Materiały źródłowe

• #1 The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7649866/

  Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. […] The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a leaky BBB which facilitates cytokines and LPS entry into the central nervous system. […] Abnormally increased IL-1 levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. […] The increase of IL-1 in the CNS also results in an imbalance in glutamate and GABA causing an imbalance in excitation and inhibition transmission in the brain resulting in convulsions which accompany the fever, giving rise to the onset of febrile seizures.

• #2 Febrile Seizure – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448123/

  Febrile seizures are generalized seizures, typically in children between the ages of 6 months and 5 years, that occur with a fever greater than 100.4 F (38 C) not associated with a central nervous system (CNS) infection, a known seizure-provoking etiology (eg, electrolyte imbalance, hypoglycemia, or substance abuse), or history of an afebrile seizure. […] The primary febrile seizure risk factors appear to include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress. […] Some experts believe that either an underlying neurologic abnormality or the effect of a febrile seizure on a developing nervous system predisposes patients toward a seizure disorder. […] The exact pathophysiology of febrile seizures is not understood fully, but there is a recognized complex genetic predisposition, immaturity and vulnerability of the central nervous system, and various environmental factors. […] As a result of these various risk factors, the immature brain, with fever-enhanced neuronal excitation, is more susceptible to seizures and is one explanation as to why they occur more commonly in those younger than 3.

• #3 Pathogenetic and etiologic considerations of febrile seizures

  https://www.e-cep.org/journal/view.php?number=20125555595

  Febrile seizure (FS), which occurs in febrile children without underlying health problems, is the most common type of seizure disorder in children. The suggested pathogenesis of FS derived from several animal and human studies is multifactorial and debatable. Neuronal hyperexcitability, which develops during inflammatory responses that accompany fever, provokes seizures. However, the exact role of each inflammatory mediator (e.g., cytokines) is undefined in terms of the connection between systemic or local inflammation and the central nervous system, and the mechanisms by which cytokines increase neuronal excitability remain unclear. […] In the vulnerable immature CNS, increased neuronal excitability promotes seizures, and cytokines produced and released during acute inflammatory responses accompanying fever play a role in increasing neuronal excitability. Inflammatory responses outside the CNS increase cytokine concentrations in the CNS (neuro-immune network), and the released cytokines trigger neuronal hyperexcitability in the CNS (cytokine roles in the brain parenchyma) to generate FS. This concept can be applied to the generation of afebrile seizures or epilepsy accompanied by various types of inflammation with non-infectious causes, including trauma, toxic injury, hypoxic injury, and autoimmune reactions. […] The pathogenesis of FS is multifactorial and heterogeneous. There are no consistent and definite results regarding the connection between systemic or local inflammation and the CNS or on the mechanisms for increasing neuronal excitability in the CNS during fever.

• #4 Pathogenetic and etiologic considerations of febrile seizures

  https://e-cep.org/journal/view.php?number=20125555595

  The pathogenesis of FS seems theoretical and hypothetical. The neuro-immune network plays a crucial role in the pathogenesis of febrile seizures, where cytokines increase neuronal excitability and provoke seizures in the absence of direct CNS invasion of pathogens, disruptive BBB changes, and definite brain parenchymal inflammation. […] The pathogenesis of FS is multifactorial and heterogeneous. There are no consistent and definite results regarding the connection between systemic or local inflammation and the CNS or on the mechanisms for increasing neuronal excitability in the CNS during fever.

• #5 Febrile Seizure – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448123/

  Febrile seizures are generalized seizures, typically in children between the ages of 6 months and 5 years, that occur with a fever greater than 100.4 F (38 C) not associated with a central nervous system (CNS) infection, a known seizure-provoking etiology (eg, electrolyte imbalance, hypoglycemia, or substance abuse), or history of an afebrile seizure. […] The primary febrile seizure risk factors appear to include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress. […] Some experts believe that either an underlying neurologic abnormality or the effect of a febrile seizure on a developing nervous system predisposes patients toward a seizure disorder. […] The exact pathophysiology of febrile seizures is not understood fully, but there is a recognized complex genetic predisposition, immaturity and vulnerability of the central nervous system, and various environmental factors. […] As a result of these various risk factors, the immature brain, with fever-enhanced neuronal excitation, is more susceptible to seizures and is one explanation as to why they occur more commonly in those younger than 3.

• #6 Febrile Seizure – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448123/

  Febrile seizures are generalized seizures, typically in children between the ages of 6 months and 5 years, that occur with a fever greater than 100.4 F (38 C) not associated with a central nervous system (CNS) infection, a known seizure-provoking etiology (eg, electrolyte imbalance, hypoglycemia, or substance abuse), or history of an afebrile seizure. […] The primary febrile seizure risk factors appear to include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress. […] Some experts believe that either an underlying neurologic abnormality or the effect of a febrile seizure on a developing nervous system predisposes patients toward a seizure disorder. […] The exact pathophysiology of febrile seizures is not understood fully, but there is a recognized complex genetic predisposition, immaturity and vulnerability of the central nervous system, and various environmental factors. […] As a result of these various risk factors, the immature brain, with fever-enhanced neuronal excitation, is more susceptible to seizures and is one explanation as to why they occur more commonly in those younger than 3.

• #7 Clinical review of febrile seizure and updates – Karnataka Paediatric Journal

  https://iap-kpj.org/clinical-review-of-febrile-seizure-and-updates/

  FS is an age-dependent response of immature brain to fever. […] The exact etiology is still undetermined, though possible causal relationship with genetic and environmental factors have been reported. Releasing high levels of cytokines like interleukin 1 and tumor necrosis factor during a fever may alter normal brain physiology including certain temperature sensitive ion channels, triggering seizures. Developing brain especially under 3 years has inherent increased vulnerability to neuronal excitation and low seizure threshold that explains high fever related seizure burden in children. […] FS may develop due to mutations in the gene that encodes for the -aminobutyric acid A receptor and sodium channels. Mild loss of function or polymorphisms in SCN1A gene of NaV1.1 channels may cause a remarkable portion of FS. This mutation depletes peak sodium current for positive shift in the voltage dependent activation when expressed in nonneuronal cells.

• #8 Febrile seizures | MedLink Neurology

  https://www.medlink.com/articles/febrile-seizures

  Three features interact to produce a febrile seizure: immature brain, fever, and genetic predisposition. […] Febrile seizures rarely occur before 6 months of age or after 5 years of age, suggesting a relationship with brain maturation. However, the nature of this maturation process is unclear and could be related to increasing myelination, normal dying back of excessive neurons, and/or increasing synaptic complexity. […] The pathophysiology of febrile seizures is incompletely understood; however, it appears to be an age-dependent process with a multifactorial pathogenesis. The role of activation of the cytokine network continues to be studied. […] It is possible that circulating toxins and immune reaction products modulate neuronal excitability. […] Preclinical research suggests possible mechanisms by which fever induces seizures.

• #9 Febrile convulsions – Don’t Forget the Bubbles

  https://dontforgetthebubbles.com/febrile-seizures/

  Febrile seizures are benign. […] A febrile seizure represents the meeting point of a lower threshold for seizures and a trigger—the fever. […] Mutations in sodium ion channel genes and neurotransmitter genes (e.g. gamma-aminobutyric acid) have been identified in children with febrile seizures. These findings suggest the hypothesis of neuronal hyperexcitability to certain triggers. […] Fever is the main trigger for febrile seizures. […] The hypothalamus is responsible for homeostatic core temperature regulation. It is still developing in a young child, so it is more susceptible to rapid rises in body temperature.

• #10 Febrile convulsions – Don’t Forget the Bubbles

  https://dontforgetthebubbles.com/febrile-seizures/

  Febrile seizures are benign. […] A febrile seizure represents the meeting point of a lower threshold for seizures and a trigger—the fever. […] Mutations in sodium ion channel genes and neurotransmitter genes (e.g. gamma-aminobutyric acid) have been identified in children with febrile seizures. These findings suggest the hypothesis of neuronal hyperexcitability to certain triggers. […] Fever is the main trigger for febrile seizures. […] The hypothalamus is responsible for homeostatic core temperature regulation. It is still developing in a young child, so it is more susceptible to rapid rises in body temperature.

• #11 The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7649866/

  Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. […] The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a leaky BBB which facilitates cytokines and LPS entry into the central nervous system. […] Abnormally increased IL-1 levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. […] The increase of IL-1 in the CNS also results in an imbalance in glutamate and GABA causing an imbalance in excitation and inhibition transmission in the brain resulting in convulsions which accompany the fever, giving rise to the onset of febrile seizures.

• #12 Febrile Seizures: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/801500-overview

  Febrile seizures occur in young children at a time in their development when the seizure threshold is low. […] Animal studies suggest a possible role of endogenous pyrogens, such as interleukin 1beta, that, by increasing neuronal excitability, may link fever and seizure activity. […] Preliminary studies in children appear to support the hypothesis that the cytokine network is activated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathological significance of these observations is not yet clear. […] Whereas polygenic inheritance is likely, a small number of families are identified with an autosomal dominant pattern of inheritance of febrile seizures, leading to the description of a „febrile seizure susceptibility trait” with an autosomal dominant pattern of inheritance with reduced penetrance. […] Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma amino-butyric acid A receptor.

• #13 Febrile seizures | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/febrile-seizures/

  The cause of febrile seizures is unknown, although theyre linked to the start of a fever (a high temperature of 38C (100.4F) or above). […] Some researchers think that the biological processes associated with a high temperature may be responsible. […] A high temperature is thought to be caused by a bacterial or viral infection that stimulates the release of cytokines. Cytokines are proteins that affect the parts of the brain and nervous system responsible for regulating the bodys temperature. Their release causes a rise in the bodys temperature. […] One theory is that in certain people, high levels of cytokines may temporarily scramble the workings of the brain and nervous system, triggering a seizure.

• #14 Clinical review of febrile seizure and updates – Karnataka Paediatric Journal

  https://iap-kpj.org/clinical-review-of-febrile-seizure-and-updates/

  FS is an age-dependent response of immature brain to fever. […] The exact etiology is still undetermined, though possible causal relationship with genetic and environmental factors have been reported. Releasing high levels of cytokines like interleukin 1 and tumor necrosis factor during a fever may alter normal brain physiology including certain temperature sensitive ion channels, triggering seizures. Developing brain especially under 3 years has inherent increased vulnerability to neuronal excitation and low seizure threshold that explains high fever related seizure burden in children. […] FS may develop due to mutations in the gene that encodes for the -aminobutyric acid A receptor and sodium channels. Mild loss of function or polymorphisms in SCN1A gene of NaV1.1 channels may cause a remarkable portion of FS. This mutation depletes peak sodium current for positive shift in the voltage dependent activation when expressed in nonneuronal cells.

• #15 The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7649866/

  Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. […] The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a leaky BBB which facilitates cytokines and LPS entry into the central nervous system. […] Abnormally increased IL-1 levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. […] The increase of IL-1 in the CNS also results in an imbalance in glutamate and GABA causing an imbalance in excitation and inhibition transmission in the brain resulting in convulsions which accompany the fever, giving rise to the onset of febrile seizures.

• #16 The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7649866/

  Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. […] The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a leaky BBB which facilitates cytokines and LPS entry into the central nervous system. […] Abnormally increased IL-1 levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. […] The increase of IL-1 in the CNS also results in an imbalance in glutamate and GABA causing an imbalance in excitation and inhibition transmission in the brain resulting in convulsions which accompany the fever, giving rise to the onset of febrile seizures.

• #17 The Pathogenesis of Fever-Induced Febrile Seizures and Its Current State

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7649866/

  Febrile seizures, commonly in children between the ages of 3 months to 5 years, are a neurological abnormality characterized by neuronal hyper-excitability, that occur as a result of an increased core body temperature during a fever, which was caused by an underlying systemic infection. […] The cytokines, along with pathogen-associated molecular patterns (PAMPs) expressed on pathogens for example, lipopolysaccharide (LPS), interact with the blood brain barrier (BBB) causing a leaky BBB which facilitates cytokines and LPS entry into the central nervous system. […] Abnormally increased IL-1 levels also progressively increases excitatory (glutamatergic) neurotransmission, and decreases inhibitory (GABAergic) neurotransmission, thus mediating the pathogenesis of convulsions. […] The increase of IL-1 in the CNS also results in an imbalance in glutamate and GABA causing an imbalance in excitation and inhibition transmission in the brain resulting in convulsions which accompany the fever, giving rise to the onset of febrile seizures.

• #18 Relation between IL-1 β and IL1-ra in Pathogenesis of Febrile Convulsions

  https://ejhm.journals.ekb.eg/article_14999.html

  febrile seizures are the most common form of childhood seizures. […] The cytokine network may contribute to the generation of febrile seizures in children. Interleukin beta (IL-1 ) and Interleukin receptor antagonist (IL-1ra) have been implicated in the pathogenesis of febrile seizures. […] serum IL-1 and IL-1ra levels were significantly higher in febrile seizure patients than in fever in controls. […] Our study suggest that the inflammatory cytokine may play role in the generation of febrile seizures in children. […] These information may allow the development of anti-inflammatory therapy targeting these cytokines to prevent febrile seizures or subsequent epileptogenesis.

• #19 Recurrent febrile seizures and serum cytokines: a controlled follow-up study | Pediatric Research

  https://www.nature.com/articles/s41390-022-02282-7

  The role of cytokines in the pathogenesis of febrile seizures (FSs) is unclear, and information regarding cytokine production outside of FS episodes is scarce. […] Cytokines may play a role in pathogenesis of FSs. […] The exact pathogenesis of FSs is unknown, but during a specific developmental stage, certain genetically determined features of the central nervous and inflammatory systems may induce responses that cause seizures during febrile infections. […] It has been suggested that virus-induced release of cytokines in the central nervous system is one of the factors that causes neuronal hyperexcitability, which can lead to seizures. […] Our results indicate that patients with FSs produce exaggerated inflammatory reactions during FS episodes but not during other febrile episodes or healthy periods after FSs. […] Rather than a single, specific cytokine, the balance between pro- and anti-inflammatory cytokines might be essential in the multifactorial pathogenesis of FSs.

• #20 Recurrent febrile seizures and serum cytokines: a controlled follow-up study | Pediatric Research

  https://www.nature.com/articles/s41390-022-02282-7

  The role of cytokines in the pathogenesis of febrile seizures (FSs) is unclear, and information regarding cytokine production outside of FS episodes is scarce. […] Cytokines may play a role in pathogenesis of FSs. […] The exact pathogenesis of FSs is unknown, but during a specific developmental stage, certain genetically determined features of the central nervous and inflammatory systems may induce responses that cause seizures during febrile infections. […] It has been suggested that virus-induced release of cytokines in the central nervous system is one of the factors that causes neuronal hyperexcitability, which can lead to seizures. […] Our results indicate that patients with FSs produce exaggerated inflammatory reactions during FS episodes but not during other febrile episodes or healthy periods after FSs. […] Rather than a single, specific cytokine, the balance between pro- and anti-inflammatory cytokines might be essential in the multifactorial pathogenesis of FSs.

• #21 Recurrent febrile seizures and serum cytokines: a controlled follow-up study | Pediatric Research

  https://www.nature.com/articles/s41390-022-02282-7

  The role of cytokines in the pathogenesis of febrile seizures (FSs) is unclear, and information regarding cytokine production outside of FS episodes is scarce. […] Cytokines may play a role in pathogenesis of FSs. […] The exact pathogenesis of FSs is unknown, but during a specific developmental stage, certain genetically determined features of the central nervous and inflammatory systems may induce responses that cause seizures during febrile infections. […] It has been suggested that virus-induced release of cytokines in the central nervous system is one of the factors that causes neuronal hyperexcitability, which can lead to seizures. […] Our results indicate that patients with FSs produce exaggerated inflammatory reactions during FS episodes but not during other febrile episodes or healthy periods after FSs. […] Rather than a single, specific cytokine, the balance between pro- and anti-inflammatory cytokines might be essential in the multifactorial pathogenesis of FSs.

• #22 Inflammatory Biomarkers in Febrile Seizure: A Comprehensive Bibliometric, Review and Visualization Analysis

  https://www.mdpi.com/2076-3425/11/8/1077

  The anti-inflammatory cytokines, such as IL-1 receptor antagonist (IL-1RA) and IL-10 along with anti-inflammatory cholinergic signals from the efferent vagus nerve, provide a negative feedback on the inflammation. Nevertheless, in susceptible patients, it seems that the negative feedback control is lost, and the elevated systemic levels of pro-inflammatory cytokine elicit the seizure event. […] Pro-inflammatory cytokines involved in febrile seizures’ pathogenesis frequently reported in the research papers were (i) IL-1β, IL-6, IL-8, IL-12, IL-22, (TNF)-α, (ii) IFN-γ (important activator of macrophages involved in autoimmune disorders), (iii) transforming growth factor beta (TGF-β) suspected to trigger astrocytes’ activity leading to EEG modified patterns toward seizures, and (iv) high mobility group box 1 protein (HGMB1) secreted by activated macrophages and monocytes.

• #23 Association between high-mobility group box 1 levels and febrile seizures in children: a systematic review and meta-analysis | Scientific Reports

  https://www.nature.com/articles/s41598-023-30713-w

  The relationship between High-mobility group box 1 (HMGB1) and febrile seizures (FS) in children remains unclear. […] Meta-analysis showed that the children with FS had significantly higher HMGB1 levels compared with healthy children and children with fever but no seizures. […] The level of HMGB1 may be implicated in the prolongation, recurrence and development of FS in children. […] In addition, there are no effective means to predict and intervene in febrile seizures into epilepsy. […] Some studies believe that fever is a normal response to infection, and releasing high levels of cytokines during fever may change normal brain activity and cause seizures. […] Furthermore, the level of HMGB1 in children with FS was higher than that in healthy control children, suggesting that fever or seizure or both of them caused the increase of HMGB1 level in children with FS.

• #24 Association between high-mobility group box 1 levels and febrile seizures in children: a systematic review and meta-analysis | Scientific Reports

  https://www.nature.com/articles/s41598-023-30713-w

  In a comprehensive analysis, the level of HMGB1 in children with FS was significantly higher than that in children with FN, which could be considered as an important cytokine mediator in the pathogenesis of FS in children, and it had the ability to distinguish whether there is seizure or not. […] However, the exact mechanism of the relationship between the HMGB1 level and the development of FS still needs to be fully understood. […] We speculate that HMGB1 may play a regulatory role that it indirectly participated in the mechanism of glutamat-ergic and GABA-ergic neurotransmission disorders and fever-mediated febrile seizure during inflammation by increasing the expression of IL-1 and other proinflammatory cytokines. […] The level of HMGB1 in children with complex FS is higher than that in children with simple FS, and that in children with FS with convulsion duration 15 min is higher than that in children with seizure duration 15 min, indicating that high level of serum HMGB1 is positively correlated with the duration of febrile seizure in children, and children with high level of HMGB1 are more prone to complex FS.

• #25 Association between high-mobility group box 1 levels and febrile seizures in children: a systematic review and meta-analysis | Scientific Reports

  https://www.nature.com/articles/s41598-023-30713-w

  In a comprehensive analysis, the level of HMGB1 in children with FS was significantly higher than that in children with FN, which could be considered as an important cytokine mediator in the pathogenesis of FS in children, and it had the ability to distinguish whether there is seizure or not. […] However, the exact mechanism of the relationship between the HMGB1 level and the development of FS still needs to be fully understood. […] We speculate that HMGB1 may play a regulatory role that it indirectly participated in the mechanism of glutamat-ergic and GABA-ergic neurotransmission disorders and fever-mediated febrile seizure during inflammation by increasing the expression of IL-1 and other proinflammatory cytokines. […] The level of HMGB1 in children with complex FS is higher than that in children with simple FS, and that in children with FS with convulsion duration 15 min is higher than that in children with seizure duration 15 min, indicating that high level of serum HMGB1 is positively correlated with the duration of febrile seizure in children, and children with high level of HMGB1 are more prone to complex FS.

• #26

  https://journals.lww.com/10.4103/JPN.JPN_73_18

  Febrile seizure is a benign condition in children. Susceptibility genes associated with febrile convulsions have been identified, but the precise pathophysiologic mechanism that triggers febrile seizure is unclear. […] Our data indicates that febrile seizures may be associated with fever induced hyperventilation and ensuing hypocapnia may be one of the precipitating factor in inducing seizures. However, well-structured human trials are needed to demonstrate the same. […] Pathological mechanism that triggers FS is still not clear. FS pathophysiology is difficult to study because it mostly occurs at home, so there is access to only postictal data and physiological changes occurring during that period are missed. […] However, it is known that pH changes have central role in the control of electrical activity in brain, leading to seizures. Brain alkalosis is known to enhance neuronal excitability and promote epileptiform activity.

• #27

  https://journals.lww.com/10.4103/JPN.JPN_73_18

  Using an animal model of experimental FSs, it has been shown that hyperthermia causes respiratory alkalosis triggers seizures. […] Our findings are in accordance with previous animal studies showing any changes in blood pH and pCO2 levels increase or decrease neuronal excitability. These studies concluded that fall in pCO2 increases neuronal excitability of postsynaptic cells without altering neurotransmitter release in anesthetized rats. It was further shown that hypocapnia increases spike trigger in hippocampus in both the in situ and in vitro population. […] This study concludes that FS may be associated with respiratory alkalosis and might be one of the precipitating factors in genetically susceptible children.

• #28 New Therapy for Fever-Induced Seizures in Children Targets Calcium Channels – News Center

  https://news.feinberg.northwestern.edu/2013/06/12/martina_toddler_seizures/

  Fever-induced childhood seizures, known as febrile seizures, can be terrifying for parents to witness. […] While scientists know these seizures typically occur when a fever is above 100.4 degrees Fahrenheit (38 degrees Celsius), the exact mechanism at work has been unclear. […] The team further found that nimodipine, a commonly available L-type calcium-channel blocker, dramatically reduced the incidence and duration of febrile seizures in animals. […] We show that the activation of these channels, which are temperature sensitive, actually drives the electrical activity, not just follows it. As such, these channels may play a key role in seizure associated with high body temperature. […] This observation provides an alternative therapeutic target for febrile seizures that is distinct from current epilepsy drug therapy, which commonly focuses on blocking sodium channels.

• #29 New Therapy for Fever-Induced Seizures in Children Targets Calcium Channels – News Center

  https://news.feinberg.northwestern.edu/2013/06/12/martina_toddler_seizures/

  The results were striking: nimodipine dramatically reduced both the incidence and duration of febrile seizures in rat pups. […] Therefore, if proven effective in clinical trials, this could be an important advance in clinical care. […] Because L-type calcium channel blockers such as nimodipine are safe drugs, every toddler with febrile seizures can potentially be treated to stop or prevent seizures triggered by high fever and reduce the risk of long-term neurological consequences of uncontrolled recurrent or prolonged febrile seizures. […] Sookyong Koh, MD, PhD, associate professor in pediatricsneurology at Feinberg, and co-author on the paper, adds that these findings could be helpful for one group of children in particular: those with genetic epilepsy syndromes whose seizures are triggered by fever, and for whom most anticonvulsants acting on sodium channels are harmful.

• #30 Febrile Seizure – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448123/

  Febrile seizures are generalized seizures, typically in children between the ages of 6 months and 5 years, that occur with a fever greater than 100.4 F (38 C) not associated with a central nervous system (CNS) infection, a known seizure-provoking etiology (eg, electrolyte imbalance, hypoglycemia, or substance abuse), or history of an afebrile seizure. […] The primary febrile seizure risk factors appear to include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress. […] Some experts believe that either an underlying neurologic abnormality or the effect of a febrile seizure on a developing nervous system predisposes patients toward a seizure disorder. […] The exact pathophysiology of febrile seizures is not understood fully, but there is a recognized complex genetic predisposition, immaturity and vulnerability of the central nervous system, and various environmental factors. […] As a result of these various risk factors, the immature brain, with fever-enhanced neuronal excitation, is more susceptible to seizures and is one explanation as to why they occur more commonly in those younger than 3.

• #31 Febrile seizure – Wikipedia

  https://en.wikipedia.org/wiki/Febrile_seizure

  Febrile seizures are triggered by fever, typically due to a viral infection. […] The underlying mechanism is not fully known, but it is thought to involve genetics, environmental factors, brain immaturity, and inflammatory mediators. […] The exact underlying mechanism of febrile seizures is still unknown, but it is thought to be multi-factorial involving genetic and environmental factors. […] Speculation includes immaturity of the central nervous system at younger ages, making the brain more vulnerable to the effects of fever. […] Other proposed mechanisms include the interactions of inflammatory mediators, particularly cytokines, which are released during a fever, causing elevated temperatures in the brain, which may somehow lead to a seizure.

• #32 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #33 Febrile Seizures: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/801500-overview

  Febrile seizures occur in young children at a time in their development when the seizure threshold is low. […] Animal studies suggest a possible role of endogenous pyrogens, such as interleukin 1beta, that, by increasing neuronal excitability, may link fever and seizure activity. […] Preliminary studies in children appear to support the hypothesis that the cytokine network is activated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathological significance of these observations is not yet clear. […] Whereas polygenic inheritance is likely, a small number of families are identified with an autosomal dominant pattern of inheritance of febrile seizures, leading to the description of a „febrile seizure susceptibility trait” with an autosomal dominant pattern of inheritance with reduced penetrance. […] Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma amino-butyric acid A receptor.

• #34 Febrile Seizures: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/801500-overview

  Febrile seizures occur in young children at a time in their development when the seizure threshold is low. […] Animal studies suggest a possible role of endogenous pyrogens, such as interleukin 1beta, that, by increasing neuronal excitability, may link fever and seizure activity. […] Preliminary studies in children appear to support the hypothesis that the cytokine network is activated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathological significance of these observations is not yet clear. […] Whereas polygenic inheritance is likely, a small number of families are identified with an autosomal dominant pattern of inheritance of febrile seizures, leading to the description of a „febrile seizure susceptibility trait” with an autosomal dominant pattern of inheritance with reduced penetrance. […] Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma amino-butyric acid A receptor.

• #35 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #36

  https://journals.lww.com/cmrp/fulltext/2021/06040/role_of_scn1a,_gabra1,_and_gabra2_in_pathogenesis.10.aspx

  The commonest seizure disorder in childhood are febrile seizures (FS). The aim of the study was to show the role of some genes (SCN1A, GABRA1, and GABRA2) in pathogenesis of the development of febrile convulsions. […] FS is believed to occur due to the susceptibility of either the developing or immature brain to be affected by fever in association with genetic and environmental factors. […] The genetic predisposition to FSs can be mediated either through autosomal-dominant inheritance with reduced penetrance or multifactorial/polygenic factors. […] The most commonly involved genes are SCNIA, IL-1, CHRNA4, and GABRG2. […] There are several genetic loci responsible for increased risk of febrile convulsion and they include 1q31, 2q2334, 3p24, 3q26, 5q1415, 5q34, 6q2224, 8q1321, 18p11, 19p13, 19q, and 21q22.

• #37 Generalized epilepsy with febrile seizures plus – Wikipedia

  https://en.wikipedia.org/wiki/Generalized_epilepsy_with_febrile_seizures_plus

  A second subtype of GEFS+, type 2, is the result of mutations in SCN1A, a gene encoding a sodium channel subunit. […] Most of the functional mutant channels result in hyperexcitability due to decreased frequency dependent rundown. […] Patients with GEFS+ type 3 have mutations in the GABRG2 gene, which encodes the GABAA 2 subunit. […] This abnormal current is not the result of non-incorporation of mutant subunits since mutant containing receptors are still sensitive to benzodiazepines, a property for which functional subunits are required. […] As with the previous mutation, this mutation is expected to result in neuronal hyperexcitability. […] The final type of GEFS+ is caused by mutations in the SCN2A gene, which encodes a sodium channel subunit. […] Electrophysiological examination of this mutant revealed that it increases the time constant for inactivation, presumably increasing sodium current and leading to hyperexcitability.

• #38 Generalized epilepsy with febrile seizures plus – Wikipedia

  https://en.wikipedia.org/wiki/Generalized_epilepsy_with_febrile_seizures_plus

  Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. […] Known causative gene mutations are in the sodium channel subunit genes SCN1A, an associated subunit SCN1B, and in a GABAA receptor subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. […] GEFS+ type 1 is a subtype of GEFS+ in which there are mutations in SCN1B, a gene encoding a sodium channel subunit. […] The subunit is required for proper channel inactivation. […] Coexpression of SCN1B with sodium channel subunits in oocytes and other cells results in channels that inactivate more slowly. […] Further investigation of this mutation has indicated that it results in decreased frequency dependent rundown and, thus, likely hyperexcitability when compared to cells expressing the wild-type subunit.

• #39 GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05387-1

  Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait. […] GEFS+ exhibits significant genetic heterogeneity, with polymerase chain reaction, exon sequencing, and single nucleotide polymorphism analyses all showing that the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene. The most common mutations in GABRG2 are separated in large autosomal dominant families, but their pathogenesis remains unclear. […] All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy.

• #40 GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05387-1

  These mutations may further alter GABAAR expression, gating, and/or trafficking on the cell surface. […] All pathophysiological mechanisms that lead to reduced GABA-evoked currents in neurons can cause neuronal disinhibition and predispose affected patients to manifest seizures. […] The pathological mechanism is complex, including fever, inflammatory mediators, and genetic susceptibility, among which changes in genetic susceptibility factors and corresponding molecules are the most important causes of the disease. […] Although mutations or polymorphisms of these genes are related to the pathogenesis of GEFS+, the pathogenesis of GEFS+ has not yet been elucidated. […] Each mutation is linked to a different GABRG2 protein synthesis disorders through different molecular mechanisms as detailed below in Table 2.

• #41 New mechanism for febrile seizures in young children discovered | Technology Networks

  https://www.technologynetworks.com/neuroscience/news/new-mechanism-febrile-seizures-young-children-discovered-282646

  Febrile seizures are among the most dreaded complications of infectious diseases in small children. An international research team composed of experts from the Universities of Tbingen, Leuven and Luxembourg has now made a breakthrough by demonstrating the existence of a previously unknown cause for this most frequent form of epileptic attacks in small children. […] As a study just published in the medical journal Nature Genetics shows, mutations in the STX1B gene are responsible for the children’s pathological reactions to fever. The gene mutations lead to an impaired regulation in the release of certain nerve cell messenger substances. The consequence of this is an increase of involuntary electrical discharges in the brain, accompanied by epileptic febrile seizures. […] The factors which contribute to the development of epilepsy from simple febrile seizures are still largely unknown. „Genetic predisposition plays an important role. But up to now there has been an inadequate understanding of which genomic mutations are involved in detail,” says the study’s co-initiator, Professor Yvonne Weber, M.D., Assistant Medical Director of the Department of Neurology and Epileptology at the University of Tbingen.

• #42 New mechanism for febrile seizures in young children discovered | ScienceDaily

  https://www.sciencedaily.com/releases/2014/11/141102160006.htm

  The STX1B mutations gave us an important clue: they do more than trigger epileptic febrile seizures, which of themselves often subside in these small patients by the time of the first school year; the mutations may also be the cause of serious cases of epilepsy, with consequent impairment of intellectual development. […] Together with experts in the field of zebrafish research from the University of Leuven, Belgium and the University of Luxembourg’s Centre for Systems Biomedicine (LCSB), the neuroscientists were able to confirm the impact of the newly discovered STX1B mutations with the aid of a model system. […] We were able to show not only that similar patterns of epileptiform attacks also occur in zebrafish with genetically altered STX1B genes, but also that brainwave changes appeared which were clearly aggravated by hyperthermia — as in the case of fever.

• #43 Discovery of genetic variants linked to febrile seizures

  https://en.ssi.dk/news/news/2022/discovery-of-genetic-variants-linked-to-febrile-seizures

  The study identified seven new gene regions robustly linked to increased risk of developing febrile seizures. […] Two of the new regions contained genes of major importance in the development of fevers in mammals. […] We hypothesize that genetic changes that affect the way the PTGER3 and IL10 genes function may lead to a more pronounced fever response, which in turn could increase the susceptibility of children to febrile seizures. […] The link between febrile seizures and epilepsy has been known for years but its genetic underpinnings are only now emerging. […] GABRG2 is increasingly recognized as an important gene for epilepsy and this new clear link to febrile seizures is another important piece in this puzzle. […] Understanding the genetic similarities and differences between febrile seizures and epilepsies is a fascinating area of research that we plan to investigate in future studies.

• #44 Febrile Seizure – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448123/

  Febrile seizures are generalized seizures, typically in children between the ages of 6 months and 5 years, that occur with a fever greater than 100.4 F (38 C) not associated with a central nervous system (CNS) infection, a known seizure-provoking etiology (eg, electrolyte imbalance, hypoglycemia, or substance abuse), or history of an afebrile seizure. […] The primary febrile seizure risk factors appear to include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress. […] Some experts believe that either an underlying neurologic abnormality or the effect of a febrile seizure on a developing nervous system predisposes patients toward a seizure disorder. […] The exact pathophysiology of febrile seizures is not understood fully, but there is a recognized complex genetic predisposition, immaturity and vulnerability of the central nervous system, and various environmental factors. […] As a result of these various risk factors, the immature brain, with fever-enhanced neuronal excitation, is more susceptible to seizures and is one explanation as to why they occur more commonly in those younger than 3.

• #45 Febrile seizure – Wikipedia

  https://en.wikipedia.org/wiki/Febrile_seizure

  Febrile seizures are triggered by fever, typically due to a viral infection. […] The underlying mechanism is not fully known, but it is thought to involve genetics, environmental factors, brain immaturity, and inflammatory mediators. […] The exact underlying mechanism of febrile seizures is still unknown, but it is thought to be multi-factorial involving genetic and environmental factors. […] Speculation includes immaturity of the central nervous system at younger ages, making the brain more vulnerable to the effects of fever. […] Other proposed mechanisms include the interactions of inflammatory mediators, particularly cytokines, which are released during a fever, causing elevated temperatures in the brain, which may somehow lead to a seizure.

• #46 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #47 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #48 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #49 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #50 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #51 Febrile Seizures – TeachMePaediatrics

  https://teachmepaediatrics.com/emergency/emergency-medicine/febrile-seizures/

  The specific cause a febrile seizure is unknown. It is generally believed to be multifactorial with a combination of predisposing genetic and environmental factors. […] One theory is that it is a reaction of the developing brain to a fever. As the child’s brain develops there is an increase in neuronal excitability, and it is thought that this increased excitability, in combination with environmental factors, makes the child more prone to a seizure. […] In one third of cases, there is a positive family history in either or both parents. Twin studies have shown a predisposing genetic component along with numerous possible loci which are thought to be associated with febrile convulsions. However, a single susceptibility gene for febrile seizures has not yet been identified. […] Viral infections are associated and triggering factors in 80% of febrile convulsion cases. The most common causes include upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), otitis media, and urinary tract infections (UTI). Gastroenteritis and fever post-vaccination are also associated, but are not as common.

• #52 Febrile seizure – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/febrile-seizure/symptoms-causes/syc-20372522

  A febrile seizure is a convulsion in a child that’s caused by a fever. The fever is often from an infection. Febrile seizures occur in young, healthy children who have normal development and haven’t had any neurological symptoms before. […] The fevers that trigger febrile seizures are usually caused by a viral infection, and less commonly by a bacterial infection. The flu (influenza) virus and the virus that causes roseola, which often are accompanied by high fevers, appear to be most frequently associated with febrile seizures. […] Most febrile seizures produce no lasting effects. Simple febrile seizures don’t cause brain damage, intellectual disability or learning disabilities, and they don’t mean your child has a more serious underlying disorder. […] Febrile seizures are provoked seizures and don’t indicate epilepsy. Epilepsy is a condition characterized by recurrent unprovoked seizures caused by abnormal electrical signals in the brain.

• #53 Environmental Factors Associated with Febrile Seizures | Pediatric Neurology Briefs

  https://pediatricneurologybriefs.com/articles/10.15844/pedneurbriefs-28-5-4

  Investigators from Taichung, Taiwan, conducted a nationwide population-based retrospective study of the association between febrile seizure (FS) and allergic rhinitis. […] COMMENTARY. Fever and height of the body temperature as a measure of the FS threshold have an essential role in the mechanism of the FS. The cause of fever is almost always viral, most frequently HHV-6 in the United States and influenza in Japan. Some viruses have neurotropic properties, leading to the theory of a transient encephalitic or encephalopathic process in some cases. Additional factors involved in the mechanism of the FS include a genetic susceptibility, age and maturation, and cytokine and immune response to infection. […] Allergies and immune reactions are proposed as factors in the etiology of FS. […] A significant association between proinflammatory cytokine, IL-1B, and both ADHD and FS may be a link in the mechanism of these disorders.

• #54 Febrile seizures | MedLink Neurology

  https://www.medlink.com/articles/febrile-seizures

  Animal models have demonstrated hyperthermia-induced changes in expression of hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN). […] An autosomal dominantly inherited variant in the gamma-2 subunit of GABAA receptors (also known as GABRG2) has been associated in vitro with decreased receptor trafficking and endocytosis in the setting of fever—a property that is not seen with the wild-type receptors. […] Case-control studies have shown decreased serum zinc levels in patients with febrile seizures, whereas a controlled study in Bangladesh found depressed zinc levels in both serum and cerebrospinal fluid among children with febrile seizures compared to febrile controls without seizures. […] In the case of HHV-6, it is postulated that direct viral invasion of the brain, when combined with fever, causes the initial febrile seizure and that the virus might be reactivated by fever during subsequent illnesses, causing recurrent febrile seizures.

• #55 Clinical review of febrile seizure and updates – Karnataka Paediatric Journal

  https://iap-kpj.org/clinical-review-of-febrile-seizure-and-updates/

  Perinatal stress and exposure to nicotine and/or alcohol may potentiate FS due to increase in cortisol level in the offspring. Approximately 80% of cases of FS are related with viral infection and the most frequent infections are middle ear infections, tonsillitis, sinusitis, pneumonia, bronchiolitis, tooth infections, and gastroenteritis.

• #56 Do Vaccines Cause Seizures? – Institute for Vaccine Safety

  https://www.vaccinesafety.edu/do-vaccines-cause-seizures/

  Fever is associated with febrile seizures in infants. […] However, all vaccines that cause fever in young children also have a small inherent risk of causing febrile seizures. […] The pathogenesis may be explained by alteration of brain ion channel function due to change in temperature, modification of neuronal excitability or fever-induced respiratory alkalosis. […] Studies have shown that genetic susceptibility plays an important role in the pathogenesis of febrile seizures, and various loci have been mapped on different chromosomes in individuals with febrile seizures.

• #57 Febrile seizures | MedLink Neurology

  https://www.medlink.com/articles/febrile-seizures

  Animal models have demonstrated hyperthermia-induced changes in expression of hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN). […] An autosomal dominantly inherited variant in the gamma-2 subunit of GABAA receptors (also known as GABRG2) has been associated in vitro with decreased receptor trafficking and endocytosis in the setting of fever—a property that is not seen with the wild-type receptors. […] Case-control studies have shown decreased serum zinc levels in patients with febrile seizures, whereas a controlled study in Bangladesh found depressed zinc levels in both serum and cerebrospinal fluid among children with febrile seizures compared to febrile controls without seizures. […] In the case of HHV-6, it is postulated that direct viral invasion of the brain, when combined with fever, causes the initial febrile seizure and that the virus might be reactivated by fever during subsequent illnesses, causing recurrent febrile seizures.

• #58 Analysis of cytokines and trace elements in children with febrile seizures – Chen – Translational Pediatrics

  https://tp.amegroups.org/article/view/58986/html

  Febrile seizure (FS) is a common neurological condition in children and affects 25% of cases of fever. FS occurs with temperature 38 C without symptoms of central nervous system infection, severe electrolyte imbalance, or clear cause. […] At present, the pathogenesis of FS is not fully understood, but is generally believed to be related to multiple factors such as genetic factors, infection, inflammatory factors, and trace elements. Cytokines also play a very important role. Studies show that tumor necrosis factor-alpha (TNF-), interleukin (IL)-1, IL-6 and other pro-inflammatory factors are closely related to FS in children. When the levels of TNF- and IL-6 increase, the risk of FS increases, and the probability of recurrence increases accordingly. […] Our study found that the SC and SI levels of children in the FS group were significantly lower than in the two control groups, and we also found that during FS, the blood calcium level of children with CFS was lower than that of children with SFS, with a statistically significant difference, suggesting that hypocalcemia may be one of the causes of multiple seizures in the same febrile course.

• #59 Pathogenetic and etiologic considerations of febrile seizures

  https://e-cep.org/journal/view.php?number=20125555595

  The pathogenesis of FS seems theoretical and hypothetical. The neuro-immune network plays a crucial role in the pathogenesis of febrile seizures, where cytokines increase neuronal excitability and provoke seizures in the absence of direct CNS invasion of pathogens, disruptive BBB changes, and definite brain parenchymal inflammation. […] The pathogenesis of FS is multifactorial and heterogeneous. There are no consistent and definite results regarding the connection between systemic or local inflammation and the CNS or on the mechanisms for increasing neuronal excitability in the CNS during fever.

• #60 Pathogenetic and etiologic considerations of febrile seizures

  https://e-cep.org/journal/view.php?number=20125555595

  Febrile seizure (FS), which occurs in febrile children without underlying health problems, is the most common type of seizure disorder in children. The suggested pathogenesis of FS derived from several animal and human studies is multifactorial and debatable. Neuronal hyperexcitability, which develops during inflammatory responses that accompany fever, provokes seizures. However, the exact role of each inflammatory mediator (e.g., cytokines) is undefined in terms of the connection between systemic or local inflammation and the central nervous system, and the mechanisms by which cytokines increase neuronal excitability remain unclear. […] In the vulnerable immature CNS, increased neuronal excitability promotes seizures, and cytokines produced and released during acute inflammatory responses accompanying fever play a role in increasing neuronal excitability. Inflammatory responses outside the CNS increase cytokine concentrations in the CNS (neuro-immune network), and the released cytokines trigger neuronal hyperexcitability in the CNS (cytokine roles in the brain parenchyma) to generate FS. This concept can be applied to the generation of afebrile seizures or epilepsy accompanied by various types of inflammation with non-infectious causes, including trauma, toxic injury, hypoxic injury, and autoimmune reactions.

• #61 Exploring the Role of Inflammatory Cytokines and Oxidative Stress in Febrile Seizure Pathogenesis: A Case-Control Study in Mumbai, India | Scientific Journal of Pediatrics

  https://phlox.or.id/index.php/sjped/article/view/66

  Febrile seizures (FS) are the most common childhood seizure disorder, often causing parental anxiety and posing a challenge for healthcare professionals. While the exact pathogenesis remains unclear, recent research suggests a complex interplay of genetic predisposition, fever, and inflammatory processes. […] This study provides evidence for the involvement of inflammatory cytokines and oxidative stress in FS pathogenesis. Elevated pro-inflammatory cytokines and oxidative stress markers, coupled with decreased anti-inflammatory cytokine levels, suggest a dysregulated inflammatory response and impaired antioxidant defense mechanism in children with FS.

• #62 Febrile Seizures and Mechanisms of Epileptogenesis: Insights from an Animal Model | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4757-6376-8_15

  Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. […] Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20-60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. […] Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. […] The contribution of these consequences of febrile seizures to the epileptogenic process is discussed.

• #63 Febrile Seizures and Mechanisms of Epileptogenesis: Insights from an Animal Model | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4757-6376-8_15

  Temporal lobe epilepsy (TLE) is the most prevalent type of human epilepsy, yet the causes for its development, and the processes involved, are not known. […] Among suspected etiologies, febrile seizures have frequently been cited. This is due to the fact that retrospective analyses of adults with TLE have demonstrated a high prevalence (20-60%) of a history of prolonged febrile seizures during early childhood, suggesting an etiological role for these seizures in the development of TLE. Specifically, neuronal damage induced by febrile seizures has been suggested as a mechanism for the development of mesial temporal sclerosis, the pathological hallmark of TLE. […] Neuroanatomical, molecular and functional methods have been used in this model to determine the consequences of prolonged febrile seizures on the survival and integrity of neurons, and on hyperexcitability in the hippocampal-limbic network. […] The contribution of these consequences of febrile seizures to the epileptogenic process is discussed.

• #64 Febrile Seizures | AAFP

  https://www.aafp.org/pubs/afp/issues/2008/1115/p1199.html

  Febrile seizures are defined as events in infancy or childhood that usually occur between three months and five years of age and are associated with a fever, but without evidence of intracranial infection or a defined cause for the seizure. […] Although the exact cause of simple febrile seizures is unknown, it is thought to be multifactorial, with genetic and environmental factors having been shown to contribute to its pathogenesis. […] Increasingly, a genetic predisposition is recognized, with febrile seizures occurring in families. […] Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma-aminobutyric acid A receptor. […] The risk of developing epilepsy is increased in children with a history of complex febrile seizures. A strong association exists between febrile status epilepticus or febrile seizures characterized by focal symptoms and later development of temporal lobe epilepsy.

• #65 New mechanism for febrile seizures in young children discovered | Technology Networks

  https://www.technologynetworks.com/neuroscience/news/new-mechanism-febrile-seizures-young-children-discovered-282646

  Febrile seizures are among the most dreaded complications of infectious diseases in small children. An international research team composed of experts from the Universities of Tbingen, Leuven and Luxembourg has now made a breakthrough by demonstrating the existence of a previously unknown cause for this most frequent form of epileptic attacks in small children. […] As a study just published in the medical journal Nature Genetics shows, mutations in the STX1B gene are responsible for the children’s pathological reactions to fever. The gene mutations lead to an impaired regulation in the release of certain nerve cell messenger substances. The consequence of this is an increase of involuntary electrical discharges in the brain, accompanied by epileptic febrile seizures. […] The factors which contribute to the development of epilepsy from simple febrile seizures are still largely unknown. „Genetic predisposition plays an important role. But up to now there has been an inadequate understanding of which genomic mutations are involved in detail,” says the study’s co-initiator, Professor Yvonne Weber, M.D., Assistant Medical Director of the Department of Neurology and Epileptology at the University of Tbingen.

• #66 New Therapy for Fever-Induced Seizures in Children Targets Calcium Channels – News Center

  https://news.feinberg.northwestern.edu/2013/06/12/martina_toddler_seizures/

  The results were striking: nimodipine dramatically reduced both the incidence and duration of febrile seizures in rat pups. […] Therefore, if proven effective in clinical trials, this could be an important advance in clinical care. […] Because L-type calcium channel blockers such as nimodipine are safe drugs, every toddler with febrile seizures can potentially be treated to stop or prevent seizures triggered by high fever and reduce the risk of long-term neurological consequences of uncontrolled recurrent or prolonged febrile seizures. […] Sookyong Koh, MD, PhD, associate professor in pediatricsneurology at Feinberg, and co-author on the paper, adds that these findings could be helpful for one group of children in particular: those with genetic epilepsy syndromes whose seizures are triggered by fever, and for whom most anticonvulsants acting on sodium channels are harmful.

• #67 Relation between IL-1 β and IL1-ra in Pathogenesis of Febrile Convulsions

  https://ejhm.journals.ekb.eg/article_14999.html

  febrile seizures are the most common form of childhood seizures. […] The cytokine network may contribute to the generation of febrile seizures in children. Interleukin beta (IL-1 ) and Interleukin receptor antagonist (IL-1ra) have been implicated in the pathogenesis of febrile seizures. […] serum IL-1 and IL-1ra levels were significantly higher in febrile seizure patients than in fever in controls. […] Our study suggest that the inflammatory cytokine may play role in the generation of febrile seizures in children. […] These information may allow the development of anti-inflammatory therapy targeting these cytokines to prevent febrile seizures or subsequent epileptogenesis.

• #68 New mechanism for febrile seizures in young children discovered | Technology Networks

  https://www.technologynetworks.com/neuroscience/news/new-mechanism-febrile-seizures-young-children-discovered-282646

  „In other words, the STX1B mutations gave us an important clue: they do more than trigger epileptic febrile seizures, which of themselves often subside in these small patients by the time of the first school year; the mutations may also be the cause of serious cases of epilepsy, with consequent impairment of intellectual development”, as Lerche explains. […] Together with experts in the field of zebrafish research from the University of Leuven, Belgium and the University of Luxembourg’s Centre for Systems Biomedicine (LCSB), the neuroscientists were able to confirm the impact of the newly discovered STX1B mutations with the aid of a model system. […] „We were able to show not only that similar patterns of epileptiform attacks also occur in zebrafish with genetically altered STX1B genes, but also that brainwave changes appeared which were clearly aggravated by hyperthermia – as in the case of fever,” says Dr. Camila Esguerra, the principal investigator who led this part of the study at the University of Leuven and is now in the process of forming a new research team at the University of Oslo, Norway. […] „We hope that from this we will be able to develop a new drug in a few years which will prevent the development of certain forms of serious epilepsy in childhood,” says Crawford.

• #69 Inflammatory Biomarkers in Febrile Seizure: A Comprehensive Bibliometric, Review and Visualization Analysis

  https://www.mdpi.com/2076-3425/11/8/1077

  However, the key interleukin involved in febrile seizures pathogenesis was IL-1β. HMGB1, IL-6, TNF-α positively correlated with elevated levels with IL-1β. […] The bibliometric analysis provided little evidence of studies related to common inflammatory biomarkers sensitivity and specificity in febrile seizures (e.g., total leukocytes count, neutrophils, lymphocytes and monocytes count). However, inflammatory indices, such as NLR, PLT, the NLT/PLT ratio, MPV, and RDW, seem to be useful biomarkers in this respect. These indices are easier and less expensive to evaluate in clinical practice than cytokines. […] Recent research papers explore this possibility. It seems that NLR and MPV might synergistically determine the FS occurrence.

• #70 Association between high-mobility group box 1 levels and febrile seizures in children: a systematic review and meta-analysis | Scientific Reports

  https://www.nature.com/articles/s41598-023-30713-w

  The relationship between High-mobility group box 1 (HMGB1) and febrile seizures (FS) in children remains unclear. […] Meta-analysis showed that the children with FS had significantly higher HMGB1 levels compared with healthy children and children with fever but no seizures. […] The level of HMGB1 may be implicated in the prolongation, recurrence and development of FS in children. […] In addition, there are no effective means to predict and intervene in febrile seizures into epilepsy. […] Some studies believe that fever is a normal response to infection, and releasing high levels of cytokines during fever may change normal brain activity and cause seizures. […] Furthermore, the level of HMGB1 in children with FS was higher than that in healthy control children, suggesting that fever or seizure or both of them caused the increase of HMGB1 level in children with FS.

• #71 Association between high-mobility group box 1 levels and febrile seizures in children: a systematic review and meta-analysis | Scientific Reports

  https://www.nature.com/articles/s41598-023-30713-w

  In a comprehensive analysis, the level of HMGB1 in children with FS was significantly higher than that in children with FN, which could be considered as an important cytokine mediator in the pathogenesis of FS in children, and it had the ability to distinguish whether there is seizure or not. […] However, the exact mechanism of the relationship between the HMGB1 level and the development of FS still needs to be fully understood. […] We speculate that HMGB1 may play a regulatory role that it indirectly participated in the mechanism of glutamat-ergic and GABA-ergic neurotransmission disorders and fever-mediated febrile seizure during inflammation by increasing the expression of IL-1 and other proinflammatory cytokines. […] The level of HMGB1 in children with complex FS is higher than that in children with simple FS, and that in children with FS with convulsion duration 15 min is higher than that in children with seizure duration 15 min, indicating that high level of serum HMGB1 is positively correlated with the duration of febrile seizure in children, and children with high level of HMGB1 are more prone to complex FS.

• #72 Aetiology of febrile seizures – a problem not fully understood – Pediatria i Medycyna Rodzinna

  https://pimr.pl/index.php/issues/2021-vol-17-no-2/aetiology-of-febrile-seizures-a-problem-not-fully-understood

  Febrile seizures are seizures that occur during febrile illnesses in the absence of central nervous system infection or other identifiable aetiology in children who have never had any non-febrile seizures before. […] the underlying pathomechanism is not fully explained. Immaturity of the nervous system, as well as environmental, genetic and immune factors are contemplated. […] The association between febrile seizures and vitamin D levels was reported in only few studies. […] Further research may not only contribute to a better understanding of the mechanisms underlying the pathogenesis of febrile seizures, but also determine the direction of actions that may reduce the risk of their occurrence and/or recurrence.

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