Clinical efficacy of Baijin pills in the treatment of generalized tonic-clonic seizure epilepsy with cognitive impairment

Abstract

BACKGROUND

The generalized tonic-clonic seizure (GTCS) is the most usual variety of epileptic seizure. It is mainly characterized by strong body muscle rigidity, loss of consciousness, a disorder of plant neurofunction, and significant damage to cognitive function. The effect of antiepileptic drugs on cognition should also be considered. At present, there is no effective treatment for patients with epilepsy, but traditional Chinese medicine has shown a significant effect on chronic disease with fewer harmful side effects and should, therefore, be considered for the therapy means of epilepsy with cognitive dysfunction.

AIM

To investigate the clinical efficacy of Baijin pills for treating GTCS patients with cognitive impairment.

METHODS

This prospective study enrolled patients diagnosed with GTCS between January 2020 and December 2023 and separate them into two groups (experimental and control) using random number table method. The control group was treated with sodium valproate, and the experimental group was Baijin pills and sodium valproate for three months. The frequency and duration of each seizure, the Montreal Cognitive Assessment Scale (MoCA), and the Quality of Life Rating Scale (QOLIE-31) were recorded before and after treatment.

RESULTS

There were 85 patients included (42 in the control group and 43 in the experimental group). After treatment, the seizure frequency in the experimental group was significantly reduced (P < 0.05), and seizure duration was shortened (P < 0.01). The total MoCA score in the experimental group significantly increased compared to before treatment (P < 0.01), and the sub-item scores, except naming and abstract generalization ability, significantly increased (P < 0.05), whereas the total MoCA score in the control group significantly decreased after treatment (P < 0.05). The QOLIE-31 score of the experimental group increased significantly after treatment compared to before treatment (P < 0.01).

CONCLUSION

Baijin pills have a good clinical effect on epilepsy with cognitive dysfunction.

Key Words: Epilepsy; Generalized tonic-clonic seizure; Cognitive impairment; Traditional Chinese medicine; Baijin pills

Core Tip: Generalized tonic-clonic seizure can induce the most significant damage to cognitive function. The impact of antiepileptic drugs on cognition should not be ignored. At present, there is no special treatment for patients with epilepsy, and traditional Chinese medicine has shown a significant effect on chronic diseases with fewer harmful side effects; therefore, traditional Chinese medicine should be considered for the treatment of epilepsy with cognitive dysfunction. Baijin pills have a positive clinical effect on patients with epilepsy and cognitive dysfunction.

INTRODUCTION

Epilepsy is a common type of neurological disorder disease. It is a chronic disease that is associated with temporary brain dysfunction. Sudden abnormal discharge of brain neurons caused by various triggers is its primary pathogenesis[1]. Although different brain discharge sites cause different clinical symptoms, the core features are transient, paroxysmal, stereotypical, and repetitive[2]. Cognitive dysfunction is a common clinical symptom associated with epilepsy patients, whether in newly diagnosed patients or patients with long-term epilepsy; cognitive dysfunction is common[3]. Cognitive impairment occurs in greater than 1/3 of patients with epilepsy and in up to 70%-80% of patients with chronic epilepsy[4]. Defects in the cognitive function of epilepsy patients, such as a slow pace of thinking and loss of memory, attention, and language, can cause different levels of interference in social interaction, which can make it impossible for patients to enjoy socializing fully, thus reducing their quality of life[5]. Epileptic seizures have caused great pain to the patient's body and mind, significantly reducing their quality of life. The decline in knowledge retention further reduces the quality of the patient's life, and self-harm and harm to others can occur in some epileptic patients, causing serious social problems. If the focus is only on the treatment of epileptic seizures but not on the cognitive, psychological, as well as social aspects of epilepsy, the patient, their family, and their broader community could suffer the negative consequences.

The generalized tonic-clonic seizure (GTCS) is the most common variety of seizure in epilepsy and is mainly characterized by strong body muscle rigidity, loss of consciousness, a disorder of plant neurofunction, and the most significant damage to cognitive function[6,7]. Sodium valproate is a traditional, low-cost, broad-spectrum antiepileptic drug with low application. It is the first-line drug in GTCS and multiple other types of epilepsy. With the development of bio-psycho-social medicine, the ideal treatment outcome of epilepsy treatment is to up to simple control and reduction of events and to maximize the patient’s quality of life. Therefore, treating cognitive dysfunction is very important to epilepsy patients. There are few available and effective methods for treating epilepsy, but AEDs themselves have been shown to impair cognition, especially the traditional antiepileptic drugs (AEDs)[8]. The factors affecting the cognitive function of epilepsy patients are generally summarized as following: etiology, epileptic seizures, interictal epileptiform discharges, neuronal network, AEDs, and surgery while controlling epilepsy and AEDs are more manageable factors[6,9,10]. The impact of AEDs on cognition should not be ignored. At present, there is no special treatment for patients with epilepsy, and traditional Chinese medicine has shown a significant effect on chronic diseases with fewer harmful side effects; therefore, traditional Chinese medicine should be considered for the treatment of epilepsy with cognitive dysfunction. From a Chinese traditional medical point of view, "Sputum" is a common pathological factor in the development of epilepsy and cognitive dysfunction; both can be treated by sputum. Baijin pills are made up of alumen (Bai Fan in Chinese) and Curcumae Radix (Yu Jin in Chinese), which are made up of drugs with the ability to affect the mind, heart, spittoon, epilepsy, sudden syncope, and mass salivation. It is also useful for treating laryngeal and acute tonsillitis. Modern Chinese medicine clinical Baijin pills are used in many diseases such as epilepsy, schizophrenia, hyperlipidemia, arrhythmias, and hepatobiliary disease. This study chose the most severe GTCS and the most widely used AED, sodium valproate, as the basis for research on the clinical effect of using Baijin pills for GTCS with cognitive impairment and observation of its clinical efficacy.

MATERIALS AND METHODS

This prospective study was confirmed by the Department of the Nanjing University of Chinese Medicine. The ethics committee of our hospital agreed to conducting this study. The informed consent form was obtained from the participated before enrolling the study.

Patient recruitment and selection criteria

We enrolled patients diagnosed with GTCS between January 2020 and December 2023. The inclusion criteria were as follows: (1) Meeting the diagnostic criteria of epilepsy in Western and Chinese medicine[11]; (2) Age ≥ 18 years and ≤ 70 years; (3) Duration of epilepsy ≥ 2 years, with ≥ 1 major seizure per month; (4) Montreal Cognitive Assessment Scale (MoCA) Scale score < 26 points; and (5) Signed informed consent, and good compliance. Patients who met the following criteria were excluded from the study: (1) Pregnant and lactating women and women of childbearing age; (2) Serious primary diseases of the heart, lungs, liver, kidneys, and/or bone marrow; (3) Mental disorders; (4) Failure to follow the study requirements or write disease records; and (5) Clinical observation of other drugs in the past year.

Study design

This is a prospective study. Eligible patients were enrolled and separated into two groups (experimental and control) using the random number table method. The control group was therapied with sodium valproate, and the experimental group was therapied with Baijin pills and sodium valproate treatment for six months. The frequency and duration of each seizure before and after treatment were recorded. The Montreal Cognitive Assessment Scale (MoCA) and Quality of Life Rating Scale (QOLIE-31) were used before and after treatment[12]. QOLIE-31 is the scale consisting of 31 questions, divided into 7 aspects and 1 comprehensive entry. It provides a rapid and comprehensive assessment of the major health-related quality of life issues of concern to adults with epilepsy and can be used in clinical trials to evaluate patient response to changes in treatment regimens. The higher the score, the better the quality of life. Sodium valproate (Hunan Xiangzhong Pharmaceutical Co., Ltd.; lot No. H43020874, 200 mg/tablet) was used as follows: An initial dose of 600 mg/d, three times/d, gradually increased to 1200 mg/d, three times/d[11]. Patients in both groups were not allowed to take any other drugs that had an impact on epilepsy or cognition during treatment. The control group was therapied with conventional sodium valproate for six months. The other group was therapied with conventional sodium valproate plus the Baijin pill treatment. Patients in the two groups were followed up once a month from the beginning of treatment, and seizures were recorded, including the number and duration of seizures. A general physical examination and a detailed nervous system examination were performed; three routine biochemical and electrocardiogram examinations were performed, and the therapeutic effect was evaluated three months later.

Epileptic seizures

The frequency and duration of each seizure were recorded before and after three months of treatment in both groups. The difference between seizure frequency and duration was based on the pre-treatment and post-treatment levels. Changes in epileptic seizures before and after treatment were observed and compared between the two groups.

Cognitive function

The two groups of epilepsy patients were evaluated using the MoCA scale before and after treatment, changes in cognitive function before and after treatment were observed, and the changes between the two groups were compared. One point was added if the number of years of schooling was less than 12. All the scales were assessed by the same physician.

Quality of life

The Chinese version of the Adult Epilepsy Quality of Life Scale (QOLIE-31) was used to measure the efficacy evaluation criteria before and after treatment, to observe the changes in patients' quality of life before and after treatment, and to compare the changes between the two groups. QOLIE-31 score difference = pre-treatment level–post-treatment level. All the scales were assessed by the same physician.

Statistical analysis

All data were processed using SPSS20.0 statistical software. The χ² test was used for counting data, and expression was used for measurement data. Paired t-tests were used before and after treatment in the same group, and two independent sample t-tests were used for comparisons between groups. The significance level was set at P < 0.05.

RESULTS

Patient characteristics

Eighty-five patients were included: 42 in the control group and 43 in the experimental group. Five patients dropped out of the group or were lost to follow-up: Two patients in the experimental group dropped out due to rash and poor medical compliance; one patient in the control group showed valproate encephalopathy regression, and one case each in the experimental and control groups dropped out for unknown reasons (Table 1).

Table 1 Characteristics of patients.

	Experimental group	Control group
Sample size	40	40
Female	20	18
Age (yr)	40.92 ± 13.51	42.37 ± 12.3
Clinical course	5.65 ± 2.34	5.91 ± 1.62
Education background
Bachelor's degree or above	8	10

Comparison of seizure frequency, seizure duration, and difference before and after treatment

After treatment, the frequency of seizures in the experimental group was significantly reduced (P < 0.05), and the duration of seizures was shortened (P < 0.01). The decrease in seizure frequency in the experimental group was significantly greater than in the control group (P < 0.05), and the reduction in seizure duration in the experimental group was significantly greater than in the control group (P < 0.01; Table 2).

Table 2 The frequency, duration, and difference of seizures before and after treatment were compared between the two groups.

Group	Sample size	Period	Attack frequency/6 months	Seizure duration (min/time)
Experiment group	40	Before treatment	12.60 ± 6.00	3.55 ± 1.75
		After treatment	8.77 ± 5.75	1.62 ± 1.55
		The difference before and after treatment	3.82 ± 1.53	2.49 ± 0.83
Control group	40	Before treatment	12.98 ± 6.26	3.75 ± 1.69
		After treatment	9.45 ± 5.99	2.12 ± 1.81
		The difference before and after treatment	2.72 ± 2.18	1.48 ± 0.75

Comparison of MoCA scale scores before and after treatment

After treatment, the total MoCA score in the experimental group was significantly higher than before treatment (P < 0.01). The sub-item scores, except naming and abstract generalization ability, were significantly increased (P < 0.05). In contrast, the total MoCA score in the control group was significantly decreased compared with before treatment (P < 0.05; Table 3).

Table 3 Comparison of Montreal Cognitive Assessment Scale scores before and after treatment between the two groups.

Group	Experiment group (n = 40)		Control group (n = 40)
	Before treatment	After treatment	Before treatment	After treatment
MoCA total score 30	18.25 ± 2.34	20.43 ± 2.65	17.65 ± 2.16	16.53 ± 1.98
Memory ability 5	2.75 ± 0.81	3.15 ± 0.96	2.64 ± 0.79	2.40 ± 0.73
Verbal fluency 3	2.13 ± 0.78	2.52 ± 0.92	2.06 ± 0.77	1.97 ± 0.72
Visuospatial execution ability 5	2.98 ± 0.59	3.27 ± 0.70	2.87 ± 0.61	2.71 ± 0.58
Naming capability3	2.10 ± 0.81	2.30 ± 0.85	2.07 ± 0.79	1.94 ± 0.77
Attention and calculation ability 6	3.05 ± 0.78	3.42 ± 0.84	3.01 ± 0.76	2.74 ± 0.72
Orientation ability 6	4.02 ± 0.89	4.45 ± 0.93	3.94 ± 0.85	3.79 ± 0.81
Ability of abstraction and generalization 2	1.09 ± 0.45	1.31 ± 0.56	1.04 ± 0.49	0.95 ± 0.42

Comparison of QOLIE-31 scores before and after treatment between the two groups and the difference of scores before and after treatment

The quality of life score in the experimental group increased significantly after treatment compared to that before treatment (P < 0.01). The QOLIE-31 score in the control group also increased significantly compared to that before treatment (P < 0.05), and the QOLIE-31 score of the experimental group increased more than that of the control group (P < 0.01); the difference was statistically significant (Table 4).

Table 4 The Quality of Life Rating Scale (QOLIE-31) score before and after treatment and the difference between the two groups.

Group	Sample size	Period	QOLIE-31 score
Experiment group	40	Before treatment	43.32 ± 7.45
		After treatment	51.46 ± 8.12
		The difference before and after treatment	9.44 ± 5.23
Control group	40	Before treatment	44.56 ± 6.92
		After treatment	48.42 ± 7.83
		The difference before and after treatment	4.26 ± 4.78

DISCUSSION

Epilepsy is a clinical syndrome characterized by unpredictable and transient central nervous system dysfunction caused by synchronized abnormal discharge of brain neurons with different triggers. Epilepsy is a common chronic disease affecting about 50 million people. The prevalence rates of epilepsy are 5.8‰ in developed countries and 15.4‰ in developing countries[13].

The pathogenesis of epilepsy is complex and primarily involves neurotransmitters, ion channels, immune or inflammatory responses, and abnormal neural pathways. The neurotransmitter mechanism is mainly an imbalance between Glu-mediated excitation and GABA-mediated inhibition. Other neurotransmitters such as serotonin, norepinephrine, and dopamine also play a role in the pathogenesis of epilepsy[14]. An imbalance in ion charge caused by abnormal ion channels can induce epilepsy. Inflammatory cytokines are involved in the pathogenesis of epilepsy, and glial cells play a role in regulating immune and inflammatory responses during epilepsy. It has been found that inflammatory cytokines have harmful effects on neurons, altering their excitability, producing toxic mediators, and increasing the impermeability of the blood-brain barrier. Abnormal hippocampal neurogenesis and brain injury lead to the generation of new neural circuits, which is also important in the pathogenesis of epilepsy[15,16]. Epilepsy is a complex disease, and the challenges people face are not just the damage and suffering caused by the seizures. Epilepsy may also be accompanied by a series of comorbidities that have bad impact on the patient’s health and quality of life. Common epileptic comorbidities include cognitive dysfunction, such as memory, attention, or processing problems; mental health conditions, including depression or anxiety; and somatic comorbidities, such as sleep disorders and migraines[17-19]. Comorbidities are common and for many patients with epilepsy, they are often more serious than the harm caused by seizures. Cognitive dysfunction is one of the most common and distressing epileptic comorbidities. The literature reports that different degrees of cognitive dysfunction exist in more than one-third of epilepsy patients, and the incidence of cognitive impairment in patients with a long history of epilepsy can reach 70%-80%[20,21].

Out of all the seizure types, the GTCS is the most serious type of seizure associated with cognitive impairment. The GTCS, also known as a grand mal seizure, is the most prominent form of seizure. One of the main reasons is that during the onset of GTCS, the muscles of the whole body are tetanic and convulsive, with extreme energy consumption, and apnea during the onset causes the brain tissue to be in a state of severe hypoxia[22,23]. Of all the organs, the brain is the most sensitive to hypoxia. The hippocampus, which is closely related to cognition, is the most sensitive region[24-26].

Sodium valproate is routinely used for clinical treatment. The study results showed that the number and duration of seizures in the control group after sodium valproate treatment alone were reduced compared to those before treatment. The effect of sodium valproate on seizure control was satisfactory, but epilepsy was not completely cured and the patient still had some less severe seizures, and the cognitive damage of epilepsy was still aggravated. Therefore, the total MoCA score in the control group after treatment was lower than that before treatment, which did not indicate that sodium valproate had a damaging effect on cognition. Therefore, the relationship between sodium valproate levels and cognition requires further research. Platinum pills with alum and stasis gold as the main ingredients can clear phlegm, clear the heart, and calm the mind, and are used for spittoon choking, epilepsy, sudden fainting, and hypersalivation. It also treats laryngeal wounds, milk moths, and other diseases. Modern Chinese medicine clinical platinum pills have been used for the treatment of epilepsy, schizophrenia, hyperlipidemia, arrhythmias, hepatobiliary disease, and many other diseases. This study showed that platinum pills have good clinical efficacy in treating the syndrome of phlegm-turbidizing obstruction of the GTCS accompanied by cognitive dysfunction. From the perspective of seizure control, the seizure frequency in the experimental group was significantly reduced after treatment (P < 0.05), the seizure duration was shortened (P < 0.01). The platinum pill combined with sodium valproate has a better effect on seizure control than sodium valproate alone; therefore, the platinum pill has an antiepileptic effect. From the point of view of the impact on cognitive function, the MoCA score in the experimental group was significantly increased after treatment (P < 0.01). The scores of subitems except naming and abstract generalization ability were significantly increased (P < 0.05), while the total MoCA score in the control group was decreased after treatment (P < 0.05). The platinum pill has a significant positive effect on cognitive dysfunction associated with epilepsy. In terms of quality of life, the QOLIE-31 scale score in the experimental group significantly increased after treatment (P < 0.01), and the QOLIE-31 scale score in the experimental group was significantly higher than that of the control group (P < 0.01). The degree of improvement due to platinum pills combined with sodium valproate on the quality of life of patients with epilepsy is significantly higher than that of sodium valproate alone because the addition of sodium valproate combined with Diitan decoction can improve the control of seizures and cognitive function, further improving the quality of life of patients.

Our study had a number of limitations. First of all, the sample size is not large enough, and a larger sample size study is needed to verify the test results. Second, the study was not a multicenter randomized controlled trial. So our findings should be treated with caution.

CONCLUSION

AEDs and epileptic seizures damage cognitive function, and there is currently no specific treatment for epileptic cognitive impairment in Western medicine; therefore, Chinese medicine is a possible new treatment method. Considering that "phlegm" is the common pathological factor of epilepsy and cognitive impairment in traditional Chinese medicine, it is possible to treat epilepsy with cognitive dysfunction based on phlegm. The results showed that Baijin pills have a good clinical effect on epilepsy with cognitive dysfunction.