Epilepsy - Treatment

Drug treatment of epilepsy can completely eliminate the 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 efficiency of anticonvulsants and achievement of complete seizure control can eventually stop taking the drugs without relapse of epilepsy.

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Drug treatment of epilepsy

Bromide salts were the first effective antiepileptic drug. Beginning in 1850, bromides were used in the mistaken belief that reducing sexual desire would reduce the severity of epilepsy. Although bromides did have antiepileptic effects, they were toxic and fell out of use when barbiturates were introduced 60 years later. Phenobarbital was originally used as a sedative and hypnotic. Eventually, its antiepileptic potential was discovered by chance. Other antiepileptic drugs, usually chemical derivatives of phenobarbital, gradually became available, such as phenytoin, developed in 1938 and the first non-sedating antiepileptic drug. Meanwhile, carbamazepine, introduced in the 1950s, was originally used to treat depression and pain. Valproic acid was initially used only as a solvent, and its antiepileptic properties were discovered quite by accident when it was used to dissolve compounds that were being tested as antiepileptic drugs.

The potential for drug treatment of 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 seizures in mice or rats subjected to electric shock is tested. The ability to protect against maximum electric shock allows one to predict the effectiveness of the drug in partial and secondarily generalized seizures. The antiepileptic properties of phenytoin were discovered using this method.

In the early 1950s, ethosuximide was shown to be effective against absence seizures (petit mal). Interestingly, although this drug does not protect against the effects of maximal electric shock, it inhibits seizures induced by pentylenetetrazole (PTZ). Pentylenetetrazole seizures have therefore become a model for assessing the efficacy of antiabsence drugs. Epilepsy induced by other convulsants, such as strychnine, picrotoxin, allylglycine, and N-methyl-D-acncapate, are also sometimes used to test the efficacy of drug treatments for epilepsy. If a drug protects against seizures induced by one agent but not another, this may indicate selectivity for certain seizure types.

More recently, kindling seizures and other models of complex partial seizures have been used to test the efficacy of drug treatment for epilepsy. In the kindling seizure model, electric shocks are delivered via electrodes implanted in deep parts of the brain. Although the electric shocks initially leave no residual changes, when repeated over several days or weeks, complex electrical discharges occur that tend to persist and lead to seizures. In this situation, the animal is said to be "kindled" (from the English word kindling - ignition, kindling). Kindling seizures are used to evaluate the efficacy of drugs that may be useful in temporal lobe epilepsy. Since kainic acid, an analogue 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 lobe epilepsy. Some strains of rats and mice are used to create models of different types of epilepsy. Of particular interest in this regard is the creation of a model of absences in rats.

Although different experimental models are used to evaluate the efficacy of epilepsy drugs for different seizure types, there is not always a correlation between the effect in experimental models and the efficacy for a particular type of epilepsy in humans. In general, drugs that are effective at relatively nontoxic doses in several experimental models of epilepsy tend to be more effective in clinical settings. However, demonstrating an effect in an experimental model is only a necessary first step toward testing a drug in humans and does not guarantee that the drug will be safe and effective in human patients.

The development of antiepileptic drugs has gone through several stages. Bromides symbolize the era of erroneous theories, phenobarbital - the era of accidental discoveries, primidone and mephorbarbital - the era of imitation of phenobarbital, phenytoin - the era of testing antiepileptic drugs using the maximum electric shock technique. Most new antiepileptic drugs were developed with the aim of selectively affecting neurochemical systems in the brain. Thus, vigabatrin and tiagabine increase the synaptic availability of GABA. The first blocks GABA metabolism, the second - the reuptake of GABA in neurons and glial cells. The action of lamotrigine and remacemide is partly associated with 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 an effect on sodium channels in neurons, as a result of which these channels after their inactivation remain closed for a longer time. This prolongation prevents the axon from generating the next action potential too quickly, which reduces the frequency of discharges.

The development of new treatments for epilepsy in the future will likely be based on knowledge of the genes responsible for the development of epilepsy and their products. Substituting compounds missing as a result of genetic mutation may create conditions for curing epilepsy, not just suppressing epilepsy.

When choosing drug treatment for epilepsy, several aspects should be taken into account. First, it should be decided whether antiepileptic drugs should be prescribed at all. For example, some simple partial seizures, which are 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 bother the patient and do not pose a risk of falling or injury, and the patient does not need to drive a car or work near dangerous machinery. In addition, a single seizure may also not require antiepileptic drugs, since 50% of people with generalized tonic-clonic seizures of unknown origin in the absence of changes in EEG, MRI, and laboratory studies do not experience a second seizure. If a second case of epilepsy does occur, antiepileptic treatment should be started.

Epilepsy treatment does not necessarily have to be lifelong. In some cases, medications can be gradually withdrawn. This is especially true when epilepsy has been absent for at least 2-5 years, the patient has no structural changes in the brain on MRI, there is no identified hereditary disorder (eg, juvenile myoclonic epilepsy, in which epileptic activity persists throughout life), there is no history of status epilepticus, and there is no epileptic activity on the background EEG. However, even under these conditions, there is a one in three chance that seizures will recur within 1 year of stopping drug treatment for epilepsy. Therefore, the patient should be advised not to drive for 3 months after stopping the antiepileptic drug. Unfortunately, many patients are hesitant to stop taking antiepileptic drugs because of the need to limit driving.

Basic principles of drug treatment of epilepsy

• Decide whether it is appropriate to start drug treatment.
• Estimate the expected duration of treatment.
• If possible, resort to monotherapy.
• Prescribe the simplest regimen for taking the drug.
• Reinforce the patient's willingness to follow the proposed regimen.
• Select the most effective medication taking into account the type of epilepsy.

The regimen for taking antiepileptic drugs should be as simple as possible, because the more complex the regimen, the worse the patient follows it. Thus, when taking the drug once a day, patients are much less likely to violate the treatment regimen than when it is necessary to take the drug two, three or four times a day. The worst regimen is one that requires taking different drugs at different times. Monotherapy, which is successful in about 80% of patients with epilepsy, is simpler than polypharmacotherapy and allows avoiding drug interactions.

Treatment of epilepsy with some drugs should be started gradually to avoid side effects. This primarily concerns carbamazepine, valproic acid, lamotrigine, primidone, topiramate, felbamate and vigabatrin - 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 be started with therapeutic doses. The treatment regimen 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 medications can be challenging. If the dose of a new drug is to be increased gradually, it is usually not recommended to stop the first drug until the therapeutic dose of the new drug has been reached. If this precaution is not taken, the patient may experience seizures during the transition period. The downside of this approach is the increased likelihood of toxicity due to the overlapping action of the two drugs. Patients should be warned of the possibility of temporary side effects and the development of epilepsy when discontinuing previously used drugs during the change of treatment.

Although measuring blood drug levels can be useful for adjusting treatment, this technique should not be overused. Unless the patient has epilepsy and has evidence of drug toxicity, there is usually no need to monitor blood levels. When two or more drugs are prescribed, measuring blood levels is useful in situations where it is necessary to determine which drug may be causing toxicity.

Choosing an Antiepileptic Drug

Carbamazepine or phenytoin are the drugs of choice for partial epilepsy, while valproic acid is preferred for primary generalized seizures but is somewhat less effective than carbamazepine in partial seizures. Because 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 opinion of the author. Some recommendations for the use of certain drugs for certain types of seizures have not yet received official FDA approval.

Partial epileptic seizures

Carbamazepine and phenytoin are the most commonly used drugs for treating partial seizures. If one of these drugs is ineffective, another drug should usually be tried as monotherapy. Valproic acid is sometimes used as a third drug when used as monotherapy. More commonly, if neither carbamazepine nor phenytoin is effective, one of these drugs is used in combination with valproic acid, gabapentin, lamotrigine, vigabatrin, or topiramate. Although phenobarbital and primidone are used as adjuvants or as second-line monotherapy, they can cause significant sedation. Felbamate can also be effective as monotherapy, but it can cause aplastic anemia and liver damage.

A comparison of phenytoin, carbamazepine, phenobarbital, and primidone in a large clinical trial found that all four agents were about equally effective, although patients taking primidone were more likely to drop out of the study due to drowsiness. However, overall, carbamazepine provided the best control of epilepsy. This result was subsequently confirmed in another study.

Secondary generalized epileptic seizures

For secondarily generalized seizures, the same medications are used as for partial seizures.

Absences

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

Primary generalized tonic-clonic seizures

Valproic acid is the drug of choice for primary generalized tonic-clonic seizures, especially those with a myoclonic component. Phenytoin, carbamazepine, phenobarbital, lamotrigine, and topiramate may 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 for this type of epilepsy.

Atonic seizures

Atonic seizures are often difficult to treat. Valproic acid and benzodiazepines, such as clonazepam, may be effective in this type of epilepsy. Some new-generation drugs, such as lamotrigine, vigabatrin, and topiramate, may also be effective. Although felbamate has been shown to be effective in atonic seizures, its use is limited by potential toxicity.

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Neurosurgical treatment of epilepsy

Antiepileptic drugs are effective in 70-80% of patients. In the rest, the use of drugs does not achieve good seizure control or causes unacceptable side effects. The criteria for good seizure control are very vague. In many US states, a patient cannot get a driver's license if he or she has had at least one seizure in the last 12 months. Therefore, the criterion for good seizure control may be the absence of seizures for 1 year. However, the acceptable level of control is often set too low: for example, many doctors believe that 1-2 seizures per month or several months are acceptable. However, even a single episode of epilepsy can have a significant impact on the quality of life of a person with epilepsy. In this regard, the task of epilepsy specialists is to instill in the treating physicians and patients a desire for better seizure control, and not just adaptation and acceptance of the limitations associated with episodic seizures.

Those patients with epilepsy whose seizures cannot be controlled with antiepileptic drugs may be candidates for surgical treatment. It is estimated that approximately 100,000 patients with epilepsy in the United States are eligible for surgical treatment. Since only a few thousand surgeries are performed each year in the United States, the potential for surgical treatment of epilepsy is underutilized. Although the high cost of surgery, which can reach $50,000, may dampen enthusiasm for this treatment, economic analysis shows that after successful surgery, the cost is recouped within 5 to 10 years. If the person returns to work and can lead a normal life, the cost is recouped even more quickly. Although epilepsy surgery is an adjunctive treatment, for some patients it is probably the most effective way to completely eliminate epilepsy.

A prerequisite for the success of surgical treatment of epilepsy is the precise localization of the epileptic focus. Surgery usually eliminates epilepsy arising in the left or right medial temporal structures, including the amygdala, hippocampus, and parahippocampal cortex. In bilateral temporal seizures, surgical treatment is impossible, since bilateral temporal lobectomy leads to severe memory impairment with a defect in both memorization and reproduction. In surgical treatment, the paths of epileptic activity are not of decisive importance. The target for surgery is the zone generating 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 is the most common target for epilepsy surgery. Although epilepsy surgery can be successfully performed on other lobes of the cerebral hemispheres, the targets and extent of extratemporal surgery are not clearly defined. Exceptions include surgery to remove lesions that cause epilepsy, such as cavernous angioma, arteriovenous malformations, post-traumatic scars, brain tumors, abscesses, or areas of brain dysplasia.

Before considering temporal lobe surgery, it is important to exclude conditions that mimic epilepsy, such as psychogenic seizures. In this regard, EEG is important because it can help localize the epileptic focus. Although interictal peaks can indicate the location of the focus, they are not as important as the electrical activity recorded at the onset of an epileptic seizure. For this reason, patients scheduled for surgery usually undergo videoelectroencephalographic monitoring in a hospital setting to record a few typical seizures (usually during which antiepileptic drugs are discontinued). The prognosis for surgical treatment is most favorable 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 to rule out diseases that may be the cause of seizures, as well as to detect mesotemporal sclerosis. Although mesotemporal sclerosis cannot always be detected by MRI, its presence is a strong argument in favor of the fact that the temporal lobe is the source of epilepsy.

Positron emission tomography (PET) is based on measuring glucose utilization in the brain. The patient is first injected intravenously with 11C-fluorodeoxyglucose, which accumulates in brain cells. The positron isotope decays at each point in the brain where the radiopharmaceutical penetrates. Tomographic imaging is used to obtain a picture of the distribution of radioactive glucose. In approximately 65% of patients with an epileptic focus in the temporal lobe, less glucose accumulates in it between attacks than on the opposite side. If PET is performed during a partial seizure, the epileptic focus absorbs much more glucose than the same area of the brain on the opposite side.

Neuropsychological testing is performed to detect impairments in the verbal sphere, usually reflecting damage to the dominant (usually left) hemisphere, or the ability to recognize pictures, faces and shapes, which usually reflects damage to the right hemisphere. Personality testing is also useful and allows for the diagnosis of depression, which is very common in this group of patients. Postoperative psychosocial rehabilitation is crucial to the overall success of treatment, since its goal, in addition to alleviating epilepsy, is also to improve quality of life.

The Wahl test, also called the intracarotid amobarbital test, is performed to localize the speech and memory functions in patients with epilepsy who are scheduled for surgical treatment. The function of one of the cerebral hemispheres is switched off by injecting amobarbital into the carotid artery. Speech and memory functions are checked 5-15 minutes after the drug is administered. In principle, the operation can also be performed on the temporal lobe of the dominant (in terms of speech function) hemisphere, but in this case, the removal of the neocortex should be approached much more carefully than when intervening on the subdominant hemisphere. Global amnesia after an injection into one of the carotid arteries is a dangerous signal indicating the possibility of severe memory impairment after the operation.

In some patients, despite the fact that surgical treatment is indicated, it is not possible to clearly localize the epileptic focus using surface electrodes even with EEG monitoring. In these cases, an invasive procedure is indicated with the implantation of electrodes in those areas of the brain that are believed to generate epileptic activity, or the placement of special electrodes in the form of a grid or strips directly on the surface of the brain. With the help of these electrodes, it is also possible to conduct electrical stimulation of individual areas 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 the speech or sensorimotor zones and its boundaries must be determined with exceptional accuracy. Electrodes are usually left in place for 1 week and then removed during surgery. Only a small number of epilepsy patients have to resort to the help of an electrode grid placed on the surface of the brain, but approximately 10-40% of patients require some invasive methods of recording the electrical activity of the brain.

Surgical treatment of epilepsy is successful in approximately 75% of cases. Complete recovery is possible with discontinuation of antiepileptic drugs, usually within 1 year. However, some patients prefer to continue taking antiepileptic drugs. Others, despite the absence of epilepsy, may still need some medications. However, the success of surgical intervention is not always absolute. Some patients may have episodic recurrence of auras (simple partial seizures) or, less commonly, more extensive seizures. In approximately 25% of patients, surgery is ineffective, usually due to the fact that the epileptic focus could not be completely removed during surgery, or due to multifocality of seizures.

In addition to partial temporal lobectomy, other surgical interventions are performed, although much less frequently. Resection of the corpus callosum (collosotomy, commonly known as "split-brain" surgery) involves cutting the main bundle of fibers connecting the right and left hemispheres. This operation almost never cures epilepsy, but it can slow the onset of seizures and prevent their rapid generalization, giving the patient the opportunity to protect himself from the possible consequences of a seizure. Collosotomy is therefore performed primarily to avoid damage during seizures, not to eliminate them.

Hemispherectomy involves removing most of one of the cerebral hemispheres. This radical procedure is performed in individuals (usually children) with severe hemispheric damage or Rasmussen's encephalitis, in which local hemispheric damage progresses over a number of years. Although the child will have hemiparesis after the operation, good recovery of function is common if the operation is performed before age 10. Such children usually retain only some clumsiness of the hand and a slight limp.

Surgical treatment of epilepsy is indicated in patients whose epilepsy diagnosis is beyond doubt, whose seizures are focal, and whose epileptic focus is presumably located in one of the temporal lobes. The patient must be adequately motivated to undergo surgery. It is performed only in cases where a reduction in epilepsy cases 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 approximately 2% of cases. Surgical treatment is resorted to only in cases where drug therapy is ineffective. However, the criteria for the ineffectiveness of drug therapy are changing as the range of antiepileptic drugs expands. Previously, if a patient's epilepsy could not be controlled with phenytoin, phenobarbital, and carbamazepine, he was considered a candidate for surgical intervention. With the advent of a whole group of new drugs, the question arises: should a patient be referred for surgery only after he has undergone trial treatment with all of these drugs? Since this may take 5-10 years, it is unlikely to be worthwhile to delay surgery for that long. In practice, most patients with complex partial seizures that do not respond to carbamazepine or phenytoin can be helped by adding one of the new drugs, although this does not always result in complete freedom from seizures. Most epileptologists now recommend trying only one or two of the new drugs before referring a patient for surgery.

Ketogenic Diet for Epilepsy

In the early 20th century, it was noted that cases of epilepsy decrease during fasting. The ketogenic diet is designed to imitate the biochemical changes that occur during fasting. It involves depriving the brain of carbohydrates by providing low levels of carbohydrates in the foods consumed, while consuming a high level of lipids and proteins. As a result of the biochemical changes that occur, the brain becomes more resistant to epilepsy. Although the effect of the ketogenic diet, achieved in a number of cases, is widely advertised, it does not lead to improvement in most patients. Studies show that the ketogenic diet is more effective in children under 12 years of age with falling attacks (atonic or tonic seizures) and less effective after puberty. Partial adherence to the diet does not bring results - to achieve success, it is necessary to strictly adhere to all its requirements. The safety of the long-term diet has not been established. It can lead to increased levels of triglycerides and cholesterol in the blood, inhibit growth, and lead to decalcification of bones. In some cases, if the effect is good, the diet can be discontinued after 2 years. The diet can be combined with taking antiepileptic drugs, but can also be used as the only method of treatment. The diet under the supervision of experienced medical personnel is a mandatory condition for using this method of treatment.

Biofeedback for the treatment of epilepsy

There have been numerous attempts to use various forms of biofeedback to treat epilepsy. The simplest form uses special machines to help patients control muscle tension or body temperature, which may be useful in some patients with epilepsy. Another form of biofeedback uses EEG to train patients to change certain characteristics of their EEG. Although biofeedback techniques are harmless, their effectiveness has not been proven in controlled clinical trials.

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