Summary. Epilepsy can be caused by several factors. Seizures contribute to progressive neurodegeneration with mild neurofunctional and psychosocial consequences, but epilepsy in the child can often be refractory to existing antiepileptic medications. Development of epilepsy takes place in a complex neurobiological environment characterized by continuous processes of secondary lesions induced by seizures. One of the mechanisms that determine the development of epilepsy is related to the changes in activity of neurons, i. e., hypersynchronic activity, and excitability, i. e., processes of excitation and inhibition. Older conceptions about exclusive participation of neurons in epileptogenesis are now changed, and currently special attention is given to the role in the pathogenesis of epilepsy of glia and neuroinfl ammatory immune factors. It is suggested that immune and infl ammatory reactions occur in the epileptic brain, being closely linked to the presence of cerebral vascular barrier that strictly regulates infi ltration with blood monocytes and lymphocytes. According to current concepts, from a clinical point of view, neuroinfl ammation is considered as a distinctive phenomenon of epileptogenic foci outbreaks in various types of refractory epilepsy. Th ese processes are determined probably by immune mediators that are characteristic for the brain and peripheral leukocytes that infi ltrate the brain. Understanding the immune neuroinfl ammation mechanisms in refractory epilepsy in humans will help to correctly use immunotherapeutic medications to resolve the causes of the disease. Th e present study describes a clinical case of a child with convulsive seizures refractory to antiepileptic therapy.
Keywords: Epileptogenesis, epilepsiy, mechanisms, neuroinfl ammation, immune, refractoriness to pharmaceutic therapy
Epilepsy is a chronic disease that affects the brain, having various causes, characterized by the repetition of (epileptic) seizures. The term “seizure” is preferred to the term “epilepsy” because it is incorrectly considered that in epilepsy there is permanent brain damage or is a trend for unfavorable outcome in patients. Epileptic seizures are periodic disturbances of the electrical activity of the brain, which lead to temporary cerebral dysfunction. Seizures often begin in the infancy or adulthood . Recently, the causes and mechanisms of pathogenesis which are the basis for the development of epilepsy are being extensively discussed. Among the discussed phenomena are inflammatory as well as immune processes, which can occur in epilepsy, especially in the case of resistance to pharmacological treatment . Understanding the immune mechanisms, which underlying the evolution of epilepsy refractory to antiepileptic drugs and epileptic encephalopathy, represents a new target in antiepileptic tactics. Understanding the role of neuroinflammation in the pathogenesis of epilepsy is essential for the discovery of selective therapies that concern the causes of epilepsy, but not its symptoms. In particular, clinical analysis of laboratory results may suggest the benefit of anti-inflammatory drugs, already used in therapy of inflammatory autoimmune disorders occurring in epilepsy [3, 4]. In present study we will present a review of reports supporting the role of brain inflammation in the pathogenesis of seizures.
Scope of study is in describing the role of neuroinflammation and neuroimmune phenomena in the development of epilepsy resistant to pharmaceitucal treatment based on the review of the literature as well as based on a presenting of clinical case of epilepsy with immune component.
MATERIALS AND METHODS
Study of basic preclinical and clinical reports, as well as new studies in literature that summarize the influence of inflammation in epilepsy, as well as mechanisms which contribute of inflammation in the development of refractory epilepsy. Will be presented a clinical case of a child who developed epilepsy resistant to pharmaceutical treatment on the background of a primary immunodeficiency.
We present the case of a girl SI, age of 1 year 11 months (date of birth – 29.01.2016), from the urban area, admitted in January 09, 2018, with the following symptoms: Frequent polymorphic seizures with mioclonic component, repeated 7 – 8 times a day, with a loss of consciousness, during last 3 months, which are not controlled by the initiated treatment with valproic acid and phenobarbital.
Diagnosis of primary care: Non-precised convulsive syndrome.
Diagnosis at arrival: Non-precised epilepsy, with polymorph frequent epileptic seizures.
Diagnosis at discharge: Epileptic encephalopathy of immune etiology, frequent polymorph epileptic seizures, refractory to pharmaceutical treatment.
Concomitant diseases: Primary Immunodeficiency. Viral EBV encephalitis. Bilateral pneumonia, medium severity. Respiratory insufficiency grade 1. Status epilepticus.
Medical history: The disease manifested from the age of 1 year and 8 months of age manifesting the first seizure, i. e., generalized tonic-clonic seizure, on the background of fever. Phenobarbital therapy was initiated during one month, with control of seizures. Child’s mother cancelled phenobarbital, causing relapse of seizures with a high frequency which become polymorph, 7 – 8 times a day. Seizures were resistant to phenobarbital treatment. Child was admitted to a hospital for treatment with anticonvulsants, but without effect. Subsequently, at the age of 2,1 years, the patient was admitted to the Department of Neurology of the Institute of Mother and Child for diagnosis and treatment.
History of pregnancy. Child was born from 3rd pregnancy, with supported viral infection in a 2, 8, and 9 months of gestation, birth to 40 – 41 weeks with Apgar score of 7 – 8 points, weight 3250 g, cranial perimeter – 34 cm, the evolution of neonatal period was physiological. At the age of 1,5 years the child suffered a purulent lymphadenitis. Physical and neuro-psychical development of child before current addressing: The dynamics of body weight and height growth of the child and the stages of neuropsychical development by months correspond to age standard; the child was vaccinated according to the vaccination shedule. Patient examination: Skin clean, lymph nodes do not palpate; coarse breath sounds, wheezing, respiratory rate 36 per minute; rhythmic heart beat, 110 per minute, blood pressure – 108/77 mm Hg; the liver does not palpate, the spleen at the edge of rib; free urinating. Neurologic assessment by Tison – Gosselin: neuro-psychic development corresponds to age, in a girl presents paroxysmal seizures expressed by fixation of gaze, chewing, loss of consciousness, head fall, frequent myoclonic seizures. During admission to the Department of Neurology was determined: the body temperature (from 36,6 to 38,5˚C), restless, crying, periodically apathetic, restless sleep, has paroxysmal manifestations from 4 to 7 times during different periods of the day and at night. On the 7th day the patient transferred to the Department of Intensive Care due to worsening of convulsive syndrome with repetitive seizures associated to tonic clonic frequent afebrile seizures up to 15 – 20 times in a day. Date of objective examination: sleepiness, apathy, visual reaction on light preserved, no signs acused by irritation of the meninges, clean and pale skin, coarse breationg on lungs auscultation, respiratory rate 36 per min, rhythmic pulse, rate of 110 beats per min, abdomen is soft, liver and spleen under edge of rib, blood pressure 108/77 mm Hg, SpO2 is 92%. Laboratory findings: WBC – lymphopenia (20% 1680 abs.); human immunodeficiency virus (HIV) – negative; Immunologic data: Ig M (0,94 g/L), Ig A (0,5 g/L), Ig G significantly decreased (4,44 g/L), Ig E (8,5 KU/L); IgM CMV – Suspicion 0,265 g/l (N = 0,280 g/l), IgG CMV – Positive 1,609 g/l (N = 0,290 g/l), EBV VCA IgM – Positive, EBV EA Ig – Positive, EBV VCA IgG – Positive, EBV EBNA IgG – Positive; Cellular immunity – CD3 1058 abs., CD4 – 520 abs., CD8 – 184,8 abs., CD16 – 268,8 abs., CD19 – 67,2 abs, ImmuneRegulatory Index (IRI) – 2,82. CSF examination with proteins and lymphocytes increased, and Immunological CSF examination with DNA EBV Positive; hypoproteinemia (50 g/l); hypocalcaemia (1,8 g/L); IL-6 – 48,7 pg/mL. Molecular genetic analysis: 1. To determine the presence of primary immunodeficiency was measured concentration of and T-cell receptor excision circles and light kappachain of immunoglobulin, i. e., TREC/KREC assay, using qPCR with hydrolysis probes . TREC concentration was 496.38 copies per 100000 of cells and KREC 6426.8 copies per 100000 of cells, TREC concentration was out of age normal range (minimum 14000 TREC copies and minimum 1000 KREC copies per 100000 of cells ). The analysis was carried out at the Laboratory of Human Molecular Genetics, Municipal Scientific and Practical Institute Mother and Child, Chisinau, Republic of Moldova. 2. Was made the search for mutations associated with hereditary epilepsies, epileptic encephalopathy and others hereditary diseases with similar phenotypic manifestations by determining of panel of genes, in total 500 genes. Was revealed heterozygous mutation of exon 5 of EIF2B2 gene (chr14Ș75472635A>G, rs 142977089), which lead to substitution of aminoacid in position 222 of protein (p.Ile222Val, NM_014239.3). Homozygous and compound heterozygous mutations in EIF2B2 gene are suggestive for pathology related to leukoencephalopathy with atrophic changes in intracerebral white matter (OMIM: 603896). The analysis was carried out in the laboratory “Genomed”, Moscow, Russia.
Chest X-ray – medium basal pneumonia of right lung. Nasopharyngean culturre revealed Streptococcus viridans 106. USG of abdomen revealed hepatomegaly.
Cerebral MRI: suggestive signs of encephalitis (Fig. 1).
Electroencephalography 1 (EEG): Before the examination the child developed a seizure with eyes deviation and fixing, involuntary movements of upper limbs (Fig. 2).
Encephalogram 2: The child is in the second stage of sleeping (Fig. 3).
Encephalography 3: Sleep recording (Fig. 4).
ECG: Disorders of conductibility of right ventricle, hyperfunction of left ventricle. Ophthalmoscopy: Optic nerve disc with blurred temporal border, pale rose, veins moderately dilated, retina with normal aspects. Infectionist: EBV infection, generalized type, EBV encephalitis, with daily polymorph convulsive seizures.
Administered treatment: anticonvulsants (Phenobarbital, Depakine, Lamotrigine, Clonazepam, Levetiracetam), corticosteroids, Antibiotic therapy, Antiviral drugs (Aciclovir), human antiviral immunoglobulin Imunoglobulină umană antivirală (Cytotec), Mannitol, Acetazolamide. The condition of the child has improved after administration of human immunoglobulin.
Conclusions of clinical case. Epilepsy can be caused by many factors, including mentioned in literature viral infections that are responsible for inflammatory and immune changes. These can affect in particular children with immunodeficiency. In the case discussed above, the child presented Epstein-Barr viral encephalitis on the background of primary immunodeficiency (PID), which caused the development of epilepsy, with the involvement of inflammatory-immune mechanisms and development of a resistance to antiepileptic drugs. It is assumed the considerable influence of the genetic factor on the realization of pathological processes, i. e., epilepsy. Decreasing in the function of T lymphocytes, manifested by decreasing of TREC number, presumable, may lead to insufficient functioning of T suppressors. As a result, there is no suppression of the proliferation of B cells producing autological immunoglobulins and T cells with autologic receptors. These changes can lead to the emergence of inflammatory and autoimmune processes and have an impact on the development of reviewed pathology due to destruction of the white matter of the brain. Heterozygous mutation in EIF2B2 gene, which controls the processes of using GTP and GDP and protein synthesis, can also have an impact on development of leukodystrophy. Other mutations in the above mentioned gene, which have been described previously, can also lead to development of leukoencephalopathy. Immune therapy is indicated in such cases.
Studies in the last decade confirm the need for comprehensive research of the pathogenetic mechanisms of epilepsy, which are frequently devastating, especially in children. These needs is due to the occurrence of seizures that often do not respond to administering of antiepileptic drugs, but also have a long-term cognitive and socio-economic consequences following intractable epilepsy, frequently beginning in childhood . In order to control the pathogenetic processes that take place in the brain it is important to understand the processes that occur in damage. Preclinical studies in the last decade on some models of acute seizures and chronic epilepsy have highlighted that neuroinflammation in epileptogenic cerebral foci is a key factor in the development of neural hyperexcitation which is a cause of seizures .
It is known the fact that seizures develops in a children with susceptibility caused to peculiarities of brain development. The incidence of convulsive status epilepticus (CSE), as well as prolonged or repeated seizures lasting more than 30 minutes increased in children less than 1 year of age and varies depending of socio-economic and ethnic status of the population , and increased incidence of CSE in non-Caucasian populations suggests the presence of genetic susceptibility. However, in many cases, it may be suggested that a genetic susceptibility is not recognized in children with CSE [5,6]. Were described several genetic syndromes that are often associated with the development of an epileptic encephalopathy. Epileptic encephalopathy is a pathology in which neurological deterioration is fully or partially attributed to epileptic activity. Epileptic encephalopathy can be caused by the increased frequency of seizures and/ or a paroxysmal interictal activity . A prolonged seizure can have acute as well as long-term effects on developing brain. It is suggested that currently there are no effective treatments to promote the recovery and regeneration of neurons after seizures. Moreover, currently available antiepileptic drugs do not improve cognitive function, and often, as some animal studies show, may have harmful effects . Finding pharmaceutical products with targeted pathogenetic actions would allow the improvement of the quality of life of children with epilepsy, which often suffering from cognitive impairment, attention deficit hyperactivity disorder or behavioral problems, being a lifelong susceptible to significant implications for health and social skills [7, 8]. Understanding the pathophysiological basis of cognitive deficits induced by seizures should allow researchers to develop new objectives for therapeutic interventions in prolonged seizures and seizures refractory to antiepileptic therapy . Thus, modeling the immune response by suppressing and normalizing the excessive production of inflammatory mediators can prevent cellular lesion induced by the CSE and increase resistance to subsequent seizures, as well as improve restoring of neuronal functions .
In the last 10 years, clinical and experimental research supports the concept of involvement of inflammatory mechanisms in etiopathogenesis of epileptic seizures. It is known that neuroinflammation is an important secondary pathologic process involved in epilepsy, although the mode of involvement in epileptogenesis and in chronic process of spontaneous convulsive activity remains insufficiently explained. Experimental research has shown the important role of glial cells, which can be activated by various lesions occurring in the brain, especially the mechanisms of induced and recurrent convulsions . Microglia and astrocytes are pivotal cells involved in both inducing and perpetuating inflammatory response in seizures. Other cell contributors are neurons, cellular components of the hematoencephalic barrier and leukocytes .
Thus, the results of a study identify new paths for the communication of glia to glia and glia to neurons that may be relevant for the normal function of brain and for neurodegenerative diseases. The authors argue that neurons, which are much more in number than glia, support excitability in the brain. However, glia strongly influences neurons and their ability to process information. Persistent changes in the neural excitability are occurring in epilepsy and this process is mediated by neuroglia [3, 9]. In addition, some results support the hypothesis that astrocytes can respond to external stimuli and communicate with neighboring cells through rapid release of glutamate . Furthermore, some studies reveal the crucial role of astrocytes and oligodendrocytes in neurotransmission and signal transmission, suggesting that specific processes of astrocytes could help prevent pathology of myelin and successfully remodeling the myelin sheath after demyelination . Is plausible the innovative concept that brain inflammation can be a common substrate that contributes to the development of refractory convulsions and resistance to pharmaceutical therapy, and recurrent seizures can be a major cause of long-term inflammation. The neuropathological processes that occur in the epileptogenic tissue can also contribute to the perpetuation of inflammation .
The evidences accumulated show that neuroinflammation is a common consequence of epileptic seizure activity, which also contributes to epileptogenesis, as well as to seizures initiation and maintenance. The authors evidenced the presence of several inflammatory mediators in traumatic epilepsy and the presence of properties of these mediators to cause epilepsy and seizures, with action on glia and neurons, directly and indirectly influencing neural excitability, as protein-1, interleukin-1β and transforming growth factor beta .
Persistence of abnormal neuroinflammation in epilepsy can have a profound impact on neural function, causing a chain of uncontrolled phenomena and disturbance of brain functions. The concept of the major role of the blood-brain barrier in maintaining the integrity of the brain was not considered. Involvement of the blood-brain barrier in initiation, progression and maintenance of seizures has been demonstrated on mouse models. Thus, it is considered that disruption of the blood-brain barrier can be a main cause of seizures. At the same time, peripheral leukocytes can promote the development of epilepsy by mediating damage of blood-brain barrier . Likewise, seizures have been shown to induce increased expression of cell vascular adhesion molecules, and interaction of endothelial leukocyte may be a potential target for the prevention and treatment of epilepsy . Finally, inflammation increases the vulnerability of immature hippocampus by neurons injury induced by seizures, and worsens the long-term outcome of seizures . Inflammatory response caused by prolonged seizures initially causes activation of glia and disrupts the blood-brain barrier. Immune system is rapidly reactivated by a second CSE subsequently occurring, which cause the infiltration of peripheral leukocytes into the brain, the exaggerated activation of microglia, increased susceptibility to seizures and increase the lesion of neurons [2, 3, 13]. Thus, relapsing seizures crises cause further lesion of the blood-brain barrier, lead to progression of epileptogenesis and have an impact on neuroprotection .
Several attempts have been made to establish the potential causal role of hereditary features of immunity and adaptation in the development of chronic epilepsy with infantile onset. The role of activation of IL-1 was identified in the propagation of inflammatory response resulting from seizures . Likewise, the role of IL-1beta (IL-1β) and glia was demonstrated by revealing the activation of these factors associated with the propagation of inflammatory response after seizures. The data of a study on an immature animal model shows that IL-1β signaling critically contributes to febrile seizures induced by hyperexcitability which is caused by fever, which is a potential objective for their prevention . It is known fact that febrile seizures are closely related to the temporal lobe epilepsy in adults. A recent study demonstrated that phosphorylation GluN2B at site Tyr1472 is mediated by the transient growth of IL-1β, which associated with increased susceptibility to seizures in adults after prolonged febrile seizures. In this case is taking place involvement of NMDA receptor containing GluN2B. Blocking of GluN2B subunits can reverse the increased susceptibility to seizures after prolonged febrile seizures, allowing a wide therapeutic window with a possibility to prevent epileptogenesis in patients with acute inflammatory diseases . Thus, IL-1β has an important place in activating of glia and in propagation of inflammatory response resulting from seizures. Likewise, IL-1β increases the activity of NMDA receptor by activating tyrosine kinases and subsequent phosphorylation of subunit NR2A/B. These effects may contribute to glutamate-mediated neurodegeneration .
The inflammatory response to seizures is associated with TNF-A, IL-1 β, IL-6 and IL-18 cytokines in the acute period (up to 72 hours) and IL-18 during the subacute period (up to 10 days). In addition, it is suggested that expression of genes encoding classical inflammatory mediators are significantly increased after prolonged seizures. Other genes include chemokines, complement components, metalloproteases and their inhibitors, tissue plasminogen activator (tPA) and its inhibitor, annexins, adhesion molecules, immune receptors such as complex molecules of major histocompatibility complex, i. e., MHC I, peptides derived from cytosolic proteins, with a role in the degradation of cytosolic proteins by proteasome, and Fc receptors, i. e., protein found on the surface of certain cells that bind to antibodies attached to cells infected by pathogens, galectin, also called lectin type S because of its dependence on disulfide bonds for stability and binding carbohydrates; they participate in mediation of cell-cell interactions, adhesion to the cellular matrix and transmembrane signaling, and thermal shock proteins. All these components are likely to compromise the integrity of the blood brain barrier and initiate the infiltration of leukocytes into the central nervous system [3, 19].
Detection of proinflammatory biomarkers will help explain the pathogenetic mechanisms in various types of epilepsy, which will benefit from antiinflammatory therapies with a mechanism of action very different from the standard antiepileptic drugs. Thus, new studies show evidences of clinical efficacy of targeted antiinflammatory interventions in epilepsy with diverse etiology .
Several studies investigate the involvement of microglia in development of severe epilepsy and epileptic encephalopathy. Microglia can increase vulnerability in seizures, especially in infants and young children. Specifically, microglia is very dynamic and is closely associated with neurons and astrocytes. Astrocytes reacts and transforms rapidly according to environmental changes by releasing molecules that perform control of neural function and synaptic transmission. Activated microglia undergoes rapid proliferation, facilitating effective immune responses by releasing inflammatory cytokines and chemokines . Proinflammatory factors being released, facilitates hyperexcitability and contributes to epileptogenesis . Microglia can exert effects on neural excitability through several mechanisms. On the one hand, effect can be achieved due to the action of proinflammatory cytokines released by activated microglia, and, on the other hand, through an independent cytokine mechanism [3, 20].
Some authors who have studied temporal lobe epilepsy providing the information concerning the involvement of microglia in the mediation of inflammation. It has been found that seizures lead to an acute inflammatory response in the brain, characterized mainly by the activation of parenchymal cells of microglia. In this case there is a significant increase in the expression of CX3CR1, i. e., a transmembrane protein and chemokine involved in the adhesion and migration of leukocytes. Treatment with CX3CR1 antibodies resulted in a reduction of activation of microglia, decreasing of neurodegeneration and neuroblast production. Thus, these results are confirming the role of signaling path of fractalkine-CX3CR1 in the seizures induced by activation of microglia and suggest that the production of neuroblasts after seizures may occur at least partially due to activation of microglia .
It is known that proinflammatory cytokines are produced in excess during seizures, and, e. g., the level of IL-1β is quickly regulated in microglia after inducing of acute seizures, and IL-1β receptors are present in high density in the hippocampus [4, 20]. IL-1β decreases the current of GABA inhibitors and can lead to increased synaptic excitability, causing seizures . Reducing the biological active form of IL-1β by interleukin conversion enzyme significantly reduces the onset and duration of seizures, and intracerebral injection of IL-1 receptor antagonist (RA) produces an anticonvulsant effect. Likewise, the microglia expresses the neurotransmitter receptors and modulates the neural activity indirectly by influencing the astrocytes. Pathological activation of microgla and neurotransmission alteration are two early phenomena accompanying most diseases of brain . Recent research suggests that seizures generated by the immature brain can cause permanent injury of tissue, making it more susceptible to subsequent seizures, and activating of glial and inflammatory-specific mediators can play an important role in predisposing of the brain to excitability and subsequent neural injury .
Recently, several opinions have been expressed about the mechanisms that could remedy the activation of microglia to block processes of epileptogenesis, especially at early ages. These include antagonists AMPA receptor, i. e., partially blocking activation of microglia, and antiinflammatory therapy after CSE, using minocycline or dexamethasone [3, 25]. Short-term dexamethasone administration inhibits inflammation caused by seizures, alleviates excessive activation of microglia and cellular damage after seizures, as well as increased susceptibility to subsequent seizures .
Authors of a study on cortical tissue from patients with refractory epilepsy have elucidated the involvement of brain inflammation and cell death, expressed by significant accumulation in the seizure focus of IL-1β, IL-8, IL-12p70 and MIP-1beta, as well as IL-6 and MCP-1, which were significantly more elevated in patients with a family history of epilepsy. Significant infiltration of the brain parenchyma with leukocytes was found in children with a diagnosis of epileptic encephalopathy including West and Lennox-Gastaut syndromes. Proinflammatory T lymphocytes were concentrated in the seizure focus, and their number correlated positively with the severity of seizures, while the number of regulatory T cells (Tregs) correlates inversely with the severity of disease. The findings of the study supports the concept that hereditary and adaptive immune inflammatory processes play a potential role in the pathogenesis of epilepsy, and immunomodulation can cause a new therapeutic strategy in reducing neurological morbidity in children with epilepsy . In order to confirm these findings, further researches are needed to establish causality between the inflammatory signaling cascades and the development of postlesional epilepsy, to assess the therapeutic potential of pharmaceutical products targeting inflammatory pathways to prevent or mitigate the development of epilepsy . At the same time, taking into account known results, such as signaling of inflammatory cytokines is a key process underlying the development of epilepsy after an acquired brain injury, it is clear that the mediation of inflammatory cytokines is a feasible therapeutic target for improving the quality of life of patients with epilepsy [27, 28].
Are described perspectives in the treatment of epilepsy which includes anti-inflammatory therapies. Has been recognized the efficiency of Palmitoylethanolamide (PEA), an endogenous amide of fatty acid linked to the Arachidonoyl ethanolamide or Anandamide of the endocannabinoid system, a natural nutrient that has long been appreciated for its analgesic and anti-inflammatory properties, which has no potential of dependency, and it makes this substance an attractive candidate as antiepileptic drug. Subchronic administering of PEA significantly alleviates the intensity of seizures, promotes neuroprotection and induces modulation of levels of endocannabinoids and eicosanoids in plasma and hippocampus in mice injected with kainic acid .
The results of recent studies and also our findings support the concept that neuroinflammation which appears in pediatric epilepsy can play a crucial role in the common pathogenesis of epilepsy of various etiology and its consequences. Targeted immunomodulation can be a new therapeutic strategy for reducing neurological morbidity and preventing the development of epilepsy. Acute shortterm steroid therapy after status epilepticus may be useful for blocking the epileptic process and for treatment of long-term harmful effects of epilepsy. Lack of treatments that can prevent the development of epilepsy or improve the prognosis of the disease is an urgent clinical need. Further research is needed to establish correlation between inflammatory signaling cascades and development of epilepsy, but also for assessing the therapeutic potential of proinflammatory pharmaceutical products and those aimed at immune response having a role in blocking of specific proepileptic inflammatory pathways.
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