures secondarily generalized. Seizure frequency: once, a month, no seizures recurred after the start of CBZ treatment. The EEG prior to the medication displayed left mid-temporal and anterio-temporal spikes, which disappeared completely after one and a half year medication (Fig 2). Case 2: Male, 13 years old, partial seizures secondarily generalized. Seizure frequency: once every two months. No seizures occurred after the initiation of CBZ therapy. The EEG before the treatment demonstrated spikes in the left posterior and parietal areas or sometimes bilaterally synchronous spike and wave discharges. Spikes decreased markedly after six months medication.
3. Side effects A few days after CBZ treatment, several patients complained of drowsiness but it soon disappeared. Only one patient had severe drowsiness, which necessitated a dosage reduction from 4 to 2 mg/kg/day. In four patients transient leucopenia (under 3,000) was observed after six months treatment. Their serum levels were 4.5, 15.6, 7.3 and 6.8 mcg/mI, respectively. Elevated levels of GOT and GPT were observed in two patients and within one year, one regained normal levels but the other continued to have slightly elevated levels, GOT 121, GPT 32. It is very interesting to note that both patients showed high serum levels of CBZ, respectively, 13.6 and 15.6 mcq/mI. All other laboratory tests were within normal ranges in all patients. 4. Correlation between doses and serum levels Serum CBZ levels are plotted against doses (Fig 3). In patients treated with CBZ alone, correlation coefficient between doses and serum levels was 0.3217, that is not significant. The patients treated with CBZ combined with other antiepileptic drugs also showed no significant correlation between doses and serum levels. The serum level to dose ratio (S/D ratio) was 0.74 ± 0.19 in the group of 5-10 years of age and 1.04 ± 0.14 in the group of 11-17 years of age in the patients treated with CBZ only. In patients
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Fig 1 The schema of the extraction of serum carbamazepine.
Sato et al: Carbamazepine in children
99
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treated with CBZ combined with other antiepileptic drugs, the SID ratio was 0.49 ± 0.18 in the 5-10 years of age group and 0.53 ± 0.22 in the 11-20 years group. Thus, in both groups the SID ratios in the patients over 11 years of age were higher than those in the patients of 5-10 years of age. Furthermore, the group of CBZ alone had a significantly higher SID ratio than that of CBZ combined with other antiepilep~ic drugs.
5. Effects on behaviors 100 Brain & Development, Vall, No 2, 1979
The hyperkinetic behavior of a few patients were improved under the CBZ monotherapy. One of them had still seizures but others had no seizures. Discussion Haneke [10], Fichsel et al [8], Wunsch et al [25], Scheffner et al [20]. Lerman et al [13], Gamstorp [9] and Schain [22] reported on the treatment with CBZ for epileptic children, concluding that CBZ is an effective anticonvulsant
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against focal and psychomotor seizures. Lerman et al (13] reported all of 40 children with focal seizures became seizure-free . Scheffner et al [21] also reported that 89% (80-95%) of subjects were benefitted from CBZ. In our children with partial seizures, 70% became free of seizures on CBZ alone. With regard to EEG, Scheffner et al reported the decrease of focal spikes in 9-12 years old children and of focal slowing in all children. Lerman et al [13] reported that in 12 out of 40 epileptic children Rolandic foci disappeared. We found that focal spikes in EEG disappeared on five out of 19 patients with seizure control. CBZ is considered as an effective drug against psychomotor and grand mal seizures either by monotherapy or combined therapy in many studies on adults [14,20,24,26] as well as those on children. But it was also suggested by several authors that EEG deteriorated during the CBZ administration even though seizures would be con-
trolled by it. Rodin et al [20] concluded that CBZ tended to produce slowing of background EEG rhythms and sometimes diffuse paroxysmal activity during 3-week trial. In Wilkus et al [26] double blind cross over four months trial, an increase in generalized epileptiform discharges and in diffuse slow waves was observed without significant acompanying changes in seizure incidence. The data above-cited are incompatible with that observed in children [13, 21] including ours. It would be said that the observation of Rodin et al [20] and Wilkus et al [26] are mainly concerned with acute CBZ effect on EEG. Whereas, the data of Lerman et al [13]. Scheffner et al [21] and ours were concerned with chronic CBZ effect over at least one year, revealing the fact that CBZ was effective in diminishing focal spikes. Many investigators [I 9, 22] have been impressed by the psychotropic effect of CBZ. We also noted that the behavior of a few patients was improved. In one of them , hyperkinetic behavior was subsided though seizure was not completely controlled. It might be possible that not only the liberation from seizures may contribute to the improvement of behavior but also CBZ itself may have a beneficial effect on behavior. Wi th regard to serum levels, Meinardi [16] and Cereghino et al [5] reported that no relationships existed between daily dosage and plasma levels in adults. In children, Morselli et al [17] similarly reported that relationship between daily dosage and plasma levels was not significantly correlative. This is in accord with our data. As for therapeutic levels, recent data indicate that they may range between 5 and 12 mcg/ml [5 , 7, 18]. But in our findings, serum levels of CBZ in the seizure-free group were not significantly different from those in the group with seizures; that was also reported by Troupin et al [24]. Johannessen et al [II] reported that the group of CBZ combined with other antiepileptic drugs had significantly lower serum CBZ levels than the CBZ mono therapy group. This is in accord with the reports of Ferrer-Vidal et al [7], Cereghino [5] and ours. Concerning to the side effects, we never found severe side effects except transient leucopenia. Thus the authors would like to conclude that CBZ monotherapy should be recommended as one of the first choice regimen for children with partial seizures. Sato et al: Carbamazepine in children 101
References 1. Blom S: Trigeminal neuralgia: Its treatment with a new anticonvulsant drug (G-32883). Lancet I: 839-840, 1962. 2. Bonduelle M, Bouygues P, Sallou C, et al: Experimentation clinique de l'anti-epileptique G 32883 (Tegretol). Resultats portant sur 100 cas observes en trois ans. Rev Neurol 110: 209, 1964. 3. Callaghan N, O'Callaghan M, Duggan B, et al: Carbamazepine as a single drug in the treatment of epilepsy. A prospective study of serum levels and seizure control. J Neurol Neurosurg Psychiatry 41: 907-912, 1978. 4. Cereghino 11, Van Meter JC, Brock JT, et al: Carbamazepine for epilepsy. A controlled prospectiveevaluation.Neurology 24: 401410, 1974. 5. Cereghino JJ: Serum carbamazepine concentration and clinical control. In Penry JK, Dalby DD (eds): Complex Partial Seizures and Their Treatment. Raven Press, New York, 1975, pp 309-330. 6. Dalby MA: Antiepileptic and psychotropic effect of carbamazepine (Tegretol) in the treatment of psychomotor epilepsy. Epilepsia 12: 325-334, 1971. 7. Ferrer-Vidal La, Sabater-Tobella J, OllerDaure11a L: Preliminary report on serum carbamazepine determinations and. their application to the treatment of epilepsy. In Birkmayer W (ed): Epileptic Seizures-Behavior-Pain. Hans Huber Publ, Bern.Stuttgart.Vienna, 1976, pp 165-174. 8. Fichsel H, Heyer R: Karbamazepin in der Behandlung kindlichen Epilepsien. Dtsch Med Wochenschr 95: 2367-2374, 1970. 9. Gamstorp I: Carbamazepine in the treatment of epileptic disorders in infancy and childhood. In Birkmayer W (ed): Epileptic Seizures-BehaviorPain. Hans Huber Publ, Bern.Stuttgart.Vienna, 1976, pp 98-103. 10. Haneke K: Tegretol bei kindlichen Anfallsleiden. Med Klin 61: 804-807, 1966. 11. Johannessen SI, Strandjord RE: A preliminary study of serum carbamazepine levels in healthy subjects and in patients with epilepsy. In Schneider H, Janz D, Gardner-Thorpe C, Meinardi H, Sherwin AL (eds): Clinical Pharmacology of Antiepi/eptic Drugs. Springer Verlag, New York.Heidelberg.Berlin, 1975, pp 181-188. 12. Kupferberg HJ: Personal communication, 1976. 13. Lerman P, Kivity-Ephraim S: Carbamazepine as
102 Brain & Development, Vol 1, No 2, 1979
14. 15.
16.
17. 18.
19.
20.
21.
22. 23. 24. 25. 26.
a sole anticonvulsant for focal epilepsy of childhood. Epilepsia 15: 229-234, 1974. Livingston S, Villamater C, Sakata Y: Use of carbamazepine in epilepsy. Results in 87 patients. JAMA 200: 116-120,1967. Lorge M: Clinical experiences with Tegretol (G 32883); A new antiepileptic with special influence on epileptic character change. Schweiz Med Wochenschr 93: 1042-1047, 1963. Meinardi H: Other antiepileptic drugs: Carbamazepine: In Woodbury DM, Penry JK, Schmidt RP (eds): Antiepileptic Drugs. Raven Press, New York, 1972, pp 487496. Morselli PL, FrigerioA: Metabolism and pharmacokinetics of carbamazepine. Drug Metabolism Rev 4: 97-113, 1975. Morselli PL, Bossi L, Gerna M: Pharmacokinetic studies with carbamazepine in epileptic patients. In Birkmayer W (ed): Epileptic SeizuresBehavior-Pain. Hans Huber Publ, Bern.Stuttgart. Vienna, 1976, pp 141-150. Rett A: The so-called psychotropic effect of Tegretol in the treatment of convulsions of cerebral origin in children. In Birkmayer W (ed): Epileptic Seizures-Behavior-Pain. Hans Huber Publ, Bern.Stuttgart.Vienna, 1976, pp 194-204. Rodin EA, Rim CS, Rennick PM: The effects of carbamazepine on patients with psychomotor epilepsy. Results of a double-blind study. Epilepsia 15: 547-561, 1974. Scheffner D, Schiefer I: The treatment of epileptic children with carbamazepine. Follow-up studies of clinical course and EEG. Epilepsia 13: 819-828, 1972. Schain RJ, Ward JW, Guthrie D: Carbamazepine as an anticonvulsant in children. Neurology 27: 476480,1977. Theobald W, Kunz HA: Zur Pharmakologie des Antiepilepticums 4-carbamyl-5-H-dibenzo(b,f) azepine. Arzneim Forsch 13: 122-125,1963. Troupin AS, Green JR, Levy RH: Carbamazepine as an anticonvulsant: A pilot study. Neurology 24: 863-869, 1975. Wiinsch W, Todt H, Munde B: Behandlung mit Tegretol bei kindlichen Anfallsleiden. Dtsch Gesundh Wes 26: 745-749, 1971. Wilkus RJ, Dodrill CB, Troupin AS: Carbamazepine and electroencephalogram of epileptics: A double blind study in comparison to phenytoin. Epilepsia 19: 283-291,1978.
The efficacy, serum concentration and side effects of CBZ for partial seizures in children were evaluated. The study was undertaken on 27 patients with partial seizures ranging from 5 to 17 years of age. Further 15 patients with various types of epilepsy taking CBZ with other anticonvulsants were selected as controls to compare the serum levels ofCBZ. In nineteen of the 27 patients seizures were controlled completely, in whom serum CBZ levels varied from trace to 15.6 mcg/ml, average being 8.18 j; 3.40 mcg/mI, while those of uncontrolled ones ranged from 3.5 to 11.3 mcg/ml, average being 7.50 j; 2.97 mcg/ml. There was no significant difference between both groups of the above. EEG was improved in the seven of 19 seizure-free cases, serum levels of which ranged from 5.9 to 13.2 mcg/ml. With regard to the side effects, transient leucopenia was observed in four patients and serum GOT and GPT slightly elevated in two. Correlation between dose and serum level in the mono therapy group was not significant as well as in the combined therapy group. Serum CBZ levels in the mono therapy group were significantly higher than those in combined therapy group. Sato H, Doi M, Okuno T: Carbamazepine as a sole anticonvulsant for partial seizures, Brain Dev 2:97-102,1979
Carbamazepine (CBZ) was synthesized in the late 1950s. It is a tricyclic compound related to imipramine and thereby represents a departure from the structure of previous anticonvulsants. It was found to be clinically useful as an anticonvulsant by Theobald et al [23], Lorge [15] and Bonduelle et al [2]. In 1962, it was also shown to be useful for the treatment of trigeminal neuralgia by Blom and has been now c~msidered as the drug of choice against epilepsies and trigeminal neuralgia. Since its psychotropic effect was also recognized, CBZ has been preferentially used against psychomotor seizures, but mostly in combination with other From the Department of Child Health, Osaka City University, Osaka (HS), Department of Pediatrics, Kyoto University, Kyoto (MD, TO). Received for publication: December 29, 1978. Accepted for publication: September 12, 1979.
Key words: Carbamazepine, serum level, partial seizure. Correspondence address: Dr. Hitomi Sato, Department of Child Health, Faculty of Science of Living, Osaka City University, Sugimoto-cho, Sumiyoshi-ku, Osaka.
anticonvulsants such as diphenylhydantoin or phenobarbital [4, 6, 7, 9, 20, 21]. However, recent studies showed that it would be proved to be beneficial even if it be administered as a single anticonvulsant in cases with generalized as well as partial seizures, no matter subjects be children [6, 7, 13, 22] or adults [3, 4, 6]. In this paper, we report the result of single CBZ treatment for partial seizures in children. Subjects and Methods CBZ was administered to 27 children with partial seizures. All these patients treated with CBZ orily for at least 12 months, have been followed at the neuropsychiatric clinic of Department of Pediatrics, Kyoto University Hospital. Another 15 patients treated with CBZ in combination with .other anticonvulsants have been followed to compare the serum levels of CBZ. The average dosage of CBZ was 8.1 mg/kg (the range from 2 to 21.0 mg/kg), given daily in two separate doses. Blood samples were taken 4-8 hours after
the morning dose and serum thus obtained was used for the determination of CBZ levels by means of gas chromatography [12] . Extraction schema is shown in Fig 1. Laboratory tests and EEG examinations were carried out prior to treatment and every 6 months after the start of medication. Age, seizure type, seizure frequency and daqy dosage in 27 patients are shown in Table 1. Twenty out of the 27 patients suffered from partial seizures secondarily generalized, three partial seizures with simple symptomatology and four partial seizures with complex symptomatology. EEG recordings at rest prior to medication were obtained from all patients.
EEG in five patients showed slight slowing background activities. The others were within normal limits. Paroxysmal abnormalities were found in 23 cases, the contents of which were summarized in Table 2. Spike or sharp wave focus was present in anterio- or mid- temporal area in most cases and in frontal area in fewer cases. Only four patients demonstrated no paroxysmal abnormality. Results 1. Effects on seizures Nineteen of the 27 patients (70.4%) were ren-
Table 1 Data on 27 patients with partial seizures receiving carbamazepine alone Patient no
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Age
Seizure type
Seizure frequency
6 12 10 5
WSS SG SG SG SG SG WCS WCS WCS SG SG WSS SG SG SG SG SG SG SG WCS SG SG SG SG SG SG WSS
116m 116m 113m
11 10 12 8 10 15 13 15 12 11 14 15 13 17 9 13 11 15 13 11 5 13 8
113m 114m 116m 113m 2/1w 112m 116m 112m 113m 111m 114m 111m 116m 112m 1/2w 111w 112m
111m 111m 113m 111d 113m 113m I11d
Oral dose ofCBZ (mg/kg) 9.0 6.0 6.0 18.2 5.4 6.9 7.3 4.0 14.3 7.2 7.1 4.1 5.3 10.3 4.8 7.7 5.0 4.0 13.8 6.9 5.7 4.0 2.9 21.0 5.0 9.5 16.7
Serum level ofCBZ (meg/ml) 8.3 9.6 4.5 5.9 6.0 4.8 4.9 3.8 13.2 15.6 9.6 7.3 7.6 6.3 13.6 9.6 8.4 6.8 9.6 6.7 10.0 3.0 trace 10.7 3.5 6.5 11.3
WSS: partial seizures with simple symptomatology, SG: partial seizures secondarily generalized, WCS: partial sei7ures with complex symptomatology, m: month, w: week, d: day.
98
Brain & Development, Vol 1, No 2. 1979
Table 2 Paroxysmal EEG abnormalities prior to the medication Paroxysmal EEG abnormalities Focal spikes Focal sharp waves Generalized spike and waves Slow wave focus
Number of cases
15 2 5 1
dered seizure-free. But in eight of the 27 cases the seizures did not improve, their seizure types being secondarily generalized partial seizures in five, partial seizures with simple symptomatology in two and with complex symptomatology in one. With regard to serum levels of CBZ, seizurefree group had levels that ranged from trace to 15.6 mcg/mI, average being 8.18 ± 3.40 mcg/mI, while the levels of the group that failed to respond ranged from 3.5 to 11.3 mcg/mI, average being 7.50 ± 2.97 mcg/mI. The difference in serum levels between both groups is not Significant.
2. Effect on EEG Seven of the 19 whose seizures were controlled completely showed improvement in EEG_ Focal spikes disappeared in five patients. In other two patients spike activities were markedly decreased. None of the subjects studied presented the trend of worsening in their background activities. Illustrative two cases will be described below in whom EEG findings remarkably improved under CBZ monotherapy: Case 1: Male, 12 years old, partial seizures secondarily generalized. Seizure frequency: once, a month, no seizures recurred after the start of CBZ treatment. The EEG prior to the medication displayed left mid-temporal and anterio-temporal spikes, which disappeared completely after one and a half year medication (Fig 2). Case 2: Male, 13 years old, partial seizures secondarily generalized. Seizure frequency: once every two months. No seizures occurred after the initiation of CBZ therapy. The EEG before the treatment demonstrated spikes in the left posterior and parietal areas or sometimes bilaterally synchronous spike and wave discharges. Spikes decreased markedly after six months medication.
3. Side effects A few days after CBZ treatment, several patients complained of drowsiness but it soon disappeared. Only one patient had severe drowsiness, which necessitated a dosage reduction from 4 to 2 mg/kg/day. In four patients transient leucopenia (under 3,000) was observed after six months treatment. Their serum levels were 4.5, 15.6, 7.3 and 6.8 mcg/mI, respectively. Elevated levels of GOT and GPT were observed in two patients and within one year, one regained normal levels but the other continued to have slightly elevated levels, GOT 121, GPT 32. It is very interesting to note that both patients showed high serum levels of CBZ, respectively, 13.6 and 15.6 mcq/mI. All other laboratory tests were within normal ranges in all patients. 4. Correlation between doses and serum levels Serum CBZ levels are plotted against doses (Fig 3). In patients treated with CBZ alone, correlation coefficient between doses and serum levels was 0.3217, that is not significant. The patients treated with CBZ combined with other antiepileptic drugs also showed no significant correlation between doses and serum levels. The serum level to dose ratio (S/D ratio) was 0.74 ± 0.19 in the group of 5-10 years of age and 1.04 ± 0.14 in the group of 11-17 years of age in the patients treated with CBZ only. In patients
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Sato et al: Carbamazepine in children
99
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treated with CBZ combined with other antiepileptic drugs, the SID ratio was 0.49 ± 0.18 in the 5-10 years of age group and 0.53 ± 0.22 in the 11-20 years group. Thus, in both groups the SID ratios in the patients over 11 years of age were higher than those in the patients of 5-10 years of age. Furthermore, the group of CBZ alone had a significantly higher SID ratio than that of CBZ combined with other antiepilep~ic drugs.
5. Effects on behaviors 100 Brain & Development, Vall, No 2, 1979
The hyperkinetic behavior of a few patients were improved under the CBZ monotherapy. One of them had still seizures but others had no seizures. Discussion Haneke [10], Fichsel et al [8], Wunsch et al [25], Scheffner et al [20]. Lerman et al [13], Gamstorp [9] and Schain [22] reported on the treatment with CBZ for epileptic children, concluding that CBZ is an effective anticonvulsant
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10 dose
Fig 3 Serum carbamazepine levels plotted against the carbamazepine dose. • indicates patient with CBZ monotherapy. o indicates patients under CBZ therapy combined with other antiepileptics.
against focal and psychomotor seizures. Lerman et al (13] reported all of 40 children with focal seizures became seizure-free . Scheffner et al [21] also reported that 89% (80-95%) of subjects were benefitted from CBZ. In our children with partial seizures, 70% became free of seizures on CBZ alone. With regard to EEG, Scheffner et al reported the decrease of focal spikes in 9-12 years old children and of focal slowing in all children. Lerman et al [13] reported that in 12 out of 40 epileptic children Rolandic foci disappeared. We found that focal spikes in EEG disappeared on five out of 19 patients with seizure control. CBZ is considered as an effective drug against psychomotor and grand mal seizures either by monotherapy or combined therapy in many studies on adults [14,20,24,26] as well as those on children. But it was also suggested by several authors that EEG deteriorated during the CBZ administration even though seizures would be con-
trolled by it. Rodin et al [20] concluded that CBZ tended to produce slowing of background EEG rhythms and sometimes diffuse paroxysmal activity during 3-week trial. In Wilkus et al [26] double blind cross over four months trial, an increase in generalized epileptiform discharges and in diffuse slow waves was observed without significant acompanying changes in seizure incidence. The data above-cited are incompatible with that observed in children [13, 21] including ours. It would be said that the observation of Rodin et al [20] and Wilkus et al [26] are mainly concerned with acute CBZ effect on EEG. Whereas, the data of Lerman et al [13]. Scheffner et al [21] and ours were concerned with chronic CBZ effect over at least one year, revealing the fact that CBZ was effective in diminishing focal spikes. Many investigators [I 9, 22] have been impressed by the psychotropic effect of CBZ. We also noted that the behavior of a few patients was improved. In one of them , hyperkinetic behavior was subsided though seizure was not completely controlled. It might be possible that not only the liberation from seizures may contribute to the improvement of behavior but also CBZ itself may have a beneficial effect on behavior. Wi th regard to serum levels, Meinardi [16] and Cereghino et al [5] reported that no relationships existed between daily dosage and plasma levels in adults. In children, Morselli et al [17] similarly reported that relationship between daily dosage and plasma levels was not significantly correlative. This is in accord with our data. As for therapeutic levels, recent data indicate that they may range between 5 and 12 mcg/ml [5 , 7, 18]. But in our findings, serum levels of CBZ in the seizure-free group were not significantly different from those in the group with seizures; that was also reported by Troupin et al [24]. Johannessen et al [II] reported that the group of CBZ combined with other antiepileptic drugs had significantly lower serum CBZ levels than the CBZ mono therapy group. This is in accord with the reports of Ferrer-Vidal et al [7], Cereghino [5] and ours. Concerning to the side effects, we never found severe side effects except transient leucopenia. Thus the authors would like to conclude that CBZ monotherapy should be recommended as one of the first choice regimen for children with partial seizures. Sato et al: Carbamazepine in children 101
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