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Epileptogenesis

December 31, 2022

Epileptogenesis is the gradual process by which a typical brain develops epilepsy.[1] Epilepsy is a chronic condition in which seizures occur.[2] These changes to the brain occasionally cause neurons to fire in an abnormal, hypersynchronous manner, known as a seizure.[3]

Epileptogenesis is a chronic disorder.[4] Genetic factors are the most triggering factor.[4] The treatment is difficult to find.[4] There is almost no therapy available for epileptogenesis patients.[4] In epileptogenesis, a normal brain is transformed into an epileptic brain and generates spontaneous seizures.[5] Epileptogenesis is the process by which brain injury leads to chronic epilepsy.[5] Epileptogenesis can be triggered by both acquired as well as genetic factors.[6] Previously, epileptogenesis was considered to be represented by the latent period, but recently, based on clinical observations, epileptogenesis is now considered to extend beyond the latent period.[6] The procedure of epileptogenesis typically happens in three phases:[7] first, the occurrence event, second, a ‘latent’ period and third, chronic conventional epilepsy.[7] In recent studies, it has been finding out that mTOR and REST pathways are responsible for temporal lobe epileptogenesis.[7] The original mechanisms of epileptogenesis are debatable.[8] There is not a singular mechanism that applies to all epilepsy syndromes.[8] It can be brought by an “epilepsy gene”, long-lasting neurodegenerative illnesses, or different kinds of acute brain insults.[9] Brain pathologies that are associated with Epileptogenesis are microgliosis, astrocytosis, neuronal cell death; chronic axonal changes, etc.[9] Epileptogenesis refers to the expansion of tissue that causes repeated unprovoked seizures leading to the development of an epileptic situation.[10] The frequency of seizures and epilepsies is comparatively more throughout the neonatal and infantile periods.[10] Certain conditions, like cell loss due to seizure, and metabolic and genetic changes, lead to epileptogenesis.[10] Epileptogenesis is also the development of epileptic indications in some forms of epilepsy after the preliminary seizures occur.[11] To prevent epilepsy, studies are aimed to identify the important neuronal mechanisms of epileptogenesis in diverse types of epilepsy.[11] Then the abort or reverse of the procedure is denoted as antiepileptogenesis.[11] Antiepileptogenesis can lead to complete prevention which stops the development of epilepsy.[11] It can also prevent partially which delays in the progress of epilepsy or lessens its severity.[11]

Causes

The causes of epilepsy are broadly classified as genetic, structural/metabolic, or unknown.[12] Anything that causes epilepsy causes epileptogenesis, because epileptogenesis is the process of developing epilepsy. Structural causes of epilepsy include neurodegenerative diseases, traumatic brain injury, stroke, brain tumor, infections of the central nervous system, and status epilepticus (a prolonged seizure or a series of seizures occurring in quick succession).[13]

Latent period

After a brain injury occurs, there is frequently a "silent" or "latent period" lasting months or years in which seizures do not occur;[14] Canadian neurosurgeon Wilder Penfield called this time between injury and seizure "a silent period of strange ripening".[15] During this latent period, changes in the physiology of the brain result in the development of epilepsy.[14] This process, during which hyperexcitable neural networks form, is referred to as epileptogenesis.[14] If researchers come to better understand epileptogenesis, the latent period may allow healthcare providers to interfere with the development of epilepsy or to reduce its severity.[14]

Pathophysiology

Changes that occur during epileptogenesis are poorly understood but are thought to include cell death, axonal sprouting, reorganization of neural networks, alterations in the release of neurotransmitters, and neurogenesis.[13] These changes cause neurons to become hyperexcitable and can lead to spontaneous seizures.[13]

Brain regions that are highly sensitive to insults and can cause epileptogenesis include temporal lobe structures such as the hippocampus, the amygdala, and the piriform cortex.[14]

Neural reorganization

In addition to chemical processes, the physical structure of neurons in the brain may be altered. In acquired epilepsy in both humans and animal models, pyramidal neurons are lost, and new synapses are formed.[3]

Hyperexcitability, a characteristic feature of epileptogenesis in which the likelihood that neural networks will be activated is increased, may be due to loss of inhibitory neurons, such as GABAergic interneurons, that would normally balance out the excitability of other neurons.[3] Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons (those that usually increase excitation) and GABAergic ones (those that decrease it).[14] In addition, the levels of GABA and the sensitivity of GABAA receptors to the neurotransmitter may decrease, resulting in less inhibition.[3]

Another proposed mechanism for epileptogenesis in TBI is that damage to white matter causes hyperexcitability by effectively undercutting the cerebral cortex.[16]

Glutamate receptor activation

It is believed that activation of biochemical receptors on the surfaces of neurons is involved in epileptogenesis; these include the TrkB neurotrophin receptor and both ionotropic glutamate receptors and metabotropic glutamate receptors (those that are directly linked to an ion channel and those that are not, respectively).[2] Each of these types of receptor may, when activated, cause an increase in the concentration of calcium ions (Ca2+) within the area of the cell on which the receptors are located, and this Ca2+ can activate enzymes such as Src and Fyn that may lead to epileptogenesis.[2]

Excessive release of the neurotransmitter glutamate is widely recognized as an important part of epileptogenesis early after a brain injury, including in humans.[14] Excessive release of glutamate results in excitotoxicity, in which neurons are excessively depolarized, intracellular Ca2+ concentrations increase sharply, and cellular damage or death results.[14] Excessive glutamatergic activity is also a feature of neuronal circuits after epilepsy has developed, but glutamate does not appear to play an important role in epileptogenesis during the latent period.[14] Another factor in hyperexcitability may include a decrease in the concentration of Ca2+ outside cells (i.e. in the extracellular space) and a decrease in the activity of ATPase in glial cells.[3]

Blood brain barrier disruption

Blood brain barrier (BBB) disruption occurs in high prevalence following all brain lesions that may cause post injury epilepsy such as stroke, traumatic brain injury, brain infection or brain tumor.[17] BBB disruption was shown to underlay epileptogenesis by several experimental models.[18][19] Furthermore, it was shown that albumin, the most frequent protein in the serum is the agent that leaks from the blood into the brain parenchyma under BBB disruption conditions and induces epileptogenesis by activation of the transforming growth factor beta receptor on astrocytes.[20][21][22] Additional investigation exposed that this process is mediated by a unique inflammatory pattern [21][23] and the formation of excitatory synapses.[24] Pathogenic influence was attributed also to the extravasation of other blood born substances such as hemosiderin or iron.[16] Iron from hemoglobin, a molecule in red blood cells, can lead to the formation of free radicals that damage cell membranes; this process has been linked to epileptogenesis.[25]

Treatment

A major goal of epilepsy research is the identification of therapies to interrupt or reverse epileptogenesis. Studies largely in animal models have suggested a wide variety of possible antiepileptogenic strategies although, to date, no such therapy has been demonstrated to be antiepileptogenic in clinical trials.[26] Some anticonvulsant drugs, including levetiracetam and ethosuximide have shown promising activity in animal models. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin (mTOR) by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. The discovery of the role played by TGF-beta activation in epileptogenesis raised the hypothesis that blocking this signaling may prevent epileptogenesis. Losartan, a commonly used drug for the treatment of hypertension was shown to prevent epilepsy and facilitate BBB healing in animal models. Testing the potential of antiepileptogenic agents (e.g. losartan) or BBB healing drugs necessitates biomarkers for patients selection and treatment-followup.[27] BBB disruption imaging was shown capacity in animal model to serve as a biomarker of epileptogenesis [28] and specific EEG patterns were also shown to predict epilepsy in several models.[29]

History

Throughout most of history for which written records exist on the subject, it was probably generally believed that epilepsy came about through a supernatural process.[30] Even within the medical profession, it was not until the 18th century that ideas of epileptogenesis as a supernatural phenomenon were abandoned.[30] However, biological explanations have also long existed, and sometimes explanations contained both biological and supernatural elements.[30]

Research

Epileptogenesis that occurs in human brains has been modeled in a variety of animal models and cell culture models.[2] Epileptogenesis is poorly understood,[14] and increasing understanding of the process may aid researchers in preventing seizures, diagnosing epilepsy,[31] and developing treatments to prevent it.[2]

See also

References

  1. ^ Lukasiuk, K. (2014). "Epileptogenesis". In Aminoff, Michael J; Daroff, Robert B (eds.). Encyclopedia of the Neurological Sciences (Second Edition). Vol. 2 (Second ed.). London: Academic Press. pp. 196–199. ISBN 978-0-12-385157-4.
  2. ^ a b c d e McNamara JO, Huang YZ, Leonard AS (October 2006). "Molecular signaling mechanisms underlying epileptogenesis". Sci. STKE. 2006 (356): re12. doi:10.1126/stke.3562006re12. PMID 17033045. S2CID 42882078.
  3. ^ a b c d e Armijo JA, Valdizán EM, De Las Cuevas I, Cuadrado A (2002). "Advances in the physiopathology of epileptogenesis: Molecular aspects". Rev Neurol (in Spanish). 34 (5): 409–29. PMID 12040510.
  4. ^ a b c d Pitkänen, A; Engel J, Jr (April 2014). "Past and present definitions of epileptogenesis and its biomarkers". Neurotherapeutics. 11 (2): 231–41. doi:10.1007/s13311-014-0257-2. PMC 3996117. PMID 24492975.
  5. ^ a b "Epileptogenesis - an overview | ScienceDirect Topics". www.sciencedirect.com.
  6. ^ a b Pitkänen, A; Lukasiuk, K; Dudek, FE; Staley, KJ (18 September 2015). "Epileptogenesis". Cold Spring Harbor Perspectives in Medicine. 5 (10): a022822. doi:10.1101/cshperspect.a022822. PMC 4588129. PMID 26385090.
  7. ^ a b c Goldberg, EM; Coulter, DA (May 2013). "Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction". Nature Reviews. Neuroscience. 14 (5): 337–49. doi:10.1038/nrn3482. PMC 3982383. PMID 23595016.
  8. ^ a b Goldberg, Ethan M.; Coulter, Douglas A. (May 2013). "Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction". Nature Reviews Neuroscience. 14 (5): 337–349. doi:10.1038/nrn3482. PMC 3982383. PMID 23595016.
  9. ^ a b "Epilepsy and Epileptogenesis". News-Medical.net. 9 September 2019.
  10. ^ a b c Katsarou, AM; Galanopoulou, AS; Moshé, SL (June 2018). "Epileptogenesis in neonatal brain". Seminars in Fetal & Neonatal Medicine. 23 (3): 159–167. doi:10.1016/j.siny.2017.12.004. PMC 6015538. PMID 29467100.
  11. ^ a b c d e Engel J, Jr (March 2019). "Epileptogenesis, traumatic brain injury, and biomarkers". Neurobiology of Disease. 123: 3–7. doi:10.1016/j.nbd.2018.04.002. PMC 6170720. PMID 29625256.
  12. ^ Noebels, Jeffrey L.; Avoli, Massimo (2012-06-29). Jasper's Basic Mechanisms of the Epilepsies. Oxford University Press. p. 3. ISBN 9780199746545. Retrieved 2014-10-16.
  13. ^ a b c Herman ST (January 2006). "Clinical trials for prevention of epileptogenesis". Epilepsy Res. 68 (1): 35–8. doi:10.1016/j.eplepsyres.2005.09.015. PMID 16377141. S2CID 46017678.
  14. ^ a b c d e f g h i j Aroniadou-Anderjaska V, Fritsch B, Qashu F, Braga MF (February 2008). "Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy". Epilepsy Res. 78 (2–3): 102–16. doi:10.1016/j.eplepsyres.2007.11.011. PMC 2272535. PMID 18226499.
  15. ^ "Post-traumatic epilepsy". Br Med J. 2 (6132): 229. 1978. doi:10.1136/bmj.2.6132.229. PMC 1606365. PMID 98198.
  16. ^ a b Firlik KS, Spencer DD (2004). "Surgery of post-traumatic epilepsy". In Dodson WE, Avanzini G, Shorvon SD, Fish DR, Perucca E (eds.). The Treatment of Epilepsy. Oxford: Blackwell Science. p. 775. ISBN 0-632-06046-8. Retrieved 2008-06-09.
  17. ^ Schevon CA, Tobochnik S, Eissa T, Merricks E, Gill B, Parrish RR, Bateman LM, McKhann GM Jr, Emerson RG, Trevelyan AJ (2019). "Multiscale recordings reveal the dynamic spatial structure of human seizures". Neurobiol Dis. 127: 303–311. doi:10.1016/j.nbd.2019.03.015. PMC 6588430. PMID 30898669.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Seiffert E, Dreier JP, Ivens S, Bechmann I, Heinemann U, Friedman A (2004). "Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J". Neuroscience. 24 (36): 7829–36. doi:10.1523/JNEUROSCI.1751-04.2004. PMC 6729929. PMID 15356194.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ van Vliet EA, da Costa Araujo S, Redeker S, van Schaik R, Aronica E, Gorter JA (2007). "Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy". Brain. 130 (2): 521–534. doi:10.1093/brain/awl318. PMID 17124188.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Ivens S, Kaufer D, Seiffert E, Bechmann I, Tomkins O, Heinemann U, Friedman A (2007). "TGF-beta receptor mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis". Brain. 130 (Pt 2): 535–47. doi:10.1093/brain/awl317. PMID 17121744.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ a b Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, Heinemann U, Friedman A, Kaufer D (2009). "Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis". Journal of Neuroscience. 29 (28): 8927–8935. doi:10.1523/JNEUROSCI.0430-09.2009. PMC 2875073. PMID 19605630.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ David Y, Flores LP, Ivens S, Heinemann U, Kaufer D, Friedman A (2009). "Astrocytic dysfunction in epileptogenesis: consequences of altered potassium and glutamate buffering?". Journal of Neuroscience. 29 (34): 10588–99. doi:10.1523/JNEUROSCI.2323-09.2009. PMC 2875068. PMID 19710312.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Levy N, Milikovsky DZ, Baranauskas G, Vinogradov E, David Y, Ketzef M, Abutbul S, Weissberg I, Kamintsky L, Fleidervish I, Friedman A, Monsonego A (2015). "Differential TGF-β Signaling in Glial Subsets Underlies IL-6-Mediated Epileptogenesis in Mice". J Immunol. 195 (4): 1713–22. doi:10.4049/jimmunol.1401446. PMID 26136430.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A, Oppenheim H, Ardizzone C, Becker A, Frigerio F, Vezzani A, Buckwalter MS, Huguenard JR, Friedman A, Kaufer D (2015). "Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction". Neurobiol Dis. 78: 115–25. doi:10.1016/j.nbd.2015.02.029. PMC 4426044. PMID 25836421.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Beghi E (2004). "Aetiology of epilepsy". In Dodson WE, Avanzini G, Shorvon SD, Fish DR, Perucca E (eds.). The Treatment of Epilepsy. Oxford: Blackwell Science. p. 61. ISBN 0-632-06046-8. Retrieved 2008-06-09.
  26. ^ Kaminski, R. M.; Rogawski, M. A.; Klitgaard, H (2014). "The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments". Neurotherapeutics. 11 (2): 385–400. doi:10.1007/s13311-014-0266-1. PMC 3996125. PMID 24671870.
  27. ^ Friedman A, Bar-Klein G, Serlin Y, Parmet Y, Heinemann U, Kaufer D (2014). "Should losartan be administered following brain injury?". Expert Rev Neurother. 14 (12): 1365–75. doi:10.1586/14737175.2014.972945. PMID 25346269. S2CID 207193826.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Bar-Klein G, Lublinsky S, Kamintsky L, Noyman I, Veksler R, Dalipaj H, Senatorov VV Jr, Swissa E, Rosenbach D, Elazary N, Milikovsky DZ, Milk N, Kassirer M, Rosman Y, Serlin Y, Eisenkraft A, Chassidim Y, Parmet Y, Kaufer D, Friedman A (2017). "Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis". Brain. 140 (6): 1692–1705. doi:10.1093/brain/awx073. PMID 28444141.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Milikovsky DZ, Weissberg I, Kamintsky L, Lippmann K, Schefenbauer O, Frigerio F, Rizzi M, Sheintuch L, Zelig D, Ofer J, Vezzani A, Friedman A (2017). "Electrocorticographic Dynamics as a Novel Biomarker in Five Models of Epileptogenesis". J Neurosci. 37 (17): 4450–4461. doi:10.1523/JNEUROSCI.2446-16.2017. PMC 6596657. PMID 28330876.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ a b c Eadie MJ, Bladin PF (2001). "The interpretation of the epileptic process". A Disease Once Sacred: A History of the Medical Understanding of Epilepsy. London: John Libbey. p. 80. ISBN 0-86196-607-4. Retrieved 2008-06-12.
  31. ^ Leśkiewicz M, Lasoń W (2007). "The neurochemical mechanisms of temporal lobe epilepsy: an update". Prz. Lek. (in Polish). 64 (11): 960–4. PMID 18409413.

December 31, 2022
epileptogenesis, gradual, process, which, typical, brain, develops, epilepsy, epilepsy, chronic, condition, which, seizures, occur, these, changes, brain, occasionally, cause, neurons, fire, abnormal, hypersynchronous, manner, known, seizure, chronic, disorder. Epileptogenesis is the gradual process by which a typical brain develops epilepsy 1 Epilepsy is a chronic condition in which seizures occur 2 These changes to the brain occasionally cause neurons to fire in an abnormal hypersynchronous manner known as a seizure 3 Epileptogenesis is a chronic disorder 4 Genetic factors are the most triggering factor 4 The treatment is difficult to find 4 There is almost no therapy available for epileptogenesis patients 4 In epileptogenesis a normal brain is transformed into an epileptic brain and generates spontaneous seizures 5 Epileptogenesis is the process by which brain injury leads to chronic epilepsy 5 Epileptogenesis can be triggered by both acquired as well as genetic factors 6 Previously epileptogenesis was considered to be represented by the latent period but recently based on clinical observations epileptogenesis is now considered to extend beyond the latent period 6 The procedure of epileptogenesis typically happens in three phases 7 first the occurrence event second a latent period and third chronic conventional epilepsy 7 In recent studies it has been finding out that mTOR and REST pathways are responsible for temporal lobe epileptogenesis 7 The original mechanisms of epileptogenesis are debatable 8 There is not a singular mechanism that applies to all epilepsy syndromes 8 It can be brought by an epilepsy gene long lasting neurodegenerative illnesses or different kinds of acute brain insults 9 Brain pathologies that are associated with Epileptogenesis are microgliosis astrocytosis neuronal cell death chronic axonal changes etc 9 Epileptogenesis refers to the expansion of tissue that causes repeated unprovoked seizures leading to the development of an epileptic situation 10 The frequency of seizures and epilepsies is comparatively more throughout the neonatal and infantile periods 10 Certain conditions like cell loss due to seizure and metabolic and genetic changes lead to epileptogenesis 10 Epileptogenesis is also the development of epileptic indications in some forms of epilepsy after the preliminary seizures occur 11 To prevent epilepsy studies are aimed to identify the important neuronal mechanisms of epileptogenesis in diverse types of epilepsy 11 Then the abort or reverse of the procedure is denoted as antiepileptogenesis 11 Antiepileptogenesis can lead to complete prevention which stops the development of epilepsy 11 It can also prevent partially which delays in the progress of epilepsy or lessens its severity 11 Contents 1 Causes 2 Latent period 3 Pathophysiology 3 1 Neural reorganization 3 2 Glutamate receptor activation 3 3 Blood brain barrier disruption 4 Treatment 5 History 6 Research 7 See also 8 ReferencesCauses EditThe causes of epilepsy are broadly classified as genetic structural metabolic or unknown 12 Anything that causes epilepsy causes epileptogenesis because epileptogenesis is the process of developing epilepsy Structural causes of epilepsy include neurodegenerative diseases traumatic brain injury stroke brain tumor infections of the central nervous system and status epilepticus a prolonged seizure or a series of seizures occurring in quick succession 13 Latent period EditAfter a brain injury occurs there is frequently a silent or latent period lasting months or years in which seizures do not occur 14 Canadian neurosurgeon Wilder Penfield called this time between injury and seizure a silent period of strange ripening 15 During this latent period changes in the physiology of the brain result in the development of epilepsy 14 This process during which hyperexcitable neural networks form is referred to as epileptogenesis 14 If researchers come to better understand epileptogenesis the latent period may allow healthcare providers to interfere with the development of epilepsy or to reduce its severity 14 Pathophysiology EditChanges that occur during epileptogenesis are poorly understood but are thought to include cell death axonal sprouting reorganization of neural networks alterations in the release of neurotransmitters and neurogenesis 13 These changes cause neurons to become hyperexcitable and can lead to spontaneous seizures 13 Brain regions that are highly sensitive to insults and can cause epileptogenesis include temporal lobe structures such as the hippocampus the amygdala and the piriform cortex 14 Neural reorganization Edit In addition to chemical processes the physical structure of neurons in the brain may be altered In acquired epilepsy in both humans and animal models pyramidal neurons are lost and new synapses are formed 3 Hyperexcitability a characteristic feature of epileptogenesis in which the likelihood that neural networks will be activated is increased may be due to loss of inhibitory neurons such as GABAergic interneurons that would normally balance out the excitability of other neurons 3 Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons those that usually increase excitation and GABAergic ones those that decrease it 14 In addition the levels of GABA and the sensitivity of GABAA receptors to the neurotransmitter may decrease resulting in less inhibition 3 Another proposed mechanism for epileptogenesis in TBI is that damage to white matter causes hyperexcitability by effectively undercutting the cerebral cortex 16 Glutamate receptor activation Edit It is believed that activation of biochemical receptors on the surfaces of neurons is involved in epileptogenesis these include the TrkB neurotrophin receptor and both ionotropic glutamate receptors and metabotropic glutamate receptors those that are directly linked to an ion channel and those that are not respectively 2 Each of these types of receptor may when activated cause an increase in the concentration of calcium ions Ca2 within the area of the cell on which the receptors are located and this Ca2 can activate enzymes such as Src and Fyn that may lead to epileptogenesis 2 Excessive release of the neurotransmitter glutamate is widely recognized as an important part of epileptogenesis early after a brain injury including in humans 14 Excessive release of glutamate results in excitotoxicity in which neurons are excessively depolarized intracellular Ca2 concentrations increase sharply and cellular damage or death results 14 Excessive glutamatergic activity is also a feature of neuronal circuits after epilepsy has developed but glutamate does not appear to play an important role in epileptogenesis during the latent period 14 Another factor in hyperexcitability may include a decrease in the concentration of Ca2 outside cells i e in the extracellular space and a decrease in the activity of ATPase in glial cells 3 Blood brain barrier disruption Edit Blood brain barrier BBB disruption occurs in high prevalence following all brain lesions that may cause post injury epilepsy such as stroke traumatic brain injury brain infection or brain tumor 17 BBB disruption was shown to underlay epileptogenesis by several experimental models 18 19 Furthermore it was shown that albumin the most frequent protein in the serum is the agent that leaks from the blood into the brain parenchyma under BBB disruption conditions and induces epileptogenesis by activation of the transforming growth factor beta receptor on astrocytes 20 21 22 Additional investigation exposed that this process is mediated by a unique inflammatory pattern 21 23 and the formation of excitatory synapses 24 Pathogenic influence was attributed also to the extravasation of other blood born substances such as hemosiderin or iron 16 Iron from hemoglobin a molecule in red blood cells can lead to the formation of free radicals that damage cell membranes this process has been linked to epileptogenesis 25 Treatment EditA major goal of epilepsy research is the identification of therapies to interrupt or reverse epileptogenesis Studies largely in animal models have suggested a wide variety of possible antiepileptogenic strategies although to date no such therapy has been demonstrated to be antiepileptogenic in clinical trials 26 Some anticonvulsant drugs including levetiracetam and ethosuximide have shown promising activity in animal models Other promising strategies are inhibition of interleukin 1b signaling by drugs such as VX 765 modulation of sphingosine 1 phosphate signaling by drugs such as fingolimod activation of the mammalian target of rapamycin mTOR by drugs such as rapamycin the hormone erythropoietin and paradoxically drugs such as the a2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A rimonabant with proexcitatory activity The discovery of the role played by TGF beta activation in epileptogenesis raised the hypothesis that blocking this signaling may prevent epileptogenesis Losartan a commonly used drug for the treatment of hypertension was shown to prevent epilepsy and facilitate BBB healing in animal models Testing the potential of antiepileptogenic agents e g losartan or BBB healing drugs necessitates biomarkers for patients selection and treatment followup 27 BBB disruption imaging was shown capacity in animal model to serve as a biomarker of epileptogenesis 28 and specific EEG patterns were also shown to predict epilepsy in several models 29 History EditThroughout most of history for which written records exist on the subject it was probably generally believed that epilepsy came about through a supernatural process 30 Even within the medical profession it was not until the 18th century that ideas of epileptogenesis as a supernatural phenomenon were abandoned 30 However biological explanations have also long existed and sometimes explanations contained both biological and supernatural elements 30 Research EditEpileptogenesis that occurs in human brains has been modeled in a variety of animal models and cell culture models 2 Epileptogenesis is poorly understood 14 and increasing understanding of the process may aid researchers in preventing seizures diagnosing epilepsy 31 and developing treatments to prevent it 2 See also EditKindling model Post traumatic epilepsy Post traumatic seizureReferences Edit Lukasiuk K 2014 Epileptogenesis In Aminoff Michael J Daroff Robert B eds Encyclopedia of the Neurological Sciences Second Edition Vol 2 Second ed London Academic Press pp 196 199 ISBN 978 0 12 385157 4 a b c d e McNamara JO Huang YZ Leonard AS October 2006 Molecular signaling mechanisms underlying epileptogenesis Sci STKE 2006 356 re12 doi 10 1126 stke 3562006re12 PMID 17033045 S2CID 42882078 a b c d e Armijo JA Valdizan EM De Las Cuevas I Cuadrado A 2002 Advances in the physiopathology of epileptogenesis Molecular aspects Rev Neurol in Spanish 34 5 409 29 PMID 12040510 a b c d Pitkanen A Engel J Jr April 2014 Past and present definitions of epileptogenesis and its biomarkers Neurotherapeutics 11 2 231 41 doi 10 1007 s13311 014 0257 2 PMC 3996117 PMID 24492975 a b Epileptogenesis an overview ScienceDirect Topics www sciencedirect com a b Pitkanen A Lukasiuk K Dudek FE Staley KJ 18 September 2015 Epileptogenesis Cold Spring Harbor Perspectives in Medicine 5 10 a022822 doi 10 1101 cshperspect a022822 PMC 4588129 PMID 26385090 a b c Goldberg EM Coulter DA May 2013 Mechanisms of epileptogenesis a convergence on neural circuit dysfunction Nature Reviews Neuroscience 14 5 337 49 doi 10 1038 nrn3482 PMC 3982383 PMID 23595016 a b Goldberg Ethan M Coulter Douglas A May 2013 Mechanisms of epileptogenesis a convergence on neural circuit dysfunction Nature Reviews Neuroscience 14 5 337 349 doi 10 1038 nrn3482 PMC 3982383 PMID 23595016 a b Epilepsy and Epileptogenesis News Medical net 9 September 2019 a b c Katsarou AM Galanopoulou AS Moshe SL June 2018 Epileptogenesis in neonatal brain Seminars in Fetal amp Neonatal Medicine 23 3 159 167 doi 10 1016 j siny 2017 12 004 PMC 6015538 PMID 29467100 a b c d e Engel J Jr March 2019 Epileptogenesis traumatic brain injury and biomarkers Neurobiology of Disease 123 3 7 doi 10 1016 j nbd 2018 04 002 PMC 6170720 PMID 29625256 Noebels Jeffrey L Avoli Massimo 2012 06 29 Jasper s Basic Mechanisms of the Epilepsies Oxford University Press p 3 ISBN 9780199746545 Retrieved 2014 10 16 a b c Herman ST January 2006 Clinical trials for prevention of epileptogenesis Epilepsy Res 68 1 35 8 doi 10 1016 j eplepsyres 2005 09 015 PMID 16377141 S2CID 46017678 a b c d e f g h i j Aroniadou Anderjaska V Fritsch B Qashu F Braga MF February 2008 Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy Epilepsy Res 78 2 3 102 16 doi 10 1016 j eplepsyres 2007 11 011 PMC 2272535 PMID 18226499 Post traumatic epilepsy Br Med J 2 6132 229 1978 doi 10 1136 bmj 2 6132 229 PMC 1606365 PMID 98198 a b Firlik KS Spencer DD 2004 Surgery of post traumatic epilepsy In Dodson WE Avanzini G Shorvon SD Fish DR Perucca E eds The Treatment of Epilepsy Oxford Blackwell Science p 775 ISBN 0 632 06046 8 Retrieved 2008 06 09 Schevon CA Tobochnik S Eissa T Merricks E Gill B Parrish RR Bateman LM McKhann GM Jr Emerson RG Trevelyan AJ 2019 Multiscale recordings reveal the dynamic spatial structure of human seizures Neurobiol Dis 127 303 311 doi 10 1016 j nbd 2019 03 015 PMC 6588430 PMID 30898669 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link Seiffert E Dreier JP Ivens S Bechmann I Heinemann U Friedman A 2004 Lasting blood brain barrier disruption induces epileptic focus in the rat somatosensory cortex J Neuroscience 24 36 7829 36 doi 10 1523 JNEUROSCI 1751 04 2004 PMC 6729929 PMID 15356194 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link van Vliet EA da Costa Araujo S Redeker S van Schaik R Aronica E Gorter JA 2007 Blood brain barrier leakage may lead to progression of temporal lobe epilepsy Brain 130 2 521 534 doi 10 1093 brain awl318 PMID 17124188 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link Ivens S Kaufer D Seiffert E Bechmann I Tomkins O Heinemann U Friedman A 2007 TGF beta receptor mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis Brain 130 Pt 2 535 47 doi 10 1093 brain awl317 PMID 17121744 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link a b Cacheaux LP Ivens S David Y Lakhter AJ Bar Klein G Shapira M Heinemann U Friedman A Kaufer D 2009 Transcriptome profiling reveals TGF beta signaling involvement in epileptogenesis Journal of Neuroscience 29 28 8927 8935 doi 10 1523 JNEUROSCI 0430 09 2009 PMC 2875073 PMID 19605630 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link David Y Flores LP Ivens S Heinemann U Kaufer D Friedman A 2009 Astrocytic dysfunction in epileptogenesis consequences of altered 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