d 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 is defined by scholars in China as an epilepsy that is ineffective after regular treatment with at least two first-line antiepileptic drugs (with blood concentrations in the effective range) and that has been observed for at least 2 years, remains uncontrolled with at least 4 seizures per month, severely affects the patient’s daily life, and has no progressive CNS disease or occupying lesions.
The International League Against Epilepsy (ILAE) 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 of monotherapy or combination therapy with two tolerated antiepileptic drugs.
In 2010, the International League Against Epilepsy published a consensus that patients with epilepsy who have received two tolerable, reasonably selected and applied past antiepileptic treatment regimens that are not effective, either 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 d epilepsy
Clinical studies have shown that cerebrovascular disease, encephalitis and cortical developmental disorders are important causes of refractory d epilepsy. In addition, diseases such as West syndrome, Lennox-Gastaut syndrome and tuberous sclerosis are refractory as long as they are clearly diagnosed. The pathogenesis of d epilepsy is still not completely clear, but the following mechanisms may exist: (1) expression of drug-resistant genes; (2) neuronal network theory; (3) abnormal synaptic transmission function; and (4) abnormal ion channels.
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 or more.
Regular treatment with the application of appropriate first-line anti-d epileptic drugs, and the blood concentration of the drugs reaches the effective range without serious adverse drug reactions, and the seizures remain uncontrolled for at least 2 years of observation, affecting daily life.
Those without progressive neurological disease or occupying lesions.
The definitions and clinical diagnostic criteria have both their commonality and their individuality, and should neither be mutually exclusive nor confused with each other.
IV. 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. In addition, there are herbal treatments and stereotactic radiotherapy.
The principles of epilepsy treatment should be strictly observed.
(1) Pay attention to the quality of life of patients: The 2006 guidelines for the treatment of adult d epilepsy proposed that anti-d epileptic drugs should not emphasize complete control of epileptic seizures, but should pay more attention to improving the quality of life of patients. The guidelines consider that drugs with efficacy but also significant adverse effects can be considered as not superior to drugs with no efficacy but also no significant 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.
The application of new antiepileptic drugs and drug combination therapy: In recent years, many new antiepileptic drugs have been introduced in China, such as levetiracetam, pregabalin and brivaracetam. The study reported that carbamazepine, oxcarbazepine and lamotrigine are the most frequently used anti-d epileptic 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 in combination with other drugs. In the pharmacological treatment of symptomatic partial d disease, valproic acid is commonly combined with lamotrigine, carbamazepine (oxcarbazepine) with topiramate or levetiracetam or valproic acid.
Physiotherapy: When drug therapy is not effective, physiotherapy can be tried. The main physical therapies proposed so far are vagus nerve stimulation, deep brain electrical stimulation, magnetic brain stimulation and cooling method, the following are 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 arrhythmia, deserve further exploration.
(2) Deep brain electrical stimulation: It has been found that low frequency and low output intensity deep brain electrical stimulation can safely and effectively control d-epileptic 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 d epilepsy.
4. Ketogenic diet therapy: proposed by Wilder in 1921, it refers to the treatment of d-epilepsy with a high-fat, protein and low-carbohydrate diet formula that produces ketone bodies and simulates the starvation process to allow the body to achieve and maintain a state of ketosis. Studies have shown that the intermediates of ketogenic therapy, such as acetoacetic acid and acetone, can control d epileptic seizures and have neuroprotective effects. This treatment has been used abroad for many years, but it has only been introduced in China in recent years, but it is still not widely carried out, probably due to poor compliance of patients and changes in dietary habits.
Surgical treatment: When drugs and physiotherapy still cannot control seizures and seriously endanger the quality of life of patients, surgical intervention becomes the main treatment for refractory 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, hemispherectomy, etc.
6. Chinese herbal medicine: When western medicine is not effective in treating refractory d epilepsy, Chinese herbal medicine can be tried, but there is a lack of evidence-based medical evidence for its efficacy.
Radiation therapy: In recent years, the research of stereotactic radiation technology has promoted the development of radiation therapy for d epilepsy, but the selection of dose, the accurate positioning of d epileptic foci, the volume of the target area, and how to evaluate 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 the sleep disorder in d epilepsy patients; cognitive behavioral therapy, although it cannot reduce the frequency of d epilepsy seizures, can improve the social viability and psychological disorders of patients.