The Japanese Journal of Psychiatry and Neurology, Vol. 46, No. 2, 1992
Can We Predict Carbamazepine Responsiveness in Partial Epilepsy? Kyoon Huh, M.D., Byung I. Lee, M.D., So0 C. Park, M.D. and Sung S . Lee, M.D. Department of Neurology, College of Medicine, Yonsei University, Seoul
Abstract: We studied 153 patients with partial epilepsy who were placed on a carbamazepine monotherapy plan in order to evaluate the clinical factors that may determine drug responsiveness to carbamazepine. The subjects were divided into 3 groups based on their therapeutic outcome-complete seizure control (44%), significant seizure reduction (32% 1 and unsatisfactory control (24%). Fifteen tentative clinical factors were examined in relation to the therapeutic outcomes. Factors such as seizure type, number of generalized tonic-clonic seizures, age of onset, duration of illness, seizure frequency, previous treatment and EEG Anding were relevant to drug responsiveness. However, other variables including mental retardation, etiology, febrile convulsion, positive family history and abnormal neurologic examination showed no significant correlation. Our data suggest that a potential success of carbamazepine treatment should not be underestimated even in patients with complicated clinical features. Jpn J Psychiatr N e w 1 46: 391-394, 1992
INTRODUCTION
Carbamazepine is known to be the most effective drug for the treatment of epilepsy. Particularly in epilepsies with partial seizures, carbamazepine monotherapy is regarded as the first line antiepileptic treatment. Although there are numerous studies available in the literature confirming the therapeutic efficacy of carbamazepine, a certain fraction of patients remains to experience continuing uncontrolled seizures. The reason for these individual differences in drug responsiveness has not been well elucidated. This study was conducted to address this issue. We investigated the posMailing address: Kyoon Huh, M.D., Department of Neurology, College of Medicine, Yonsei University, Seoul, Republic of Korea.
sibility that whether we can define any clinical factors which may determine the responsiveness to carbamazepine in patients with partial epilepsy. METHODOLOGY
Subjects
This series consists of 153 patients with clear-cut simple partial or complex partial seizures. The subjects were registered and followed in Yonsei Epilepsy Clinic from April 1989 to August 1991. The patients with equivocal seizure type, partial seizures associated with acute or progressive neurological illness were excluded. They were 96 men and 57 women, age range was 6 to 54, a mean 24, follow-up period was 8 to 28 months with a mean 15 months.
K. Huh
392
et
al. Table 1: Profiles of the Subjects
Therapeutic Outcome All the subjects were placed on carbamazepine monotherapy as an initial therapeutic plan. Drug responsiveness was determined by comparison of average seizure frequency prior and after the carbamazepine administration. The subjects were divided into 3 groups based on their therapeutic outcomes. Group 1: Complete seizure control-67 patients (42%) remained seizure free for a minimum 6 months of a period, Group 2: significant seizure c o n t r o l 4 9 patients (32%) achieved more than a 60% reduction of seizures, Group 3: unsatisfactory seizure control-37 patients (24%) achieved less than a 60% of seizure reduction.
Tentative Clinical Factors Fifteen clinical factors including age and sex were examined in this study. The profiles of the factors in the subjects are described in Table 1. Each factor was analyzed in relation to group differences of the therapeutic outcome. Parametric and nonparametric variables were analyzed by ANOVA and Chi-square test respectively, using SPSS/PC .
+
RESULTS
A statistical analysis revealed that certain clinical factors were significantly correlated with the carbamazepine responsiveness as follows. Seizure Type: 30 out of 54 patients with simple partial seizures (56%) achieved complete control, whereas 37 out 99 patients with complex partial seizures eventually entered into Group 1 (37%). Combined Generalized Tonic-Clonic (GTC) Seizure: 21 subjects had no GTC seizure, 59 subjects less than 5 and 73 subjects more than 5 GTC seizures. The subjects who had less than 5 GTC seizures achieved significantly better drug responsiveness. Age of Onset: The mean age of onset in
Factor Seizure type Simple partial Complex partial Combined GTC seizure None 5 Mental retardation Well defined etiology Febrile convulsion Positive family history Age of onset < 1 0 yrs >10 yrs Duration of illness < 4 yrs > 4 yrs Seizure frequency < l/mo > l/mo Previous treatment Focal CT abnormality Focal neurol exam Abnormal EEG '98
Number of Patients 54 99 21 59 73 13 33 30 12 36 117 66 87 57 96 116 24' 17 97
CT Scans were available
Groups 1, 2 and 3 are 17, 17 and 12, respectively, showing that poor responders had earlier onset of seizures. Chi-square test demonstrated that the age of onset relevant to the therapeutic outcome takes place around the age of 10. Duration of Illness: The mean duration of illness in Groups 1, 2 and 3 are 7, 7 and 9 years, respectively. A non-parametric analysis demarcated the duration of illness of significant correlation around 4 years. Seizure Frequency: Chi-square test showed that the patients with less than 1 seizure per month were correlated with the favorable drug responsiveness. Previous Treatment: The subjects who were not taking antiepileptic drugs at the time of registration responded better than those already taking drugs. Whether the patient was on a single drug or multiple drug regimen made no significant differences.
Carbamazepine Responsiveness in Partial Epilepsy Table 2: Factors Relevant to Drug Responsiveness Factors
P Value
1. Seizure type: simple >complex
2. 3. 4. 5. 6. 7.
Combined GTC Sz: less than 5 GTC Sz Age of onset: over 10 years old Duration of illness: less than 4 years Seizure frequency: less than Vmonth Previous treatment: no AED Tx EEG findings: normal EEG
.0455
.0336 .a16 ,0460 .OOO1 .OOO1
.0202
Table 3: Factors of No Significance Factors 1. Mental retardation
2. 3. 4. 5. 6. 7.
Symptomatic epilepsy Febrile convulsion Positive family history Positive CT abnormality Abnormal neurologic exam Location of EEG epileptiform discharges
EEG: EEG findings were categorized into 1) normal, 2) background abnormal, 3) temporal epileptiform discharges, 4) extratemporal and 5 ) multifocal epileptiform discharges. Normal EEG was correlated with better drug responsiveness. However, the location of epileptiform activity was of no significant correlation with the therapeutic outcome. Other clinical features, such as age, sex, mental retardation, presence of definite etiology, febrile convulsion, positive family history, focal lesion on CT scan and abnormal neurological examination do not appear to be correlated with the degree of responsiveness to carbamazepine treatment. DISCUSSION Our study questions whether careful consideration of various clinical features of epilepsy may contribute to predictive assessment of therapeutic responsiveness. However, this study focuses upon a rather narrow aspect of the issue, that is, single
393
drug responsiveness in a single seizure category. Our data do suggest that some clinical factors may be associated with the therapeutic outcome as summarized in Table 2. However, many other factors previously known to be predictors of intractability were not correlated with poor responsiveness to carbamazepine treatment. Most of the clinical features in Table 3 are believed to represent the degree of focal brain damage, but these factors played no significant role in the prediction of therapeutic outcome. In other words, the patient who has evidences for obvious brain damage may respond to carbamazepine as much as the patient without prominent signs of focal brain damage does. The present study also suggests that the prediction of poor drug responsiveness would be more difficult than the prediction of favorable responsiveness. This provides an important clinical implication, that is, the potential success of carbamazepine treatment should not be underestimated even in patients with complicated clinical features. However, the application of the conclusion from this study will require a cautious approach, because of the fact that cultural influences unique to Korean society in the management of epileptic patients might have been also reflected in the therapeutic outcome. The majority of patients enrolled in our Epilepsy Clinic have been previously treated inadequately. The primary management of epilepsy in Korea is somewhat behind that of the most developed countries. Subsequently, the magnitude of intractability could have been falsely exaggerated in this atmosphere. This may explain the observation that a number of tentative clinical variables was not relevant to the therapeutic outcome in this study. The role of medical culture in determination of prognosis of epilepsy has been seldom addressed in the past. Therefore, a cooperative cross-cultural study will be required to answer the many unresolved questions in
K. Huh
394
the research field of prognosis of epilepsy. REFERENCES
et
al. Rodin, E. and Chayasirisobohn, S.:Epileptic patients who are refractory to anticonvulsant medications. Neurology 32: 13821384, 1982.
Elwes, R.D., Shorvon, S.D. and Reynolds, E.H.: The prognosis for seizure control in newly diagnosed epilepsy. N Eng J Med 311: 944-947, 1984.
Ohtaka, T. and Miyasaka M.: A study on the factors responsible for chronicity of intractable epilepsy with complex partial seizures: A statistical study. Jpn J Psy Neurol 41: 365-372, 1987.
Reynolds, E.H., Elwes, R.D. and Shorvon, S.D.: Why does epilepsy become intractable? Lancet: 952-954, 1983.
Schmidt, D.: Prognosis of chronic epilepsy with complex partial seizures. J Neurol Neurosurg Psy 47: 1274-1278, 1984. Schmidt, D., Tsai, J.J. and Janz, D.: Generalized tonic-clonic seizures in patients with complex partial seizures: Natural history and prognostic relevance. Epilepsia 2 4 43-48, 1983.
Shorvon, S.D.and Reynolds, E.H.: Early prognosis of epilepsy. Brit Med J 285: 16991701, 1982.
Can We Predict Carbamazepine Responsiveness in Partial Epilepsy? Kyoon Huh, M.D., Byung I. Lee, M.D., So0 C. Park, M.D. and Sung S . Lee, M.D. Department of Neurology, College of Medicine, Yonsei University, Seoul
Abstract: We studied 153 patients with partial epilepsy who were placed on a carbamazepine monotherapy plan in order to evaluate the clinical factors that may determine drug responsiveness to carbamazepine. The subjects were divided into 3 groups based on their therapeutic outcome-complete seizure control (44%), significant seizure reduction (32% 1 and unsatisfactory control (24%). Fifteen tentative clinical factors were examined in relation to the therapeutic outcomes. Factors such as seizure type, number of generalized tonic-clonic seizures, age of onset, duration of illness, seizure frequency, previous treatment and EEG Anding were relevant to drug responsiveness. However, other variables including mental retardation, etiology, febrile convulsion, positive family history and abnormal neurologic examination showed no significant correlation. Our data suggest that a potential success of carbamazepine treatment should not be underestimated even in patients with complicated clinical features. Jpn J Psychiatr N e w 1 46: 391-394, 1992
INTRODUCTION
Carbamazepine is known to be the most effective drug for the treatment of epilepsy. Particularly in epilepsies with partial seizures, carbamazepine monotherapy is regarded as the first line antiepileptic treatment. Although there are numerous studies available in the literature confirming the therapeutic efficacy of carbamazepine, a certain fraction of patients remains to experience continuing uncontrolled seizures. The reason for these individual differences in drug responsiveness has not been well elucidated. This study was conducted to address this issue. We investigated the posMailing address: Kyoon Huh, M.D., Department of Neurology, College of Medicine, Yonsei University, Seoul, Republic of Korea.
sibility that whether we can define any clinical factors which may determine the responsiveness to carbamazepine in patients with partial epilepsy. METHODOLOGY
Subjects
This series consists of 153 patients with clear-cut simple partial or complex partial seizures. The subjects were registered and followed in Yonsei Epilepsy Clinic from April 1989 to August 1991. The patients with equivocal seizure type, partial seizures associated with acute or progressive neurological illness were excluded. They were 96 men and 57 women, age range was 6 to 54, a mean 24, follow-up period was 8 to 28 months with a mean 15 months.
K. Huh
392
et
al. Table 1: Profiles of the Subjects
Therapeutic Outcome All the subjects were placed on carbamazepine monotherapy as an initial therapeutic plan. Drug responsiveness was determined by comparison of average seizure frequency prior and after the carbamazepine administration. The subjects were divided into 3 groups based on their therapeutic outcomes. Group 1: Complete seizure control-67 patients (42%) remained seizure free for a minimum 6 months of a period, Group 2: significant seizure c o n t r o l 4 9 patients (32%) achieved more than a 60% reduction of seizures, Group 3: unsatisfactory seizure control-37 patients (24%) achieved less than a 60% of seizure reduction.
Tentative Clinical Factors Fifteen clinical factors including age and sex were examined in this study. The profiles of the factors in the subjects are described in Table 1. Each factor was analyzed in relation to group differences of the therapeutic outcome. Parametric and nonparametric variables were analyzed by ANOVA and Chi-square test respectively, using SPSS/PC .
+
RESULTS
A statistical analysis revealed that certain clinical factors were significantly correlated with the carbamazepine responsiveness as follows. Seizure Type: 30 out of 54 patients with simple partial seizures (56%) achieved complete control, whereas 37 out 99 patients with complex partial seizures eventually entered into Group 1 (37%). Combined Generalized Tonic-Clonic (GTC) Seizure: 21 subjects had no GTC seizure, 59 subjects less than 5 and 73 subjects more than 5 GTC seizures. The subjects who had less than 5 GTC seizures achieved significantly better drug responsiveness. Age of Onset: The mean age of onset in
Factor Seizure type Simple partial Complex partial Combined GTC seizure None 5 Mental retardation Well defined etiology Febrile convulsion Positive family history Age of onset < 1 0 yrs >10 yrs Duration of illness < 4 yrs > 4 yrs Seizure frequency < l/mo > l/mo Previous treatment Focal CT abnormality Focal neurol exam Abnormal EEG '98
Number of Patients 54 99 21 59 73 13 33 30 12 36 117 66 87 57 96 116 24' 17 97
CT Scans were available
Groups 1, 2 and 3 are 17, 17 and 12, respectively, showing that poor responders had earlier onset of seizures. Chi-square test demonstrated that the age of onset relevant to the therapeutic outcome takes place around the age of 10. Duration of Illness: The mean duration of illness in Groups 1, 2 and 3 are 7, 7 and 9 years, respectively. A non-parametric analysis demarcated the duration of illness of significant correlation around 4 years. Seizure Frequency: Chi-square test showed that the patients with less than 1 seizure per month were correlated with the favorable drug responsiveness. Previous Treatment: The subjects who were not taking antiepileptic drugs at the time of registration responded better than those already taking drugs. Whether the patient was on a single drug or multiple drug regimen made no significant differences.
Carbamazepine Responsiveness in Partial Epilepsy Table 2: Factors Relevant to Drug Responsiveness Factors
P Value
1. Seizure type: simple >complex
2. 3. 4. 5. 6. 7.
Combined GTC Sz: less than 5 GTC Sz Age of onset: over 10 years old Duration of illness: less than 4 years Seizure frequency: less than Vmonth Previous treatment: no AED Tx EEG findings: normal EEG
.0455
.0336 .a16 ,0460 .OOO1 .OOO1
.0202
Table 3: Factors of No Significance Factors 1. Mental retardation
2. 3. 4. 5. 6. 7.
Symptomatic epilepsy Febrile convulsion Positive family history Positive CT abnormality Abnormal neurologic exam Location of EEG epileptiform discharges
EEG: EEG findings were categorized into 1) normal, 2) background abnormal, 3) temporal epileptiform discharges, 4) extratemporal and 5 ) multifocal epileptiform discharges. Normal EEG was correlated with better drug responsiveness. However, the location of epileptiform activity was of no significant correlation with the therapeutic outcome. Other clinical features, such as age, sex, mental retardation, presence of definite etiology, febrile convulsion, positive family history, focal lesion on CT scan and abnormal neurological examination do not appear to be correlated with the degree of responsiveness to carbamazepine treatment. DISCUSSION Our study questions whether careful consideration of various clinical features of epilepsy may contribute to predictive assessment of therapeutic responsiveness. However, this study focuses upon a rather narrow aspect of the issue, that is, single
393
drug responsiveness in a single seizure category. Our data do suggest that some clinical factors may be associated with the therapeutic outcome as summarized in Table 2. However, many other factors previously known to be predictors of intractability were not correlated with poor responsiveness to carbamazepine treatment. Most of the clinical features in Table 3 are believed to represent the degree of focal brain damage, but these factors played no significant role in the prediction of therapeutic outcome. In other words, the patient who has evidences for obvious brain damage may respond to carbamazepine as much as the patient without prominent signs of focal brain damage does. The present study also suggests that the prediction of poor drug responsiveness would be more difficult than the prediction of favorable responsiveness. This provides an important clinical implication, that is, the potential success of carbamazepine treatment should not be underestimated even in patients with complicated clinical features. However, the application of the conclusion from this study will require a cautious approach, because of the fact that cultural influences unique to Korean society in the management of epileptic patients might have been also reflected in the therapeutic outcome. The majority of patients enrolled in our Epilepsy Clinic have been previously treated inadequately. The primary management of epilepsy in Korea is somewhat behind that of the most developed countries. Subsequently, the magnitude of intractability could have been falsely exaggerated in this atmosphere. This may explain the observation that a number of tentative clinical variables was not relevant to the therapeutic outcome in this study. The role of medical culture in determination of prognosis of epilepsy has been seldom addressed in the past. Therefore, a cooperative cross-cultural study will be required to answer the many unresolved questions in
K. Huh
394
the research field of prognosis of epilepsy. REFERENCES
et
al. Rodin, E. and Chayasirisobohn, S.:Epileptic patients who are refractory to anticonvulsant medications. Neurology 32: 13821384, 1982.
Elwes, R.D., Shorvon, S.D. and Reynolds, E.H.: The prognosis for seizure control in newly diagnosed epilepsy. N Eng J Med 311: 944-947, 1984.
Ohtaka, T. and Miyasaka M.: A study on the factors responsible for chronicity of intractable epilepsy with complex partial seizures: A statistical study. Jpn J Psy Neurol 41: 365-372, 1987.
Reynolds, E.H., Elwes, R.D. and Shorvon, S.D.: Why does epilepsy become intractable? Lancet: 952-954, 1983.
Schmidt, D.: Prognosis of chronic epilepsy with complex partial seizures. J Neurol Neurosurg Psy 47: 1274-1278, 1984. Schmidt, D., Tsai, J.J. and Janz, D.: Generalized tonic-clonic seizures in patients with complex partial seizures: Natural history and prognostic relevance. Epilepsia 2 4 43-48, 1983.
Shorvon, S.D.and Reynolds, E.H.: Early prognosis of epilepsy. Brit Med J 285: 16991701, 1982.
