Epilepsy: Treatment

Medicinal treatment of epilepsy can completely eliminate this disease in 1/3 of patients and significantly reduce their frequency in more than half of cases in the other 1/3. Approximately 60% of patients with high efficacy of anticonvulsants and full control of seizures may eventually stop taking drugs without relapse of epilepsy.

[1], [2], [3], [4],

Medicinal treatment of epilepsy

Bromine salts were the first effective antiepileptic agent. Since 1850, bromides have been used based on the erroneous belief that, by relaxing sexual desire, it is possible to reduce the severity of epilepsy. Although the bromides really had antiepileptic effect, they were toxic and stopped to be used as soon as barbiturates were introduced into practice in 60 years. Phenobarbital was originally used as a sedative and hypnotic drug. Over time, by a fluke, his antiepileptic potential was also discovered. Gradually began to appear and other antiepileptic drugs, which were usually chemical derivatives of phenobarbital - for example, phenytoin, developed in 1938 and became the first non-sedative antiepileptic agent. At the same time, carbamazepine, which appeared in the 1950s, was originally used as a treatment for depression and pain. Valproic acid was first used only as a solvent, and its antiepileptic properties were discovered quite by chance, when it was used to dissolve compounds that were tested as antiepileptic agents.

The potential of drug treatment for epilepsy is tested using experimental models created on laboratory animals, for example, using maximum electric shock. In this case, the ability of drugs to inhibit tonic convulsions in mice or rats subjected to electrical shock is tested. In this case, the ability to protect against maximal electroshock allows to predict the effectiveness of the drug in partial and secondarily generalized seizures. Antiepileptic properties of phenytoin were detected with the help of this method.

In the early 1950s, the efficacy of ethosuximide in absences (petit mal) was demonstrated . Curiously, although this drug does not protect against the effects of maximum electric shock, it inhibits seizures caused by pentylenetetrazole (PTZ). In this regard, pentylenetetrazole seizures have become a model for assessing the effectiveness of antisense drugs. Epilepsy induced by other convulsants, for example, strychnine, picrotoxin, allylglycine and N-methyl-D-acnapatate, is also sometimes used to test the efficacy of drug treatment for epilepsy. If the drug protects against seizures caused by a single agent, but not by another agent, this may indicate a selectivity of its action against certain types of seizures.

Relatively recently, to test the efficacy of medicinal treatment of epilepsy, we began to use hand-fitting seizures, as well as other models of complex partial seizures. On the model of handling fits, electric shock is applied with the help of electrodes implanted in the deeper parts of the brain. Although electric shock does not leave residual changes at first, when repeated over several days or weeks, complex electrical discharges tend to persist and lead to convulsive seizures. In this situation, they say that the animal is "wound up" (from the English kindling - ignition, kindling). Kindling seizures are used to evaluate the effectiveness of drugs that can be useful for temporal epilepsy. Since kainic acid, which is an analog of glutamic acid, has a selective toxic effect on the deep structures of the temporal lobes, it is also sometimes used to create a model of temporal epilepsy. Some lines of rats and mice serve to create models of different types of epilepsy. Of particular interest in this respect is the creation of the absences model in rats.

Although different experimental models are used to evaluate the effectiveness of drug treatment for epilepsy in various types of seizures, the correspondence between the effect on experimental models and the efficacy for a particular type of epilepsy in humans is not always discerned. In general, drugs that are effective at relatively non-toxic doses in several experimental models of epilepsy usually demonstrate a higher efficacy in clinical settings. Nevertheless, the demonstration of the effect of the drug on the experimental model is only the first necessary step to testing it on a person and it does not guarantee that the drug will be safe and effective in sick people.

The development of an antiepileptic drug has gone through several stages. Bromides symbolize an era of erroneous theories, phenobarbital - the era of accidental discoveries, primidone and meforbarbital - the era of imitation of phenorbarbital, phenytoin - the era of testing antiepileptic drugs using the technique of maximum electric shock. Most new antiepileptic drugs have been developed to selectively affect neurochemical systems in the brain. Thus, vigabatrin and tiagabin increase the synaptic availability of GABA. The first blocks the metabolism of GABA, the second - the reverse capture of GABA in neurons and glial cells. The effects of lamotrigine and remacemid are partly related to the blockade of glutamate release or blockade of its receptors. The action of phenytoin, carbamazepine, valproic acid, felbamate, lamotrigine, and some other drugs is associated with exposure to sodium channels in neurons, as a result of which these channels after being inactivated are closed for a longer time. This prolongation prevents unnecessarily rapid axon generation of the next action potential, which reduces the frequency of discharges.

The development of new methods of treating epilepsy in the future will likely be based on knowledge of the genes responsible for the development of epilepsy and their products. Substitution of compounds lacking as a result of a genetic mutation can create conditions for the cure of epilepsy, and not just for the suppression of epilepsy.

When choosing a drug treatment for epilepsy, several aspects should be considered. First, it is necessary to decide whether anti-epileptic agents should be prescribed at all. Thus, some simple partial seizures, manifested only by paresthesia or minimal motor activity, may not require treatment. Even absences or complex partial seizures may not require treatment if they do not disturb the patient and do not pose a threat of falling or trauma, and the patient does not need to drive or work near dangerous mechanisms. In addition, a single fit may also not require the appointment of antiepileptic drugs, since 50% of persons with a generalized tonic-clonic seizure of unknown origin do not arise in the absence of changes in EEG, MRI, laboratory tests of the second fit. If the second case of epilepsy does occur, antiepileptic treatment should be started.

Treatment for epilepsy is not necessarily carried out for the rest of life. In some cases, drugs can be gradually canceled. This is especially often done in situations where epilepsy is absent for at least 2-5 years, the patient has no structural changes to the brain according to MRI, there is no identified hereditary disease (eg, juvenile myoclonic epilepsy, in which the epileptic activity persists for all life), in the anamnesis there was no epileptic status and no epileptic activity on the background EEG. However, even in these conditions, there is one chance out of three that seizures will resume within 1 year after the withdrawal of the drug treatment for epilepsy. In this regard, the patient should be advised not to drive the car within 3 months after the antiepileptic remedy. Unfortunately, because of the need to limit driving, many patients are hesitant to cancel antiepileptic treatment.

Basic principles of drug treatment of epilepsy

• Decide how expedient to start a drug treatment.
• Estimate the estimated duration of treatment.
• If possible, resort to monotherapy.
• Assign the most simple scheme for taking the drug.
• To support the patient's readiness to follow the proposed scheme.
• Choose the most effective drug taking into account the type of epilepsy.

The scheme for taking antiepileptic drugs should be as simple as possible, since the more complex the scheme, the worse the patient should be. So, when taking the drug once a day, patients significantly less often violate the treatment regimen than if necessary to take the drug two, three or four times a day. The worst scheme is one that involves taking different drugs at different times. Monotherapy, which is successful in approximately 80% of patients with epilepsy, is simpler than polypharmacy, and it avoids the interaction of drugs.

Treatment of epilepsy with some drugs should be started gradually to avoid side effects. This primarily applies to carbamazepine, valproic acid, lamotrigine, primidon, topiramate, felbamate and vigabatrine - the therapeutic dose of these drugs is selected gradually over several weeks or months. At the same time, treatment with phenytoin, phenobarbital and gabapentin can begin with therapeutic doses. The treatment plan should be thought out in advance and given to patients and their relatives in writing. In addition, it is important to maintain contact with the patient, especially at the beginning of treatment, when side effects are most likely.

Changing the drug can be a difficult problem. If the dose of the new drug should be increased gradually, it is usually not recommended to cancel the first remedy until the therapeutic dose of the new drug is reached. If this precaution is not observed, the patient may experience seizures during the transitional period. The negative side of this approach is an increase in the likelihood of a toxic effect due to the overlapping action of the two drugs. Patients should be warned about the possibility of temporary side effects and the emergence of epilepsy against the background of the abolition of previously used drugs during the change of treatment.

Although measuring the concentration of drugs in the blood is useful for adjusting treatment, this technique should not be abused. If the patient does not have epilepsy and manifestations of the toxic effect of the drug, there is usually no need to monitor his blood level. When you designate two or more drugs, measuring the level of drugs in the blood is useful in situations where it is necessary to determine which of them can cause a toxic effect.

Choosing an antiepileptic drug

Carbamazepine or phenytoin are the drugs of choice for partial epilepsy, while valproic acid is preferable to primary generalized seizures, but somewhat less effective than carbamazepine, with antiepileptic agents in the serum partial seizures. Because of the fact that the effectiveness of most antiepileptic drugs is comparable, the choice can be made based on possible side effects, ease of use and cost. It should be emphasized that the recommendations presented reflect the author's opinion. Some recommendations on the use of certain drugs for certain types of seizures have not yet received official approval from the FDA.

Partial epileptic seizures

For the treatment of partial seizures, carbamazepine and phenytoin are most often used. If one of these remedies is ineffective, then as a rule, as a monotherapy, you should try another remedy. Staying in the monotherapy, sometimes as the third drug is prescribed valproic acid. But more often, if neither carbamazepine nor phenytoin had the necessary effect, a combination of one of these drugs with valproic acid, gabapentin, lamotrigine, vigabatrin or topiramate is used. Although phenobarbital and primidone are used as adjuvant or as second-line drugs for monotherapy, a significant sedative effect may occur with their use. Felbamate can also be effective as a monotherapy, but it can cause aplastic anemia and liver damage.

A comparison of the effects of phenytoin, carbamazepine, phenobarbital and primidone in a large clinical trial showed that the efficacy of all four agents is approximately the same, although patients taking primidone withdrew from the study more often because of drowsiness. Nevertheless, in general, carbamazepine provided the best control over epilepsy. This result was subsequently confirmed in another study.

Secondary generalized epileptic seizures

With secondary generalized seizures, the same remedies are used as in partial seizures.

Absenses

The drug of choice for absences (petit mal) is ethosuximide. When combined absences with tonic-clonic seizures and in the ineffectiveness of ethosuximide, valproic acid is used. However, due to possible hepatotoxicity and relatively high cost valproic acid is not a drug of choice for simple absences. Neither phenytoin nor carbamazepine is effective at absences. Moreover, with this type of epilepsy, these drugs can cause deterioration. At absences, lamotrigine is effective, but in the US this indication is not officially registered. Although benzodiazepines are useful in the treatment of generalized seizures, because of the sedative effect and the possible decrease in efficacy due to the development of tolerance, their use is limited.

Primary generalized tonic-clonic seizures

Valproic acid is the drug of choice for primary generalized tonic-clonic seizures, especially when there is a myoclonic component. Phenytoin, carbamazepine, phenobarbital, lamotrigine and topiramate can also be effective in this type of epilepsy.

Myoclonic seizures

Although myoclonic seizures respond better to valproic acid, other drugs, including benzodiazepines, lamotrigine, and topiramate, may also be effective in this type of epilepsy.

Atonic seizures

Atonic seizures are often difficult to treat. In this type of epilepsy, valproic acid and benzodiazepines can be effective, for example, clonazepam. A therapeutic effect in this case can also have some new generation drugs, in particular lamotrigine, vigabatrin and topiramate. Although felbamate has a positive effect with atonic seizures, its use is limited by possible toxic effects.

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Neurosurgical treatment of epilepsy

Antiepileptic drugs are effective in 70-80% of patients. The rest do not achieve good control of seizures when using medicines, or unacceptable side effects occur. The criteria for good control of seizures are very vague. In many US states, a patient can not obtain a license to drive a car if he has had at least one seizure in the last 12 months. Consequently, the criterion for good control of seizures can be their absence for 1 year. However, an acceptable level of control is often set too low: for example, many doctors believe that 1-2 seizures may occur within a month or several months. Nevertheless, even one case of epilepsy can have a significant effect on the quality of life of a person with epilepsy. In this regard, the task of specialists in epilepsy is to create a desire for treating physicians and patients to better control seizures, and not only to adapt and accept limitations associated with episodic seizures.

Those patients with epilepsy who can not control seizures with antiepileptic drugs can be considered as candidates for surgical treatment. It is estimated that approximately 100,000 patients with epilepsy in the United States can claim surgical treatment. Since every year in the United States only a few thousand operations are performed, the possibilities of prompt treatment of epilepsy are not fully utilized. Although the high cost of the operation, which can reach 50,000 US dollars, can cool the enthusiasm for this method of treatment, economic analysis shows that after a successful operation the cost of it pays off within 5-10 years. If a person returns to work and can lead a normal life, the costs pay off even faster. Although surgical treatment of epilepsy is an auxiliary method, in some patients, this seems to be the most effective way to completely eliminate epilepsy.

The condition for the success of surgical treatment of epilepsy is the precise definition of the localization of the epileptic focus. The operation usually eliminates epilepsy that occurs in the left or right medial temporal structures, including the amygdala, the hippocampus and the para-hippocampal cortex. With bilateral temporal seizures, surgical treatment is not possible, since bilateral temporal lobectomy leads to severe memory impairment with a defect in both memorization and reproduction. With surgical treatment, the ways of spreading epileptic activity are not critical. The target for the operation is the zone that generates epileptic activity, the epileptic focus. Secondarily generalized tonic-clonic seizures can be eliminated only if the focus in which they originate is removed.

The temporal lobe often serves as a target for surgery for epilepsy. Although epilepsy is successful in other parts of the cerebral hemispheres, the targets and volume of extramemporal operations are not clearly defined. An exception is surgery to remove epilepsy-causing entities, such as cavernous angioma, arteriovenous malformations, post-traumatic scars, brain tumors, abscesses, or areas of brain dysplasia.

Before considering the possibility of surgery on the temporal lobe, it is important to exclude states that mimic epilepsy, for example, psychogenic seizures. In this respect, the EEG is important, which can help localize the epileptic focus. Although interstitial peaks may indicate localization of the focus, they are not as important as the electrical activity recorded at the onset of epileptic seizures. For this reason, patients who are scheduled for surgical treatment are usually provided with videoelectroencephalographic monitoring in inpatient settings - in order to record several typical seizures (usually antiepileptic drugs are canceled for this period). The prognosis of surgical treatment is most favorable in the case when all seizures occur in the same focus in the anterior or middle part of one of the temporal lobes.

Another important part of the preoperative examination is MRI, which is performed in order to exclude diseases that can cause seizures, as well as to identify mesotemporal sclerosis. Although mesotemporal sclerosis can not always be detected with MRI, the presence of its signs is a weighty argument in favor of the fact that it is the temporal lobe that is the source of epilepsy.

Positron emission tomography (PET) is based on the measurement of glucose utilization in the brain. Initially, the patient is injected intravenously with 11C-fluorodeoxyglucose, which accumulates in the brain cells. The positron isotope decays at every point in the brain where the radiopharmaceutical penetrated. Tomophaxic technique is used to obtain a picture of the distribution of radioactive glucose. Approximately 65% of patients with an epileptic focus in the temporal lobe in the interictal period accumulate less glucose in it than on the opposite side. If PET is performed during a partial fit, the epileptic focus absorbs much more glucose than the analogous brain zone on the opposite side.

Neuropsychological research is conducted to identify abnormalities in the verbal sphere, usually reflecting the defeat of the dominant (most often left) hemisphere, or the ability to recognize patterns, faces and forms, which usually reflects damage to the right hemisphere. The study of personal characteristics is also useful and allows you to diagnose depression, which is very common in this group of patients. Postoperative psychosocial rehabilitation is crucial in the overall success of treatment, since its goal, in addition to reducing epilepsy, is also to improve the quality of life.

The Val test, also called an intracarotid amobarbital test, is performed to localize the function of speech and memory in patients with epilepsy who are scheduled for surgical treatment. The function of one of the large hemispheres is turned off by inserting amobarbital into the carotid artery. After 5-15 minutes after drug administration, verbal and mnestic functions are checked. In principle, the operation can be performed on the temporal lobe of the dominant (in relation to the speech function) hemisphere, but the removal of the neocortex should be treated much more carefully than with intervention on the subdominant hemisphere. Global amnesia after injection into one of the carotid arteries is a dangerous signal, indicating the possibility of severe memory impairment after surgery.

In some patients, despite the fact that they have surgical treatment, it is not possible to clearly localize the epileptic focus with the help of surface electrodes, even with EEG monitoring. In these cases, an invasive procedure is shown with the implantation of electrodes in those parts of the brain that are supposed to generate epileptic activity, or the placement of special electrodes in the form of a lattice or strips directly on the surface of the brain. With the help of these electrodes, it is also possible to conduct electrostimulation of individual parts of the brain in order to determine their function. This almost heroic procedure is used in cases where the epileptic focus is located in close proximity to speech or sensorimotor zones and its boundaries must be determined with exceptional accuracy. Electrodes are usually left for 1 week, and then they are removed during surgery. Only a small number of patients with epilepsy have to resort to the help of an electrode array placed on the surface of the brain, but approximately 10-40% of patients need some invasive methods for recording the electrical activity of the brain.

Operative treatment of epilepsy is successful in about 75% of cases. It is possible to completely cure the patient with the abolition of antiepileptic drugs, usually within 1 year. However, some patients prefer to continue taking antiepileptic drugs. In others, despite the absence of epilepsy, there may be a need for some medicines. Nevertheless, the success of surgical intervention is not always absolute. Some patients may occasionally recur auras (simple partial seizures) or, more rarely, more detailed seizures. In approximately 25% of patients, the operation is ineffective, usually due to the fact that during it the epileptic focus could not be completely removed, or because of the multifocal seizures.

In addition to partial temporal lobectomy, other operative interventions are performed, albeit significantly less often. Resection of the corpus callosum (collosotomy, commonly known as the "brain splitting" operation) consists in crossing the main fiber bundle that connects the right and left hemispheres. This operation almost never leads to the elimination of epilepsy, but it can slow the onset of seizures and prevent their rapid generalization, giving the patient the opportunity to protect themselves from the possible consequences of a seizure. Collosotomy, therefore, is carried out mainly in order to avoid damage during seizures, and not to eliminate them.

Hemisferectomy consists in removing most of one of the large hemispheres. This radical procedure is performed in individuals (usually children) with severe hemispheric injury or Rasmussen encephalitis, in which local hemispheric injury progresses over a number of years. Although after the operation the child has hemiparesis, in the future, as a rule, a good recovery of function occurs if the operation is performed before the age of 10 years. These children usually have only a slight awkwardness in their hands and slight lameness.

Surgical treatment of epilepsy is indicated in patients whose diagnosis of epilepsy is not in doubt, seizures are focal, and the epileptic focus is presumably located in one of the temporal lobes. The patient must have an appropriate motivation for the operation. It is performed only in cases where a reduction in epilepsy can lead to a significant change in lifestyle. At the same time, patients should be informed of the possibility of serious complications, which are observed in about 2% of cases. To surgical treatment resorted only in those cases when drug therapy is ineffective. However, the criteria for the ineffectiveness of drug therapy vary with the expansion of the spectrum of antiepileptic drugs. Previously, if the patient did not manage to control epilepsy with phenytoin, phenobarbital and carbamazepine, he was considered as a candidate for surgical intervention. With the advent of a whole group of new drugs, the question arises: should the patient be referred to an operation only after he has been tested by all these drugs. Since this can take 5-10 years, it is hardly advisable to postpone the operation for this time. In practice, most patients with complex partial seizures that do not respond to carbamazepine or phenytoin can be helped by the addition of one of the new drugs, although this does not always lead to complete elimination of seizures. Most epileptologists currently recommend trying only one or two of the new drugs before referring the patient to surgery.

Ketogenic diet for epilepsy

At the beginning of the 20th century, it was noted that epilepsy cases decrease during fasting. The ketogenic diet is designed to simulate biochemical changes occurring in a state of starvation. It involves depriving the brain of carbohydrates due to their low content in consumed foods with a high content of lipids and proteins in them. As a result of the resulting biochemical changes, the brain becomes more resistant to epilepsy. Although the effect of the ketogenic diet, achieved in a number of cases, is widely advertised, in most patients it does not lead to improvement. Studies show that the ketogenic diet is more effective in children under 12 years with attacks of fall (atonic or tonic seizures) and less effective after puberty. Partial adherence to a diet is not effective - to achieve success, you must strictly adhere to all of its requirements. The safety of a long-term diet is not established. It can lead to an increase in the level of triglycerides and cholesterol in the blood, inhibit growth, lead to decalcification of bones. In some cases, with a good effect, the diet can be canceled after 2 years. The diet can be combined with the use of antiepileptic drugs, but it can also be used as the only method of treatment. Carrying out a diet under the supervision of experienced medical personnel is an indispensable condition for the application of this method of treatment.

Biological feedback for the treatment of epilepsy

Repeated attempts have been made to use various biofeedback options for the treatment of epilepsy. In the simplest form, special devices are used to help patients control muscle tension or body temperature, which can be useful in some patients with epilepsy. Another form of biofeedback is based on the use of EEG in order to train patients to change some of their EEG characteristics. Although biofeedback methods are harmless, its effectiveness has not been proven in controlled clinical trials.

[10], [11], [12], [13], [14], [15], [16]