Introduction
Epilepsy is a common and worldwide nervous system disease, ranking second after cerebrovascular disease among the common diseases of the nervous system. According to statistics, the prevalence of epilepsy in developed countries is 0.3%-0.7%, whereas that in developing countries is high at 1.5%-3.5% [
1,
2]. Approximately six million people have epilepsy in China, with a prevalence of 0.5%. Each year, about 0.65-0.70 million new cases appear, around 75% of which can be treated by the conventional first-line antiepileptic drugs with satisfactory efficacy. In China, more than 1.5 million people with refractory epilepsy account for 25% of all epilepsy patients [
3]. Epilepsy has been treated with traditional Chinese medicine since over a thousand years ago. Wind, fire, phlegm, stagnation, and deficiency are considered the primary pathogenesis of epilepsy. The therapeutic principle and prescriptions, which are based on the four methods of diagnosis and eight principal syndromes, regulate the functions of the Zang-fu organs and balance the Yin and Yang. Stable efficacy and safety of the medicines are the advantages of this treatment [
4]. After 14 years of hard work, Yunnan University of Traditional Chinese Medicine finally developed a pure Chinese medicine product called Dianxianning Pian, whose components are
Saruma henry, Rhizoma Acori Tatarinowii, Ramulus Uncariae cum Uncis,
Semen Pharbitidis, Semen Euphorbiae, Radix et Rhizoma Valerianae, Rhizoma et Radix Nardostachys, and menthol crystal, among others. Eliminating phlegm for resuscitation, stopping wind, and calming the spirit are the main effects of this medicine. In our study, randomized and controlled multicenter clinical trials were carried out. The result of using Dianxianning Pian as additive treatment to control the severity of seizures has been previously published [
5]. In the current paper, the effect of using Dianxianning Pian on the seizure rate of refractory epilepsy is presented.
Materials and methods
Source of patients
The cases were recruited from all research units from May 2007 to January 2008. In total, 212 patients were randomly divided into two groups: the treatment group and the control group with a ratio of 2∶1. The experimental group comprised 141 patients, whereas the control group had 71 cases, excluding the cases that did not meet the inclusion criteria. Ultimately, we obtained the intention to treat (ITT) data set of 206 patients (i.e. 137 patients in the experimental group, and 69 patients in control group) and the Per-Protocol (PP) data set of 196 cases, among which 129 cases belonged to the experimental group and 67 belonged to the control group, with a dropout rate of 7.55%. In total, 206 qualified patients were gathered from Wangjing Hospital of China Academy of Chinese Medical Sciences (33 cases), Inner Mongolia People’s Hospital (70 cases), the First Affiliated Hospital of Kunming Medical College (33 cases), Beijing University of Traditional Chinese Medicine Oriental Hospital (35 cases), and Tongliao Hospital (35 cases). Included in the treatment group were 87 cases of males and 50 cases of females. The treatment group was composed of 117 Han cases, 10 Mongolian cases, and 10 cases of other nationalities. The mean age was 33.99±15.05 years, and the first seizure age was 25.42±16.82 years. The average height was 166.96±7.57 cm, and the average weight was 62.77±9.98 kg. In the control group, there were 41 males and 28 females, among whom there were 60 Han cases, 7 Mongolian cases, and 2 cases of other nationalities. The mean age was 33.90±16.30 years, and the first seizure age was 26.39±18.71 years. The average height was 167.80±6.90 cm, and the average weight was 62.71±8.59 kg. The general data of these two groups had no significant difference (P>0.05) and were comparable. The two groups maintained the original treatment of carbamazepine or valproate; the medication type and dosage of the two groups had no significant statistical difference. The protocol was approved by Wangjing Hospital Ethics Review Committee of China Academy of Chinese Medical Sciences.
Patient selection standards
Diagnostic criteria of traditional Chinese medicine
The following are according to the “Guiding principles for clinical research on new drugs of traditional Chinese medicine. Guiding Principles of Traditional Chinese Medical Treatment of Epilepsy Syndrome” (formulated and released by the Ministry of Health, 1993, 179-181) [
6]. ① Epilepsy seizure usually has such symptoms as sudden collapse, unconsciousness, supraduction, limb spasms, and foaming of drool at the mouth. Patients sometimes become wild and then lose consciousness. They return to their normal selves upon waking. ② A mild case is manifested by a dull expression, pale face, blank eyes, and head leaning forward. Patients experiencing these symptoms return to normal right away. ③ The majority of repeated and irregular seizures usually last from a few seconds to several minutes, whereas the minority can last for over several hours. Patients are commonly unaware of what has happened to them. ④ Patients with epilepsy have abnormal electroencephalogram(EEG) results.
Clinical types of epilepsy seizure
Epilepsy seizures are categorized into partial and generalized seizures according to the seizure classification scheme revised by the International Union in 1981 [
7]. (1) Partial seizures (focal and localized onset seizures) include the following: ① simple partial seizures (no loss of consciousness): seizure movements, onset of autonomic nerve symptoms, sensory seizures, and mental symptoms seizures; ② complex partial seizures (impaired consciousness; sometimes with onset of simple symptoms): beginning with simple partial seizures, followed by a disturbance of consciousness; caused by disturbance of consciousness; ③ development of partial seizures into generalized tonic-clonic seizures: development of simple partial seizures into generalized seizures; development of complex partial seizures into generalized seizures; development of simple partial seizures into complex partial seizures and secondary systemic onset. (2) Generalized seizures include the following: ① atypical absence seizures and absence seizures, ② generalized tonic-clonic seizures, ③ myoclonic seizures, ④ clonic seizure, ⑤ tonic seizures, and ⑥ atonic seizures.
Inclusion and exclusion criteria
The inclusion criteria are as follows: ① meet the diagnostic criteria of traditional Chinese medicine, diagnosed with wind-phlegm stagnation syndrome (wind-phlegm disturbance syndrome) [
8], and have symptoms consistent with the diagnosis of generalized tonic-clonic seizures or partial seizures of the whole body [
9]; ② experienced at least two seizures (including two) over the past three months; ③ patients with previous seizures taking antiepileptic medicine still experienced more than two seizures (including two) over the past three months; ④ above 18 years old (including 18 years old); ⑤ with epileptic discharge confirmed by the EEG; ⑥ willing to participate and have good compliance; and ⑦ signed the informed consent. The exclusion criteria are as follows: ① patients with cardiovascular, liver, kidney, and hematopoietic system diseases and other serious diseases; ② patients with a history of drug and alcohol abuse; ③ pregnant or lactating women; ④ persons with active mental illnesses, which can affect the determination of efficacy or safety; and ⑤ patients taking two or more antiepileptic medicine.
Criteria of the curative effect
The calculation formula of the seizure rate of refractory epilepsy is as follows:
Where A=seizure frequency in three months before study, B=seizure frequency in three months in the period of observation.
The ranks of the curative effect based on the seizure frequency are as follows: ① controlling seizure: there is no seizure during the period of observation; ② special effect: the seizure frequency decreases by 75%–99%; ③ valid: seizure frequency decreases by 74%–50%; ④ invalid: seizure frequency decreases by 0–50%; and ⑤ deterioration: seizure frequency increases by more than 25%.
Methods of treatment
Grouping and treatment
Patients were divided randomly into two groups, i.e. the experimental group and the control group, with a ratio of 2∶1. Patients in the experimental group suffered from epilepsy and took western antiepileptic medicine for it. They were also given Dianxianning. Patients in the control group suffered from epilepsy and took western antiepileptic medicine for it. Patients were asked to provide their basic information and baseline figure. They were followed up once a month in three months after treatment. All patients continued to take their original western medicine through its original administration. If there were changes, they were asked to note them down. Dianxianning and its placebo were produced by Kunming Chinese Medicine Factory Co., Ltd. (License Number: H.M.L.N. Z53020771). Patients in the experimental group took four Dianxianning pills orally three times a day. Those in the control group took four pills of the placebo of Dianxianning orally three times a day. The course of treatment of the two groups lasted for three months.
Symptomatic treatment and the rule for combined medication
If a seizure occurred, the corresponding measure would be given to prevent death during the observation period. If the patients contracted a cold, diarrhea, or other diseases, they would be given symptomatic treatment. The doctor would note these down. If the patients took other antiepileptic Chinese medicine before enrolment, they were included in the group 15 days after they had stopped taking it.
Data management and statistical analysis
Data management and statistical analysis were conducted by third parties.
Randomized methods and the concealment of blind code: Random assignment was conducted by a central randomization system developed by the Clinical Evaluation Center of China Academy of Chinese Medical Sciences. When the patients were enrolled, the researchers obtained random numbers by telephone and gave them medicine in numerical order. A blind code was concealed in the system. The database was designed to be accessed, and the data were input by appointed people. Specific inspectors went to every hospital, checked the data, and filled out the tables regularly.
Locking the data: Data were compared with the blind code to verify the group number of all patients. The trial was designed with a ratio of 2∶1; it was unblinded at once. Statistical analysis was conducted by SAS9.1.3. All statistical tests were two-sided tests. There was a significant difference between these groups when the value of P was less than or equal to 0.05.
Results
Analysis of the causes of epilepsy
Based on the causes of the epilepsy, cases of epilepsy were clearly apparent in some patients in the two patients groups. Among these patients, 11 cases had brain injury history during the perinatal period (6 cases in the experimental group and 5 cases in control group); 12 cases had neonatal febrile convulsion (9 cases in the experimental group and 3 cases in the control group); and 27 cases had other central nervous system diseases (14 cases in the experimental group and 13 cases in the control group). The difference between the two groups was not significant. Based on their family history, several cases had a family history of epilepsy (2 cases in the experimental group and 8 cases in the control group, P>0.05). The difference between the two groups was not significant.
Effect on the epilepsy seizure rate
Effect on the epilepsy seizure rate
Some differences in the epilepsy seizure rate emerged between two groups when they joined the groups three months before and three months after treatment. The sum of the epilepsy seizure rate in the experimental group was less than that in the control group. Based on Wilcoxon rank sum test, the difference was not significant (P>0.05). The difference was significant (P<0.05) when the variation of the epilepsy seizure rate in the two groups was compared. The sum of the seizure rate variation after treatment shows that the rate in the experimental group decreased by 37.84% on average, and the rate in the control group decreased by 13.18% on average. After performing Wilcoxon rank sum test, the results show that the difference in the two groups was significant (P = 0.0443). The ITT and PP analysis results were consistent. The results show that the treatment effect of Dianjianning as additive treatment was superior to that of the single western medicine treatment group (See Table 1 for details).
Effect on the epilepsy frequency
In dynamically observing the variation of epilepsy frequency, the results show that the epilepsy frequency decreased at different levels in both groups at different times. Table 2 shows that there is a significant difference between the two groups in the third month, indicating that, as additive treatment, Danjianning has an obvious effect on controlling epilepsy frequency in the third month. As shown in Table 3 and Table 4, comparing the epilepsy seizure rate at different times after treatment with the baseline before the treatment in each group, the epilepsy seizure rate clearly decreases after treatment. There is a significant difference between the two groups, indicating that both treatment programs of the two groups are effective.
Analysis of safety and compliance
Patients in the two groups were examined before and after treatment. Their vital signs, blood, urine and stool routine, ALT, BUN, Cr, and electrocardiogram clearly did not change. During the trial, two cases showed an adverse effect in the control group. These cases had symptoms of urinary frequency, weakness, and fever due to unknown reasons. One of the cases eventually withdrew from the trial because of this. All patients in the groups took their medicines on time; the medication rate was 100%.
Discussion
The onset of epilepsy has sudden, transitory, repeat, and long-term characteristics. Completely controlling and curing epilepsy in clinical practice is very difficult. The main principles of the medical treatment of epilepsy are as follows: should be administered at the earlier stage, should have enough dosage, and treatment should be continued and symptomatic. Various medicines can be used to treat epilepsy, but enough dosage is required to control its onset. To prevent the toxic reaction of medicines, the medicine concentration in the blood must be monitored. The traditional Chinese medicine doctors in all the dynasties considered the pathogenesis of epilepsy to be complex. The symptoms are mixed and confusing: the disease is located in the brain; evil blurs the orifice during the stage of attack; it is associated with phlegm and stagnation; it is also related to the heart, liver, spleen, and kidneys; the heart and spleen should be tonified; and the liver and kidneys should be nourished at the rest stage. Many doctors use Chinese medicine to induce calm, open the orifice, ease the mind, counteract toxicity, and eliminate stasis when treating epilepsy. The most commonly used Chinese medicine are Cinnabaris, Concretio Silicea Bambusae, and Calculus Bovis combined with Realgar, Margarita, Arisaema cum Bile, Succvinum, Moschus, Scorpio, Scolopendra, Rhizoma Arisaematis, Radix Scutellariae, Rhizoma Coptidis, Radix et Rhizoma Rhei, Radix Gentianae, and Aloe. In clinic treatment, the onset of epilepsy is controlled by regulating Zang-fu to dissolve the hidden evil.
Dianxianning used in this research is a traditional Chinese herbal health product. It is a Chinese medicine formula clinically used for more than 20 years. It eliminates phlegm to induce resuscitation, tranquilizes, and calms the wind. It is used to treat wind-phlegm in upward-type epilepsy. The main medical plant used in the formula is
Valeriana jatamansii Jones [
10]. The chemical study of this plant shows that it has volatile oils, secoiridoid, and other active components. Its pharmacological activities include calmness and hypnosis for the central nervous system, antibacterial, antivirus, and antitumor.
Rhizoma Acori Tatarinowii is a Chinese medicine commonly used in treating epilepsy. Its active components have sedative action on the central nervous system and good effects on the metabolism of some of the central nervous transmitters.
Ramulus Uncariae cum Uncis can clear heat, pacify the hyperactivity of the liver, subdue the liver-wind and stop convulsion, and relieve smooth muscle spasm.
Radix et Rhizoma Nardostachyos is an anti-depressant and can invigorate spleen function. Menthol can be used to resuscitate with aromatics.
Semen Pharbitidis can remove the stagnation of undigested food and dissolve phlegm.
Valeriana officinalis can dispel wind and stop convulsions. Combining these Chinese medicines together will not only dispel phlegm, invigorate spleen function, and allow resuscitation with aromatics but also subdue liver-wind, stop convulsion, and relieve smooth muscle spasm. They are effective in relieving epilepsy symptoms, such as unconsciousness, limb spasms, and stagnation of phlegm in the pharynx.
Through a multicenter, prospective, randomized, and controlled clinical trial design, the results show that the treatment has certain curative effects on controlling the seizure rate of epilepsy, onset frequency, and severity level of onset. Our data show that the treatment effect is slightly superior to that in the single western medicine treatment group. No safety issues regarding Dianxianning emerged during the trial. Patients showed good compliance, indicating that the medicine is safe. In the trial, patients were assigned to the groups randomly using the central random ization system. Through blind method and placebo management, interference of human factors was avoided, which improves the research quality and the reliability of the research evidence.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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