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Prognosis and Predictive Factors of Partial Seizures in Children
Prognosis and Predictive Factors of Partial Seizures in Children Zhiping Wang, MD, PhD*†, Lei Qi, BS†, and Xiaoqing Song, MS† Our objective was to determine factors that influence the prognosis of cryptogenic partial seizures in children. In total, 233 patients were included in a hospitalbased observational survey. Clinical characteristics of patients were reviewed and analyzed. Patients were characterized as having poor control of their seizures, or as having a >50% decrease in their number of seizures. Student t test or Pearson’s chi-square test were used to determine the differences between the groups with regard to clinical data. Multiple logistic regression analysis was used to investigate the independent effect of each risk factor. Complete seizure control was achieved in 71.7% of patients; improved seizure control was achieved in 13.3%; and poor seizure control was observed in 15.0%. Patients who had poor control of their seizures had a significantly younger age of onset (P ⴝ 0.03). In addition, chi-square analysis revealed that these patients had a higher seizure frequency (P < 0.001), and that seizure control was dependent on seizure type (P < 0.001). Multiple logistic regression analysis revealed that an initial seizure frequency of >3 per month (odds ratio [OR], 3.07; 95% confidence interval [CI], 1.37-6.88), age of onset (OR, 1.14; 95% CI, 1.0-1.31), and seizure type (OR, 0.48; 95% CI, 0.22-1.01) were predictors of poor seizure control. © 2007 by Elsevier Inc. All rights reserved. Wang Z, Qi L, Song X. Prognosis and predictive factors of partial seizures in children. Pediatr Neurol 2007;37:16-20.
Introduction Epilepsy is one of the most common neurologic disorders of childhood. It affects up to 1% of all children through age 16 years [1]. Of these children who have epilepsy, approximately 40-50% have partial (focal) sei-
From *Department of Pediatrics, Shanghai Xin Hua Hospital and † Department of Pediatrics, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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zures [2,3]. Studies of adults who have partial seizures demonstrated that approximately 70-80% of these patients enter into remission [4]. Even though many studies were conducted on the prognosis of partial seizures in children, the findings have led to no consensus [5-11]. These results arose because the studies were heterogeneous in study design, in the selection of study participants, and in the decisions regarding medication usage. Some studies, for example, included patients who had abnormalities on neuroimaging or who had developmental delays, whereas other studies excluded patients with these types of abnormalities. The published reports that determined the prognostic factors of partial seizures in children found that certain factors, such as structural damage of the brain, previous history of brain injury, and neonatal seizures, are associated with persistent seizures [4,7,9,11,12]. In our study, we did not include patients who had these types of factors. Hence we could identify prognostic factors in children who have cryptogenic partial seizures. It is important that accurate prognostic factors be determined for children who have partial seizures. These factors are needed to help make treatment decisions for these patients, such as when to use quick and aggressive treatment, when to gradually withdraw medications, or when to use surgical intervention for epilepsy. In addition, parents often request this type of information, which they use to help them understand their child’s epilepsy and help them make informed decisions regarding their child’s treatment. The objective of this study was to determine the factors that influence the prognosis of cryptogenic partial seizures in children. These patients constitute approximately 17% of pediatric patients who have epilepsy [13]. It is important that studies be done on this particular population, so that accurate predictive models can be developed for patients who have this type of epilepsy. In addition, this
Communications should be addressed to: Dr. Wang; Shanghai Children’s Medical Center; 1678 Dongfang Road; Shanghai 200127, China. E-mail: [email protected] Received July 5, 2006; accepted March 22, 2007.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.03.005 ● 0887-8994/07/$—see front matter
study was one of the first to evaluate the outcome of partial seizures in Chinese children.
Table 1.
Seizure characteristics of study subjects (n ⴝ 233)
Seizure Characteristics
Patients and Methods Patients All patients enrolled for this study had partial seizures, were treated with antiepileptic drugs, and were followed at the outpatient clinic of the Shanghai Xin Hua Hospital, affiliated with the Medical School of Shanghai Jiaotong University in Shanghai, China, between September 1988-September 2005. Patients were selected for this study if they had had two or more partial seizures (with or without secondarily generalized seizures) and had been followed at the outpatient clinic. Partial seizures were diagnosed and classified according to the classification of seizures by the International League Against Epilepsy [14]. No patient was identified as having a metabolic disease. Medical therapy for all patients began with the use of a first-line antiepileptic drug (e.g., carbamazepine, sodium valproate, or phenobarbital). If a patient’s seizures were resistant to treatment with the maximum levels of one or two antiepileptic drugs, then the medications for that patient would either be replaced or be combined with additional antiepileptic drugs. Exclusion criteria included a history of acquired postnatal brain lesions, a family history of seizures, a clinical diagnosis of an epileptic syndrome, progressive neurologic disease, or other abnormalities (e.g., neurocutaneous syndrome, mental retardation, or abnormal findings on an intracranial imaging evaluation). All patients had at least one routine interictal electroencephalogram. Patients whose routine electroencephalograms were normal received 24-hour, long-term electroencephalogram monitoring. Patients’ records were rated according to the following predominant electroencephalographic abnormalities: diffuse slowing, localized slowing, generalized epileptiform activity or rhythms, or localized epileptiform discharges. Patients’ records were divided into six groups according to the origin of epileptiform discharges: temporal lobe, central-temporal lobe, occipital lobe, frontal lobe, bilateral, unilateral, or other areas. Clinical features and electroencephalogram results from patient charts were retrospectively analyzed. Age of seizure onset, seizure type, seizure frequency, number of seizures before treatment, seizure features, duration of seizures, and time interval from seizure onset to first medical treatment were evaluated by two of the authors. Patients were grouped according to their outcome as being seizure-free, having improved seizure control (i.e., greater than 50% reduction in seizure frequency), or showing no improvement. Remission was defined as having no seizure activity within 1 year of follow-up.
Statistical Analysis Normal distribution was tested with the Kolmogoroff-Smirov test. The significance of efficacy of treatment between different ages of onset was assessed by Student t test. All statistical analyses were performed using SPSS 10.0 (SPSS, Inc., Chicago, IL). The Pearson’s chi-square test was used to analyze the significance between the two groups for clinical data, including the difference of efficacy of treatment with regard to duration of seizures, seizure frequency, total seizure times before treatment, time interval from first seizure to first medical treatment, and clinical manifestations. The outcome of treatment between the three seizure types and the origin of the epileptiform discharges were also assessed by Pearson’s chi-square test. Multiple logistic regression analysis was used to investigate the independent effect of each risk factor. Odds ratios with 95% confidence intervals were calculated, using a logistic regression model. Odds ratios were used as an approximation of relative risk to indicate the magnitude of association between each factor and intractable epilepsy. P ⱕ 0.05 was designated as significant.
Seizure type Simple partial Complex partial Complex partial/generalized Clinical manifestations Motor attack Sensory attack Autonomic attack Psychic attack Mixed attack
Number (%)
41 (17.6) 162 (69.5) 30 (12.9) 192 (82.4) 5 (2.1) 24 (10.3) 6 (2.6) 6 (2.6)
Results In total, 233 patients (136 males and 97 females) were enrolled in this study. Their mean age of seizure onset was 6 years (range, 3 months to 12 years), and the mean duration of follow-up was 4.5 years (range, 2-13 years). The seizure characteristics of the study subjects are described in Table 1. A majority of patients were diagnosed as having complex partial seizures, and had the clinical manifestation of a motor attack. The range of seizure duration was several seconds to over 3 hours, and seizure frequency was noted to be between once a year to more than 10 times per day. In addition, the total number of seizures prior to receiving treatment ranged from 2-16. The time interval from first seizure to medical treatment was between 1 week and 1 year, and the time to reach efficacy was between 1-24 weeks after initiating drug treatment. With regard to antiepileptic drug treatment, 194 patients were treated with monotherapy, 29 patients received two antiepileptic drugs, and 10 patients were treated with three or more antiepileptic drugs. Of the 233 patients in the study, 198 responded well to receiving antiepileptic drugs. Of these 233 patients, 167 (71.7%) were seizure-free, 31 patients (13.3%) were well-controlled with a seizure reduction of more than 50%, and 35 patients (15.0%) had refractory seizure activity during their follow-up period. When patients who had an initial onset of seizures before 3 years of age were compared with those who had their first seizures at or after 3 years of age, the difference in prognosis was significant: the younger the onset age, the worse the prognosis (Table 2). A reliable estimate of seizure frequency before treatment was obtained in all patients. A large majority of patients (89%) who had three or fewer seizures per month were well-controlled (seizurefree or greater than 50% seizure reduction). In comparison, only 72% of patients who had a high seizure frequency (more than three seizures per month) were well-controlled. The difference in seizure prognosis with regard to seizure frequency and outcome was statistically significant (Table 2). No significant differences in seizure prognosis were observed when considering the duration of seizures, the time to seizure treatment, and the total number of seizures before treatment (Table 2).
Wang et al: Prognosis and Predictive Factors of Partial Seizures 17
Table 2. Association of clinical characteristics with seizure outcome (n ⴝ 233)
Clinical Characteristic
Seizure Response (n) Improved Poor
Age of onset ⬍3 years ⱖ3 years Seizure frequency ⱕ3/month ⬎3/month Duration of seizures (min) ⬍15 15-30 ⱖ30 Total seizures before treatment (n) ⱕ2 3-5 ⬎5 Time to treatment (years) ⬍0.5 ⬍1 ⱖ1
Table 4. Linear regression analysis of characteristics associated with poor seizure outcome
P Value 0.026*
36 169
14 14
56 140
21 16 0.452
161 15 21
29 1 6 0.071
101 79 35
15 3 0
28 2 4
131 17 51
0.217
Significant differences in seizure prognosis were also associated with seizure type. The prognosis tended to be best in the group of patients who had simple partial seizures, and worst in the group of patients who had partial seizures with secondary generalized seizures. The group of patients who had complex partial seizures had an intermediate prognosis (Table 3). In addition, the presence of secondary generalization was significantly lower in the well-controlled group (P ⬍ 0.001). No differences in prognosis were observed when considering the clinical Table 3. Association of seizure type, clinical manifestations, and electroencephalogram results with seizure outcome (n ⴝ 233) Seizure Response (n) Improved Poor
Classification Simple partial Complex partial Partial/generalized Clinical manifestation Motor Sensory Autonomic Psychic Mixed Epileptic discharge area Temporal Frontal Occipital Temporal-central Bilateral Unilateral Other areas
P Value* ⬍0.001
36 144 18
5 18 12
161 5 21 6 5
31 0 3 0 1
44 13 23 31 17 15 55
4 0 6 6 6 2 11
0.687
0.299
* P values were determined by using Pearson’s chi-square test.
18
Odds Ratio
95% Confidence Interval
P Value
Age of seizure onset ⬎3 seizures per month Type of epilepsy
1.14 3.07 0.48
1.0-1.31 1.37-6.88 0.22-1.01
0.05 0.007 0.054
⬍0.001
* P value for age of onset was determined by using Student t test. All other P values were determined by using Pearson’s chi-square test.
Seizure Characteristic
Characteristic
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manifestations of seizures or epileptic discharge areas (Table 3). Multiple logistic regression analysis revealed that an initial seizure frequency of more than three per month, age of seizure onset, and seizure type were predictors of poor seizure control. None of the other calculated variables were associated with poor seizure control (Table 4). Discussion In this study, we observed that 72% of patients had complete seizure control. It is difficult to compare directly the rates of complete seizure control among studies because of varying study designs. However, other studies also indicated high rates of seizure control. In several studies that included patients who had all types of epilepsy, the rates of seizure control ranged from approximately 50-70% [15-17]. In those studies that included only patients who had partial epilepsies, the rates ranged from approximately 50-85% [7,9,11]. The studies that demonstrated a lower rate of seizure control were most likely hospital-based, and included only the most severe cases of epilepsy. In contrast, those studies that demonstrated a higher rate of seizure control were most likely from population-based surveys, and included all cases of epilepsy. Even though our study was based on a hospitalbased survey, it was likely that our patients were wellrepresentative of those in the general population. In Shanghai, primary-care physicians do not provide care for epileptic patients; therefore, all cases of epilepsy are seen by pediatric neurologists. Even though a new classification for seizures was suggested in 2001 by the International League Against Epilepsy, the 1981 classification is still widely accepted. We found that the classification of 1981 was useful in the assessment of patients who had partial seizures. Based on this classification, epilepsy is divided into two main categories: partial seizures and generalized seizures. Partial seizures are then further categorized into simple partial seizures, complex partial seizures, and partial seizures with secondary generalized seizures. Based on results from the current study, there are significant differences among these three types of partial seizures in children. The prognosis was best in the group of patients who had simple partial seizures, followed by the group of patients who had complex partial seizures, and was worst in the group of patients who had partial seizures and secondary generalized seizures. The results of logistic regression analysis
also confirmed a correlation between type of partial seizure in children and their prognosis. Therefore, the 1981 classification may confer prognostic information in addition to its guidance in therapeutic strategies. In a 1989 classification by the International League Against Epilepsy, there was a detailed description of partial epilepsy, based on the anatomic location of the seizure [18]. It is widely accepted that several types of epilepsy, including benign childhood epilepsy with centrotemporal spikes, benign childhood epilepsy with occipital paroxysm, benign parietal lobe epilepsy, and autosomaldominant nocturnal frontal lobe epilepsy, have a better prognosis. Verrotti et al. [8], however, argued that not all epilepsy with occipital paroxysms has a good prognosis, because it is rare to have benign childhood epilepsy that only involves occipital paroxysms. Hirsch et al. [12] also concluded that it is rare for a partial seizure to involve only one lobe, and that the origin of epileptiform discharges should not be a deciding factor for prognosis. In the current study, there were no significant differences between patients with regard to the origin of their epileptiform discharges. Furthermore, we observed that some patients had similar clinical manifestations, even though the origins of their electroencephalogram waves were different. For example, among 192 patients with clonic seizures, electroencephalogram abnormalities had originated from different locations of the brain, including frontal, occipital, temporal, centro-temporal, unilateral, and bilateral. In addition, among 29 patients with an electroencephalogram abnormality in the occipital lobe, only one had visual symptoms. The seizures of the other patients manifested as clonus, tonus, seizures of the facial muscles, headache, dizziness, and syncope. These findings argue against a correlation between the location of an electroencephalogram abnormality, clinical signs, and responsiveness to therapy. There have been few reports on the correlation between clinical symptoms of epilepsy and its prognosis. Panayiotopoulos [19] conducted a study of prognoses in epileptic patients with autonomic symptoms, and reported that the incidence of this type of epilepsy was approximately 13% and that it had a benign prognosis. The current study included 24 patients (10%) who displayed autonomic symptoms such as headache, dizziness, vomiting, stomachache, and syncope. The prognosis of these patients was not statistically different from that of patients who had motor, perception, and psychiatric symptoms. In the present study, it was reported that age of seizure onset is a predictive factor for partial epilepsy. This result was consistent with those from other studies of partial epilepsy [7,20,21]. In addition, recent studies that included all seizure types also indicated that age is a predictive factor [17,22,23]. However, other studies of partial epilepsy indicated that age is not always a predictive factor [7,9]. This finding most likely results from differences in study design and in the types of patients included in the study. In Verotti et al. [8], for example, only those patients
with complex partial epilepsy were included. In contrast, our study included patients with either simple or complex partial epilepsy. Although the mechanisms of seizure intractability are not fully understood, age-dependent vulnerability to seizures is likely to be important [24]. A high initial seizure frequency of more than three seizures per month was associated with a poor prognosis in the present study. Further study by regression analysis demonstrated that seizure onset and frequency were related to prognosis. This result was similar to those in other studies. Schmidt [25] elegantly demonstrated that a high number of seizures was an adverse prognostic factor for patients with complex partial epilepsy. In addition, Ohtuska et al. reported that a high initial seizure frequency was a predictor for poor outcome in patients with partial epilepsy. Large-scale studies also revealed that patients with a history of a large number of seizures before treatment had a lower probability of achieving control with antiepileptic drug treatment [26]. In the present study, the time interval from first seizure to start of antiepileptic drug treatment did not influence the prognosis. This observation accorded with the findings of large epidemiologic studies in previously untreated populations, i.e., that neither the duration of epilepsy nor the number of seizures before antiepileptic drug treatment were predictors of outcome [27,28]. This suggests that treatment can be as effective in patients with a long history of epilepsy as in those with a short history of epilepsy. This observation is especially significant for physicians who provide care for epilepsy patients in underdeveloped and developing countries. In these areas, many patients do not receive care in a timely manner because of financial constraints and inaccessibility of medical care. Many of these patients will have manifested seizures for a long time before receiving any treatment. In this study, we demonstrated that a young age of seizure onset, a high initial seizure frequency, and certain seizure types are predictors of a poor outcome for patients who have partial seizures. These conclusions need to be verified by additional, large-scale studies before this information can be used to help predict the prognosis of patients who have partial seizures. Even though many studies have been performed on the outcome of seizures, much work still needs to be done before reliable and accurate models can be developed to determine the prognosis of seizures.
References [1] Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1993;34:453-68. [2] Williamsom PD, Engel Jr, J. Complex partial seizures. In: Engel Jr, J, Pedley TA, editors. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott-Raven, 2001:557-66. [3] Engel Jr, J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE task force on classification and terminology. Epilepsia 2001;42:796-803.
Wang et al: Prognosis and Predictive Factors of Partial Seizures 19
[4] Trinka E, Martin F, Luef G, Unterberger I, Bauer G. Chronic epilepsy with complex partial seizures is not always medically intractable—a long-term observational study. Acta Neurol Scand 2001;103:219-25. [5] Sztriha L, Gururaj AK, Bener A, Nork M. Temporal lobe epilepsy in children: Etiology in a cohort with new-onset seizures. Epilepsia 2002;43:75-80. [6] Major P, Décarie JC, Nadeau A, et al. Clinical significance of isolated hippocampal volume asymmetry in childhood epilepsy. Neurology 2004;63:1503-6. [7] Ohtsuka Y, Yoshinaga H, Kobayashi K, et al. Predictors and underlying causes of medically intractable localization-related epilepsy in childhood. Pediatr Neurol 2001;24:209-13. [8] Verrotti A, Domizio S, Guerra M, Sabatino G, Morgese G, Chiarelli F. Childhood epilepsy with occipital paroxysms and benign nocturnal childhood occipital epilepsy. J Child Neurol 2000;15:218-21. [9] Verrotti A, Latini G, Giannuzzi R, et al. Factors associated with poor control in partial complex epilepsy. J Child Neurol 2004;19:262-4. [10] Hughes JR, Fino JJ. Focal seizures and EEG: Prognostic considerations. Clin Electroencephalogr 2003;34:174-81. [11] Okumura A, Hayakawa F, Kato T, Kuno K, Negoro T, Watanabe K. Five-year follow-up of patients with partial epilepsies in infancy. Pediatr Neurol 2001;24:290-6. [12] Hirsch E, de Saint-Martin A, Arzimanoglou A. New insights into the clinical management of partial epilepsies. Epilepsia 2000;41 (Suppl. 5):S13-7. [13] Shinnar S, Pellock JM. Update on the epidemiology and prognosis of pediatric epilepsy. J Child Neurol 2002;17(Suppl. 1):S4-17. [14] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501. [15] Tang-Wai R, Oskoui M, Webster R, Shevell M. Outcomes in pediatric epilepsy: Seeing through the fog. Pediatr Neurol 2005;33: 244-50.
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[16] Oskoui M, Webster RI, Zhang, X, Shevell MI. Factors predictive of outcome in childhood epilepsy. J Child Neurol 2005;20:898-904. [17] Kwong KL, Sung WY, Wong SN, So KT. Early predictors of medical intractability in childhood epilepsy. Pediatr Neurol 2003;29: 46-52. [18] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndrome. Epilepsia 1989;30:389-99. [19] Panayiotopoulos CP. Autonomic seizures and autonomic status epilepticus peculiar to childhood: Diagnosis and management. Epilepsy Behav 2004;5:286-95. [20] Berg AT, Levy SR, Novotny EJ, Shinnar S. Predictors of intractable epilepsy in childhood: A case-control study. Epilepsia 1996; 37:24-30. [21] Kim WJ, Park SC, Lee SJ, et al. The prognosis for control of seizures with medications in patients with MRI evidence for mesial temporal sclerosis. Epilepsia 1999;40:290-3. [22] Chawla S, Aneja S, Kashyap R, Mallika V. Etiology and clinical predictors of intractable epilepsy. Pediatr Neurol 2002;27: 186-91. [23] Gururaj A, Sztriha L, Hertecant J, Eapen V. Clinical predictors of intractable childhood epilepsy. J Psychosom Res 2006;61:343-7. [24] Sperber EF, Veliškova J, Gernamo IM, Friedman LK, Moshé SL. Age dependent vulnerability to seizures. Adv Neurol 1999;79:161-9. [25] Schmidt D. Prognosis of chronic epilepsy with complex partial seizures. J Neurol Neurosurg Psychiatry 1984;47:1274-8. [26] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314-9. [27] Placencia M, Shorvon SD, Paredes V, et al. Epileptic seizures in an Andean region of Ecuador. Incidence and prevalence and regional variation. Brain 1992;115:771-82. [28] Watts AE. The natural history of untreated epilepsy in a rural community in Africa. Epilepsia 1992;33:464-8.
Introduction Epilepsy is one of the most common neurologic disorders of childhood. It affects up to 1% of all children through age 16 years [1]. Of these children who have epilepsy, approximately 40-50% have partial (focal) sei-
From *Department of Pediatrics, Shanghai Xin Hua Hospital and † Department of Pediatrics, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
16
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zures [2,3]. Studies of adults who have partial seizures demonstrated that approximately 70-80% of these patients enter into remission [4]. Even though many studies were conducted on the prognosis of partial seizures in children, the findings have led to no consensus [5-11]. These results arose because the studies were heterogeneous in study design, in the selection of study participants, and in the decisions regarding medication usage. Some studies, for example, included patients who had abnormalities on neuroimaging or who had developmental delays, whereas other studies excluded patients with these types of abnormalities. The published reports that determined the prognostic factors of partial seizures in children found that certain factors, such as structural damage of the brain, previous history of brain injury, and neonatal seizures, are associated with persistent seizures [4,7,9,11,12]. In our study, we did not include patients who had these types of factors. Hence we could identify prognostic factors in children who have cryptogenic partial seizures. It is important that accurate prognostic factors be determined for children who have partial seizures. These factors are needed to help make treatment decisions for these patients, such as when to use quick and aggressive treatment, when to gradually withdraw medications, or when to use surgical intervention for epilepsy. In addition, parents often request this type of information, which they use to help them understand their child’s epilepsy and help them make informed decisions regarding their child’s treatment. The objective of this study was to determine the factors that influence the prognosis of cryptogenic partial seizures in children. These patients constitute approximately 17% of pediatric patients who have epilepsy [13]. It is important that studies be done on this particular population, so that accurate predictive models can be developed for patients who have this type of epilepsy. In addition, this
Communications should be addressed to: Dr. Wang; Shanghai Children’s Medical Center; 1678 Dongfang Road; Shanghai 200127, China. E-mail: [email protected] Received July 5, 2006; accepted March 22, 2007.
© 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.03.005 ● 0887-8994/07/$—see front matter
study was one of the first to evaluate the outcome of partial seizures in Chinese children.
Table 1.
Seizure characteristics of study subjects (n ⴝ 233)
Seizure Characteristics
Patients and Methods Patients All patients enrolled for this study had partial seizures, were treated with antiepileptic drugs, and were followed at the outpatient clinic of the Shanghai Xin Hua Hospital, affiliated with the Medical School of Shanghai Jiaotong University in Shanghai, China, between September 1988-September 2005. Patients were selected for this study if they had had two or more partial seizures (with or without secondarily generalized seizures) and had been followed at the outpatient clinic. Partial seizures were diagnosed and classified according to the classification of seizures by the International League Against Epilepsy [14]. No patient was identified as having a metabolic disease. Medical therapy for all patients began with the use of a first-line antiepileptic drug (e.g., carbamazepine, sodium valproate, or phenobarbital). If a patient’s seizures were resistant to treatment with the maximum levels of one or two antiepileptic drugs, then the medications for that patient would either be replaced or be combined with additional antiepileptic drugs. Exclusion criteria included a history of acquired postnatal brain lesions, a family history of seizures, a clinical diagnosis of an epileptic syndrome, progressive neurologic disease, or other abnormalities (e.g., neurocutaneous syndrome, mental retardation, or abnormal findings on an intracranial imaging evaluation). All patients had at least one routine interictal electroencephalogram. Patients whose routine electroencephalograms were normal received 24-hour, long-term electroencephalogram monitoring. Patients’ records were rated according to the following predominant electroencephalographic abnormalities: diffuse slowing, localized slowing, generalized epileptiform activity or rhythms, or localized epileptiform discharges. Patients’ records were divided into six groups according to the origin of epileptiform discharges: temporal lobe, central-temporal lobe, occipital lobe, frontal lobe, bilateral, unilateral, or other areas. Clinical features and electroencephalogram results from patient charts were retrospectively analyzed. Age of seizure onset, seizure type, seizure frequency, number of seizures before treatment, seizure features, duration of seizures, and time interval from seizure onset to first medical treatment were evaluated by two of the authors. Patients were grouped according to their outcome as being seizure-free, having improved seizure control (i.e., greater than 50% reduction in seizure frequency), or showing no improvement. Remission was defined as having no seizure activity within 1 year of follow-up.
Statistical Analysis Normal distribution was tested with the Kolmogoroff-Smirov test. The significance of efficacy of treatment between different ages of onset was assessed by Student t test. All statistical analyses were performed using SPSS 10.0 (SPSS, Inc., Chicago, IL). The Pearson’s chi-square test was used to analyze the significance between the two groups for clinical data, including the difference of efficacy of treatment with regard to duration of seizures, seizure frequency, total seizure times before treatment, time interval from first seizure to first medical treatment, and clinical manifestations. The outcome of treatment between the three seizure types and the origin of the epileptiform discharges were also assessed by Pearson’s chi-square test. Multiple logistic regression analysis was used to investigate the independent effect of each risk factor. Odds ratios with 95% confidence intervals were calculated, using a logistic regression model. Odds ratios were used as an approximation of relative risk to indicate the magnitude of association between each factor and intractable epilepsy. P ⱕ 0.05 was designated as significant.
Seizure type Simple partial Complex partial Complex partial/generalized Clinical manifestations Motor attack Sensory attack Autonomic attack Psychic attack Mixed attack
Number (%)
41 (17.6) 162 (69.5) 30 (12.9) 192 (82.4) 5 (2.1) 24 (10.3) 6 (2.6) 6 (2.6)
Results In total, 233 patients (136 males and 97 females) were enrolled in this study. Their mean age of seizure onset was 6 years (range, 3 months to 12 years), and the mean duration of follow-up was 4.5 years (range, 2-13 years). The seizure characteristics of the study subjects are described in Table 1. A majority of patients were diagnosed as having complex partial seizures, and had the clinical manifestation of a motor attack. The range of seizure duration was several seconds to over 3 hours, and seizure frequency was noted to be between once a year to more than 10 times per day. In addition, the total number of seizures prior to receiving treatment ranged from 2-16. The time interval from first seizure to medical treatment was between 1 week and 1 year, and the time to reach efficacy was between 1-24 weeks after initiating drug treatment. With regard to antiepileptic drug treatment, 194 patients were treated with monotherapy, 29 patients received two antiepileptic drugs, and 10 patients were treated with three or more antiepileptic drugs. Of the 233 patients in the study, 198 responded well to receiving antiepileptic drugs. Of these 233 patients, 167 (71.7%) were seizure-free, 31 patients (13.3%) were well-controlled with a seizure reduction of more than 50%, and 35 patients (15.0%) had refractory seizure activity during their follow-up period. When patients who had an initial onset of seizures before 3 years of age were compared with those who had their first seizures at or after 3 years of age, the difference in prognosis was significant: the younger the onset age, the worse the prognosis (Table 2). A reliable estimate of seizure frequency before treatment was obtained in all patients. A large majority of patients (89%) who had three or fewer seizures per month were well-controlled (seizurefree or greater than 50% seizure reduction). In comparison, only 72% of patients who had a high seizure frequency (more than three seizures per month) were well-controlled. The difference in seizure prognosis with regard to seizure frequency and outcome was statistically significant (Table 2). No significant differences in seizure prognosis were observed when considering the duration of seizures, the time to seizure treatment, and the total number of seizures before treatment (Table 2).
Wang et al: Prognosis and Predictive Factors of Partial Seizures 17
Table 2. Association of clinical characteristics with seizure outcome (n ⴝ 233)
Clinical Characteristic
Seizure Response (n) Improved Poor
Age of onset ⬍3 years ⱖ3 years Seizure frequency ⱕ3/month ⬎3/month Duration of seizures (min) ⬍15 15-30 ⱖ30 Total seizures before treatment (n) ⱕ2 3-5 ⬎5 Time to treatment (years) ⬍0.5 ⬍1 ⱖ1
Table 4. Linear regression analysis of characteristics associated with poor seizure outcome
P Value 0.026*
36 169
14 14
56 140
21 16 0.452
161 15 21
29 1 6 0.071
101 79 35
15 3 0
28 2 4
131 17 51
0.217
Significant differences in seizure prognosis were also associated with seizure type. The prognosis tended to be best in the group of patients who had simple partial seizures, and worst in the group of patients who had partial seizures with secondary generalized seizures. The group of patients who had complex partial seizures had an intermediate prognosis (Table 3). In addition, the presence of secondary generalization was significantly lower in the well-controlled group (P ⬍ 0.001). No differences in prognosis were observed when considering the clinical Table 3. Association of seizure type, clinical manifestations, and electroencephalogram results with seizure outcome (n ⴝ 233) Seizure Response (n) Improved Poor
Classification Simple partial Complex partial Partial/generalized Clinical manifestation Motor Sensory Autonomic Psychic Mixed Epileptic discharge area Temporal Frontal Occipital Temporal-central Bilateral Unilateral Other areas
P Value* ⬍0.001
36 144 18
5 18 12
161 5 21 6 5
31 0 3 0 1
44 13 23 31 17 15 55
4 0 6 6 6 2 11
0.687
0.299
* P values were determined by using Pearson’s chi-square test.
18
Odds Ratio
95% Confidence Interval
P Value
Age of seizure onset ⬎3 seizures per month Type of epilepsy
1.14 3.07 0.48
1.0-1.31 1.37-6.88 0.22-1.01
0.05 0.007 0.054
⬍0.001
* P value for age of onset was determined by using Student t test. All other P values were determined by using Pearson’s chi-square test.
Seizure Characteristic
Characteristic
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manifestations of seizures or epileptic discharge areas (Table 3). Multiple logistic regression analysis revealed that an initial seizure frequency of more than three per month, age of seizure onset, and seizure type were predictors of poor seizure control. None of the other calculated variables were associated with poor seizure control (Table 4). Discussion In this study, we observed that 72% of patients had complete seizure control. It is difficult to compare directly the rates of complete seizure control among studies because of varying study designs. However, other studies also indicated high rates of seizure control. In several studies that included patients who had all types of epilepsy, the rates of seizure control ranged from approximately 50-70% [15-17]. In those studies that included only patients who had partial epilepsies, the rates ranged from approximately 50-85% [7,9,11]. The studies that demonstrated a lower rate of seizure control were most likely hospital-based, and included only the most severe cases of epilepsy. In contrast, those studies that demonstrated a higher rate of seizure control were most likely from population-based surveys, and included all cases of epilepsy. Even though our study was based on a hospitalbased survey, it was likely that our patients were wellrepresentative of those in the general population. In Shanghai, primary-care physicians do not provide care for epileptic patients; therefore, all cases of epilepsy are seen by pediatric neurologists. Even though a new classification for seizures was suggested in 2001 by the International League Against Epilepsy, the 1981 classification is still widely accepted. We found that the classification of 1981 was useful in the assessment of patients who had partial seizures. Based on this classification, epilepsy is divided into two main categories: partial seizures and generalized seizures. Partial seizures are then further categorized into simple partial seizures, complex partial seizures, and partial seizures with secondary generalized seizures. Based on results from the current study, there are significant differences among these three types of partial seizures in children. The prognosis was best in the group of patients who had simple partial seizures, followed by the group of patients who had complex partial seizures, and was worst in the group of patients who had partial seizures and secondary generalized seizures. The results of logistic regression analysis
also confirmed a correlation between type of partial seizure in children and their prognosis. Therefore, the 1981 classification may confer prognostic information in addition to its guidance in therapeutic strategies. In a 1989 classification by the International League Against Epilepsy, there was a detailed description of partial epilepsy, based on the anatomic location of the seizure [18]. It is widely accepted that several types of epilepsy, including benign childhood epilepsy with centrotemporal spikes, benign childhood epilepsy with occipital paroxysm, benign parietal lobe epilepsy, and autosomaldominant nocturnal frontal lobe epilepsy, have a better prognosis. Verrotti et al. [8], however, argued that not all epilepsy with occipital paroxysms has a good prognosis, because it is rare to have benign childhood epilepsy that only involves occipital paroxysms. Hirsch et al. [12] also concluded that it is rare for a partial seizure to involve only one lobe, and that the origin of epileptiform discharges should not be a deciding factor for prognosis. In the current study, there were no significant differences between patients with regard to the origin of their epileptiform discharges. Furthermore, we observed that some patients had similar clinical manifestations, even though the origins of their electroencephalogram waves were different. For example, among 192 patients with clonic seizures, electroencephalogram abnormalities had originated from different locations of the brain, including frontal, occipital, temporal, centro-temporal, unilateral, and bilateral. In addition, among 29 patients with an electroencephalogram abnormality in the occipital lobe, only one had visual symptoms. The seizures of the other patients manifested as clonus, tonus, seizures of the facial muscles, headache, dizziness, and syncope. These findings argue against a correlation between the location of an electroencephalogram abnormality, clinical signs, and responsiveness to therapy. There have been few reports on the correlation between clinical symptoms of epilepsy and its prognosis. Panayiotopoulos [19] conducted a study of prognoses in epileptic patients with autonomic symptoms, and reported that the incidence of this type of epilepsy was approximately 13% and that it had a benign prognosis. The current study included 24 patients (10%) who displayed autonomic symptoms such as headache, dizziness, vomiting, stomachache, and syncope. The prognosis of these patients was not statistically different from that of patients who had motor, perception, and psychiatric symptoms. In the present study, it was reported that age of seizure onset is a predictive factor for partial epilepsy. This result was consistent with those from other studies of partial epilepsy [7,20,21]. In addition, recent studies that included all seizure types also indicated that age is a predictive factor [17,22,23]. However, other studies of partial epilepsy indicated that age is not always a predictive factor [7,9]. This finding most likely results from differences in study design and in the types of patients included in the study. In Verotti et al. [8], for example, only those patients
with complex partial epilepsy were included. In contrast, our study included patients with either simple or complex partial epilepsy. Although the mechanisms of seizure intractability are not fully understood, age-dependent vulnerability to seizures is likely to be important [24]. A high initial seizure frequency of more than three seizures per month was associated with a poor prognosis in the present study. Further study by regression analysis demonstrated that seizure onset and frequency were related to prognosis. This result was similar to those in other studies. Schmidt [25] elegantly demonstrated that a high number of seizures was an adverse prognostic factor for patients with complex partial epilepsy. In addition, Ohtuska et al. reported that a high initial seizure frequency was a predictor for poor outcome in patients with partial epilepsy. Large-scale studies also revealed that patients with a history of a large number of seizures before treatment had a lower probability of achieving control with antiepileptic drug treatment [26]. In the present study, the time interval from first seizure to start of antiepileptic drug treatment did not influence the prognosis. This observation accorded with the findings of large epidemiologic studies in previously untreated populations, i.e., that neither the duration of epilepsy nor the number of seizures before antiepileptic drug treatment were predictors of outcome [27,28]. This suggests that treatment can be as effective in patients with a long history of epilepsy as in those with a short history of epilepsy. This observation is especially significant for physicians who provide care for epilepsy patients in underdeveloped and developing countries. In these areas, many patients do not receive care in a timely manner because of financial constraints and inaccessibility of medical care. Many of these patients will have manifested seizures for a long time before receiving any treatment. In this study, we demonstrated that a young age of seizure onset, a high initial seizure frequency, and certain seizure types are predictors of a poor outcome for patients who have partial seizures. These conclusions need to be verified by additional, large-scale studies before this information can be used to help predict the prognosis of patients who have partial seizures. Even though many studies have been performed on the outcome of seizures, much work still needs to be done before reliable and accurate models can be developed to determine the prognosis of seizures.
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