etiologies of epilepsy: a comprehensive review · 3 etiologies of epilepsy: a comprehensive review...

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Epilepsy is a major neurological disorder, the symptoms of which are preventable and con-trollable to some extent and which has deep clinical, psycho–socio–demographic and eco-nomic implications that vary across different regions of the world [1–3] and are associated with varied incidence, prevalence and mortal-ity [1–3]. Despite substantial advances in epilep-tology for identification of newer syndromes, molecular and structural patterns and so on, a wide gap still exists that stems mainly from epilepsy’s extremely heterogeneous and com-plex set of risk factors. Past subjective reviews in epileptology have concentrated mainly on single risk factors and on other aspects, such as isolated seizures. In this review, we have addressed epilepsy as a whole, defined as a dis-order of the brain characterized by an enduring predisposition to generate epileptic seizures. This predisposition or underlying mechanism can be the result of a variety of risk factors and their significance varies from population to population. The objective of this paper is to systematically and comprehensively review epi-lepsy risk factors, excluding provoked seizure, in order to provide a glimpse into epidemio-logical and clinical differences within epilepsy, based upon these risk factors. We discuss major factors that may influence the risk of epilepsy in Figure 1.

Genetic epilepsyAlthough several genes and their corresponding mutations have been identified, these represent only a small proportion of idiopathic epilepsy and other rarer epilepsy forms [4] and specific genetic influences remain to be identified in the majority of cases. In general, studies have shown a high concordance rate of epilepsy among mono-zygotic compared with dizygotic twins (62 vs 18%) [4], as well as a fivefold higher epilepsy risk in close relatives of epilepsy cases [5]. This con-cordance is significantly higher among monozy-gotic pairs for generalized (both idiopathic and symptomatic) than for partial epilepsy, which implies the existence of syndrome-specific genetic determinants. However, in contrast to this assumption, genetic contribution, based on familial aggregation studies, varies for gen-eralized and partial epilepsy, suggesting some common genetic mechanisms increase the risk for both epilepsy types. Genetic mechanisms that can be implicated in epilepsy syndromes are poorly understood and may involve devel-opment abnormalities, neuronal death, changes in neuronal excitability via modifications in voltage and ligand-dependent ionic canals, with effect from a single gene (simple pattern of inheritance) or a combined influence of mul-tiple genes and environmental factors (acting as gene modulators) specific to each syndrome

Devender Bhalla1, Bertrand Godet1, Michel Druet-Cabanac1 and Pierre-Marie Preux†1

1Université de Limoges ; IFR 145 GEIST; Institut de Neurologie Tropicale ; EA 3174 NeuroEpidémiologie Tropicale et Comparée, Limoges, F-87025, France †Author for correspondence:Institut d’Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Marcland, 87025, Limoges Cedex, France Tel.: +33 555 435 820 Fax: +33 555 435 821 [email protected]

Epilepsy is a heterogeneous disorder; the symptoms of which are preventable and controllable to some extent. Significant inter- and intra-country differences in incidence and prevalence exist because multiple etiologic factors are implicated. Many past reviews have addressed sole etiologies. We considered a comprehensive view of all etiologies (genetic/structural/metabolic) to be significant for both the developing and the developed world as well as routine clinical/epidemiology practice. We therefore carried out a comprehensive search for peer-reviewed articles (irrespective of year, region, language; chosen based on novelty, importance) for each etiology. This article was felt to be essential since newer etiologic knowledge has emerged in recent years. Many new genetic links for rarer epilepsy forms have emerged. Epilepsy risk in limbic encephalitis, mechanisms of Alzheimer’s-related epilepsy and the genetic basis of cortical malformations have been detailed. An etiological approach to epilepsy in combination with the conventional classification of epilepsy syndromes is required to synthesize knowledge.

Keywords: epidemiology • epilepsy • etiology • genetic • metabolic • risk factors • seizure • structural

Etiologies of epilepsy: a comprehensive reviewExpert Rev. Neurother. 11(6), xxx–xxx (2011)

THeMed ArTICLe y Epilepsy

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Review Bhalla, Godet, Druet-Cabanac & Preux

(complex patterns of inheritance) [6]. For most epilepsy forms, the relationship between the clinical syndrome and the genetic mechanism may either involve locus heterogeneity (e.g., benign familial neonatal convulsions) or variable expressivity (e.g., gen-eralized epilepsy with febrile seizures plus). Various genetic epi-lepsy forms are described in Table 1. Various metabolic causes of genetically-determined epilepsy (in early life years) by age (Table 2) and progressive myoclonic epilepsy forms are described in Table 3.

Epilepsy also occurs in chromosomal disorders. A total of 1–10 % of trisomy 21 patients present with seizures and nearly 20 % have EEG abnormalities. Epilepsy begins either early in life or in the third decade in parallel to the progression of Alzheimer’s-like dementia [7]. Angelman syndrome (1/15,000–1/20,000 births), associated with defects present in the chromosome 15q11–q13 region, is associated with a 90% incidence of epilepsy. Epilepsy usually begins within the first 3 years of life. Seizures are general-ized (myoclonic and absence status, tonic–clonic seizures). The most effective treatments seem to be valproic acid and clonazepam [8]. Ring chromosome 20 syndrome is characteristically associated with drug-resistant epilepsy. Children present nonconvulsive sta-tus epilepticus characterized on EEG by high-voltage, rhythmic,

slow waves. Age of onset varies from infancy to 14 years and severity depends upon the extent of chromosomal deletion and importance of mosaicism [9].

Brain tumors & epilepsyBrain tumors, benign or malignant, are a common cause of epilepsy and yield an epilepsy incidence of nearly 30% [10], whereas on the other hand, almost 4% of epilepsy patients have brain tumors [11]. The risk for developing epilepsy is higher among adults than chil-dren [11] and this epilepsy risk depends upon many factors including tumor type, tumor grade or location, presence of cerebral hemi-spheric dysfunction or incomplete tumor resection [10,12]. The factors that are mostly associated with adult epilepsy include melanoma, hemorrhagic lesions, multiple metastases, and slowly growing pri-mary tumors. Factors among children include gangliogliomas, low-grade astrocytomas, dysembryoplastic neuroepithelial tumor and oligodendrogliomas [12]. WHO grade I tumors (such as ganglioglio-mas, pilocytic astrocytomas) may be the most significant epilepsy predictor since they are most commonly seen (70% cases) among patients with primary brain tumor and drug-resistant epilepsy [13]. The highest risk for development of epilepsy occurs when the tumor

0–2 3 –20 21 –40 41–60 >60

Developed countriesDeveloping countries

Age (years)

Brain tumors

Traumatic epilepsy

Alzheimer’s disease

Stroke

Cavernomas and arteriovenous malformations

Cerebral immunological disorder

Hippocampal sclerosis

Malformations of cortical development

Genetic

Neurocutaneous syndrome

Perinatal adverse events

Bacterial /viral brain infection

Bacterial /viral brain infection

Parasitic brain infection

Predominantly acquired

Predominantly genetic or developmental

Figure 1. Distribution of epilepsy etiologies by age.

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ReviewEtiologies of epilepsy: a comprehensive review

is located in the temporal cortex, around the central sulcus or in supplementary areas [14]. A study showed that prevalence of epilepsy varied from 22–37% among those with high-grade and 50–90% among low-grade primary brain tumors [15]. Low-grade tumors are more likely to be associated with epilepsy since their slow progres-sion may allow more time for epileptogenesis to develop, whereas high-grade tumors (e.g., glioblastomas) are malignant, would grow rapidly and most likely destroy nearby neurons instead of stimulat-ing them. In low-grade tumors, intractable epilepsy could be due to the tendency to develop secondary epileptogenic foci that appear to be related to temporal location, young age and duration of illness [16]. Seizures may be the only presenting feature [17].

The underlying epileptogenic mechanisms are poorly under-stood. Alterations in peritumoral microenvironment have been implicated, for example:

• Altered BBB function may lead to the generation of seizure foci [18];

• Enzymatic changes in lactate dehydrogenase and cAMP phos-phodiesterase may lead to metabolic imbalance [19];

• Impaired cellular connections and altered connexins expression are reported in epilepsy-associated brain tumors [20], and may predispose the perilesional epileptic cortex to hyperexcitability.

In addition, primary brain tumors have a higher metabolic rate that may lead to relative hypoxia and interstitial acidosis and may thus have some role in epileptogenesis. Marked peri-lesional

vasogenic brain edema is commonly observed among these patients and has been reported to have a modulating role in neural excitability [19]. Altered expression of several neurotrans-mitters could be another competing epileptogenic theory. For instance, in gliomas a high concentration of ionotropic glutamate or N-methyl-D-aspartic acid (NMDA) receptors contribute to neuronal hyperexcitability [21]. Increased g-amino butyric acid (GABA) immunoreactivity [22], as well as its potential to depolar-ize neurons (determined by expression of chloride transporters) may also precipitate seizures.

Traumatic epilepsy Brain injury (BI) is one of the most important risk factors for epi-lepsy. In a large population-based study conducted in Rochester (MN, USA), head trauma was identified as the cause of epilepsy in 6% of the population [23]. Generally, up to 20% of all symptom-atic epilepsy cases are attributed to brain injury [24]. The epilepsy risk depends closely on the degree of injury. Cases with mild brain injury (MBI), defined as a direct head trauma against the head and characterized by changes in brain functions, that is, loss of consciousness, amnesia, confusion, focal temporary neurological deficit should be distinguished from severe brain injury (SBI), which presents structural injuries including brain contusion or intracranial hemorrhage. In MBI, the risk of epilepsy was twice as high than in people without BI (relative risk (RR): 2.22; 95% CI: 2.07–2.38), whereas it is sevenfold higher among cases with SBI (RR: 7.40; 95% CI: 6.16–8.89) [25]. The epilepsy risk also varies

Table 1. Various genetic forms of idiopathic (generalized/partial) epilepsy syndromes.

Syndrome Incidence Gene/linkages

Benign febrile neonatal convulsions Rare; ~44 families since 1964 KCNQ2 (20q)KCNQ3 (8q)

Autosomal dominant frontal lobe epilepsy 100 families worldwide CHRNA4 (20q,15q)

Autosomal dominant temporal lobe epilepsy Unknown LGI1, chr 10 (3cM loci)

Juvenile myoclonic epilepsy 5–11% of all epilepsies GABRA1,EFHC1 (6p, 15q)

Absence epilepsy 2–8% of all epilepsies; more girls affected (60–70%)

CACNA1A, chr 8q24 (ECA1 loci)

GEFS+ or ADEFS and Dravet syndrome Rare AD, SCN1A, SCN1B et GABRG2

Benign familial infantile seizures Unknown AD, 19q, 16p12-q12, 2q24

Benign familial infantile convulsions and choreathetosis AD, 16p12-q12 (KST1)

Benign epilepsy of childhood with centro-temporal spikes 15q14

Rolandic epilepsy with paroxysmal exercise induced dystonia AR, 16p12–11.2

Rolandic epilepsy with oral and speech dyspraxia AD, SRPX2 (Xq22)

Partial epilepsy with pericentral spikes AD, 4p15

Familial temporal lobe epilepsy with febrile seizures with digenic inheritance

AD, 1q, 18q

Familial partial epilepsy with variable foci AD, 22q11-q12

Benign familial neonatal infantile seizures AD, SCN2A (voltage-gated Na+ channel)

AD: Autosomal dominant. ADEFS: Autosomic dominant epilepsy with febrile seizure; AR: Autosomal recessive; Chr: Chromosome. GEFS+: generalized epilepsy with febrile seizure; KST: Sodium/glucose cotransporter gene; SRPX: Sushi repeat-containing protein. Data taken from [5,171].

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with time since injury. The epilepsy risk is greatest in the first year following trauma (>20-fold increased risk in SBI) and continues to remain significant even 10 years after injury (4.4-fold increase in SBI) or even longer [26]. The incidence of epilepsy in four stud-ies on soldiers who were exposed to craniocerebral missile wounds in armed conflicts has been estimated to be 50% even ten or more years after the injury [24]. Other factors may have a role in yield-ing an increased risk for epilepsy: acute seizure in the first week after BI, necessity of neurosurgical procedures, prolonged post-traumatic amnesia, missile injuries [27], people older than 15 years at the time of injury, and people with family history of epilepsy [25]. Studies on the level of consciousness post-injury (Glasgow Coma Scale) have given conflicting results.

Surgical procedures are a form of BI and may increase the epi-lepsy risk depending upon site, type and extent of damage. The disorder for which surgery is being conducted may itself lead to seizures in the first place. The risk is especially high in young patients, those who had early onset seizures and those with con-siderable neurological deficits [28].

Epilepsy after BI can be a consequence of several complex pro-cesses, for instance as a result of direct cerebral damage, iron deposi-tion from extravasated blood, increased excitotoxicity due to accu-mulation of glutamate, diffuse axonal injury, edema, or ischemia [27]. Evidence for cortical damage, presence of hemosiderin deposits and gliotic scarring on MRI could be important predictor for epilepsy.

Infectious epilepsyBacterial or viral meningitis/viral encephalitisMeningitis is one of the most common causes of unprovoked symptomatic seizures associated with fever [29] and those who have a persistent neurological deficit (except sensorineural hearing loss) are at an increased risk of having at least one late unprovoked seizure [30] but the risk of epilepsy as a direct result of infection is low (up to 10%) [31]. Epilepsy risk is sixfold higher in those who convulse during acute illness compared with those who do not (13 vs 2%) [31]. Epileptogenesis may involve a series of changes, such as a concentrational increase in pro-inflammatory cytokines, such as TNF, in response to chronic inflammation or activation of immune system agents in response to endotoxemia [32–33], sug-gesting their role in mechanisms that induce an increase in sei-zure susceptibility during brain infection. Furthermore, activation of host pattern recognition receptors such as Toll-like receptors (TLR)-4, which are known to initiate harmful inflammatory reactions through interaction of bacterial products (such as in meningitis), may play a role. Further studies show a precipitation of chronic epilepsy following TLR-4 activation [34].

In the case of viral encephalitis, herpes simplex virus (HSV) is the most common causative agent and so herpes simplex encephalitis (HSE) is most commonly associated with epilepsy [35]. Hospital-based studies suggest seizures occur in 40–65% cases [36]. The risk for epilepsy is high in those patients who experience an early-onset

Table 2. Various metabolic causes of seizures/epilepsy by age.

Age/syndrome Cause

Neonates

Pyridoxine dependent seizures Mutation in ALDH7A1 encoding antiquitin

Pyridoxal phosphate dependent seizures Mutation in PNPO gene encoding pyridine 5-phosphate oxidase

Non-ketotic hyperglycenemia Impaired function of glycine cleavage system

Folinic acid convulsions Metabolism of biogenic amino acids

Deficiency of serine biosysnthesis 3 enzyme deficiency (3 phosphoglycerate dehydrogenase)

Hyperglycemia without cetosis Degradation of glycine difficulty

Sulfite oxidase and molybdenum cofactor deficiency Deficiency of catabolic pathways

Adenyl succinate lyase deficiency Deficiency of de novo synthesis of purine

Deficiency of GABA metabolism GABA degradation pathways (GABA transaminase deficiency) dysfunction

Infancy

GLUT 1 deficiency Mutations of SLC2A1 encoding GLUT1

GAMT deficiency Autosomal recessive disorder of creatine synthesis

Biotinidase deficiency Due to inactivity of mitochondrial carboxylases (propionyl-CoA, pyruvate and b-methylcrotonyl-CoA)

Menkes disease X-linked disorder with defect in copper transporting ATPase

Childhood adolescent

Late infantile neuronal ceroidlipofuscinosis Autosomal recessive due to mutation in TPP1

Alpers disease Mitochondrial disorder. Autosomal recessive with mutation in polymerase-g-1AED: Antiepileptic drugs; CoA: Coenzyme A; EPC: Epilepsia partialis continua; GABA: g-amino butyric acid; GAMT: Guanidinoacetate N-methyltransferase; GLUT: Glucose transporter type 1; GTCS: Generalized tonic clonic seizures; SSADH: Succinic semialdehyde dehydrogenase deficiency; SE: Status epilepticus. Data taken from [171,172].

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seizure [31]. The risk is most significant within the first 5 years, although it remains persistent until 20 years, primarily due to the reactivation potential of latent virus in the brain [37]. Seizures are recurrent, generally focal in approximately 40% of cases [38] and may become secondary generalized [37]. The high incidence of epilepsy following HSE may be owing to the necrotizing nature of HSV-1 infection and involvement of highly epileptogenic mesial temporal and basifrontal cortices. Several autopsy-based and post-surgical examinations of brain tissues reveal chronic inflammation within the mesial temporal lobe structures in addi-tion to the identification of the HSV genome and antigen in some patients [39]. Conversely, in some patients, HSV-1 DNA has been detected without evidence of inflammation [40]. An animal study suggested a direct change in the excitability of the hippocampal CA3 neuronal network that could play an important role in facili-tating the development of acute seizures and subsequent epilepsy [41]. In general, following any viral encephalitis, there is a 16-fold increased risk of developing an unprovoked seizure that may not necessarily recur [31]. Other viruses provide variable and lower epilepsy risks than HSE: for instance, epilepsy incidence rates in La Crosse encephalitis is 10–12% or in cases with acute nipah virus encephalitis, is 2.2% over 8 years.

Bacterial brain abscessesBacterial brain abscesses are usually related to head trauma, contiguous suppurating process, blood-bourne infection or complications of brain surgery. Epilepsy begins generally within 3 years after abscess. Predictors of seizures in a 22-years retrospective study were frontoparietal location, and valvular heart diseases (endocarditis) [42]. In this study, 4.3% of surviv-ing patients had epilepsy. Gram-negative bacilli, Streptococcus species, anerobic pathogens and Staphylococcus species may be involved. Tuberculoma causes nearly 3% of all cerebral mass lesions and is found in 13% of HIV patients in India [43]. Partial epilepsy can be the onset feature in many tuberculoma cases

and should be considered in patients with unexplained neu-rological manifestations, particularly in endemic tuberculosis regions [44–45].

NeurocysticercosisNeurocysticercosis (NCC) is associated with 30–50% of all epilepsy in endemic zones, such as Peru, where nearly half of the population lives under conditions in which Taenia solium transmission is an everyday occurrence [46,47]. Many commu-nity-based surveys yield high seroprevalence (determined by enzyme-linked immunoelectrotransfer blot techniques) in vari-ous countries of Latin America (10–23%) and Asia (20–47%) [47]. A relationship between seroprevalence and epilepsy as dem-onstrated in case–control studies, reflected by high odds ratio (OR) of 1.8–4.6 [48–51] which, as suggested, in a large meta-ana lysis, is even higher in various African populations (mean OR of 3.4 (95% CI: 2.7–4.3; p < 0.001) [52]. Chronic epilepsy is associated with calcified cysts [53]. Cysts that are active and undergoing degeneration (colloidal cysts) are more epileptogenic and degenerate fastest (within 6–12 months) – with the highest epilepsy risk occuring during this period [53]. There can also be a long delay in seizure onset related to either the presence of differing pathogenicity and different genetic variants of Taenia solium [52], the number of lesions or extent of conversion from vesicular to colloidal cysts [53]. These factors are associated with a variable degree of epilepsy onset, treatment response or resis-tance, since infection with some variants in some populations does not lead to epilepsy [54]. Epileptogenesis may involve factors such as inflammation, edema, gliosis, genetics, and predilection for the cysts to lodge in the frontal and temporal lobes [55]. The host response to degenerating cysts may also play an important role in epileptogenesis that may vary significantly; for instance, a more profound response is observed among women or children and secondly, within same-subject, varying degree (profound or even absent) of pericystic inflammation is observed [53,55].

Table 3. Classical progressive myoclonic epilepsy forms.

Syndrome Age of onset/incidence Cause

ULD 6–13 years onset. Prev. especially high in Finland, Reunion, Morocco (due to consanguinity). Prev in France 1 per 500,000. Finland: prev: 1 per 25000, Inc: 1 per 20,000)

AR; mutation in cystatin B, chr 21

Lafora disease 6–19 years onset. Occurs especially in populations with consanguinity (especially the Mediterranean, central Asia, SEA, north Africa) except USA, Canada, China and Japan. Onset GTC seizures

AR; Chr 6q by linkage for EPM2A encoding for protein tyrosine phosphatase; mutation in NHLRC1 (most common)

Sialidosis Birth–25 years onset; epidemiology unknown AR; Gene encoding glycoprotein specific a-d-neuraminidase, Neu1 gene on chr 6p21

MERRF Age of onset variable. Prev: North Finland (0–1.5/100000); North England (0.25/100000); West Sweden (0–0.25/100000)

Mitochondrial disorder: adenine to guanine transition mutation at nucleotide 8344 (80% cases)

NCL Age of onset variable. Prev. (1.5–9/100,000); inc. (varied, range: 1.3–7 per 100,000 live births)

AR. Infantile form (CLN 1 at chr 1p); late infantile (CLN2 at 11p). Juvenile type (CLN3 at 16p); Finnish variant (CLN5 at 13q)

AR: Autosomal recessive; Chr: Chromosome; GTC: Generalized tonic clonic; Inc: Incidence; MERFF: Myoclonic epilepsy with ragged red fibers; NCL: Neuronal ceroid lipofuscinosis; Prev: Prevalence; SEA: South East Asia; ULD: Unverricht–Lundborg disease. Data taken from [171,173].

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Cerebral malaria The risk of epilepsy in cerebral malaria is not well quantified [56]. The few studies from Kenya (OR: 4.4; 95%CI: 1.4–13.7; p = 0.01), Mali (incidences: 17/1000 vs 1.8/1000; adjusted relative risk: 14.3 [95% CI: 1.6–132.0]; p = 0.01) and Gabon (adjusted OR: 3.9; 95% CI: 1.7–8.9; p < 0.001) [56] suggest higher epilepsy frequency especially among those who have complicated febrile seizures [57]. Genetic propensity to develop epilepsy (OR: 1.41; 95%CI: 1.06–1.88) among relatives of severe malaria is reported [58]. There is often an absence of a long delay period for seizure onset [59]. MRI studies yield vascular ischemic lesions resulting from sequestration of parasitic erythrocytes and are confirmed in other autopsy studies [60]. Durck’s malarial granuloma com-prising of reactive astrocytes is also reported to have epilepto-genic potential [61]. Neurotoxins such as quinolinic acid [62] and auto-antibodies to voltage-gated calcium channels may have an epileptogenic role since they are found in high concentration in children with both severe malaria and seizures [63].

OnchocerciasisThe nature of onchocerciasis’ relationship with epilepsy is con-troversial. A few population-based African studies [64,65] reported significant correlation between prevalence of epilepsy, oncho-cerciasis and its microfilarial load. A large meta-ana lysis showed that overall increased risk [66] and epilepsy prevalence increased by 0.4% with every 10% increase in Onchocerca volvulus preva-lence [64]. Some studies on the other hand, show lack of any association, especially in regions where onchocerciasis prevalence is low [67]. Microfilaria, usually intradermal, have been found in the CSF of onchocerciasis patients, either after treatment with a filaricidal drug [68] or in untreated patients [69], but they may have also been introduced to the CSF by needles. Cytokine levels, such as interleukin-1, in immunologic response to Onchocerca volvulus, are increased in animal models [70] and studies of the hippocampus have shown that interleukin-1b inhibits the func-tion of the GABA-A receptor [71] and increases the intracellular calcium concentration [72], which may in turn cause an increase in neuronal excitability.

ToxoplasmosisToxoplasmosis is an opportunistic infection among immuno-compromised individuals, such as those with AIDS and those who have a low (<200) CD4 cell count. In these patients, toxoplasmosis is a frequent etiology for acute seizures and epi-lepsy, as are progressive multifocal leukoencephalopathy and other acute cerebral infections [73]. Moreover, high levels of Toxoplasma gondii IgG among the general population, in USA (20%), France (80%) and Turkey (36%) have been reported [74]. A meta-ana lysis showed a higher epilepsy rate in concor-dance with high toxoplasmosis prevalence [75], which could indicate that some cases of cryptogenic epilepsy may be a con-sequence of latent toxoplasmosis. The rupture of some cysts may cause a marked inflammation leading to a microglial reaction and scar tissue formation that is reported to be an epileptogenic factor [76].

Toxocariasis Toxocariasis is one of the most common zoonotic helminthic infec-tions predominantly seen in children (aged <5 years) in rural and non-western tropical general populations (63.2–93% seropreva-lence). Western seroprevalence varies from 2–5% in urban zones to 14.2–37.0% in rural ones. The human form is caused by larvae of Toxocara canis, which for a long time has been known to have a tendency to lodge in the brain. A high seroprevalence is observed among people with intellectual difficulties. Some studies have dem-onstrated a link between seroprevalence and epilepsy, while few show coincidental presence of higher seroprevalence in epilepsy [77]. A set of studies indicated a >twofold higher seropositivity among epilepsy cases with at least twofold higher odds for developing epilepsy (OR: 2.0; 95% CI: 1–4) and fivefold for partial epilepsy (OR: 4.70; 95% CI: 1.47–15.10) [77]. Confusion regarding the nature of the relationship between the parasite and epilepsy may be due to the fact that the parasite does not completely mature in humans and most infections remain asymptomatic or latent. The host immune response may lead to generalized seizures while gran-ulomas may lead to focal seizures [78]. There is also a possibility that migrating larva carry other infectious epilepsy trigger agents since eosinophilic meningitis, encephalitis or meningo-encephalitis [79] are observed. Those with pathological CT or MRI with solitary mass lesions should be screened for such infection.

Stroke & epilepsyStroke is a major risk factor for epilepsies. It may explain one-third of those that occur in the elderly population and there is probably a relationship between epilepsy and stroke risk in later life [80–81]. In several large and well-designed prospective studies, 2–4% of stroke cases were shown to experience epilepsy during their life-time. These rates are much higher in smaller (e.g., 6–9%) or retrospective studies (e.g., 39% over 30 months) [82]. These rates also vary from population to population and between different periods of follow-up, for instance 3.8% in a UK population over 5 years. The risk of epilepsy associated with stroke has been shown to be 3.4% in a US population over 5.5 years, 2.5% over 9 months in a Scandinavian population, 32% (of those who had early onset of seizures) over 26 months in Australian population [82]. The diagnosis of a post-stroke seizure is difficult because seizure can be characterized by negative motor symptoms, and may resemble transient ischemic attacks.

Risk factors for epilepsy or early seizure are dependent on stroke subtype, stroke location, and stroke disability. Hemorrhagic stroke is often reported in patients affected with early seizures in recent cohorts [83], while it was also associated with post-stroke epilepsy (PSE) in older works [84]. Atherothrombotic and cardioembolic stroke types are together responsible for almost 74% of cases, but contrary to previous understanding, lacunar infarct is also signifi-cantly associated with PSE [83,85]. Cortical location is reported to be an independent predictor of early seizure, but its role as a risk factor for epilepsy is less clear. In a French prospective cohort of 581 patients, the presence of cortical deficits including Wernicke’s aphasia, isolated hemianopsia, hemineglect and apraxia were pre-dictors of epilepsy [85], whereas in a prospective multicenter study

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of 1897 patients, cortical location of stroke was not an independent risk factor [83]. Size of stroke (i.e., extended to a half hemisphere or more) seems to be in some studies associated with PSE [85]. There may also be a specific greater risk for epilepsy among those who develop an initial seizure as late onset (>2 weeks) after ischemic stroke [83]. Severity of the initial and later disability (Rankin Scale) is associated with early epileptic seizures but not PSE [82,85].

Epileptogenic mechanisms are poorly understood. The regional metabolic dysfunction and excitotoxic neurotransmitter release secondary to neuronal death and ischemic penumbra surrounding the infarct is probably the substrate of early-onset seizures. Brain damage involving enhanced release of excitotoxic glutamate, ionic imbalances, breakdown of membrane phospholipids and release of free fatty acids promote epileptogenic processes. In hemor-rhagic stroke, a combination of focal ischemia, blood products (hemosiderin), and the sudden development of a space-occupying lesion may elicit seizure activity. The cause of PSE is thought to be an epileptogenic effect of gliotic scarring [86] .

Cerebral cavernous malformations & epilepsy Cerebral cavernous malformations are benign and rare vascular malformations affecting 0.02–0.5% of the population [87] and are supratentorial in 65–90% of cases [88]. Seizures are often associated with them and can be a sole presenting feature in 40–79% of cases [89]. The risk of epilepsy is variable (30–64%) [90] and is higher in children (perhaps owing to a greater propensity to hemorrhage) [91] and in those with multiple lesions (1.51% per person/year for those with a single lesion or 2.48% per lesion/year for those with multiple lesions) [92]. Congenital venous malformations can be associated with cavernomas but are frequent abnormalities (3% of population) and don’t seem to be associated with cerebral hemor-rhage or epilepsy. Temporal cavernomas show a tendency to be associated with intractable epilepsy [93]. When cavernomas are responsible for intractable epilepsy, surgical resection has shown good results, with seizure remission in 94% cases [88].

Cavernomas have no capsule separating the lesion from the surrounding brain parenchyma. Glial changes and hemosiderin deposition can be found in surrounding neuronal parenchyma [94]. Cavernomas are dynamic lesions and follow-up MRI studies reveal changes in size and signal characteristics. Mechanisms underlying epilepsy are complex. Studies have reported that neurons adjacent to cerebral cavernous malformations are twice as excitatory than neurons adjacent to similar intracellular mass lesions [95], while in another study, cerebral cavernous malformations yielded twice as high a seizure frequency than other mass lesions such as arte-riovenous malformations (20–40%) or gliomas (10–30%) [96]. More than its effect as space-occupying lesion, microhemorrhages and deposits of hemosiderin surrounding the cavernoma appear to induce epileptic activities [97] via neuronal excitotoxicity and reactive glial proliferation [98].

Arteriovenous malformation & epilepsyEpilepsy risk with arteriovenous malformation (AVM) can be as high as 40% with higher rates in older people [99]. Epileptogenicity increases particularly with temporal and rolandic locations, which

constitute 40–45% of AVM-related epilepsy. Seizures are the first symptom in 17–36% of cases, while in 40% of cases it is bleeding that reveals AVM. The majority of patients show improvement in their epilepsy after respective surgery or radiosurgery of the AVM [100].

Mesial temporal lobe epilepsy with hippocampal sclerosisNo precise epidemiological information is available but accord-ing to one estimate mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) may account for 20% of all epilepsy and 65% of all MTLE [101]. One study reported HS in 36% of new onset temporal lobe epilepsy [102]. These estimates could, in fact, be higher owing to the increasing use of MRI scans leading to increased identification and bias towards selection of drug-resistant patients. MTLE may occur many years after the occurence of febrile seizures. Seizures have a gradual onset, are drug-refractory, begin with subjective symptoms before frequent secondary loss of contact [103]. Secondary generalized tonic–clonic seizures are unusual. A randomized controlled trial showed sig-nificant chances for seizure freedom post-surgery as compared with drug treatment [104]. Anterior temporal lobectomy is associ-ated with a high rate of seizure-free patients according to Engel’s class I (seizure-free group included those who experienced auras [simple partial seizures only]) of 97.6, 95 and 71.1% at 1, 2 and 10 years after surgery, respectively [105].

Epileptogenesis is accompanied by numerous changes: extensive hilar and pyramidal layer neuron loss from Ammon’s horn (CA1, CA3) with partial or majority survival of dentate granule cells and CA2 pyramidal cells, synaptic reorganization with sprouting of glutamatergic granule cells in dentate gyrus (mossy fibers) and neurogenesis [106] causing hypersynchronization and excitability.

The question remains of the determinants of epileptogenesis leading to HS. The preferred hypothesis is that HS results from damage following prolonged febrile convulsions frequently found in patients’ medical histories [106]. Febrile seizure, particularly in an age-specific time window, could explain hippocampic insult, but why unilateral injury? Current evidence suggests that pre-existing cortical dysplasia, especially in the temporal lobe, may increase the pro-epileptogenic effect of prolonged febrile seizures and thus ensure the later development of temporal epi-lepsy [107,108]. Dual pathology associating HS and cortical dyspla-sia is more frequent in patients with a history of febrile seizures [108], and in those patients with HS, focal cortical dysplasia is located in the temporal lobe. However, it is not yet elucidated whether HS is a consequence of repeated seizures due to corti-cal dysplasia or whether a congenital pathology can be respon-sible for this dual pathology. Other developmental lesions such as microdysgenesis of the temporal lobe are associated with HS and MTLE [109]. In the past, perinatal damages were suspected of being able to provoke HS but such medical histories are extremely rare in MTLE-HS patients. Finally, the question of a genetic contribution remains. An association of a polymorphism in the interleukin-1b gene in patients with HS and MTLE has been reported. This polymorphism may result in increased production

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of the proinflammatory interleukin-1b and promote hippocam-pic damage after febrile seizure [110]. However, another study disproves this association [111]. Several forms of familial mesial temporal lobe epilepsy have been described, but HS is unusual in these forms [112].

Alzheimer’s disease & epilepsyNeurodegenerative disorders such as Alzheimer’s disease (AD) are progressively recognized as a cause of epilepsy onset. A high prevalence rate of epilepsy, with at least one unprovoked late-onset generalized tonic–clonic (GTC) seizure, is found in 16% of sporadic advanced AD cases [113] and similar rates are observed in retrospective studies [114]. Nonetheless, another study reported equally high risk for epilepsy early (within 6 months) in the course of AD onset [115]. In fact, the inci-dence of seizures appears to be independent of disease stage. Retrospective studies have suggested a greater epilepsy risk, of nearly tenfold for AD patients [116]. Seizures are mostly GTC, both in prospective and retrospective studies [113] [114]. Seizure in AD has been widely interpreted as a secondary pro-cess. Indeed, aging-related cofactors and neurodegeneration may contribute to the development of seizures in AD. Several observations support a direct relationship: one of the princi-pal animal models of AD is hAPP mice. The brains of these transgenic mice are exposed to high levels of human b-amyloid peptides (Ab), which is suspected to have a pathogenic role in AD. Electroencephalograms of these mouse models reveal epileptiform activity and intermittent seizures involving the neocortex and hippocampus without any overt neuronal loss. This makes it possible to assume that Ab is an important cause of aberrant neural network activities, thus being able to lead to epilepsy [115,117]. Moreover, in autosomal dominant early-onset AD, including those with mutations in presenilin-1, preseni-lin-2, or the amyloid precursor protein (APP), the relation-ship between clinically apparent seizures and AD is stronger. More than 30 mutations in presenilin-1 are associated with epilepsy [118] and 56% of patients with early-onset AD with APP duplications have seizures [119]. Finally, apolipoprotein E4 also exacerbates epilepsy or epileptiform activity [120] and contributes to AD pathogenesis through both Ab-dependent and Ab-independent pathways [121].

Epilepsy of inflammatory originAutoimmune encephalitisRasmussen encephalitis (RE) is a rare childhood syndrome [122] initially described by Rasmussen as ‘focal seizures due to chronic localized encephalitis’. A typical disease course involves a pro-gressive decline in functions associated with the affected hemi-sphere along with frequent intractable unilateral focal motor seizures or secondarily generalized seizures. Epilepsia partialis continua is frequent. After an acute period of 8–12 months, the patient passes into a residual stage with stable neurological deficit but persistent drug-resistant seizures. The role of some antibody-mediated immune responses such as AMPA recep-tor antibodies (GLuR3), acetylcholine receptor antibodies (a7 AChR), and synaptic protein Munc18–1 antibodies or cytotoxic T cells, causing apoptotic death of neurons and astrocytes [123], has been suggested.

Systemic lupus erythematosus (SLE) is the most common rheu-matic disease of greater significance in children. Epilepsy preva-lence is eightfold higher in these cases than in the general popu-lation and varies between 10–20%. Quite significantly, seizures precede the clinical onset of SLE in a considerable number of cases (up to 10%) and may suggest some role of antiepileptic drugs in precipitating SLE. The auto-immune mechanism in these cases primarily involves anti-phospholipid or anti-cardiolipin antibod-ies (later present in up to 60% of cases). There is threefold greater epilepsy risk among those who have anti-cardiolipin antibodies compared with those who don’t [124–125].

In Behcet’s disease (BD), the brain is frequently involved in 2.5–49% cases. Epilepsy risk is not known; however, seizures are frequently reported and frequency varies from 2.2–27% in neu-rological forms of BD [126–127]. This risk may vary with ethnicity and environmental factors (seizure-provoking factors or exacerba-tion of disease). Epilepsy may have a direct causative relationship with BD or to be secondary to parenchymal lesions [128].

In the rarer Hashimoto’s encephalopathy, epileptic seizures are often present, although these could be provoked in nature. The pathogenesis depends upon the anti-thyroid antibodies and a response to corticosteroids is consistently found [129]. Within a series of seven such patients, one had complex partial epilepsy and recurrent status epilepticus without other clinical features [130].

Auto-immune limbic encephalitis is of paraneoplastic or non-paraneoplastic origin. Several anti-neuronal antibodies have been associated with this disease (Table 4). Voltage-gated potassium channel antibodies (VGKC) are most frequently coupled with epilepsy [131]. VGKC-encephalitis often involves complex partial and generalized seizures, sleep behavior disorder and confusion. Characteristic epileptiform abnormalities (such as focal or generalized slow wave abnormalities, electrographic seizures or periodic lateralized epileptiform dis-charges in the temporal regions) are pres-ent on encephalogram and, sometimes,

Table 4. Antibodies in autoimmune epilepsy.

Encephalitis Antibody (associated main tumors)

Rasmussen Anti-GluR3, Anti-7 AChR, Anti-Munc18–1

Paraneoplastic Anti-Hu (small cell lung cancer)Anti-Ma-1 (testicular) Anti-Ma-2 (testicular)Anti-Yo (ovarian)Anti-NMDAR (ovarian teratomas)

Non-paraneoplastic Anti-VGKCAnti-GAD

Hashimoto Anti-thyroid peroxidase (anti-TPO) antibodies

Data taken from [124,130,131].

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MRI shows abnormalities of medial temporal areas. In the later stages of the disease, a relapse involving HS and chronic epilepsy may evolve as sequelae.

Post-vaccination encephalopathy & epilepsy There is no evidence that vaccination causes epilepsy. The term of ‘vaccine encephalopathy’ used to describe seizures and encepha-lopathy following a vaccination is linked by several studies to the beginning of myoclonic severe epilepsy of infancy or Dravet syndrome [132–133]. In this epileptic encephalopathy, prolonged febrile seizures in the first 6 months of life are frequently provoked by a vaccination. In 2005, the World Health Organization ruled that pertussis vaccines, often blamed, do not cause brain damage or encephalopathy.

Multiple sclerosisIt is unclear whether a relationship between epilepsy and mul-tiple sclerosis (MS) is either symptomatic or coincidental. Epileptic seizures can be the first observable symptom in 10% cases [134] and could be of significance since many MS lesions, even on MRI, remain silent [135]. Epilepsy rates are particularly high in some studies in the MS population. One study found a threefold higher rate [136] (over a period of 25 years) or tenfold higher age-adjusted prevalence [137]. Seizures are particularly partial (simple and complex) and occur in a greater proportion in patients with MS than that observed in a general epilepsy population (50% versus 30%) [137,138]. Evidence suggests that cortical and subcortical demyelinating lesions are themselves irritative foci [137]. MRI studies have shown a higher frequency of MS lesions that extend into the cortex when epilepsy was present [139]. Frontal atrophy in epilepsy cases may also have a role in epileptogenesis [137,138].

Gastrointestinal inflammatory disordersA large meta-ana lysis has shown that the relative risk of epilepsy among celiac disease cases is 2.1 and that of celiac disease in epilepsy cases is 1.7 but the overall risk difference was close to zero thus suggesting a low possibility for epilepsy among these cases. Another Italian study also yielded a similar prevalence of antibodies related to celiac disease in those with epilepsy and controls [140,141].

Alcohol & epilepsyThere is significant relative risk for epilepsy in chronic alcohol users (RR: 2.19; 95% CI: 1.83–2.63) [142] and those with pre-sumed alcohol-related first seizure may experience recurrence within three years [143]. Epilepsy risk is dose-dependent and increases after four or more drinks per day (RR: 4/6/8 drinks/day: [1.81; 95%CI: 1.59–2.07]; [2.44; 95%CI: 2.00–2.97]; [3.27; 95%CI: 2.52–4.26], respectively). The seizures are mostly gen-eralized and especially tonic–clonic [144] and those with GTC are more often regular alcohol drinkers with a high daily con-sumption rate [144]. There is a low rate (5–16%) of partial sei-zures [145]. Owing to alcohol, there may also be increased risk for neural or metabolic complications that may further lead to

repeated seizures [143]. Acute consumption may raise the con-vulsive threshold and delays the occurrence of kindling effect [146], whereas chronic consumption may facilitate neurobiological modulations (excitation of R-NMDA or increase in glutamate levels in the limbic and cortical areas and inhibition of GABA-A) that in turn facilitate neuronal hyperexcitability [147]. Nearly 74% of chronic alcohol drinkers with epilepsy have a consequential cerebral atrophy and so this may have a role in hyper-excitatory pathogenesis [148]. Moreover, the potential for cerebrovascular infarctions and traumas is augmented in heavy alcohol users and therefore could mediate epilepsy [148].

Malformations of cortical development & epilepsy Malformations of cortical development (MCD) are the second leading cause of symptomatic focal epilepsy in children (13.1%) after nervous system infections (15.1%), and before perinatal brain damages (12.6%). Cerebral malformations are the first etiology of intractable epilepsy [149].

Epilepsy begins mostly in childhood and adolescence and is often associated with mild or severe cognitive impairment and other neurologic disabilities. A family history of epilepsy should always be sought in order to take into account the presence of genetic MCD forms, such as those associated with nodular hetero-topia (Filamin A), with lissencephaly or subcortical band hetero-topias (LIS1, TUBA1A, DCX ) or with polymicrogyria (GPR56, SRPX2) and schizencephaly (EMX2) [150]. Resective surgery is the only available treatment and is indicated for those with MCDs restricted to part of hemisphere (such as focal cortical dysplasias (FCD), polymicrogyria [151] with or without schizencephaly or nodular heterotopia of gray matter). Surgery provides a seizure-free outcome in ≥50% (49–76%) cases over 5–8 years [152,153] but the proportion of patients with satisfactory outcome tends to decrease during the first 3 years.

Neurocutaneous syndromes & epilepsyTuberous sclerosis complexTuberous sclerosis complex (TSC) is an autosomal dominant dis-order with an incidence at birth of one in 6000. This disorder is characterized by the development of benign tumors in multiple organ systems, including the brain. Neurological manifestations of TSC are epilepsy, mental retardation and autism. Epilepsy is the most commonly associated and 60–90% cases may develop epilepsy during their lifetime [154]. These rates are even higher in retrospective studies (93.2%) [155]. Seizures often begin early in life as partial seizures and infantile spasms, and then evolve into severe multifocal epilepsy with mixed seizure types, often characterized by a low remission rate.

Cortical and subcortical tubers and their surrounding tissue are responsible for the seizures. These tubers are characterized by proliferation of glial and neuronal cells, and loss of the six-layered cortical structure. This disorder is caused by mutations in tumor suppressor genes TSC1 or TSC2. The protein products of these genes, hamartin and tuberin, act as negative regulators of the pathway of mammalian target of rapamycin (mTOR), that regulates cell growth and proliferation [156].

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Modifications in glutamate receptor expression, such as AMPA or NMDA subunits, on neuronal or glial cells in/and around tuber may also have a role in epileptogenicity [157]. At the same time, neuronal inhibition seems to be deficient because of the molecular changes in GABA receptors [158], which may explain the high efficacy of vigabatrin, a GABAergic antiepileptic drug, in this disorder.

Neurofibromatosis 1Despite being one of the most common neurocutaneous disorders, studies on neurofibromatosis are limited in number and fail to provide any detailed perspective on epilepsy risk. However, based on available studies, the prevalence of epilepsy varies between 3 and 12%, where a significant proportion of cases show neuroim-aging abnormalities that are relevant to epilepsy [159,160]. Similar to other phacomatoses with subcortical focal brain lesions, an evolution from generalized to focal-onset epilepsy is seen and this might be related to glioma or cortical dysplasia, although it is infrequently found in neurofibromatosis 1 (NFM) cases [161]. The epileptogenesis may follow similar patterns, as observed in TSC cases, with alteration in cytoarchitecture, neurotransmit-ter receptor expression (such as for glutamate receptors), which may have a role in epileptogenicity. Since hydrocephalus is quite common among these cases, cerebral insult, due to ventricular catheterization or any associated infection, may also be relevant in epileptogenesis.

Perinatal adverse events & epilepsyInjury during the perinatal period is generally the result of hypoxia or ischemia related to stroke, sepsis, or cardiovascular insufficiency. This injury risk varies depending upon the birth term. Pre-term brain exhibits particular susceptibility of the white matter whereas at-term brain rather exhibits fragility of gray mat-ter and thus an augmented risk towards epilepsy [162]. Epilepsy is a common additional disability that may affect children with cerebral palsy who have suffered severe hypoxia/ischemia at-term, affecting up to 50% of children with spastic quadriplegia [163]. While most neonates with stroke would present with seizures, the majority do not develop epilepsy in childhood. The inci-dence of recurrent seizures after perinatal stroke ranges from 0 to 40% [164]. In a recent study, perinatal stroke was shown to be a very high rate of epilepsy (67%) [165]. Some studies suggest that pre-term birth may be an independent risk factor for epilepsy that increases with decreasing gestational age [166]. A later-life epilepsy risk increases with decreasing Apgar scores, with a relative risk of 7.1 (95% CI: 5.8–8.8) [167]. Similarly, prolonged gestation could lead to perinatal complications, especially epilepsy. However, this epilepsy risk is only significant during the first year of life. One large cohorte with children (born ≥39 gestational weeks) had high incidence ratio of epilepsy for birth at 42 weeks (1.3) , and for birth at ≥43 weeks (2.0) versus birth at 39–41 weeks (1) [168]. Finally, this epilepsy risk increased for instrument-assisted and caesarean deliveries (1.4–4.9) [168]. Epileptogenesis may result, as in adults, from many factors, but comparatively greater exci-tation than inhibition is observed in neuronal networks of the

developing brain [169]. Moreover, animal models have shown that chloride transporters (NKCC1) in the immature brain may promote neuronal excitability through modulation of the activa-tion effect of GABA that become depolarizing in the developing brain [170].

ConclusionIt is evident that epilepsy is a complex and heterogeneous disorder with a long list of risk factors. We reviewed epilepsy etiologies and highlighted the main risk-defining parameters as far as pos-sible (injury severity, low-grade tumors especially of temporal or rolandic localization and early-age onset, genetic origin of AD and so on), which might promote timely identification of a suitable target population (people at risk to develop epilepsy). Variable significance of individual etiologies (stroke, perinatal trauma, infections in low-middle income countries [LMIC]) and pres-ence of cofactors (other diseases or clinical symptoms) may lead to region-specific epilepsy frequencies. A direct role of alcohol in epilepsy onset is less convincing. The role of onchocerciasis in epilepsy onset remains possible but subject to further research. Many gene mutations representing rarer epilepsy forms have been discovered but are of limited day-to-day clinical value. Particular attention should be paid to cerebral malaria, AD and limbic encephalitis. Populations in many countries (e.g., North Europe) are aged/aging and this may lead to a consequential increase in AD-related epilepsy in the near future. Perinatal factors and infec-tions do represent significant causes of epilepsy in many pock-ets of LMICs but these conclusions are drawn in the absence of sufficient population-based studies and their independent effect as epilepsy triggers has most probably been overhighlighted; for example, the independent significance of perinatal trauma as a causal factor may get diluted by the presence of family history of epilepsy. They also overshadow other more relevant etiologies such as stroke and cerebral malaria in these populations. Moreover, the wealth of information available to develop epileptogenic drugs, for instance inhibitors of the mTOR pathway, may modify the course of tuberous sclerosis and consequentially risk towards epilepsy onset. Most drugs of today are seizure-controllers. This should go hand-in-hand with the need to develop specific epilepsy preven-tion methods that may constitute newer research avenues. Finally, there is a need to develop LMIC-specific ‘ideal epilepsy epidemiol-ogy monitoring criteria’ since the guidelines that currently exist do not fit the challenges that an epidemiological investigation on epilepsy in these countries may have. Problems is these countries are different and may need different solutions.

Expert commentarySeizure and syndromic classifications are always controversial. Unlike newer classification schemes, in this review we addressed epilepsy etiologically, which views epilepsy as due to different causes, having various localizations and occuring in conjunc-tion with other diseases, thus occuring at varying frequencies. This classification provides more biological significance, limited syndromic overlap and greater precision (e.g., with regard to age of onset) but is of limited use for idiopathic or electroclinical

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syndromes. An underlying cause can only be identified in 30% of cases. Future research may answer some pertinent questions, for instance, occurrence of differing epilepsy forms with the same SCN1a mutation (generalized febrile seizures in some and severe myoclonic epilepsy in others) or how gain or loss of function in SCN1a channel could lead to the same Dravet syndrome.

Five-year viewFirst, populations in many countries are aged/aging (e.g., North Europe), which may redirect the focus on etiologies such as AD with consequential increase in epilepsy incidence in such coun-tries. In addition, there is a need to develop specific prevention methods, for instance those based on b-amyloid, could constitute newer research avenues in the coming years. Second, perinatal and infection-related epilepsies are most likely over-represented in the absence of sufficient population-based studies, in many devel-oping countries. This may, however, not undermine the need to develop and implement better public management of childbirth

and infections. Suitable strategies may thus emerge in the coming years. Third, there has been a continuous search for antiepilepto-genic drugs in order to prevent epilepsy onset but current drugs are only seizure-controllers. This review has discussed all known causes of epilepsy and where possible highlighted the highest risk-defining parameters (injury severity, low-grade tumors, temporal versus rolandic, early-onset, genetic origin of AD and so on). Thus, we expect that many valuable works would lead to anti-epilepto-genic drug development and designate suitable targets (people at higher risk to develop epilepsy) to test for such molecules.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Key issues

• Many past reviews have addressed sole etiologies. Here we aimed to comprehensively discus all etiologies significant for both the developing and developed world and routine clinical-epidemiology practice.

• Differing etiological significances (e.g., stroke, perinatal trauma, infections in low-middle income countries [LMIC]) and presence of cofactors (other disease/symptoms) are main reasons for differing (region-specific) epilepsy frequencies.

• Some risk factors are age-specific are as follows: in those over 40 years of age, trauma, tumor and stroke are pertinent risk factors; in early-age, metabolic, cerebral anoxia, infection, developmental abnormalities; in adolescents, hippocampal sclerosis, vascular malformations and trauma are the main etiological factors.

• The chief risk-definers are as follows: injury severity, low-grade tumors especially of temporal or rolandic localization and early-onset, genetic origin of Alzheimer’s disease, hemorrhagic strokes, cortical infarcts etc.

• New information has emerged in recent years: epilepsy risk is associated with limbic encephalitis, there is a genetic basis of Alzheimer’s-related epilepsy, genetic basis to cortical malformations, and the discovery of several genes/mutations for rarer epilepsy forms of limited clinical interest.

• Need to direct research focus towards cerebral malaria, and Alzheimer’s disease, especially as populations in many countries (e.g., North Europe) are aged/aging and thus consequential increase in epilepsy in near future may occur.

• Perinatal factors and infections are significant in many pockets of LMICs but conclusions are based on insufficient population-based studies. Their independent effect as epilepsy triggers are over-highlighted and they overshadow other more relevant etiologies in these populations.

• We need to utilize existing wealth of information to develop epileptogenic drugs, for instance inhibitors of mTOR pathway, which may modify course of tuberous sclerosis, hence epilepsy onset.

• Specific epilepsy prevention methods may constitute newer research avenues.

• Need to develop LMIC-specific ‘ideal epilepsy epidemiology monitoring criteria’ since existing guidelines do not fit in the challenges.

• Many pertinent questions need to be answered: for instance, why would the same mutation on SCN1a lead to generalized febrile seizures in few cases and more severe myoclonic epilepsy form in others and how could gain or loss of function in SCN1a channel lead to the same Dravet syndrome?

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