[Abstract]
OBJECTIVE: To study the clinical efficacy and safety of combined treatment with sodium valproate and carbamazepine in frontal lobe epilepsy.
METHODS: Patients with frontal lobe epilepsy were divided into a test group and a control group, and the test group was given the combination treatment of sodium valproate and carbamazepine, and the control group was given carbamazepine, with a follow-up of six months.
Results: The efficacy of the test group was 54.7%, 30.2% and 15.1% in the apparent rate, and the efficacy of the control group was 42.2%, 14.5% and 43.3% in the apparent rate. There was a statistically significant difference in the efficacy of the two groups, P < 0.05.
Conclusion: The combined treatment of frontal lobe epilepsy with sodium valproate and carbamazepine can significantly improve the efficacy, and no significant adverse effects occurred, which is worthy of clinical application as the preferred treatment option.
[Keywords] Frontal lobe epilepsy; sodium valproate; carbamazepine.
As a special type of epilepsy, frontal lobe epilepsy is gaining more and more attention for its complex clinical seizure form and EEG characteristics. Compared with the common temporal lobe epilepsy, our understanding of frontal lobe epilepsy is still relatively small, and the level of diagnosis and treatment needs to be further improved. The efficacy of carbamazepine, the drug of choice for partial epilepsy, is not satisfactory for frontal lobe epilepsy, and a more effective treatment is clinically desired. We tried to apply sodium valproate addition to treat frontal lobe epilepsy and achieved better efficacy. The analysis of our data is reported below.
1.Data and methods
(1) Inclusion criteria ①Patients with frontal lobe epilepsy who visited hospitals and epilepsy centers from July 2004 to September 2006; ②Meet the classification criteria of the International League Against Epilepsy on epilepsy and epilepsy syndrome in 1989: clinical manifestations with typical seizures in the frontal area; ③Electroencephalogram during seizures or interictal period showed epileptic discharges in frontal leads; ④No previous encephalitis, traumatic brain injury, etc. that may cause epilepsy (2) Exclusion criteria
(2) Exclusion criteria: (1) family history of epilepsy; (2) previous epilepsy surgery; (3) multiple antiepileptic drugs other than valproate and carbamazepine prior to consultation; (4) liver and kidney disease, progressive or degenerative disease; (5) pregnant or breastfeeding women.
(3) General data 183 cases were enrolled according to the criteria, 14 cases (7.65%) were withdrawn before six months of treatment, among which 6 cases were lost, 5 cases were unable to purchase drugs, and 3 cases were discontinued by themselves due to obvious adverse reactions. 169 cases actually completed six months of treatment. In the test group, there were 47 males and 39 females; the age of onset ranged from 5 months to 33 years, with an average age of 14.32 years; the duration of the disease ranged from 3 months to 21 years, with an average of 11.54 years; the past history included a history of febrile convulsions in 6 cases, difficult birth and asphyxia in 3 cases. In the control group, there were 43 males and 40 females; the age of onset ranged from 4 months to 31 years, with an average age of 10.12 years; the duration of the disease ranged from 2 months to 18 years, with an average of 9.56 years; the past history of febrile convulsions was 5 cases, and the birth was difficult and asphyxiated in 5 cases.
(4) Methods
Patients with frontal lobe epilepsy were randomly divided into a test group and a control group, and the test group was given a combination of sodium valproate and carbamazepine, while the control group was given carbamazepine monotherapy. The dose of sodium valproate was 20 mg/kg/d, and the full dose was given at the beginning, using Sanofi’s Depakene, 500 mg/tablet, divided into two doses. /The tablets are also divided into two doses. Follow up the patients once a month for at least six months, and then evaluate the efficacy.
(5) Observation indexes Detailed records of medical history, number of seizures, medication history; cranial CT and/or MRI examination were performed before enrollment; EEG examination was performed in all cases: Japanese photoelectric 1518 video EEG tracer was used, and long-range video EEG monitoring was performed in some patients; neurological examination was routinely performed; routine blood and liver and kidney function tests were done regularly; monthly follow-ups were conducted to record the efficacy and possible adverse effects.
(6) Criteria for determining the efficacy Both groups used the seizure frequency of patients in the month before treatment as the baseline, and compared it with the seizure frequency six months after treatment, respectively. According to the efficacy criteria established by the First National Epilepsy Academic Conference: (1) significant efficacy was defined as ≥75% reduction in seizure frequency from baseline after treatment; (2) effective was defined as 50%-74% reduction from baseline; (3) ineffective was defined as <50% change from baseline or increase in seizures.
(7) Statistical methods The efficacy between the two groups was tested for significance by applying chi-square. Data were statistically analyzed using the SPSS 11.5 software package, and the comparison of rates between samples was performed using the X2 test with four-grid table information, α = 0.05.
2, Results
(1) Age of onset, duration of illness, number of episodes, gender, and past history between the two groups were statistically processed, and there was no significant difference at P > 0.05.
(2) Evaluation of efficacy
Table 1 Comparison of the efficacy of seizures between the two groups % (number of cases)
Effective Effective Ineffective Total
Test group 54.7% (47) 30.2% (26) 15.1% (13) 100% (86)
Control group 42.2% (35) 14.5% (12) 43.3% (36) 100% (83)
By X2 test, X2=17.66, P<0.05, the difference in the efficacy composition of seizures between the two groups was statistically significant.
By X2 test, X2=16.38, P＜0.05, the difference in the efficacy of seizures between the two groups was statistically significant.
(3) Seizure forms: The seizure forms were similar between the two groups and mainly included the following forms.
Table 2 Comparison of seizure forms between the two groups
Test group (cases) Control group (cases)
Postural seizures 32 30
Excessive movement 28 26
Shouting or mouth outburst 25 29
Deflective seizures 25 21
Frozen concentration 23 25
Automaticity 19 18
Secondary generalized grand mal seizure 17 20
Myoclonus 3 1
Numbness of right upper extremity 2 1
Compulsive thinking 1 1
Disorientation-like seizures 1 0
(4) EEG manifestations.
(4) EEG manifestations during the interictal period: focal spike, spike and slow spike wave synthesis in the frontal region; predominantly one-sided discharges with significant partial synchronization; easy propagation to the temporal, central and apical regions; tendency of increased discharges during sleep compared with wakefulness.
EEG manifestations during seizures: explosive fast activity in frontal area; explosive slow wave rhythm in frontal area; explosive spike-and-slow wave rhythm. The EEG often shows a lot of action artifacts when the action is more violent during the seizure.
(5) Safety and tolerability Adverse reactions: 14 potentially relevant side effects were observed in 169 patients.
Table 3. Comparison of adverse reactions between the two groups
Test group Control group
Weight gain 32 5
Nausea, nausea 24 17
Sleepiness 13 10
Liver function impairment 9 1
Dizziness 4 15
Constipation 3 2
Tremor 3 0
Fatigue 3 2
Headache 2 2
Hair loss 2 0
Tinnitus 2 1
Restlessness 1 3
Skin rash 1 6
Diarrhea 1 1
Decreased white blood cells 0 5
3. Discussion
Frontal lobe epilepsy is divided into two main categories according to etiology, idiopathic and symptomatic, and the two different etiologies leading to frontal lobe epilepsy may be very divergent in terms of treatment and prognosis. In order to investigate the best option for the treatment of frontal lobe epilepsy with different antiepileptic drugs and to avoid the influence of frontal lobe lesions on the study too much, we excluded subjects with abnormal frontal lobe signals on neuroimaging in the selection of study cases, all enrolled cases were free of structural lesions of the central nervous system, and the possibility of genetic factors was also excluded.
The clinical forms of frontal lobe seizures are complex and characteristic, with postural seizures being the most common, followed by head-eye deflection seizures, hypermobility and automatisms. Turning in place and laughing are almost exclusively seen in frontal lobe epilepsy, while oropharyngeal automatisms and groping with hands are mainly seen in temporal lobe epilepsy. There are also frontal lobe aphasia-like seizures, which are difficult to distinguish from aphasic epilepsy and need to be differentiated in detail based on EEG features.
The traditional principle of antiepileptic drug therapy is to start with one antiepileptic drug and then add another antiepileptic drug when seizure control is unsatisfactory, which can reduce the adverse effects of the drug. This can reduce the adverse effects of the medication, but on the other hand, it can also prolong the duration of the seizures.
Partial seizures are the most common form of epilepsy, and in the past, most patients could be clinically effectively controlled after the preferred carbamazepine monotherapy, but the clinical outcome for frontal lobe epilepsy was less satisfactory. There have been studies attempting to apply oxcarbazepine and topiramate for the treatment of frontal lobe epilepsy, and good results have also been found with the combined application of lamotrigine and sodium valproate for frontal lobe epilepsy. Sodium valproate, the drug of choice for the treatment of generalized seizures, is also effective for partial seizures at the same time, with an efficiency rate of about 58-76%. Most of the mechanisms of its antiepileptic effect are related to GABA activity. In our study, the efficacy of carbamazepine combined with sodium valproate treatment was statistically different from that of carbamazepine alone for frontal lobe epilepsy, with the former being significantly more effective than the latter. In some patients, the seizure frequency was not significantly reduced, but the degree of seizures was less than before. In some patients, the original secondary generalized seizures disappeared and the seizure type was converted to complex partial seizures or simple partial seizures, or complex partial seizures were converted to simple partial seizures. The EEG improvement in some patients was positively correlated with the improvement of clinical symptoms, and sodium valproate had a significant inhibitory effect on the generalized explosive spike-and-slow syndrome wave.
In some patients in treatment there was no significant improvement in seizures even after adding to the target dose, and after increasing the dose of carbamazepine to 15-20 mg/kg/d, an increase in efficacy was found in some patients, and we believe that the efficacy of carbamazepine for frontal lobe epilepsy is dose-related. When seizure control is suboptimal, a possible increase in the therapeutic dose without increasing the incidence of adverse effects will benefit some patients, as well as the chance of achieving complete seizure control.
Sodium valproate is primarily metabolized in the liver, and carbamazepine is a strong hepatic enzyme inducer, resulting in a wide range of interactions when the two drugs are combined. The hepatic enzyme-inducing effect of carbamazepine enhances the metabolism of sodium valproate in the liver, with a significant increase in the hepatotoxic substance 4-ene-valproic acid. It was found that the concentration of valproate decreased after combining carbamazepine in patients on valproate alone; when carbamazepine was discontinued, the concentration of valproate increased again. On the other hand, sodium valproate increases the concentration of carbamazepine epoxide, the active metabolite of carbamazepine, and prolongs its half-life. Therefore, it is important to adjust the dose of both drugs accordingly when combining them clinically, and to monitor the blood concentration if necessary to avoid failure to achieve therapeutic concentrations or excessive concentrations to increase adverse reactions.
We found no abnormal changes in blood, urine routine, renal function and blood glucose in the two groups before and after treatment. Adverse reactions in the control group were mainly dizziness, gastrointestinal symptoms and rash, while those in the experimental group were mainly weight gain, gastrointestinal symptoms and impairment of liver function. The nature and degree of adverse reactions can occur when sodium valproate is used alone or in combination with other antiepileptic drugs, and the incidence is especially high when the drugs are combined. Liver function impairment may occur after long-term administration, but it is generally mild and can mostly be recovered quickly after administration of liver-protective drugs. Adverse reactions in several cases withdrawn from the study were intolerable rash and emotional mania, but no serious life-threatening adverse reactions occurred. Occasionally they may occur because the dose is increased too rapidly when adjusted.
Frontal lobe epilepsy is a characteristic syndrome with a complex and varied clinical presentation. In patients with more frequent frontal lobe epilepsy, the combination of valproate and carbamazepine is significantly more effective than the carbamazepine monotherapy regimen. Once the diagnosis is confirmed, the combination can be given directly without waiting to observe the efficacy of the single drug before adjusting the medication to avoid delaying the course of the disease.