Epilepsy is a very common life-altering chronic disease in neurology, and its main treatment is the administration of antiepileptic drugs (AEDs). A domestic epidemiological study of rural populations in five provinces and cities found that 40.6% of epilepsy patients were untreated, 35.4% were treated irregularly, and the treatment gap for active epilepsy was more than 62% [1], and the current situation urgently needs improvement. After more than a century of development, the number of AEDs has been increasing and clinicians have more and more treatment options, but on the other hand, it has become more complicated to choose effective treatment rationally. The publication of the Chinese expert consensus on antiepileptic drug therapy [2] provides a programmatic basis for clinicians and will certainly vigorously promote the progress of standardized application of antiepileptic drugs in China.
1. currently available antiepileptic drugs
2. Overall treatment strategy for epilepsy
AEDs are preferred for the treatment of patients with seizures, and the treatment plan should be individualized according to the patient’s seizure type and severity, epilepsy syndrome, co-medications and co-morbidities, and the patient’s lifestyle, characteristics and preferences. Initial therapy is most often started after the second seizure, and monotherapy is preferred, starting with small doses and gradually increasing until seizure remission or adverse effects occur. If seizures are not effectively controlled with a full course of therapy, or if intolerable adverse effects occur, a second drug therapy (which may be a first- or second-line drug) should be started to an adequate dose or maximum tolerated dose, and then the first drug should be gradually discontinued. If the second drug is not beneficial, the first or second drug should be tapered before starting another drug therapy, depending on the relative efficacy, adverse effects, and tolerability of the drug [2,6-13].
3. Initial medication in patients with newly diagnosed epilepsy
3.1. Newly diagnosed idiopathic generalized epilepsy
Valproic acid is preferred in all newly diagnosed generalized epilepsy (generalized tonic-clonic seizures, atonic seizures, and myoclonic seizures). After failure of valproic acid treatment, lamotrigine is preferred for generalized tonic-clonic seizures, and first-line drugs are topiramate and levetiracetam; lamotrigine is preferred and first-line drug for atonic seizures; no preferred drug for myoclonic seizures, and first-line drug is levetiracetam. Valproic acid was preferred for all three generalized seizures after failure of lamotrigine or topiramate treatment [2].
3.2. Newly diagnosed symptomatic partial epilepsy
Carbamazepine and oxcarbazepine are preferred for initial treatment of newly diagnosed symptomatic partial epilepsy (simple partial seizures, complex partial seizures, and secondary generalized seizures), and lamotrigine is the drug of choice for all three seizure types after treatment failure, along with carbamazepine, oxcarbazepine, topiramate, and levetiracetam as first-line agents, and valproic acid is also the first-line drug for secondary generalized seizures. Carbamazepine and oxcarbazepine with lamotrigine are the drugs of choice after failure of other drugs [2].
3.3. Combination of drugs
Combination drug therapy (adjuvant or superimposed therapy) is considered only when AEDs cannot control seizures with monotherapy, and the combination of 2 drugs with different mechanisms of action is recommended, avoiding the combination of AEDs with interactions. Valproic acid in combination with other drugs (lamotrigine, levetiracetam, and topiramate) is preferred for idiopathic generalized epilepsy. The combination of carbamazepine (oxcarbazepine) + topiramate, carbamazepine (oxcarbazepine) + levetiracetam, carbamazepine (oxcarbazepine) + valproic acid, valproic acid + lamotrigine, lamotrigine + carbamazepine (oxcarbazepine) and phenytoin + topiramate is chosen for symptomatic partial epilepsy [2].
It is possible that polypharmacy may not achieve the desired goal and sometimes even lead to increased seizures and adverse effects [14], when it is appropriate to revert to the regimen that has proven to be the most acceptable for that patient (monotherapy or combination therapy), with a trade-off between effective seizure reduction and tolerance of adverse effects [6].
4. Pharmacotherapy in special populations
4.1. females
Treatment of female patients must take into account the possible interaction of AEDs with oral contraceptives, the teratogenicity of AEDs; the risk of increased seizure frequency during pregnancy, the frequency of follow-up during pregnancy, the risk of bleeding during delivery, and appropriate breastfeeding. There is no clear evidence of an increased risk of obstetric complications during pregnancy in women with epilepsy, nor does it suggest a high incidence of seizure frequency or status epilepticus during pregnancy, or an increased risk of recurrence during pregnancy in women with seizures that have been controlled [15]. Lamotrigine is preferred for idiopathic generalized versus symptomatic partial epilepsy in women of childbearing age, and the first-line agents for idiopathic generalized seizures are lamotrigine, levetiracetam, and topiramate, and for symptomatic partial seizures are lamotrigine, levetiracetam, oxcarbazepine, and topiramate. In those planning to conceive and breastfeeding, the preferred medication for both idiopathic generalized seizures and symptomatic partial seizures is lamotrigine, and the first-line agents are lamotrigine and levetiracetam [2].
4.2. Older adults
The incidence of epilepsy in the elderly tops the list of all populations and may be more prone to adverse effects due to age-related physiological changes affecting drug concentrations in elderly patients with epilepsy and often combined with other diseases or concomitant use of other drugs [16,17]. The application of newer AEDs is preferred over older AEDs in elderly patients with epilepsy. lamotrigine or oxcarbazepine is preferred in elderly patients with epilepsy but no other systemic diseases, and lamotrigine or levetiracetam is preferred in those with other systemic diseases [2].
4.3. Children
Cognitive function and various behavioral problems are more common in children with epilepsy and are associated with adverse effects of AEDs, but can also be improved by seizure control. Cognitive effects, co-morbidities, neurotoxicity, learning problems, seizure frequency and control, age, seizure type, tolerability, and adverse effects should be considered when selecting AEDs for pediatric patients. The smallest effective dose possible is used to reduce CNS adverse effects [17]. Lamotrigine is preferred for generalized seizures in school-age children, and levetiracetam is also available as a first-line agent. Oxcarbazepine and lamotrigine are preferred for symptomatic partial-onset seizures, and levetiracetam, carbamazepine, and valproic acid are also first-line agents [2].
5. Medication issues for some specific conditions
5.1. Co-morbidity
Co-morbidity refers to the presence of one or more other diseases in combination with one disease. Co-morbidities that are more common in patients with epilepsy than in the general population include depression, anxiety, sleep disorders, cognitive impairment, psychiatric disorders, and other systemic disorders. In patients with depression, valproic acid and lamotrigine are preferred for idiopathic generalized seizures, and lamotrigine, oxcarbazepine, and carbamazepine are preferred for secondary partial seizures. For those with behavioral problems, valproic acid and lamotrigine are preferred for idiopathic generalized seizures and lamotrigine, oxcarbazepine, and carbamazepine are preferred for secondary partial seizures. In children and elderly patients with epilepsy with cognitive impairment, lamotrigine is preferred for idiopathic generalized seizures, along with levetiracetam and valproic acid as first-line agents; lamotrigine or oxcarbazepine is preferred for symptomatic partial seizures, along with levetiracetam as first-line agents; in addition, levetiracetam is also preferred for elderly patients [2,18]. In patients with renal failure requiring dialysis, valproic acid is preferred for idiopathic generalized seizures, and lamotrigine and levetiracetam are the first-line agents; lamotrigine and levetiracetam are the first-line agents for symptomatic partial seizures. Regardless of the normal liver function, topiramate and levetiracetam are preferred for idiopathic full-blown seizures, and lamotrigine is the first-line drug; oxcarbazepine is preferred for secondary partial seizures in hepatitis B carriers with normal liver function, and topiramate, levetiracetam and lamotrigine are the first-line drugs. When liver function is abnormal, topiramate and levetiracetam are preferred, and lamotrigine is the first-line drug. In patients with epilepsy with other liver disease, the drugs of choice for both idiopathic generalized seizures and symptomatic partial seizures are topiramate or levetiracetam [2].
5.2. Driving
Epilepsy and driving is both a medical and social issue. Driving increases the risk of active epilepsy significantly, but patients with epilepsy who obey driving restrictions and those who are controlled with appropriate medication do not possess excessive risk. Driving bans may deprive many people with epilepsy of a convenient form of transportation and even employment opportunities, and contribute to a sense of discrimination. Some Western countries have lifted the ban, allowing patients with epilepsy who have been seizure-free for more than 2 years or patients with simple partial seizures that do not interfere with driving to obtain a driver’s license [2,19,20]. With seizure control, driving should be discontinued during medication discontinuation and medication changes, regardless of whether the antiepileptic drug is being tapered or an attempt is being made to switch to another antiepileptic drug [2].
5.3. Management of patients with epilepsy in the emergency room
Patients with emergency epilepsy are mostly unsure of their seizure type and often require rapid management by the physician, choosing drugs that are broad-spectrum, easy to use, and titrate the dose quickly. Valproic acid and levetiracetam are preferred, and topiramate is also available as a first-line agent [2].
5.4. Post-stroke epilepsy
Post-stroke epilepsy is mostly in the elderly and the seizure type is mostly symptomatic partial seizures. For patients with post-stroke epilepsy without other systemic diseases, lamotrigine or oxcarbazepine is preferred, and other first-line drugs include carbamazepine, levetiracetam and topiramate; for those with other systemic diseases, levetiracetam is preferred, and other first-line drugs include lamotrigine, oxcarbazepine and topiramate [2].
5.5. Proprietary Chinese medicine for epilepsy
Proprietary Chinese medicines are a special problem in the treatment of epilepsy in China. Most of the so-called “proprietary Chinese medicines” currently used in clinical practice are actually adulterated with “Western” ingredients, such as phenobarbital, phenytoin, valproic acid and carbamazepine, especially phenobarbital. For patients with epilepsy whose seizures are controlled by pCms and have no adverse reactions, it is best to switch to regular treatment, and for those with adverse drug reactions or poor seizure control, pCms should be discontinued. Valproic acid is preferred for idiopathic generalized seizures that have been controlled, and lamotrigine is preferred for symptomatic partial seizures; oxcarbazepine or lamotrigine is preferred for those with uncontrolled seizures [2].
6. Medication change and discontinuation
6.1. Medication change
Although not much has been stated in the Chinese expert consensus, at least 50% of patients who fail the first AED treatment clinically need to switch to another AED treatment, and the following factors need to be considered in the process of switching [21,22].
6.1.1. Medication factors
Both in-use and planned medications are included. Successful medication switching involves a gradual reduction in the medication in use and a gradual increase in the planned medication that does not cause deterioration in seizure frequency and severity, adverse effects, or quality of life. It is recommended that a reduction in the dose of the active medication be initiated only after the effective dose of the planned medication has been reached, to minimize the likelihood of relapse during the reduction in the dose of the active medication. Interactions of AEDs, including enzyme induction or de-induction, enzyme inhibition, and protein binding substitution, should be considered during single-drug switching. If the active drug is phenytoin and the planned drug is valproic acid, oxcarbazepine, or topiramate, it is important to reduce the phenytoin dose more rapidly to avoid dose-related adverse effects before its discontinuation because of the potential for increased blood levels through enzyme inhibition and increased free drug levels through plasma protein replacement; and to discontinue the active enzyme-inducible AEDs such as carbamazepine or phenytoin and replace them with inducible and discontinuing existing enzyme-inducing AEDs such as carbamazepine or phenytoin and replacing them with inducible AEDs such as oxcarbazepine, tiagabine, topiramate, and zonisamide, caution must be exercised to avoid reducing the carbamazepine or phenytoin dose too rapidly. Withdrawal episodes may occur with too rapid a dose reduction of carbamazepine or valproic acid, so taper slowly if the patient has a significant adverse reaction that requires discontinuation, and taper more rapidly with other AEDs. However, if the patient has a severe idiosyncratic reaction, the responsible AEDs should be withdrawn quickly.
6.1.2. Patient factors
The age, lifestyle, occupation, and driving status of the patient should also be considered during the drug change. Elderly patients are more prone to adverse reactions and require careful titration of the AEDs dose. Clinicians must carefully weigh the risk of seizures or adverse reactions to AEDs that provoke a switch versus the risk of exacerbating seizures by discontinuing any AEDs being used.
6.2. Discontinuation of medication
Discontinuation may be discussed in patients who have been seizure-free for at least 2 years. Discontinuation may increase the risk of recurrence, with the degree of risk influenced by the seizure-free period, history of seizure type (high risk of recurrence in juvenile myoclonic epilepsy), having 1 or more seizures since starting treatment, and whether the patient is on mono- or polypharmacy. The effect of EEG abnormalities in predicting the risk of recurrence is weak [14].
7. concluding remarks
The overall goals of epilepsy treatment are seizure-free, minimal adverse effects, improved quality of life, and long-term safety.AEDs are the treatment of choice for the vast majority of patients, and monotherapy is preferred, usually initiated after 2 seizures.Key factors affecting treatment goals should be considered at the time of initial treatment, and the patient’s coexisting conditions such as factors that may worsen the disease and drug interactions should also be assessed. Older, cheaper AEDs such as carbamazepine, phenytoin, and valproic acid continue to play an important role in first-line drug selection in adults with new-onset epilepsy; newer AEDs offer clinicians more opportunities to get patients to treatment; and broad-spectrum AEDs are chosen when seizure type is uncertain or unclear. patients treated with AEDs need to be routinely monitored for efficacy, adverse events, and changes in their status with Consider switching when adverse events, drug-drug interactions, poor tolerability, or co-existing conditions contraindicated by AEDs occur.