Epilepsy is a common neurological disorder, and about 30% of patients with poor drug therapy are referred to as drug-refractory epilepsy. In recent years, with the application of new antiepileptic drugs and improvements in neurophysiological and imaging techniques, treatment-refractory epilepsy is no longer a problem.
I. Definition of refractory epilepsy
The definition of refractory epilepsy agreed by our scholars is: ineffective after regular treatment with at least two first-line antiepileptic drugs (blood concentration in the effective range), and at least 2 years of observation, still not controlled and at least 4 seizures per month, seriously affecting the patient’s daily life, and without progressive central nervous system disease or occupying lesions.
The International League Against Epilepsy (ILAE) has considered refractory epilepsy to be seizure-free (seizure-free period of less than 3 times the maximum pre-treatment seizure interval or 12 months) after adequate courses of monotherapy or combination therapy with two tolerated antiepileptic drugs.
In 2010, the International League Against Epilepsy published a consensus that patients with epilepsy are considered to have refractory epilepsy if they receive two tolerable, reasonably selected and applied past antiepileptic treatment regimens that are still ineffective, whether monotherapy or combination therapy.
The etiology and pathogenesis of refractory epilepsy
In addition, diseases such as West syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis are considered refractory as long as they are clearly diagnosed.
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 per month; regular treatment with appropriate first-line antiepileptic drugs, and the blood concentration of drugs reaching the effective range, no serious adverse drug reactions, at least 2 years of observation still cannot control 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 a reasonable and standardized combination of drug therapy, ketogenic diet therapy for children, physical therapy and surgical treatment when drugs cannot effectively control seizures, and surgical treatment is preferred for intracranial developmental disorders, tumors, and gray matter heterotopias. In addition, there are herbal treatments and stereotactic radiotherapy.
1. Strict adherence to the principles of epilepsy treatment.
(1) Pay attention to the quality of life of patients: The 2006 guidelines for the treatment of adult epilepsy proposed that antiepileptic drugs should not only emphasize complete control of epileptic seizures, but also pay more attention to improving the quality of life of patients. The guidelines consider that drugs with efficacy but also obvious adverse effects can be considered as not superior to drugs with no efficacy but also no obvious adverse effects, so that the safety of drug therapy is given more attention.
(2) Personalization principle: Nowadays, personalized treatment has changed from the traditional individualization of dosage to the individualization of etiology and seizure type, and different treatment plans are selected for individuals according to imaging and EEG characteristics. In 2011, the first-line drug and the only drug of choice for three seizure types (generalized tonic-clonic seizures, atonic seizures and myoclonic seizures) is levetiracetam, which is the drug of choice for the treatment of generalized epilepsy in healthy women of childbearing age.
(3) Combination drug therapy: When the efficacy of a single drug is not significant, a combination of drugs can be chosen. The Italian Drug 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 the efficacy does not correlate with the loading dose of antiepileptic drugs, but with the individual sensitivity of antiepileptic drugs, the type of drug used, the medical skill of the doctor, and is affected 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 and so on. The study reported that carbamazepine, oxcarbazepine and lamotrigine are the most frequently used antiepileptic drugs when single medication is ineffective, and the combination of levetiracetam and carbamazepine, or levetiracetam and oxcarbazepine is often chosen.
The latest expert consensus on the use 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 pharmacotherapy of symptomatic partial d disease.
Physiotherapy: When drug therapy is not effective, you can try physiotherapy. 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: Some people believe that this therapy can reduce the frequency of abnormal brain discharge during seizures, and others believe that the action potential triggered by stimulating the vagus nerve can regulate the excitability of the nervous system. wheelei 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 arrhythmia are worth 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, stimulating 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 for the treatment of refractory epilepsy, but its treatment mechanism, stimulation frequency and safety factors still need to be studied in depth.
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. Studies have shown that the intermediates of ketogenic therapy, such as acetoacetic acid and acetone, can control seizures and have neuroprotective effects, and the Masino study found that a ketogenic diet can reduce the frequency of epileptic seizures by inhibiting adenosine A1 receptors.
This treatment has been used abroad for many years, but it has only been used in China in recent years, but it is still not widely carried out, probably due to poor compliance and changes in dietary habits of patients.
Surgical treatment: When drugs and physical therapy still cannot control seizures and seriously endanger the quality of life of patients, surgical intervention becomes the main means of treating intractable epilepsy. However, the indications for surgery, the precise location of the epileptogenic focus and the protection of brain function are very important. 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 epileptogenic focus. Common surgical procedures include anterior temporal lobectomy, selective amygdala and hippocampal resection, hydrazinotomy, cerebral hemisphere resection and other procedures.
6, Chinese medicine treatment: When western medicine treatment for refractory epilepsy is not effective, Chinese medicine treatment 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: such as melatonin therapy by improving the sleep disorder of epilepsy patients can significantly reduce the symptoms of epilepsy patients; cognitive behavioral therapy, although it can not reduce the frequency of seizures, but can improve the social viability of patients and improve psychological disorders.