I. Definition of refractory epilepsy
Refractory epilepsy is defined by scholars in China as epilepsy that is ineffective after regular treatment with at least two first-line antiepileptic drugs (blood levels in the effective range) and is still uncontrollable with at least 4 seizures per month after at least 2 years of observation, severely affecting the patient’s daily life and without progressive CNS disease or occupying lesions.
The International League Against Epilepsy has considered refractory epilepsy to be seizure-free (seizure-free period less than 3 times the longest interval between seizures before treatment or 12 months) after an adequate course and dose of monotherapy or combination therapy with two tolerated antiepileptic drugs.
The consensus published by the International League Against Epilepsy in 2010 states that patients with epilepsy who receive two tolerable, reasonably selected and applied past antiepileptic treatment regimens that are still ineffective, whether monotherapy or combination therapy, are considered to have refractory epilepsy, regardless of whether the definition of refractory epilepsy is uniform or not.
The etiology and pathogenesis of refractory epilepsy
Clinical studies have shown that cerebrovascular disease, encephalitis and cortical developmental disorders are important causes of refractory epilepsy. In addition, diseases such as West syndrome, Lennox-Gastaut syndrome and tuberous sclerosis are refractory as long as they are clearly diagnosed. Abnormal synchronous neuronal discharge is the underlying cause of epilepsy.
Diagnostic criteria for refractory epilepsy
The diagnostic criteria for refractory epilepsy have not been unified yet, but most scholars in China adopt the diagnostic criteria proposed by Wu Xun and Shen Dinglie: frequent seizures, at least 4 times a month; regular treatment with appropriate first-line antiepileptic drugs, and the blood concentration of the drugs reaches the effective range, no serious adverse drug reactions, at least 2 years of observation still cannot control the seizures, affecting daily life; no progressive neurological disease or occupying lesions. There is no progressive neurological disease or occupational lesion. The definition and clinical diagnostic criteria have both commonality and individuality, and should neither be mutually exclusive nor confused with each other.
Treatment of refractory epilepsy
Once a patient is diagnosed with refractory epilepsy, he or she should first choose reasonable and standardized combined drug therapy, and children can choose ketogenic diet therapy. In addition, there are herbal therapies, stereotactic radiotherapy, etc.
1, strict adherence to the principles of epilepsy treatment.
(1) Pay attention to the patient’s quality of life: The 2006 guidelines for the treatment of adult epilepsy proposed that antiepileptic drugs should not emphasize complete control of epileptic seizures, but should pay more attention to improving the patient’s quality of life. The guidelines consider that drugs with efficacy but also obvious adverse reactions can be regarded as not superior to drugs without efficacy but also without obvious adverse reactions, so that the safety of drug therapy is given more attention.
(2) Personalization principle: Nowadays, personalized treatment has changed from traditional individualized dose to individualized etiology and seizure type, and different treatment plans are selected according to imaging and EEG characteristics. Levetiracetam is the drug of choice for the treatment of generalized epilepsy in healthy women of childbearing age, etc.
(3) Combination drug therapy: When the efficacy of a single drug is not significant, a combination of drugs can be chosen. The Italian Medicines Agency study confirmed that there is no significant difference in adverse effects between patients treated with a single drug and those treated with a combination of drugs, and that the efficacy is not correlated with the loading dose of the antiepileptic drug, but with the individual sensitivity of the antiepileptic drug, the type of drug used, the medical skill of the physician, and influenced by gender, emotion and other potential factors.
The application of new antiepileptic drugs and drug combination therapy: In recent years, a variety of new antiepileptic drugs have been introduced in China, such as levetiracetam, pregabalin, brivaracetam, etc. Canevini et al. reported that carbamazepine, oxcarbazepine, and lamotrigine are the most frequently used antiepileptic drugs when single drug therapy is ineffective, and levetiracetam and The combination of levetiracetam and carbamazepine, or levetiracetam and oxcarbazepine is often chosen when single drug therapy is not effective.
The latest expert consensus on the application of antiepileptic drugs found that valproic acid is the drug of choice for combination therapy with other drugs, and valproic acid is commonly used in combination with lamotrigine, carbamazepine (oxcarbazepine) and topiramate or levetiracetam or valproic acid in the drug treatment of symptomatic partial epilepsy.
3, physical therapy: when the efficacy of drug therapy is not significant, you can try physical therapy. The main physical therapies proposed are vagus nerve stimulation, deep brain electrical stimulation, magnetic brain stimulation and cooling method, the following are the commonly used therapies.
(1) Vagus nerve stimulation: It is believed that this therapy can reduce the frequency of abnormal brain discharges during seizures, and it is also believed that the action potential triggered by stimulating the vagus nerve can regulate the excitability of the nervous system. wheeler et al. confirmed that this therapy has good efficacy and is slightly inferior to surgery, but adverse effects such as hardware failure, deep infection, and cardiac arrhythmias deserve further exploration.
(2) Deep brain electrical stimulation: It has been found that low frequency, low output intensity deep brain electrical stimulation can safely and effectively control seizures, however, stimulation of different areas of a site can produce different effects, and changes in stimulation parameters can also affect the efficacy. (3) Transcranial magnetic stimulation: low-frequency transcranial magnetic stimulation can reduce cortical excitability and inhibit abnormal firing of cortical neurons, which can be used to treat refractory epilepsy.
4. Ketogenic diet therapy: proposed by Wilder in 1921, it refers to the treatment of epilepsy by producing ketone bodies, simulating the process of starvation and allowing the body to achieve and maintain a state of ketosis with a diet high in fat, protein and low in carbohydrates. The intermediates of ketogenic therapy, such as acetoacetic acid and acetone, have been shown to control seizures and have neuroprotective effects. This treatment has been used abroad for many years, but it has only been cited in recent years in China, but it is still not widely carried out, probably due to poor compliance of patients and changes in dietary habits.
5, surgical treatment: when drugs, physical therapy and other treatment methods still can not control seizures, and seriously endanger the quality of life of patients, surgical intervention has become the main means of treatment of intractable epilepsy. Surgical treatment is often performed by routine scalp EEG, long-range video EEG monitoring, head MRI and other examination techniques and, if necessary, invasive intracranial electrode monitoring to accurately analyze the site and extent of the lesion.
Common surgical procedures include anterior temporal lobectomy, selective amygdala and hippocampal resection, corpus callosotomy, cerebral hemisphere resection and other procedures.
6. Chinese herbal medicine: When western medicine is not effective in treating intractable epilepsy, Chinese herbal medicine can be tried, but the efficacy lacks evidence-based medical evidence.
Radiation therapy: In recent years, the research of stereotactic radiation technology has promoted the development of epilepsy radiation therapy, but the choice of dose, the accurate positioning of epileptic foci, the volume of the target area and how to assess its recent and long-term effects still need to be confirmed by bulk trials.
8, adjuvant therapy: for example, melatonin therapy can significantly reduce the symptoms of epilepsy patients by improving their sleep disorders; cognitive behavioral therapy, although it cannot reduce the frequency of seizures, can improve the social viability of patients and improve psychological disorders.
In summary, although great progress has been made in the treatment of refractory epilepsy, more evidence-based medical evidence is still needed for its standardized and effective treatment.