Editing Epilepsy (section)

== Causes ==
{{See also|Causes of seizures}}
Epilepsy can result from a wide range of genetic and acquired factors, and in many cases, both play a role.<ref name=tnberkovic2006/><ref>{{cite journal | vauthors = Balestrini S, Arzimanoglou A, Blümcke I, Scheffer IE, Wiebe S, Zelano J, Walker MC | title = The aetiologies of epilepsy | journal = Epileptic Disorders | volume = 23 | issue = 1 | pages = 1–16 | date = February 2021 | pmid = 33720020 | doi = 10.1684/epd.2021.1255 | doi-access = free | hdl = 2158/1262349 | hdl-access = free }}</ref> Acquired causes include serious [[traumatic brain injury]], [[stroke]], [[Brain tumor|brain tumors]], and [[central nervous system infections]].<ref name=tnberkovic2006>{{cite journal | vauthors = Berkovic SF, Mulley JC, Scheffer IE, Petrou S | title = Human epilepsies: interaction of genetic and acquired factors | journal = Trends in Neurosciences | volume = 29 | issue = 7 | pages = 391–397 | date = July 2006 | pmid = 16769131 | doi = 10.1016/j.tins.2006.05.009 }}</ref> Despite advances in diagnostic tools, no clear cause is identified in approximately 60% of cases.<ref name="National Clinical Guideline 21_28" /><ref name=WHO2012/> The distribution of causes often varies with age. Epilepsies associated with genetic, congenital, or developmental conditions are more common in children, while epilepsy related to stroke or tumors is more frequently seen in older adults.<ref name="National Clinical Guideline 21_28" />

Seizures may also occur as a direct response to acute health conditions such as stroke, head trauma, metabolic disturbances, or toxic exposures.<ref name="Thur2011">{{cite journal |vauthors=Thurman DJ, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, Hesdorffer DC, Hauser WA, Kazis L, Kobau R, Kroner B, Labiner D, Liow K, Logroscino G, Medina MT, Newton CR, Parko K, Paschal A, Preux PM, Sander JW, Selassie A, Theodore W, Tomson T, Wiebe S |date=September 2011 |title=Standards for epidemiologic studies and surveillance of epilepsy |journal=Epilepsia |volume=52 |issue=Suppl 7 |pages=2–26 |doi=10.1111/j.1528-1167.2011.03121.x |pmid=21899536 |doi-access=free}}</ref> These are known as acute symptomatic seizures and are distinct from epilepsy, which involves a recurrent tendency to have unprovoked seizures over time.<ref name="Nel2012">{{cite book |title=Epilepsy |vauthors=Neligan A, Hauser WA, Sander JW |year=2012 |isbn=978-0-444-52898-8 |series=Handbook of Clinical Neurology |volume=107 |pages=113–33 |chapter=The epidemiology of the epilepsies |doi=10.1016/B978-0-444-52898-8.00006-9 |pmid=22938966}}</ref><ref name="National Clinical Guideline 119_129">{{cite book |author=National Clinical Guideline Centre |url=http://www.nice.org.uk/nicemedia/live/13635/57784/57784.pdf |title=The Epilepsies: The diagnosis and management of the epilepsies in adults and children in primary and secondary care |date=January 2012 |publisher=National Institute for Health and Clinical Excellence |pages=119–129 |archive-url=https://web.archive.org/web/20131216151008/http://www.nice.org.uk/nicemedia/live/13635/57784/57784.pdf |archive-date=16 December 2013 |url-status=live}}</ref>

The [[International League Against Epilepsy]] (ILAE) classifies the causes of epilepsy into six broad categories: structural, genetic, infectious, metabolic, immune, and unknown. These categories are not mutually exclusive, and more than one may apply in an individual case.<ref name="Scheffer2017">{{Cite journal |last1=Scheffer |first1=Ingrid E. |last2=Berkovic |first2=Samuel |last3=Capovilla |first3=Giuseppe |last4=Connolly |first4=Mary B. |last5=French |first5=Jacqueline |last6=Guilhoto |first6=Laura |last7=Hirsch |first7=Edouard |last8=Jain |first8=Satish |last9=Mathern |first9=Gary W. |last10=Moshé |first10=Solomon L. |last11=Nordli |first11=Douglas R. |last12=Perucca |first12=Emilio |last13=Tomson |first13=Torbjörn |last14=Wiebe |first14=Samuel |last15=Zhang |first15=Yue-Hua |date=2017 |title=ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology |journal=Epilepsia |language=en |volume=58 |issue=4 |pages=512–521 |doi=10.1111/epi.13709 |issn=0013-9580 |pmc=5386840 |pmid=28276062}}</ref>

=== Structural ===
Structural causes of epilepsy refer to abnormalities in the anatomy of the brain that increase the risk of seizures. These may be acquired — such as from a [[stroke]], [[traumatic brain injury]], [[brain tumor]], or [[central nervous system infection]] — or developmental and genetic in origin, as seen in conditions like [[focal cortical dysplasia]] or certain congenital brain malformations. A major example is mesial temporal sclerosis (MTS), a common cause of [[temporal lobe epilepsy]].<ref>{{Cite journal |last=Thom |first=Maria |date=2014 |title=Review: Hippocampal sclerosis in epilepsy: a neuropathology review |journal=Neuropathology and Applied Neurobiology |language=en |volume=40 |issue=5 |pages=520–543 |doi=10.1111/nan.12150 |issn=1365-2990 |pmc=4265206 |pmid=24762203}}</ref><ref name="Scheffer2017" />

Traumatic brain injury is estimated to cause between 6% and 20% of epilepsy cases, depending on severity, mechanism, and study population. Mild brain injury increases the risk about two-fold, while severe brain injury increases the risk seven-fold. In those who have experienced a high-powered gunshot wound to the head, the risk is about 50%.<ref name="Bh2011">{{cite journal |vauthors=Bhalla D, Godet B, Druet-Cabanac M, Preux PM |date=June 2011 |title=Etiologies of epilepsy: a comprehensive review |journal=Expert Review of Neurotherapeutics |volume=11 |issue=6 |pages=861–876 |doi=10.1586/ern.11.51 |pmid=21651333}}</ref> Stroke is a major cause of epilepsy, particularly in older adults.<ref>{{cite journal |vauthors=Zelano J, Holtkamp M, Agarwal N, Lattanzi S, Trinka E, Brigo F |date=June 2020 |title=How to diagnose and treat post-stroke seizures and epilepsy |journal=Epileptic Disorders |volume=22 |issue=3 |pages=252–263 |doi=10.1684/epd.2020.1159 |pmid=32597766 |doi-access=free}}</ref> Approximately 6% to 10% of individuals who experience a stroke develop epilepsy, most often within the first few years after the event. The risk is highest following severe strokes that involve cortical regions, especially in cases of intracerebral hemorrhage.<ref>{{cite journal |vauthors=Zöllner JP, Schmitt FC, Rosenow F, Kohlhase K, Seiler A, Strzelczyk A, Stefan H |date=December 2021 |title=Seizures and epilepsy in patients with ischaemic stroke |journal=Neurological Research and Practice |volume=3 |issue=1 |pages=63 |doi=10.1186/s42466-021-00161-w |pmc=8647498 |pmid=34865660 |doi-access=free}}</ref> Brain tumors are implicated in approximately 4% of epilepsy cases, with seizures occurring in nearly 30% of individuals with intracranial neoplasms.<ref name="Bh2011" /> 

In clinical practice, a structural cause is typically identified through [[neuroimaging]] (such as [[MRI]]), which reveals an abnormality that plausibly accounts for the individual's seizure semiology and [[Electroencephalography|EEG]] findings. The lesion must be epileptogenic, meaning that it is capable of generating seizures. Infections like [[encephalitis]] or [[brain abscess]] may lead to permanent structural damage, increasing the risk of epilepsy even after the infection resolves.<ref name="Scheffer2017" />

Structural damage can also result from perinatal brain injury, such as [[hypoxic-ischemic encephalopathy]], especially in low- and middle-income countries where access to prenatal and neonatal care may be limited. When seizures are linked to a clearly defined structural lesion, [[epilepsy surgery]] may be considered — particularly in individuals whose seizures do not respond to medication.<ref name="Scheffer2017" />

===Genetics===
Genetic causes of epilepsy are those in which a person’s genes directly contribute to the development of seizures. This includes cases where a specific mutation has been identified, as well as situations where the family history and clinical features strongly suggest a genetic basis, even if no known mutation is found. In the updated classification by the ILAE, the term genetic replaces the older term ''idiopathic'', to highlight that these epilepsies arise from inherited or spontaneous changes in a person’s biology — not from injury or infection.<ref name="Scheffer2017" />

Genetic factors are believed to contribute to many cases of epilepsy, either directly or by increasing vulnerability to other causes.<ref>{{cite journal |vauthors=Steinlein OK |date=2008-03-31 |title=Genetics and epilepsy |journal=Dialogues in Clinical Neuroscience |volume=10 |issue=1 |pages=29–38 |doi=10.31887/DCNS.2008.10.1/oksteinlein |pmc=3181863 |pmid=18472482}}</ref> Some forms are caused by a [[single-gene disorder|single gene defect]], which account for around 1–2% of cases. However, most are due to a combination of multiple genes and environmental influences.<ref name="Pand2011" /> Many of the genes known to play a role in epilepsy affect how brain cells send electrical signals, especially those involved in [[ion channel]]s, receptors, or signaling proteins.<ref name="Neuro2012" />

Genetics is believed to play an important role in epilepsies by a number of mechanisms. Simple and complex modes of [[heredity|inheritance]] have been identified for some of them. However, extensive screening have failed to identify many single [[gene]] variants of large effect.<ref>{{cite journal |vauthors=Heinzen EL, Depondt C, Cavalleri GL, Ruzzo EK, Walley NM, Need AC, Ge D, He M, Cirulli ET, Zhao Q, Cronin KD, Gumbs CE, Campbell CR, Hong LK, Maia JM, Shianna KV, McCormack M, Radtke RA, O'Conner GD, Mikati MA, Gallentine WB, Husain AM, Sinha SR, Chinthapalli K, Puranam RS, McNamara JO, Ottman R, Sisodiya SM, Delanty N, Goldstein DB |date=August 2012 |title=Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy |journal=American Journal of Human Genetics |volume=91 |issue=2 |pages=293–302 |doi=10.1016/j.ajhg.2012.06.016 |pmc=3415540 |pmid=22863189}}</ref> More recent exome and genome sequencing studies have begun to reveal a number of de novo gene mutations that are responsible for some epileptic encephalopathies, including [[CHD2]] and [[SYNGAP1]]<ref>{{cite journal |vauthors=Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC |date=July 2013 |title=Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 |journal=Nature Genetics |volume=45 |issue=7 |pages=825–830 |doi=10.1038/ng.2646 |pmc=3704157 |pmid=23708187}}</ref><ref>{{cite journal |vauthors=Chénier S, Yoon G, Argiropoulos B, Lauzon J, Laframboise R, Ahn JW, Ogilvie CM, Lionel AC, Marshall CR, Vaags AK, Hashemi B, Boisvert K, Mathonnet G, Tihy F, So J, Scherer SW, Lemyre E, Stavropoulos DJ |year=2014 |title=CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems |journal=Journal of Neurodevelopmental Disorders |volume=6 |issue=1 |pages=9 |doi=10.1186/1866-1955-6-9 |pmc=4022362 |pmid=24834135 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, Siekierska A, Djémié T, Afrikanova T, Gormley P, von Spiczak S, Kluger G, Iliescu CM, Talvik T, Talvik I, Meral C, Caglayan HS, Giraldez BG, Serratosa J, Lemke JR, Hoffman-Zacharska D, Szczepanik E, Barisic N, Komarek V, Hjalgrim H, Møller RS, Linnankivi T, Dimova P, Striano P, Zara F, Marini C, Guerrini R, Depienne C, Baulac S, Kuhlenbäumer G, Crawford AD, Lehesjoki AE, de Witte PA, Palotie A, Lerche H, Esguerra CV, De Jonghe P, Helbig I |date=November 2013 |title=De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome |journal=American Journal of Human Genetics |volume=93 |issue=5 |pages=967–975 |doi=10.1016/j.ajhg.2013.09.017 |pmc=3824114 |pmid=24207121}}</ref> and [[DNM1]], [[GABBR2]], [[Fatty acid synthase|FASN]] and [[RYR3]].<ref>{{cite journal |vauthors=((EuroEPINOMICS-RES Consortium)) |date=October 2014 |title=De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies |journal=American Journal of Human Genetics |volume=95 |issue=4 |pages=360–370 |doi=10.1016/j.ajhg.2014.08.013 |pmc=4185114 |pmid=25262651}}</ref>

Some genetic disorders, including [[phakomatoses]] such as [[Tuberous sclerosis|tuberous sclerosis complex]] and [[Sturge–Weber syndrome]], are strongly associated with epilepsy.<ref name="Stafstrom_2017">{{cite journal |vauthors=Stafstrom CE, Staedtke V, Comi AM |date=2017 |title=Epilepsy Mechanisms in Neurocutaneous Disorders: Tuberous Sclerosis Complex, Neurofibromatosis Type 1, and Sturge-Weber Syndrome |journal=Frontiers in Neurology |volume=8 |pages=87 |doi=10.3389/fneur.2017.00087 |pmc=5355446 |pmid=28367137 |doi-access=free}}</ref> These conditions are often discussed separately due to their multisystem involvement and high epilepsy burden.

=== Infectious ===
Infectious causes include [[infections of the central nervous system]] that directly affect brain tissue and lead to long-term seizure susceptibility.<ref name="Bh2011" /> Examples include [[herpes simplex encephalitis]], which carries a high risk of developing epilepsy, and [[neurocysticercosis]], a major preventable cause of epilepsy in endemic regions. Other infections such as [[Malaria|cerebral malaria]], [[toxoplasmosis]], and [[toxocariasis]].<ref name="Bh2011" /> Some infections cause seizures during the acute illness, but only a subset result in chronic epilepsy.

===Immune===
Immune causes include conditions like [[autoimmune encephalitis]], in which the immune system attacks brain tissue, often presenting with seizures. Certain autoimmune epilepsies are associated with specific autoantibodies, including those against the [[N-methyl-D-aspartate receptor|NMDA receptor]], LGI1, and CASPR2. These cases often present with rapid-onset, difficult-to-treat seizures.<ref name="Scheffer2017" />

[[Coeliac disease|Celiac disease]] has also been associated with epilepsy in rare syndromic forms, such as the triad of epilepsy, cerebral calcifications, and celiac disease.<ref name="JacksonEaton2012">{{cite journal |vauthors=Jackson JR, Eaton WW, Cascella NG, Fasano A, Kelly DL |date=March 2012 |title=Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity |journal=The Psychiatric Quarterly |volume=83 |issue=1 |pages=91–102 |doi=10.1007/s11126-011-9186-y |pmc=3641836 |pmid=21877216}}</ref><ref name="Grossman2008">{{cite journal |vauthors=Grossman G |date=April 2008 |title=Neurological complications of coeliac disease: what is the evidence? |journal=Practical Neurology |volume=8 |issue=2 |pages=77–89 |doi=10.1136/jnnp.2007.139717 |pmid=18344378}}</ref>

=== Metabolic ===
Metabolic causes of epilepsy include metabolic disorders that disrupt the brain’s normal function. In rare cases, epilepsy may result from [[inborn errors of metabolism]], such as [[Mitochondrial disease|mitochondrial diseases]], [[Urea cycle|urea cycle disorders]], or glucose transporter type 1 (GLUT1) deficiency. These often present early in life and may be associated with developmental delays, movement disorders, or other neurological symptoms.<ref name="Scheffer2017" />

Seizures can also occur in the context of acquired metabolic disturbances, such as hypoglycemia, hyponatremia, or hypocalcemia. These seizures are often considered acute symptomatic seizures, and are not epilepsy.

Some forms of malnutrition, particularly in low- and middle-income countries, have been associated with a higher risk of epilepsy, although it remains unclear whether the relationship is causal or due to other contributing factors.<ref name="Poor2012" />

=== Unknown ===
Unknown causes of epilepsy refer to cases where no clear structural, genetic, infectious, immune, or metabolic origin can be identified despite thorough evaluation. This category acknowledges the limits of current diagnostic techniques and scientific understanding. A substantial proportion of epilepsy cases still fall into this group, particularly in regions with limited access to advanced testing.<ref name="Scheffer2017" />