Epilepsy is a common and frequent disease in neurology, with the second highest incidence after cerebrovascular disease. The treatment of epilepsy in China is seriously confusing, and attention should be paid to formal treatment.
1. Treatment goals of epilepsy
The goals of epilepsy treatment include: (1) complete control of seizures; (2) reduction of malignant seizures; (3) avoidance of drug side effects; (4) reduction of adverse drug interactions; (5) suppression of subclinical epileptiform discharges; (6) reduction of morbidity and mortality; (7) avoidance of impeding the normal life of patients; and (8) stopping the occurrence of epileptic sources.
The goal of epilepsy treatment is not only to completely control seizures, but also to enable patients to achieve a high quality of life or return to society. Formal treatment is the most important means to make epilepsy cure or control epileptic seizures and reduce adverse drug reactions. If formal treatment is not taken seriously, not only can seizures not be controlled, but even “medically intractable epilepsy” can be caused, so that patients with seizures that can be controlled can prolong their lives and form chronic epileptic encephalopathy, which affects the quality of life of patients. The current status of domestic epilepsy treatment is unsatisfactory, and there are many problems that need to be corrected.
2. Principles of epilepsy treatment
2.1 First determine whether to use medication There are 5% of people who will have one to several occasional seizures in their lifetime, but the occurrence of one seizure is not the same as having epilepsy, which means that not every patient who has had an epileptic seizure needs antiepileptic treatment. For example, some patients with hypoglycemia will have seizures, but when the hypoglycemia is corrected, the seizures will naturally end, so this group of patients does not need antiepileptic treatment. In the following cases, medication can be withheld: (1) Patients who have their first seizure should not be medicated until the cause is identified and the next seizure is decided; (2) Patients with an interval of more than one year between seizures can be withheld; (3) Patients with obvious triggering factors can be withheld; (4) Patients who cannot adhere to regular medication can be withheld; (5) Some children with benign epilepsy have a tendency to heal themselves with age. (5) Some children with benign epilepsy have a tendency to heal on their own with age, and if seizures are not frequent, they can be withheld.
(1) Patients with two or more seizures in a year may be treated with monotherapy as appropriate. (2) symptomatic epilepsy caused by progressive brain disease requires antiepileptic treatment; (3) those with significant epileptic discharges on EEG require regular antiepileptic treatment.
In 2006, the International League Against Epilepsy proposed the timing of drug treatment for epilepsy based on evidence-based medicine: as long as there is a persistent susceptibility to seizures in the brain, drug treatment should be started after a single seizure. The susceptibility to seizures is demonstrated by (1) a clear family history of epilepsy, (2) significant epileptiform discharges on the EEG during the interictal period, and (3) a clear and non-eradicable etiology, such as head trauma, delayed onset epilepsy after cerebrovascular disease, and seizures caused by chronic tumors.
2.2 Selection of antiepileptic drugs according to seizure type The selection of drugs according to seizure type is the first principle of epilepsy treatment. The prerequisite for the correct selection of antiepileptic drugs is the correct diagnosis, only the diagnosis of epilepsy is the first step, but also the correct determination of seizure type or epilepsy syndrome. The type of seizure should be determined by a professional clinician, and effective, safe, inexpensive and guaranteed source drugs should be selected according to the type of seizure.
The internationally accepted principles of drug selection are: (1) valproic acid is preferred for generalized seizures and myoclonic seizures; (2) ethosuximide or valproic acid is preferred for aphasic seizures; (3) carbamazepine is preferred for partial seizures; (4) adrenocorticotropic hormone, valproic acid or aminolevulinic acid is preferred for infantile spasms; (5) topiramate, fexofenprox and lamotrigine are preferred for Lennox-Gastaut syndrome. (5) Lennox-Gastaut syndrome.
2.2.1 Generalized seizures
(1) Primary generalized tonic-clonic seizures: valproate (VPA) is preferred; carbamazepine, phenytoin sodium, phenobarbital, and paroxetine are the second choices.
(2) Anhedonic seizures: valproate is preferred; ethosuximide is the second choice; for anhedonic seizures with unsatisfactory effect of monotherapy, valproate and ethosuximide can be combined. If the above two drugs are not effective, clonidine and Valium can be considered.
(3) Idiopathic tonic-clonic seizures with typical akathisia: valproate is preferred.
(4) Myoclonic seizures: valproate is preferred; ethosuximide, clonidine, acetazolamide are the second choices.
(5) Infantile spasms: ACTH or prednisone first; valproate second, gabapentin (GBP), lamotrigine (LTG), tolterodine (TPM).
(6) Lennox-Gastaut syndrome and dystonic seizures: valproate is preferred; clonidine, Tolteraz, felbamate, lamotrigine are second choices.
Phenobarbital, phenytoin sodium, carbamazepine can aggravate akathisia, myoclonic and atonic seizures and should be avoided for these types.
2.2.2 Partial seizures: Carbamazepine is preferred for all types of partial seizures or generalized seizures secondary to partial seizures; phenytoin sodium, valproate, phenobarbital, and paroxetine. Newer antiepileptic drugs Toltea, gabapentin, lamotrigine, and aminoglutethimide (VGB) may also be considered.
Evidence-based epilepsy treatment guidelines: 2004: The American Academy of Neurology (AAN) and Scottish Intercollegiate Guidelines Network (SIGN) published guidelines for the treatment of epilepsy in the United States and Scotland, respectively.
2006: The International League Against Epilepsy published guidelines for the treatment of epilepsy based on clinical efficacy.
2.3 Try to monotherapy The combination of two or more antiepileptic drugs is prone to chronic toxicity and increased frequency of seizures after toxicity, and currently one drug is preferred. Only when the wrong drug selection, insufficient dose, irregular dosing and other factors are excluded and the failure of monotherapy is confirmed, a second drug should be added.
Monotherapy should start with a small dose and gradually increase the dose until it reaches an effective dose for seizure control without adverse effects, i.e. a steady-state effective blood concentration.
Indications for combination therapy: (1) Patients with refractory epilepsy who have tried multiple monotherapy regimens are ineffective; (2) Patients with multiple seizure types may be treated with a combination of drugs according to the seizure type.
Precautions for co-administration: Drugs with the same chemical structure, such as phenobarbital and paroxetine, clonazepam and diazepam, should not be combined. The combination of two or more drugs is contraindicated. The combination of multiple drugs will not improve the efficacy, but sometimes reduce the efficacy and increase the toxic reaction due to drug-drug interactions. Side effects should be closely observed. If a drug is ineffective for 2 to 3 months or there are adverse reactions, gradually switch to another drug, do not stop the drug suddenly.
As individualized treatment of epilepsy patients varies greatly, some are effective at lower blood concentrations, while others have obvious toxic reactions at therapeutic concentrations, so individualization of medication is required. Clinical attention should be paid to monitor the efficacy and toxic side effects of drugs and adjust the dose in time to achieve the best efficacy and avoid adverse effects.
2.5 Pay attention to drug usage Generally, it is advisable to start with a small dose and gradually increase the dose to the minimum effective dose that can control seizures without producing toxic reactions. The half-life of phenytoin sodium and phenobarbital is long, and the drug concentration can be changed to once daily after stabilization. The therapeutic concentration of phenytoin sodium is very close to the concentration of toxic reaction, and it is very easy to be poisoned by increasing the dose when the conventional dose is ineffective, so great care should be taken. Sodium lumefantrine and sodium valproate have a wide therapeutic range and can be given at regular doses at the beginning. Carbamazepine has a shortened half-life due to its self-induced metabolism, so the dose should be increased gradually to reach the regular dose in about 1 week. Lamotrigine and topiramate should be gradually increased to reach the therapeutic dose in about 1 month, otherwise skin rash and central nervous system side effects are likely to occur.
If the seizures are frequent and difficult to control, the dose of the drug should not be increased excessively for complete control of the seizures, resulting in adverse reactions, and the quality of life of the patient should be considered.
2.6 Close observation of adverse reactions All antiepileptic drugs have adverse reactions. Dose-related adverse reactions are the most common, usually occurring at the start of dosing or when the dose is increased, and are related to blood concentrations and should be observed during treatment. Most common adverse reactions are transient and can be significantly reduced by slow dose reductions.
Serious atopic reactions: rash caused by carbamazepine and lamotrigine; liver injury and thrombocytopenia caused by valproic acid and carbamazepine; neurological damage caused by phenytoin sodium; intelligent and behavioral changes caused by phenobarbital, should be classified as serious atopic reactions. Once atopic reactions are detected, dose reduction, discontinuation or drug change should be considered.
Once a drug and dose that can completely control seizures is found, it should be applied without interruption. In idiopathic epilepsy, it is usually 1 to 2 years after seizure control, and in non-idiopathic epilepsy, it is 3 to 5 years after seizure control before considering dose reduction and drug discontinuation. Symptomatic epilepsy with a history of encephalitis or birth injury, complex partial-onset epilepsy, and frequent seizures with EEG abnormalities should be treated with long-term medication, and some patients need to take medication for life. In order to maintain the steady-state effective concentration, the medication should be taken regularly to achieve the purpose of effective antiepilepsy.
The principle of medication change is to add new drugs and reduce old ones. A transition period of at least 3-7 days should be allowed for medication changes. It is not advisable to add new drugs and then stop using the old ones. The sudden discontinuation of medication may cause the seizures to worsen or even induce persistent status epilepticus.
2.9 Principles of drug reduction and discontinuation Currently, most people advocate that after the seizure is completely seizure-free, the drug should be continued for 3-5 years according to the seizure type, frequency of previous seizures, and the size of the toxic side effects of the drug, and then gradually discontinue the drug.
The principles of withdrawal of antiepileptic drugs: for idiopathic generalized tonic-clonic seizures, the discontinuation process should not be less than 1 year; for atonic seizures, the discontinuation process should not be less than 6 months; for large doses of the original drug, the discontinuation time is also long; it is important not to stop the drug abruptly, otherwise it may lead to persistent status epilepticus and even threaten life.
The following conditions affect the discontinuation time: (1) definite organic encephalopathy; (2) positive neurological examination; (3) mental disorders; (4) persistent EEG paroxysmal abnormalities; (5) partial seizures; and (6) mixed seizures. Some patients with organic encephalopathy with epilepsy may require lifelong medication; patients with epilepsy with an age of onset of 30 years or older need to be cautious in discontinuing medication, as their recurrence rate after discontinuation is more than 50%, requiring long-term medication or even lifelong medication.
In the past, there were some misconceptions about the surgical treatment of epilepsy, that any patient with epilepsy could be treated surgically, and that everything would be fine after surgery and no more drugs would be needed. Most people with epilepsy still need to continue taking antiepileptic drugs after surgery to achieve complete seizure control.
Surgical indications for epilepsy: Surgical treatment is mainly indicated for refractory epilepsy. Anyone who is diagnosed with epilepsy and cannot be controlled after 2 years of systematic drug treatment and monitored by plasma concentration, with more than 4 seizures per month and a disease duration of more than 3 years, can be considered for surgery.
The traditional view is that surgery should be considered only after antiepileptic drug therapy has failed. The current new view is that early surgery in cases where drug therapy is predictably ineffective can reduce the impact of seizures on brain tissue, especially developing brain tissue, and avoid some of the adverse consequences of epilepsy.
Surgical approaches to epilepsy.
(1) Excision of the epileptic source lesion or epileptic source area: cortical, lobotomy and hemispherectomy, etc.
(2) Blocking the diffusion meridians of epileptic discharges, raising the epileptic threshold and destroying the excitatory structures of epilepsy: e.g., cerebral association (corpus callosum) dissection, stereotactic deep brain structure destruction (amygdala, Forel-H area), etc.
(3) Stimulation of the inhibitory structures of epilepsy: e.g. chronic cerebellar stimulation.
2.11 Etiology of epilepsy Etiology should be performed if there is a clear cause. Hypoglycemia and hypocalcemia should be corrected with corresponding metabolic disorders. Surgical treatment should be considered first for intracranial occupying lesions.
3. Current problems in epilepsy treatment
3.1 Lack of attention to the selection of antiepileptic drugs according to the type of seizures In China, not much attention is paid to the determination of seizure types and syndromes, which has lost the basis for the correct selection of antiepileptic drugs. Sometimes, even if the seizure type is correctly determined, some doctors are used to choosing one antiepileptic drug for any type of seizure, which not only fails to improve the efficacy, but also sometimes aggravates the seizure. The use of carbamazepine is prohibited for myoclonic and atonic seizures because it can aggravate both types of seizures, and phenytoin sodium should also be used with caution. It is not only possible to aggravate tonic spasmodic seizures with ethosuximide, but also to cause them in patients who did not have them.
3.2 Low dose of medication
3.2.1 The concept of “effective concentration” and “target concentration”: The concept of “effective concentration” in epilepsy treatment is a statistical concept, i.e., the blood concentration at which the drug is effective for most patients. The concept of “effective concentration” in epilepsy treatment is a statistical concept. Many physicians treat the “effective concentration” as the “target concentration” and believe that every patient must reach this concentration range to be effective.
3.2.2 Correctly understand and grasp the concept of “effective concentration”: each patient’s response to antiepileptic drugs is different, and some patients have complete seizure control when the blood concentration is below the “effective concentration”. In some patients, the seizures can be controlled only when the blood concentration is slightly higher than the “effective concentration”, and the dose should not be reduced as long as there are no obvious adverse drug reactions. For most patients, the efficacy is best within the “effective concentration” range.
3.3 Unreasonable polypharmacy The international community, without exception, favors monotherapy. The advantages of monotherapy are good compliance, no drug-drug interactions, few adverse effects, low treatment costs, and easier acceptance by patients. If a drug therapy is not effective, it should be replaced by another antiepileptic drug monotherapy, and only if it is still not effective should polypharmacy be considered. It is best to use no more than three drugs in combination, and a reasonable combination of multiple drugs should be used.
3.4 Frequent drug changes and irregular medication There is no cure for epilepsy so far, only long-term regular medication can maintain a steady-state effective concentration to control seizures. After starting the application of antiepileptic drugs, it takes 5 half-lives to reach the steady-state effective concentration and exert the maximum antiepileptic effect. The use of a drug with a long half-life for a few days does not determine whether it is effective. If an antiepileptic drug is effective, it should not be switched to other drugs, much less taken only for a short period of time after each seizure, as this would be ineffective treatment.
3.5 The use of western medicine in the name of pure Chinese medicine is a kind of medical fraud. It is the most common phenomenon of irregular treatment of epilepsy in China at present. It violates the patient’s right to know, and in case of adverse reactions or allergic reactions, the unknown situation will delay the treatment. The most commonly added western drugs are inexpensive phenobarbital and/or phenytoin sodium. The prices of these so-called “pure Chinese medicines” have not been subjected to any scientific pre-marketing or post-marketing clinical studies, and their efficacy is unknown, but their prices are tens or even hundreds of times the actual price of the drugs. Some of the so-called “pure Chinese medicine” manufacturers are neither TCM doctors nor Western medicine doctors, or even have no qualifications to practice medicine at all.
3.6 Sudden discontinuation of medication This is a very dangerous form of irregular treatment. The consequences of stopping medication are often not only recurrence of epilepsy, but also a life-threatening condition that can lead to persistent epilepsy.
In some patients with intractable epilepsy, multiple or extra large doses of drugs are often taken to control seizures, resulting in significant drug side effects.
3.8 Excessive pursuit of EEG normalization In some types of epilepsy, the clinical symptoms have been controlled, and sometimes there is no need to blindly increase the dose to try to make the EEG completely normal, although the EEG is still abnormal. For example, in benign childhood epilepsy with spike-wave foci in the central temporal region, although the child has been clinically seizure-free for a long time, the EEG may still be frequently discharged on review, and there is no need to pursue EEG normalization excessively in this case.
3.9 Experimental treatment with antiepileptic drugs is given to suspected cases If the application of various tests does not confirm the diagnosis, it is best to have sufficient follow-up to determine whether the child has epilepsy and not to blindly experiment with treatment.
4. Treatment of persistent status epilepticus
4.1 Hazards of persistent status epilepticus Persistent status epilepticus is one of the common neurological emergencies, which can cause irreversible brain damage in mild cases and life-threatening in severe cases if not treated in time. Persistent status epilepticus can lead to neurological damage and even sudden death.
4.2 Epileptic status (SE) is defined as a person who has multiple consecutive seizures and fails to regain consciousness during the interictal period; or a seizure lasting more than 30 minutes. Any type of seizure can produce epileptic status, but the common clinical condition is generalized tonic-clonic seizure status.
4.3 Treatment of persistent status epilepticus
4.3.1 General treatment The first step is to keep the airway open and make a tracheotomy if necessary. Pay attention to oxygen administration and protection. Perform cardiac, blood pressure and respiratory monitoring, and check blood gas and blood biochemistry regularly. Control respiratory tract infection, correct acidosis, and maintain electrolyte balance. Find and eliminate the cause of persistent epilepsy.
4.3.2 Seizure control Persistent status epilepticus may lead to cerebral hypoxic damage, such as cerebral edema, which in turn makes seizures difficult to control. Rapid seizure control is the key to treatment. The following drugs can be applied.
(1) Valium The drug of choice. The maximum single dose should not exceed 20 mg at a rate of 5 mg per minute, and can be repeated after 15 minutes if the seizure recurs, or 100-200 mg of Valium dissolved in 5% glucose saline and administered slowly intravenously over 12 hours. Valium may occasionally depress respiration, and if this occurs, the injection should be stopped.
(2) Phenytoin sodium is administered intravenously at a rate of no more than 50mg/min to reach a loading dose of 20mg/kg. Monitor patients with cardiac disease or unsustainable blood pressure, and slow down the IV drip rate if blood pressure decreases, ECG interval widens, or arrhythmias occur.
(3) Isopentobarbital sodium 0.5g dissolved in 10ml of water for intravenous injection at a rate of not more than 0.1g per minute. Side effects: respiratory depression, hypotension, delayed resuscitation. Use often requires tracheal intubation and mechanical ventilation to ensure the stability of vital signs.
(4) 10% chloral hydrate or paraldehyde 10% chloral hydrate 20-30ml with equal amount of vegetable oil reserved for enema. Paraldehyde 8-10ml intramuscularly or diluted with vegetable oil to retain the enema.
(5) Use of cocaine is mainly used for those who are ineffective in tranquilization. Dosage 2-4mg/Kg, add 10% glucose and infuse intravenously at the rate of 50mg per hour. Use with caution in cases of heart block and bradycardia.
(6) Phenytoin sodium Phenytoin sodium 300-600mg in 500ml saline intravenously. Can be applied alone. It can also be applied after Valium 10-20mg intravenous injection to obtain therapeutic effect.
(7) Clonidine is 5 times more effective than Valium; first dose of 3mg intravenously in adults, then 5-10mg/d intravenously or overdose to oral drug. Strong respiratory and cardiac depressant effects. Good for all types of status epilepticus.
(8) Midazolam is fast-acting, easy to use, and has less inhibitory effects on blood pressure and respiration than traditional drugs. In recent years, it has been widely used to replace isopentobarbital as the standard therapy for refractory status epilepticus. The first dose of 0.15-0.2mg/kg, followed by 0.06-0.6mg/kg.h intravenous drip maintenance.
(9) Narcotic drugs Used for those who have failed to be treated by any of the above methods. Chlortalidone, thiopental sodium intravenous injection or ether inhalation anesthesia to control seizures.
4.3.3 Maintenance treatment After the seizures are controlled by the above treatment, the long-acting antiepileptic drug phenobarbital 0.1-0.2g should be administered intramuscularly every 8 hours to consolidate and maintain the therapeutic effect. At the same time, intranasal carbamazepine or phenytoin sodium should be administered, and the intramuscular injection of phenobarbital can be gradually stopped after it reaches steady-state blood concentration.
5. Summary
Epilepsy is not an incurable disease, nor is it a simple condition that can be cured in a few days, and some so-called quick cure epilepsy advertising propaganda lacks credibility. To achieve a true cure for epilepsy, it is important to pay attention to the formal treatment of epilepsy. With untreated epilepsy, the 5-year spontaneous remission rate is above 25%. With formal antiepileptic treatment 60%-80% of patients with epilepsy have complete seizure control. After 3-5 years of control, the chance of recurrence of idiopathic generalized epilepsy is low. Childhood-onset epilepsy is usually expected to stop seizures with 2 years of drug therapy. Young-onset atonic epilepsy is more likely to develop into generalized convulsions and requires longer treatment. Myoclonic epilepsy in youth is easily controlled by sodium valproate, but is highly susceptible to recurrence after discontinuation.