Epilepsy and epileptic seizures - Symptoms

An epileptic seizure is a sudden, stereotypical episode characterized by changes in motor activity, sensory functions, behavior, or consciousness, and associated with abnormal electrical discharge of neurons in the brain. Epilepsy is a condition characterized by recurrent spontaneous seizures. Therefore, an epileptic seizure is a single episode, whereas epilepsy is a disease. A single seizure does not allow a diagnosis of epilepsy, nor does a series of seizures if they are caused by provoking factors, such as alcohol withdrawal or a brain tumor. A diagnosis of epilepsy requires that the seizures be spontaneous and recurrent.

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Symptoms of epileptic seizures

The symptoms of epileptic seizures depend on several factors, the most important of which is the localization of the area in the brain where the pathological electrical discharge occurs. The cortical area that controls movement and sensitivity has the form of a strip and is located along the border of the frontal and parietal lobes. The part that controls movement is located rostrally (in the projection of the frontal cortex), and the part that ensures the perception of somatosensory afferentation is more caudally (in the projection of the parietal lobe). If we move from the upper part of this area laterally and downwards, then the zones representing the trunk, proximal part of the arms, hands, fingers, face, and lips are located in succession. The zone representing the tongue is located in this motor-sensory strip more laterally and below the others. Epileptic excitation during a seizure can spread along this zone, sequentially activating each of the muscle groups over several seconds or minutes (Jacksonian march). Broca's motor speech area is usually located in the left frontal lobe anterior to the motor strip, and Wernicke's speech comprehension area is in the parietal-temporal region. Visual perception is provided by the posterior poles of the occipital lobes. Focal epileptic activity in these regions causes a disorder of the corresponding function or distortion of the corresponding aspect of perception.

The deep temporal lobes are the brain area that is particularly important for the development of epileptic seizures. The temporal lobes include the amygdala and hippocampus, the most epileptogenic structures of the brain that are most involved in the pathogenesis of epilepsy in adults. For this reason, the amygdala and hippocampus, involved in the regulation of emotions and memory processes, are important targets in the surgical treatment of epilepsy.

If a pathological electrical discharge occurs in the frontal cortex, the patient experiences a motor seizure, if in the sensory cortex - pathological sensory perception, if in the visual cortex - flashes of light and elementary visual sensations. Seizures generated in the deep structures of the temporal lobe are manifested by a cessation of activity, mnemonic processes, consciousness and the appearance of automatisms. If epileptic activity spreads to all regions of the brain, a typical generalized tonic-clonic seizure occurs with loss of consciousness, tonic tension of the trunk and twitching in the limbs.

Epileptic seizures are caused by an electrochemical abnormality in the brain. Since neurons either activate or inhibit neighboring cells, most epileptic syndromes are caused by an imbalance between these two actions. Although virtually all neurotransmitters and neuromodulators in the brain are likely to be involved in the pathogenesis of epilepsy, glutamate and GABA play a particularly important role, since the former is the main excitatory mediator and the latter is the main inhibitory mediator in the brain. The mechanism of action of some antiepileptic drugs is associated with the blockade of glutamatergic excitatory transmission. Although inhibition of glutamatergic transmission leads to the elimination of seizures, it can also cause a number of undesirable side effects that limit the use of these drugs. GABA, which is the most potent inhibitory mediator, can also be a target for antiepileptic drugs, and a number of drugs with similar action are approved for use in epilepsy.

There has been a lively debate for a long time about whether epileptic seizures are the result of dysfunction of the entire central nervous system or only a limited group of neurons. However, the data indicating the systemic nature of the disorder are more convincing. The pathogenesis of seizures involves anatomical, physiological and neurochemical resources of the brain, which ensure the spread of excessive hypersynchronous neuronal discharge from the epileptic focus, where paroxysmal depolarization shift (PDS) is detected during intracellular recording.

Inhibitory influences in the brain have selective sensitivity to certain factors. The inhibitory circle is a polysynaptic structure formed by interconnected interneurons, uses GABA or other inhibitory neurotransmitters. These pathways are more sensitive to pathological effects (such as hypoxia, hypoglycemia or mechanical trauma) than excitatory monosynaptic pathways. If excitatory synapses function normally and inhibitory synapses do not, a seizure occurs. If the damage is severe enough and excitatory systems are affected along with the inhibitory ones, the seizures stop, followed by coma or death.

Neuronal inhibition in the brain is not a single process but rather a hierarchy of processes. The inhibitory postsynaptic potential (IPSP) generated by the GABA receptor is its most important part. As already mentioned, this receptor has a selective sensitivity to damage and to GABA receptor antagonists such as penicillin, picrotoxin, or bicuculline. Some neurons also have GABA receptors, an agonist of which is the antispastic drug baclofen. Although several GABA receptor antagonists have been developed, none of them is used in clinical practice. GABA receptors seem to be especially important for generating the wave, one of the EEG features of spike-wave absence epilepsy. A third level of inhibition is formed by calcium-dependent potassium channels, which mediate postburst hyperpolarization. The increase in intracellular calcium activates potassium channels that release potassium from the cell, resulting in hyperpolarization that lasts for 200 to 500 ms. The fourth level of inhibition is provided by the activation of metabolic pumps that use ATP as an energy source. These pumps exchange three intracellular sodium ions for two extracellular potassium ions, which increases the negative intracellular charge. Although such pumps are activated by intense neuronal discharge and serve to restore the ion balance characteristic of the equilibrium state, they can lead to prolonged hyperpolarization of the cell, persisting for many minutes. The existence of this hierarchy is important, since the disruption of one of these inhibitory processes does not eliminate the other mechanisms that can take over the protection of the brain from excessive excitation.

Absences (petit mal) are an exception to the rule that seizures result from weakening of inhibitory influences, since they probably result from increased or hypersynchronized inhibition. This is why absences are characterized by a lack of behavioral activity rather than by the involuntary, excessive or automated actions observed in other types of seizures.

During an absence, the electroencephalogram records a repetitive pattern of spikes and waves. Three forces are required to maintain this pattern: an excitatory stimulus that generates a spike; an inhibitory stimulus that generates a wave; and a pacemaker that maintains the rhythm. It is suggested that the spike is due to a glutamate-mediated EPSP (excitatory postsynaptic potential), the wave to a GABA-mediated IPSP, and the rhythm to changes in the activity of calcium channels in some thalamic nuclei. These ideas provide a basis for searching for new approaches to the treatment of absences.

There is no simple explanation for why most seizures terminate spontaneously, since the ability of neurons to fire persists after the seizure has ended. The development of a special postictal state that predetermines seizure termination may be due to several factors, including neuronal hyperpolarization, probably related to the functioning of metabolic pumps and decreased cerebral perfusion, which leads to decreased activity of neuronal circuits. Excessive release of neurotransmitters and neuromodulators due to seizure discharges may also contribute to the development of the postictal state. For example, endogenous opioid peptides released during seizures are thought to inhibit brain function after the paroxysm, since the opioid receptor antagonist naloxone has an arousing effect in rats in stupor after an electroshock seizure. In addition, adenosine released during a seizure, activating adenosine A1 receptors, can partially block subsequent excitatory synaptic transmission. Nitric oxide, a second messenger that affects the state of blood vessels and neurons in the brain, can also play a role in the development of the postictal state.

The physiological mechanisms responsible for the development of the postictal state are crucial for the termination of an epileptic seizure, but at the same time they can also be the cause of postictal disorders, which in some patients disrupt life activities to a greater extent than the seizures themselves. In this regard, the development of treatment methods aimed at reducing the duration of the postictal state is important.

Because epilepsy is characterized by recurrent seizures, a complete explanation of the mechanisms of this disorder must take into account the chronic changes in the brain that underlie these seizures. Recurrent seizures can be caused by a wide range of brain insults, including perinatal hypoxia, traumatic brain injury, intracerebral hemorrhage, and ischemic strokes. Seizures often do not occur immediately, but rather weeks, months, or years after the brain injury. Several studies have examined the changes in the brain after injury that lead to the development of chronic hyperexcitability of brain structures. A useful model for studying this process has been the hippocampus, which has been chemically treated with kainic acid (a relatively selective neurotoxin) or excessive electrical stimulation, which cause selective loss of some neurons. Cell death results in sprouting of axons of other neurons, which come into contact with the deafferented cells. A similar process occurs in motor units and results in fasciculations. From this point of view, some seizures can be considered as a kind of "brain fasciculations" caused by neuronal reorganization. The purpose of such reorganization is, of course, not to produce a seizure, but to restore the integrity of the neuronal circuits. The price to be paid for this is increased neuronal excitability.

It is known that epileptic seizures do not occur in just one area of the brain, but rather in circles formed by interacting neurons that behave like abnormal networks. Removing a specific area of the brain can, however, stop some types of seizures. The mechanism of the therapeutic effect of such surgery can be compared to cutting a telephone cable, interrupting a telephone conversation even when the interlocutors are at a great distance from each other.

Certain brain regions appear to be particularly important in generating epileptic seizures. The nonspecific thalamic nuclei, particularly the reticular nucleus of the thalamus, are key to generating spike-wave absences, and the hippocampus and amygdala, located in the medial temporal lobes, are important for generating complex partial seizures. The prepyriform cortex is known to be responsible for temporal lobe seizures in rats, cats, and primates. In rats, the pars reticularis of the substantia nigra facilitates the spread and generalization of epileptic activity. In humans, the cerebral cortex is the most important structure generating epileptic seizures. Focal seizures usually result from damage or dysfunction to the neocortex or the ancient and old cortex (archicortex and paleocortex) in the medial temporal lobes. Although the primary manifestations of seizures are related to the neocortex, subcortical systems are also involved in seizure pathogenesis, although the structures and pathways involved in seizure development are not precisely known.

Fundamental research is changing traditional ideas about the mechanisms of epilepsy development, especially focal seizures. However, many questions remain unanswered, including: what systems are involved in the mechanism of development of generalized seizures, how seizures begin and end, what processes lead to the formation of an epileptic focus after brain damage, what role does hereditary predisposition to seizure development play, what explains the association of some forms of epilepsy with certain phases of brain development, why abnormal electrical excitability manifests itself in different types of seizures.

Classification of epileptic seizures

Because seizures are classified primarily on the basis of a terminological agreement developed by a committee of experts rather than on any fundamental principles, the classification scheme will undoubtedly change as knowledge about epilepsy increases.

Epileptic seizures are divided into two broad categories: partial (focal) and generalized. Partial epileptic seizures are generated in a limited area of the brain, which leads to focal symptoms, such as twitching of the limbs or face, sensory disturbances, and even memory changes (as in temporal lobe seizures). Generalized seizures occur as a result of the involvement of the entire brain. Although some experts believe that these seizures are generated in deep brain structures, widely projected onto the cortical surface, and occur almost simultaneously as a result of dysfunction of various parts of the brain, the true mechanisms of the development of generalized seizures remain unknown.

Partial epileptic seizures are divided into simple partial (without loss of consciousness or memory) and complex partial (with loss of consciousness or memory). Simple partial epileptic seizures can manifest themselves in twitching, pathological sensations, visual images, sounds, smells, and distortion of perception. If epileptic activity extends to vegetative structures, a feeling of rush or nausea occurs. With all types of simple partial seizures, the patient remains conscious and remembers everything that happens to him. If the patient experiences confusion or cannot remember what happened to him during the seizure, then the seizure is defined as complex partial.

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International Classification of Epileptic Seizures (simplified version)

Partial epileptic seizures (generated in a limited area of the brain)

• Simple (without impairment of consciousness or memory):
  • sensory
  • motor
  • sensorimotor
  • mental (pathological ideas or altered perception)
  • vegetative (feeling of warmth, nausea, rush, etc.)
• Complex (with impaired consciousness or memory)
  • with aura (harbingers) or without aura
  • with or without automatisms
• Secondarily generalized

Generalized epileptic seizures (generated by a large area of the brain)

• Absences (petit mal)
• Tonic-clonic (grand-mall)
• Atonic (drop seizures)
• Myoclonic

Unclassifiable epileptic seizures

Complex partial seizures have previously been labeled as psychomotor, temporal, or limbic. Complex partial seizures may begin with an aura, a precursor to the seizure that often includes feelings of "deja vu," nausea, warmth, crawling, or distorted perception. However, about half of patients with complex partial seizures do not remember the aura. During a complex partial seizure, patients often perform automated actions - groping around, licking their lips, taking off their clothes, wandering aimlessly, repeating meaningless phrases. Such meaningless actions are called automatisms - they are observed in 75% of patients with complex partial seizures.

Generalized seizures are divided into several categories. Absences, previously called petit mal, usually begin in childhood. They are brief episodes of loss of consciousness, accompanied by a fixed stare, twitching of the eyelids, or nodding of the head. Absences can be difficult to distinguish from complex partial seizures, which also involve fixed stare, but absences usually last a shorter time than complex partial seizures and are characterized by a more rapid recovery of consciousness. An EEG (see below) is useful in the differential diagnosis of these seizure types.

Generalized tonic-clonic epileptic seizures, previously called grand mal, begin with a sudden loss of consciousness and tonic tension of the trunk and limbs, followed by rhythmic clonic jerking of the limbs. The patient screams, caused by contraction of the respiratory muscles with closed vocal cords. The seizure (ictus) usually lasts from 1 to 3 minutes, after which a postictal (post-ictal) state occurs, characterized by lethargy, drowsiness, confusion, which can last for hours. The postictal period can occur after any seizure.

Epileptic activity may start in a specific area and spread to the entire brain, causing a generalized tonic-clonic seizure. It is important to distinguish between true (primarily generalized) grand mal seizures and partial seizures with secondary generalization, as these two types of seizures may require different antiepileptic drugs. Furthermore, secondary generalized tonic-clonic seizures are amenable to surgical treatment, whereas primary generalized tonic-clonic seizures are not, as there is no obvious source (epileptic focus) that can be removed.

Atonic seizures usually occur after brain damage. During an atonic seizure, muscle tone suddenly decreases and the patient may fall to the ground. In some cases, patients are forced to wear a helmet to prevent serious head injuries.

A myoclonic seizure is characterized by a brief, rapid jerk or series of jerks, usually less coordinated and organized than in a generalized tonic-clonic seizure.

Status epilepticus is a seizure or series of seizures that lasts for more than 30 minutes without interruption by recovery of consciousness or other functions. Status epilepticus is an emergency condition because it can lead to neuronal damage and somatic complications. There are several types of status epilepticus, corresponding to different types of epileptic seizures. The status of simple partial seizures is known as epilepsia partialis continua. The status of complex partial seizures and absences is designated by several terms, including nonconvulsive status, spike-wave stupor, absence status, and epileptic twilight state. Recommendations for the diagnosis and treatment of status epilepticus have been developed by the Status Epilepticus Task Force.

A person may have several types of seizures, and one type may change into another as the electrical activity spreads through the brain. Typically, a simple partial seizure will change into a complex partial seizure, which will change into a secondarily generalized tonic-clonic seizure. In some cases, antiepileptic drugs enhance the brain's ability to limit the spread of epileptic activity.

In adults, complex partial seizures are most common (more than 40% of cases). Simple partial seizures are detected in 20% of cases, primary generalized tonic-clonic seizures - in 20% of cases, absences - in 10% of cases, other types of seizures - in 10% of cases. Absences are much more common in children than in adults.

Classification of epileptic syndromes

The classification of epileptic seizures does not contain information about the patient's condition, causes, severity, or prognosis of the disease. This necessitates an additional classification scheme that allows for the classification of epileptic syndromes. This is a more comprehensive classification that includes not only a description of the seizure type, but also information about other clinical features of the disease. Some of these epileptic syndromes are described below.

Infantile spasms / West syndrome

Infantile spasms occur in children aged 3 months to 3 years and are characterized by sudden flexion spasms and a high risk of mental retardation. During flexion spasms, the child suddenly straightens the limbs, bends forward, and screams. The episode lasts for several seconds but can recur several times per hour. EEG reveals hypsarrhythmia with high-amplitude peaks and disorganized high-amplitude background activity. Early active treatment can reduce the risk of permanent mental retardation. Although valproic acid and benzodiazepines are considered the drugs of choice, their effectiveness is low. Of the new drugs, the most promising results have been obtained with vigabatrin and felbamate, as well as lamotrigine and topiramate.

Lennox-Gastaut syndrome

Lennox-Gastaut syndrome is a relatively rare condition (except in epileptology centers, where it accounts for a significant proportion of patients with treatment-resistant seizures). It is characterized by the following features:

1. polymorphic seizures, usually including atonic and tonic seizures;
2. variable mental retardation;
3. EEG changes, including slow spike-wave activity.

Although the syndrome usually begins in childhood, it can also affect adults. Lennox-Gastaut syndrome is very difficult to treat, with only 10-20% of patients successfully treated. Because the seizures are almost always multifocal, surgery is of little use, although collotomy can reduce the suddenness of the seizures and prevent injury. Although valproic acid, benzodiazepines, lamotrigine, vigabatrin, topiramate, and felbamate may be helpful, treatment results are often unsatisfactory.

Febrile epileptic seizures

Febrile seizures are triggered by fever and usually occur in children aged 6 months to 5 years with tonic-clonic convulsions. Febrile seizures should be distinguished from seizures caused by more serious illnesses such as meningitis. Febrile seizures are often very frightening to parents but are usually benign. Although they are considered a risk factor for later development of complex partial seizures, there is no convincing evidence that preventing febrile seizures reduces this risk. Most children with febrile seizures do not later develop epilepsy. This has questioned the usefulness of antiepileptic drugs, which can adversely affect learning and personality. Phenobarbital is commonly used to prevent febrile seizures. However, it is only effective if taken daily because seizures usually occur immediately after a rise in body temperature. Long-term daily use of phenobarbital results in hyperactivity, behavioral problems, and learning problems in a significant percentage of children. Many pediatric neurologists believe that treating febrile seizures is more harmful than treating occasional seizures that may never recur, and advise against treatment. Several trials of other antiepileptic drugs in febrile seizures have not yielded encouraging results. Thus, the issue of treating febrile seizures remains controversial.

Benign epilepsy of childhood with central temporal peaks

Benign epilepsy of childhood with central-temporal peaks (benign rolandic epilepsy) is a genetically determined disease that usually manifests itself in childhood or adolescence (from 6 to 21 years). Rolandic is the area of the brain located in front of the border of the frontal and parietal lobes. Seizures generated in this zone are manifested by twitching and paresthesia in the face or hand, sometimes developing into secondarily generalized tonic-clonic epileptic seizures. In this condition, the EEG usually reveals pronounced peaks in the central and temporal areas. Seizures most often occur when falling asleep. The term "benign" is used not because seizures can manifest themselves with minimal symptoms, but because of the very favorable long-term prognosis. With age, seizures almost always regress. The use of antiepileptic drugs is not necessary, but in case of frequent or severe seizures, drugs effective against partial seizures are used (most often carbamazepine).

Juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is the most common cause of generalized seizures in young adults. Unlike benign epilepsy with central-temporal peaks, these seizures do not regress with age. JME is a genetically determined epileptic syndrome that usually begins in older children and adolescents. In some familial cases, a pathological gene has been found on chromosome 6. JME is usually characterized by morning myoclonus (twitching of the limbs or head) and episodic generalized tonic-clonic seizures. EEG in JME usually reveals generalized spike-wave complexes with a frequency of 3-6/sec. High efficacy of antiepileptic drugs, including valproic acid and benzodiazepines, is characteristic. In case of intolerance to these drugs, lamotrigine and topiramate can be used.

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