General information about focal epilepsy
The definition of “focal epilepsy” combines all forms of epileptic paroxysms that arise due to the presence of a local focus of increased epi-activity in cerebral structures.
Epileptic activity begins focally, but can spread from the focus of excitation to the surrounding brain tissue, which causes secondary generalization of the seizure. It is important to differentiate paroxysms of FE and attacks of generalized epilepsy with a primary diffuse nature of excitation. In addition, there is a multifocal form of epilepsy. In this form of epilepsy, there are several local epileptogenic zones in the brain. Approximately 82% of all epileptic syndromes are focal epilepsy, and in 75% of cases it begins in childhood. Most often it occurs against the background of traumatic, ischemic or infectious damage, or disorders of brain development. Secondary focal epilepsy of this nature is diagnosed in 71% of all patients suffering from epilepsy.
Levetiracetam
The active ingredient of the drug, levetiracetam, is a derivative of pyrrolidone (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), and its chemical structure differs from other anticonvulsants.
Mechanism of action
The mechanism of action of levetiracetam is not fully understood, but it differs from the mechanism of action of other anticonvulsants. in vitro experiments
and
in vivo
, levetiracetam has been shown to have no effect on basic cell properties and normal nerve transmission.
in vitro studies
It has been shown that, by partially reducing N-type calcium currents and reducing the release of calcium ions from the intracellular stores of neurons, levetiracetam changes the concentration of calcium ions inside neurons. In addition, it partially reverses the decrease in currents induced by zinc and β-carbolines through GABA- and glycine-dependent channels. One of the proposed mechanisms is based on proven binding to the synaptic vesicle glycoprotein SV2A, contained in the gray matter of the brain and spinal cord. It is believed that in this way an anticonvulsant effect is realized, which is expressed in counteracting the hypersynchronization of neural activity. Levetiracetam also acts on GABA receptors and glycine receptors, modulating these receptors through various endogenous agents. Does not alter normal neurotransmission, but suppresses epileptiform neuronal bursts induced by the GABA agonist bicuculline and excitation of glutamate receptors.
Pharmacodynamic effects
Levetiracetam has anticonvulsant effects in many animal models of partial and primary generalized seizures without concomitant proconvulsant effects. The main metabolite of levetiracetam is inactive.
Levetiracetam exhibits anticonvulsant activity in partial and generalized epilepsy in humans (epileptiform burst/photoparoxysmal response), which confirms its wide spectrum of pharmacological action.
Adjunctive therapy for partial seizures with or without secondary generalization in adults, adolescents and children over 1 month of age with epilepsy
:
Adults
. The effectiveness of levetiracetam in adults was confirmed in three double-blind, placebo-controlled studies. It was shown that the proportion of patients who demonstrated ≥50% reduction in the frequency of partial seizures per week from baseline with chronic use of levetiracetam at doses of 1000, 2000 or 3000 mg in 2 divided doses for 12-14 weeks was 27.7; 31.6 and 41.3%, respectively, and 12.6% in patients receiving placebo.
Children
. The effectiveness of levetiracetam in patients aged 4 to 16 years was established in a double-blind, placebo-controlled study of 14 weeks duration, including 198 patients. The dose of levetiracetam was 60 mg/kg/day in 2 divided doses. 44.6% of patients receiving levetiracetam and 19.6% of patients receiving placebo demonstrated a ≥50% reduction in weekly partial seizure frequency from baseline. During the treatment period, 11.4% of patients were seizure-free for at least 6 months and 7.2% for at least 1 year.
The effectiveness of levetiracetam in patients aged 1 month to 4 years was established in a double-blind, placebo-controlled study of 116 patients with a treatment duration of 5 days. Levetiracetam oral dosage for infants 1 to 6 months of age. was 20 mg/kg/day in 2 divided doses, followed by titration to 40 mg/kg/day, for infants and children over 6 months. up to 4 years - 25 mg/kg/day in 2 doses, followed by titration to 50 mg/kg/day.
At the initial efficacy assessment, response rate (percentage of patients with a ≥50% reduction in daily partial seizure frequency from baseline) was determined using an anonymous reader during 48-hour video electroencephalography. The efficacy rate is based on an analysis of 109 patients who underwent EEG for at least 24 hours. Responders were 43.6% of patients taking levetiracetam. and 19.6% in the placebo group. During long-term treatment, 8.6% of patients were seizure-free for at least 6 months and 7.8% were seizure-free for 1 year.
Placebo-controlled clinical trials included 35 infants <1 year of age with partial-onset seizures, of whom only 13 were <6 months of age.
Monotherapy for partial seizures with or without secondary generalization in patients over 16 years of age with newly diagnosed epilepsy
The efficacy of levetiracetam as monotherapy was comparable to that of controlled-release carbamazepine in a parallel group, double-blind study of 576 patients aged 16 years or older with newly diagnosed epilepsy. Only patients with unprovoked partial or generalized tonic-clonic seizures were included in the study. Patients were randomized to treatment with carbamazepine (controlled release form) at a dose of 400-1200 mg/day or levetiracetam at a dose of 1000-3000 mg/day. Treatment duration was up to 121 weeks, depending on response.
Seizure freedom at 6 months was observed in 73% of patients receiving levetiracetam and 72.8% of patients receiving carbamazepine. The matched absolute difference between treatments was 0.2% (95% CI: -7.8, 8.2). More than half of the patients were seizure-free at 12 months (56.6% in the levetiracetam group and 58.5% in the carbamazepine group, respectively).
During the study in clinical practice, concomitant antiepileptic drugs could be discontinued in a limited number of patients who responded to adjunctive levetiracetam therapy (36 of 69 adult patients).
Additional therapy of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy
The effectiveness of levetiracetam was established in a double-blind, placebo-controlled study of 16 weeks in patients aged 12 years and older with idiopathic generalized epilepsy with various myoclonic seizure syndromes. Most patients had juvenile myoclonic epilepsy. The dose of levetiracetam was 3000 mg/day in 2 divided doses. 58.3% of patients receiving levetiracetam. and 23.3% of patients in the placebo group had at least a 50% reduction in myoclonic seizures at one week. During continuous long-term treatment, 28.6% of patients were free of myoclonic seizures for at least 6 months and 21% of patients for 1 year.
Additional therapy for primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over 12 years of age with idiopathic generalized epilepsy
The effectiveness of levetiracetam was established over a 24-week, double-blind, placebo-controlled study that included adults, adolescents, and a limited number of children with idiopathic generalized epilepsy with primary generalized tonic-clonic seizures with various syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy). - epilepsy or epilepsy with generalized tonic-clonic seizures on awakening).
In this study, the daily dose of levetiracetam was 3000 mg for adults and adolescents or 60 mg/kg for children in 2 divided doses. Among patients with primary generalized tonic-clonic seizures, 72.2% of those receiving levetiracetam and 45.2% of those receiving placebo showed a ≥50% reduction in seizure frequency within a week.
During continuous long-term treatment, 47.4% of patients were free of tonic-clonic seizures for at least 6 months and 31.5% for 1 year.
Pathogenesis of focal epilepsy
The causes of the development of focal epilepsy are: developmental defects that affect a limited area of the brain (cerebral arteriovenous malformations, focal cortical dysplasia, congenital cerebral cysts, etc.), traumatic brain injuries, infections (brain abscess, encephalitis, neurosyphilis, cysticercosis), vascular system disorders (previous hemorrhagic stroke), metabolic encephalopathy, brain tumors. In PE, one of the etiological factors with preserved morphology of neurons and the medulla as a whole may be acquired and genetically determined metabolic defects of neurons in a certain zone of the cerebral cortex.
Perinatal lesions of the central nervous system are the leading cause among the factors causing focal epilepsy. Such lesions are: fetal hypoxia, asphyxia of the newborn, intracranial birth injury, intrauterine infections. The appearance of a focal pathological focus in childhood may be associated with impaired cortical maturation.
The pathophysiological basis of FE is the epileptogenic focus, in which several zones are distinguished. The zone of pathological damage corresponds to the area of morphological changes in cerebral tissue, which can be recorded using MRI.
The primary zone is the part of the cerebral cortex in which epi discharges are generated.
The symptomatogenic zone is the area of the cortex, when excited, an epileptic attack occurs. The irritative zone is an area that is recorded on the EEG during the interictal interval and is the source of an epileptic seizure.
The zone of functional deficit is the area responsible for the neurological disorders that accompany epileptic seizures.
Detailed description of the study
Levetiracetam is an antiepileptic drug. It differs from other drugs in this group in its high efficiency and fewer side effects. Analysis for levetiracetam allows you to identify the cause of treatment failure and adjust the dose of the drug.
Epilepsy is a brain disease characterized by abnormal electrical activity in neurons, leading to seizures. The impulse between the cells of the nervous system is transmitted through special synapses. During impulse transmission, special substances are released, the vesicles of which contain inhibitory molecules, such as gamma-aminobutyric acid (GABA), or excitatory molecules. Calcium also influences intercellular interaction, which promotes arousal. Levetiracetam inhibits the influx of Ca. A feature of the mechanism of action of the drug is binding to a special protein of synaptic vesicles, which ensures the proper functioning of neurons.
Epilepsy is divided into generalized and partial - with established localization in the brain. Levetiracetam is effective in stopping attacks in both forms. There is idiopathic epilepsy, the causes of which cannot be determined, it is associated with genetic factors, there is no previous brain damage and begins mainly in childhood.
Symptomatic is associated with visible causes: organic lesions of the central nervous system, previous infections (meningitis, encephalitis), high body temperature, hypoxia, and can occur at any age.
There are many types of seizures, but they are all characterized by a sudden onset and spontaneous cessation, short duration and similarity throughout the illness. Symptomatic epilepsy is most often accompanied by mental disorders: impaired attention, memory; the occurrence of anxiety, depression.
Levetiracetam is effective for the treatment of partial seizures with or without generalization, particularly for the treatment of juvenile myoclonic epilepsy. This form is quite common and is characterized by the onset of the disease in adolescence (from 12 years), presumably due to a genetic predisposition. Symptoms are involuntary muscle contractions (in the arms) and tonic convulsions of the whole body with loss of consciousness. Most often associated with sleep disturbances (insomnia). This form usually does not lead to mental disorders.
Levetiracetam may cause side effects. These include: weakness, drowsiness, mood swings, emotional instability, weight loss, nausea, abdominal pain. A skin rash, itching, and muscle pain may also appear. The drug has an effect on the health of elderly patients and people with liver and kidney diseases.
Levetiracetam does not require constant monitoring of concentrations in blood tests like other antiepileptic drugs, such as carbamazepine. But periodic determination allows you to avoid side effects, thereby improving a person’s health and quality of life.
Classification of focal epilepsy
There are symptomatic, idiopathic and cryptogenic forms of focal epilepsy. In the symptomatic form, it is possible to establish the source and cause of the pathology, as well as identify morphological changes that are recorded during tomographic studies.
A feature of cryptogenic PE is that, despite its secondary nature, none of the existing imaging methods is capable of identifying morphological abnormalities in the structure of the brain.
Idiopathic PE is not characterized by brain defects typical for this group of pathologies. The substrate for its development, as a rule, is a hereditary predisposition: genetically determined channelopathies, defects in the membranes of CNS cells, dysgenesis of the cerebral cortex. The prognosis for this disease is favorable, the course is benign. Idiopathic FE includes: benign rolandic epilepsy, childhood occipital Gastaut epilepsy, Panagiotopoulos syndrome, benign occipital epileptic syndromes.
Symptoms of focal epilepsy
Focal epilepsy is characterized by partial focal epileptic paroxysms. Paroxysms can be simple, not accompanied by loss of consciousness, and complex, without loss of consciousness. Simple partial epileptic seizures can be vegetative, somatosensory, motor, sensory, with a hallucinatory component and with mental disorders.
Complex partial epileptic seizures may begin as simple ones, but then damage consciousness occurs. There may be confusion after a seizure.
Secondarily generalized partial seizures begin as a simple or complex focal seizure, but then the excitation spreads to other parts of the cerebral cortex. Thus, the paroxysm takes on a clonic-tonic appearance. The patient may experience various types of partial paroxysms.
Symptomatic focal epilepsy is accompanied by symptoms that correspond to the underlying brain lesion. This type of epilepsy is characterized by decreased intelligence, delayed mental development and impairment of the child’s cognitive sphere.
Idiopathic focal epilepsy is benign and is not characterized by disorders of the mental and intellectual spheres.
Features of clinical manifestations of epilepsy depending on the location of the pathological focus
Temporal lobe epilepsy is the most common form of focal epilepsy. The epileptogenic focus is located in the temporal lobe of the brain. Focal temporal lobe epilepsy is characterized by seizures with loss of consciousness, the presence of automatisms and an aura. The attack lasts on average 30-60 seconds. Oral automatisms are characteristic of children, and gesture-type automatisms are characteristic of adults. Paroxysms of focal temporal lobe epilepsy have a secondary generalization. Post-ictal aphasia is recorded when the dominant hemisphere of the temporal lobe of the brain is damaged.
The epileptic focus of frontal focal epilepsy is located in the frontal lobe of the brain. This focus provokes short-term paroxysms, which can occur in series. Frontal FE is not characterized by an aura. Symptoms of frontal FE: turning the eyes and head to one side, complex automatic gestures, emotional arousal, screaming, flinching, aggression. If the focus of the pathology is in the precentral gyrus, then motor paroxysms of Jacksonian epilepsy appear. Epileptic seizures of frontal focal epilepsy occur during sleep.
When the lesion is located in the occipital lobe of the brain, epileptic seizures occur, accompanied by visual impairment. For example, narrowing of visual fields, visual hallucinations, ictal blinking, transient amaurosis, etc. The duration of visual hallucinations is 13 minutes.
The location of the focus of epileptic activity in the parietal lobe is rare. The parietal lobe is affected in the presence of a tumor or cortical dysplasia. Parietal focal epilepsy is characterized by simple somatosensory paroxysms: short-term aphasia or Todd's palsy. If the area of epileptic activity is localized in the postcentral gyrus, then Jacksonian seizures may occur.
Diagnosis of focal epilepsy
If partial paroxysm occurs for the first time, the patient needs a detailed examination, since this symptom may be a manifestation of serious cerebral pathology. During the consultation, the neurologist asks to fully describe the duration, nature, and sequence of development of the epileptic attack. The identified deviations help to establish the location of the pathology focus.
Epileptic activity is diagnosed using EEG. Epi-activity of focal epilepsy can be recorded on the EEG even during the interictal period. If the EEG without an attack is uninformative, then electroencephaloscopy should be performed with provocative tests and/or during an attack. Subdural corticography is an electroencephaloscopy with the installation of electrodes under the dura mater. Helps to accurately determine the location of the pathological focus.
Of the instrumental research methods, the most effective for elucidating the morphological basis of PE is MRI. The thickness of the sections should be about 1-2 mm in order to detect the smallest defects in the brain substance as accurately as possible. In the case of symptomatic epilepsy, MRI makes it possible to identify the root cause: focal lesions, atrophy, dysplasia. In some cases, such changes cannot be detected, and then the diagnosis is idiopathic or cryptogenic PE. As an additional, but optional study, a PET scan of the brain may be prescribed. PET will document the epileptogenic region as an area of increased metabolic activity. SPECT is also used as an additional diagnostic method, during which a specialist is able to monitor the dynamics of perfusion of the cerebral substance: during a seizure, a picture of hyperperfusion of the epileptogenic focus will be observed, and in the period of time between paroxysms, hypoperfusion will be observed.
Therapy for focal epilepsy
Treatment of focal epilepsy is prescribed by a neurologist and epileptologist, and includes taking anticonvulsants. Anticonvulsants include: carbamazepine, topiramate, phenobarbital, levetiracetam, etc. For the treatment of parietal and occipital epilepsy, pharmacotherapy will be sufficient. In case of focal temporal lobe epilepsy, after 1-2 years of therapy, resistance to anticonvulsant treatment may occur. If there is no effect from therapy, the doctor prescribes surgery.
The operation is performed by neurosurgeons and is aimed at complete removal of the focal formation (malformation, tumor, cyst) or partial removal of the epi-site. Focal resection is used if the focus of epileptic activity is well localized. If cells that are also a source of epileptic activity are adjacent to the epileptogenic zone, then extended resection is prescribed.
References
- Romanenko, I.V., Romanenko, V.I., Romanenko, Yu.I. Antiepileptic, neuroprotective and antihyperalgic effects of levetiracetam. International Neurological Journal, 2017. - No. 5(91). — P. 68-72.
- Diagnosis and treatment of mental disorders in epilepsy. Clinical recommendations. Russian Society of Psychiatrists, 2014. - 36 p.
- Mukhin, K.Yu., Freidkova, N.V., Glukhova, L.Yu. et al. Juvenile myoclonic epilepsy: focus on the effectiveness of therapy and relapse rate according to long-term follow-up data. Russian Journal of Child Neurology, 2015. - T. 10(4). — P. 7-16.
- Kolyagin, V.V. Etiology, classification and treatment of epilepsy. Irkutsk: RIO IGIUVA, 2010. - 40 p.
- Vidal reference book of medicines: website / Levetiracetam, 2021. - URL: https://www.vidal.ru/drugs/levetiracetam__33975 (access date: 08/12/2021).
Prognosis of focal epilepsy
The prognosis of focal epilepsy depends on its type.
Since idiopathic epilepsy is benign and occurs without cognitive impairment, the cessation of paroxysms occurs spontaneously in adolescence.
Cerebral pathology determines the prognosis of symptomatic epilepsy. Unfortunately, it is unfavorable for severe brain malformations and tumors. This epilepsy is manifested by mental retardation, which is observed with early onset of epilepsy.
In 60-70% of patients after surgical treatment there is a decrease or absence of epiparoxysms. Complete disappearance of epilepsy after a long time is recorded in 30%.
Levetiracetam Canon
Suction.
After oral administration, levetiracetam is well absorbed from the gastrointestinal tract. Levetiracetam is highly soluble in water and has good penetrating ability. Absorption is complete and linear, so plasma concentrations can be predicted based on the dose of levetiracetam taken, expressed in mg/kg body weight. The degree of absorption does not depend on the dose and time of food intake. Bioavailability is approximately 100%. The maximum concentration in plasma (Cmax) is achieved 1.3 hours after oral administration of levetiracetam at a dose of 1000 mg and with a single dose is 31 mcg/ml, after repeated doses (2 times a day) - 43 mcg/ml. An equilibrium state is achieved after 2 days with a double dose of the drug.
The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg/kg/day, Cmax is reached after 0.5-1 hour.
Distribution.
The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. The volume of distribution (Vd) is approximately 0.5-0.7 l/kg.
Metabolism.
The main route of metabolism (24% of the dose taken) is enzymatic hydrolysis of the acetamide group. The formation of the primary pharmacologically inactive metabolite (ucb L057) occurs without the participation of liver cytochrome P450. Levetiracetam does not affect the enzymatic activity of hepatocytes.
In vitro
levetiracetam and its main metabolite did not inhibit the main forms of cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, 1A2) as well as the activity of glucuronyl transferase (UGT1A1, UGT1A6) and epoxide hydroxylase.
Did not affect the glucuronidation of valproic acid in vitro.
Excretion.
The half-life (T1/2) from the blood plasma of an adult is 7±1 hours and does not depend on the route of administration and dosage regimen. The average total clearance is 0.96 ml/min/kg. 95% of the drug is excreted by the kidneys. The renal clearance of levetiracetam and its metabolite is 0.6 and 4.2 ml/min/kg, respectively.
In elderly patients
T1/2 increases by 40% and amounts to 10-11 hours, which is associated with impaired renal function in this category of people.
In patients with impaired renal function
clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, in patients with renal failure, dose selection is recommended depending on creatinine clearance. In end-stage renal failure in adult patients, T1/2 is 25 hours between dialysis sessions and 3.1 hours during dialysis. During a 4-hour dialysis session, up to 51% of levetiracetam is removed.
In patients with mild to moderate liver dysfunction
There are no significant changes in the clearance of levetiracetam. In most patients with severely impaired liver function and concomitant renal failure, the clearance of levetiracetam is reduced by more than 50%. T1/2 in children after a single oral administration of the drug at a dose of 20 mg/kg body weight is 5-6 hours. The total clearance of levetiracetam in children is approximately 40% higher than in adults and is directly dependent on body weight.
