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Etiologies of epilepsy: A comprehensive review

Article  in  Expert Review of Neurotherapeutics · June 2011

DOI: 10.1586/ern.11.51 · Source: PubMed


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4 authors, including:

Bertrand Godet Michel Druet-Cabanac

University of Limoges University of Limoges


Pierre-Marie Preux
University of Limoges


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THEMED ARTICLE y Epilepsy Review
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Etiologies of epilepsy:
a comprehensive review
Expert Rev. Neurother. 11(6), 861–876 (2011)

Devender Bhalla1, Epilepsy is a heterogeneous disorder, the symptoms of which are preventable and controllable
Bertrand Godet1, to some extent. Significant inter- and intra-country differences in incidence and prevalence exist
Michel Druet-Cabanac1 because multiple etiologic factors are implicated. Many past reviews have addressed sole
etiologies. We considered a comprehensive view of all etiologies (genetic/structural/metabolic)
and Pierre-Marie
to be significant for both the developing and the developed world as well as routine
Preux†1 clinical/epidemiology practice. We therefore carried out a comprehensive search for peer-reviewed
Université de Limoges; IFR 145 GEIST; articles (irrespective of year, region and language; chosen based on novelty and importance) for
Institut de Neurologie Tropicale;
each etiology. This article was felt to be essential since newer etiologic knowledge has emerged
EA 3174 NeuroEpidémiologie Tropicale
et Comparée, Limoges, F-87025, in recent years. Many new genetic links for rarer epilepsy forms have emerged. Epilepsy risk in
France limbic encephalitis, mechanisms of Alzheimer’s-related epilepsy and the genetic basis of cortical

Author for correspondence: malformations have been detailed. An etiological approach to epilepsy in combination with the
Institut d’Epidémiologie Neurologique
et de Neurologie Tropicale, Faculté de
conventional classification of epilepsy syndromes is required to gain knowledge.
Médecine, 2 rue du Docteur Marcland,
87025, Limoges Cedex, France Keywords : epidemiology • epilepsy • etiology • genetic • metabolic • risk factors • seizure • structural
Tel.: +33 555 435 820
Fax: +33 555 435 821 Epilepsy is a major neurological disorder, the Genetic epilepsy
symptoms of which are preventable and con- Although several genes and their corresponding
trollable to some extent and which has deep mutations have been identified, these represent
clinical, psycho–socio–demographic and eco- only a small proportion of idiopathic epilepsy and
nomic implications that vary across different other rarer epilepsy forms [4] , and specific genetic
regions of the world [1–3] and are associated with influences remain to be identified in the majority
varied incidence, prevalence and mortality [1–3] . of cases. In general, studies have shown a high
Despite substantial advances in epileptology for concordance rate of epilepsy among monozygotic
identification of newer syndromes, for example, compared with dizygotic twins (62 vs 18%) [4] ,
molecular and structural patterns and so on, as well as a fivefold higher epilepsy risk in close
a wide gap still exists that stems mainly from relatives of epilepsy cases  [5] . This concordance
epilepsy’s extremely heterogeneous and com- is significantly higher among monozygotic pairs
plex set of risk factors. Past subjective reviews for generalized (both idiopathic and symptom-
in epileptology have concentrated mainly on atic) than for partial epilepsy, which implies the
single risk factors and on other aspects, such existence of syndrome-specific genetic deter-
as isolated seizures. In this article, we have minants. However, in contrast to this assump-
addressed epilepsy as a whole, defined as a dis- tion, the genetic contribution, based on famil-
order of the brain characterized by an enduring ial aggregation studies, varies for generalized
predisposition to generate epileptic seizures. and partial epilepsy, suggesting some common
This predisposition or underlying mechanism genetic mechanisms increase the risk for both
can be the result of a variety of risk factors epilepsy types. Genetic mechanisms that can
and their significance varies from population be implicated in epilepsy syndromes are poorly
to population. The objective of this article is to understood and may involve development abnor-
systematically and comprehensively review epi- malities, neuronal death, changes in neuronal
lepsy risk factors, excluding provoked seizure, excitability via modifications in voltage- and
in order to provide a glimpse into epidemio- ligand-dependent ionic canals, with an effect
logical and clinical differences within epilepsy, from a single gene (simple pattern of inheritance)
based upon these risk factors. We discuss major or a combined influence of multiple genes and
factors that may influence the risk of epilepsy environmental factors (acting as gene modula-
in Figure 1. tors) being specific to each syndrome (complex 10.1586/ERN.11.51 © 2011 Expert Reviews Ltd ISSN 1473-7175 861

Review Bhalla, Godet, Druet-Cabanac & Preux

Developing countries Developed countries

Alzheimer’s disease


Cavernomas and arteriovenous

Cerebral immunological disorder

Hippocampal sclerosis

Malformations of cortical development

Age (years) 0–2 3–20 21–40 41–60 >60
Perinatal adverse
Bacterial/viral brain infection brain infection

Parasitic brain infection

Traumatic epilepsy

Brain tumors

Predominantly acquired

Predominantly genetic
or developmental

Figure 1. Distribution of epilepsy etiologies by age.

patterns of inheritance) [6] . For most epilepsy forms, the rela- rhythmic, slow waves. Age of onset varies from infancy to 14 years
tionship between the clinical syndrome and the genetic mecha- and severity depends upon the extent of chromosomal deletion
nism may either involve locus heterogeneity (e.g., benign familial and importance of mosaicism [9] .
neonatal convulsions) or variable expressivity (e.g., generalized
epilepsy with febrile seizures plus). Various genetic epilepsy forms Brain tumors & epilepsy
are described in Table 1. Various metabolic causes of genetically Brain tumors, benign or malignant, are a common cause of epilepsy
determined epilepsy (early in life) by age are descibed in Table 2 and yield an epilepsy incidence of nearly 30% [10] . On the other
and progressive myoclonic epilepsy forms are described in Table 3. hand, almost 4% of epilepsy patients have brain tumors [11] . The
Epilepsy also occurs in chromosomal disorders. A total of 1–10% risk for developing epilepsy is higher among adults than children [11]
of trisomy 21 patients present with seizures and nearly 20% show and this epilepsy risk depends upon many factors including tumor
EEG abnormalities. Epilepsy tends to begin either early in life or in type, tumor grade or location, presence of cerebral hemispheric
the third decade in parallel to the progression of Alzheimer’s-like dysfunction or incomplete tumor resection [10,12] . The factors that
dementia [7] . Angelman syndrome (1/15,000–1/20,000 births), are mostly associated with adult epilepsy include melanoma, hem-
associated with defects present in the chromosome 15q11–q13 orrhagic lesions, multiple metastases and slowly growing primary
region, is associated with a 90% incidence of epilepsy. Epilepsy tumors. Factors among children include gangliogliomas, low grade
usually begins within the first 3 years of life. Seizures are general- astrocytomas, dysembryoplastic neuroepithelial tumor and oligo-
ized (myoclonic and absence status, tonic–clonic seizures). The dendrogliomas [12] . WHO grade I tumors (such as ganglio­gliomas
most effective treatments appear to be valproic acid and clon- and pilocytic astrocytomas) may be the most significant epilepsy
azepam [8] . Ring chromosome 20 syndrome is characteristically predictor since they are most commonly seen (70% of cases) among
associated with drug-resistant epilepsy. Children present noncon- patients with primary brain tumor and drug-resistant epilepsy [13] .
vulsive status epilepticus characterized on EEG by high-voltage, The highest risk for development of epilepsy occurs when the tumor

862 Expert Rev. Neurother. 11(6), (2011)

Etiologies of epilepsy: a comprehensive review Review

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)
AD frontal lobe epilepsy 100 families worldwide CHRNA4 (20q,15q)
AD 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 CACNA1A, chr 8q24 (ECA1 loci)
girls affected (60–70%)
GEFS+ or ADEFS and Dravet syndrome Rare AD, SCN1A, SCN1B and 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 AD, 1q, 18q
digenic inheritance
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].

is located in the temporal cortex, around the central sulcus or in vasogenic brain edema is commonly observed among these
supplementary areas [14] . A study showed that the prevalence of patients and has been reported to have a modulating role in
epilepsy varied from 22–37% among those with high grade and neural excitability [19] . Altered expression of several neuro­
50–90% among low grade primary brain tumors [15] . Low grade transmitters could be another competing epileptogenic theory.
tumors are more likely to be associated with epilepsy since their slow For instance, in gliomas a high concentration of ionotropic
progression may allow more time for epileptogenesis to develop, glutamate or N-methyl-d-aspartic acid (NMDA) receptors
whereas high grade tumors (e.g., glioblastomas) are malignant, contribute to neuronal hyperexcitability  [21] . Increased GABA
grow rapidly and most likely destroy nearby neurons instead of immunoreactivity [22] , as well as its potential to depolarize neu-
stimulating them. In low grade tumors, intractable epilepsy could rons (determined by expression of chloride transporters), may
be due to the tendency to develop secondary epileptogenic foci that also precipitate seizures.
appear to be related to temporal location, young age and duration
of illness [16] . Seizures may be the only presenting feature [17] . Traumatic epilepsy
The underlying epileptogenic mechanisms are poorly under- Brain injury (BI) is one of the most important risk factors for epi-
stood. Alterations in peritumoral microenvironment have been lepsy. In a large population-based study conducted in Rochester
implicated, as follows: (MN, USA), head trauma was identified as the cause of epilepsy in
• Altered BBB function may lead to the generation of seizure 6% of the population [23] . Generally, up to 20% of all symptom-
foci [18] ; atic epilepsy cases are attributed to brain injury [24] . The epilepsy
risk depends closely on the degree of injury. Cases with mild
• Enzymatic changes in lactate dehydrogenase and cAMP brain injury (MBI), defined as a direct trauma against the head
phosphodiesterase may lead to metabolic imbalance [19] ; and characterized by changes in brain function, that is, loss of
• Impaired cellular connections and altered expression of connex- consciousness, amnesia, confusion and focal temporary neurologi-
ins are reported in epilepsy-associated brain tumors [20] , and may cal deficit, should be distinguished from severe brain injury (SBI),
predispose the perilesional epileptic cortex to hyperexcitability. which presents structural injuries including brain contusion or
intracranial hemorrhage. In MBI, the risk of epilepsy was twice
In addition, primary brain tumors have a higher metabolic as high as in people without BI (relative risk [RR]: 2.22; 95% CI:
rate that may lead to relative hypoxia and interstitial acidosis 2.07–2.38), whereas it was sevenfold higher among cases with
and may thus play a role in epileptogenesis. Marked perilesional SBI (RR: 7.40; 95% CI: 6.16–8.89)  [25] . The epilepsy risk also 863
Review Bhalla, Godet, Druet-Cabanac & Preux

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

Age/syndrome Cause
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 biosynthesis 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
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
Menkes disease X-linked disorder with defect in copper-transporting ATPase
Late infantile neuronal ceroidlipofuscinosis Autosomal recessive due to mutation in TPP1
Alpers disease Mitochondrial disorder. Autosomal recessive with mutation in polymerase-g-1
CoA: Coenzyme A; GAMT: Guanidinoacetate N-methyltransferase; GLUT: Glucose transporter type 1.
Data taken from [171,172].

varies with time since injury. The epilepsy risk is greatest in the Infectious epilepsy
first year following trauma (>20-fold increased risk in SBI) and Bacterial or viral meningitis/viral encephalitis
continues to remain significant even 10 years after injury (4.4-fold Meningitis is one of the most common causes of unprovoked
increase in SBI) or even longer [26] . The incidence of epilepsy in symptomatic seizures associated with fever  [29] and those who
four studies on soldiers who were exposed to craniocerebral missile have a persistent neurological deficit (except sensorineural hear-
wounds in armed conflicts has been estimated to be 50% even 10 ing loss) are at an increased risk of having at least one late unpro-
or more years after the injury [24] . Other factors may have a role voked seizure [30] but the risk of epilepsy as a direct result of
in yielding an increased risk for epilepsy, including: acute seizure infection is low (up to 10%) [31] . Epilepsy risk is sixfold higher
in the first week after BI, necessity of neurosurgical procedures, in those who convulse during acute illness compared with those
prolonged post-traumatic amnesia, missile injuries [27] , being older who do not (13 vs 2%) [31] . Epileptogenesis may involve a series
than 15 years of age at the time of injury, and family history of changes, such as a concentrational increase in proinflamma-
of epilepsy [25] . Studies on the level of consciousness post-injury tory cytokines, such as TNF, in response to chronic inflam-
(Glasgow Coma Scale) have given conflicting results. mation or activation of immune system agents in response to
Surgical procedures are a form of BI and may increase the endotoxemia [32,33] , suggesting their role in mechanisms that
epilepsy risk depending upon site, type and extent of damage. induce an increase in seizure susceptibility during brain infec-
The disorder for which surgery is being conducted may itself tion. Furthermore, activation of host pattern-recognition recep-
lead to seizures in the first place. The risk is especially high in tors such as Toll-like receptor (TLR)-4, which are known to
young patients, those who had early onset seizures and those with initiate harmful inflammatory reactions through interaction
considerable neurological deficits [28] . of bacterial products (such as in meningitis), may play a role.
Epilepsy after BI can be a consequence of several complex pro- Further studies show a precipitation of chronic epilepsy following
cesses, for instance as a result of direct cerebral damage, iron TLR-4 activation [34] .
deposition from extravasated blood, increased excitotoxicity due In the case of viral encephalitis, herpes simplex virus (HSV) is
to accumulation of glutamate, diffuse axonal injury, edema or the most common causative agent and so herpes simplex enceph-
ischemia [27] . Evidence for cortical damage, presence of hemo- alitis (HSE) is most commonly associated with epilepsy  [35] .
siderin deposits and gliotic scarring on MRI could be important Hospital-based studies suggest seizures occur in 40–65% of
predictor for epilepsy. cases  [36] . The risk for epilepsy is high in those patients who

864 Expert Rev. Neurother. 11(6), (2011)

Etiologies of epilepsy: a comprehensive review Review

Table 3. Classical progressive myoclonic epilepsy forms.

Syndrome Age of onset/incidence Cause
ULD 6–13 years onset. Prev. especially high in Finland, Reunion and AR; mutation in cystatin B, Chr 21
Morocco (due to consanguinity). Prev. in France 1 per 500,000.
Finland: prev.: 1 per 25000, inc.: 1 per 20,000
Lafora disease 6–19 years onset. Occurs especially in populations with AR; Chr 6q by linkage for EPM2A encoding for
consanguinity (especially the Mediterranean, central Asia, SEA protein tyrosine phosphatase; mutation in NHLRC1
and north Africa) except the USA, Canada, China and Japan. (most common)
Onset GTC seizures
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); Mitochondrial disorder: adenine-to-guanine transition
North England (0.25/100000); West Sweden (0–0.25/100000) mutation at nucleotide 8344 (80% of cases)
NCL Age of onset variable. Prev.: 1.5–9/100,000; inc.: varied, AR. Infantile form (CLN1 at Chr 1p); late infantile
range: 1.3–7 per 100,000 live births (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].

experience an early onset seizure [31] . The risk is most signifi- many tuberculoma cases and should be considered in patients with
cant within the first 5 years, although it remains persistent until unexplained neuro­logical manifestations, particularly in endemic
20 years, primarily due to the reactivation potential of latent tuberculosis regions [44,45] .
virus in the brain [37] . Seizures are recurrent, generally focal
in approximately 40% of cases [38] and may become secondary Neurocysticercosis
generalized  [37] . The high incidence of epilepsy following HSE Neurocysticercosis (NCC) is associated with 30–50% of all
may be owing to the necrotizing nature of HSV-1 infection and epilepsy in endemic zones, such as Peru, where nearly half of
involvement of highly epileptogenic mesial temporal and basifron- the population lives under conditions in which Taenia solium
tal cortices. Several autopsy-based and postsurgical examinations transmission is an everyday occurrence [46,47] . Many community-
of brain tissues reveal chronic inflammation within the mesial based surveys demonstrated high seroprevalence (determined by
temporal lobe structures in addition to the identification of the enzyme-linked immunoelectrotransfer blot techniques) in various
HSV genome and antigen in some patients  [39] . Conversely, in countries of Latin America (10–23%) and Asia (20–47%) [47] .
some patients, HSV-1 DNA has been detected without evidence A relationship between seroprevalence and epilepsy as demon-
of inflammation [40] . An animal study suggested a direct change strated in case–control studies, reflected by high odds ratio (OR)
in the excitability of the hippocampal CA3 neuronal network that of 1.8–4.6 [48–51] which, as suggested in a large meta-ana­lysis, is
could play an important role in facilitating the development of even higher in various African populations (mean OR: 3.4 (95%
acute seizures and subsequent epilepsy [41] . In general, following CI: 2.7–4.3; p < 0.001) [52] . Chronic epilepsy is associated with
any viral encephalitis, there is a 16-fold increased risk of devel- calcified cysts [53] . Cysts that are active and undergoing degenera-
oping an unprovoked seizure that may not necessarily recur [31] . tion (colloidal cysts) are more epileptogenic and degenerate fastest
Other viruses provide variable and lower epilepsy risks than HSE: (within 6–12 months) – with the highest epilepsy risk occuring
for instance, epilepsy incidence rates in La Crosse encephalitis during this period [53] . There can also be a long delay in seizure
is 10–12% and for cases of acute nipah virus encephalitis, the onset related to either the presence of differing pathogenicity and
incidence rate is 2.2% over 8 years. different genetic variants of Taenia solium  [52] , the number of
lesions or extent of conversion from vesicular to colloidal cysts [53] .
Bacterial brain abscesses These factors are associated with a variable degree of epilepsy
Bacterial brain abscesses are usually related to head trauma, con- onset, treatment response or resistance, since infection with
tiguous suppurating process, blood-bourne infection or compli- some variants in some populations does not lead to epilepsy [54] .
cations of brain surgery. Epilepsy begins generally within 3 years Epileptogenesis may involve factors such as inflammation, edema,
after abscess. Predictors of seizures in a 22‑years retrospective study gliosis, genetics and predilection for the cysts to lodge in the fron-
were frontoparietal location, and valvular heart diseases (endocar- tal and temporal lobes [55] . The host response to degenerating cysts
ditis) [42] . In this study, 4.3% of surviving patients had epilepsy. may also play an important role in epileptogenesis that could vary
Gram-negative bacilli, Streptococcus species, anerobic pathogens significantly; for instance, a more profound response is observed
and Staphylococcus species may be involved. Tuberculoma causes among women or children and secondly, within the same subject,
nearly 3% of all cerebral mass lesions and is found in 13% of HIV a varying degree of pericystic inflammation (profound or even
patients in India [43] . Partial epilepsy can be the onset feature in absent) is observed [53,55] . 865
Review Bhalla, Godet, Druet-Cabanac & Preux

Cerebral malaria Toxocariasis

The risk of epilepsy in cerebral malaria is not well quantified [56] . Toxocariasis is one of the most common zoonotic helminthic
The few studies from Kenya (OR: 4.4; 95% CI: 1.4–13.7; infections predominantly seen in children (aged <5 years) in rural
p = 0.01), Mali (incidences: 17/1000 vs 1.8/1000; adjusted relative and non-Western tropical general populations (63.2–93% sero-
risk: 14.3 [95% CI: 1.6–132.0]; p = 0.01) and Gabon (adjusted prevalence). Western seroprevalence varies from 2–5% in urban
OR: 3.9; 95% CI: 1.7–8.9; p < 0.001) [56] suggest higher epi- zones to 14.2–37.0% in rural ones. The human form is caused
lepsy frequency especially among those who have complicated by the larvae of Toxocara canis, which has long been known to
febrile seizures [57] . Genetic propensity to develop epilepsy (OR: have a tendency to lodge in the brain. A high seroprevalence is
1.41; 95% CI: 1.06–1.88) among relatives of severe malaria is observed among people with intellectual difficulties. Some studies
reported [58] . There is often an absence of a long delay period for have demonstrated a link between seroprevalence and epilepsy,
seizure onset [59] . MRI studies show vascular ischemic lesions while few show coincidental presence of higher seroprevalence
resulting from sequestration of parasitic erythrocytes and are in epilepsy [77] . A set of studies indicated a >twofold higher sero-
confirmed in autopsy studies [60] . Durck’s malarial granuloma positivity among epilepsy cases with at least twofold higher odds
comprising of reactive astrocytes is also reported to have epilep- for developing epilepsy (OR: 2.0; 95% CI: 1–4) and fivefold for
togenic potential [61] . Neurotoxins such as quinolinic acid [62] and partial epilepsy (OR: 4.70; 95% CI: 1.47–15.10) [77] . Confusion
auto-antibodies to voltage-gated calcium channels may have an regarding the nature of the relationship between the parasite and
epileptogenic role since they are found in high concentration in epilepsy may be due to the fact that the parasite does not com-
children with both severe malaria and seizures [63] . pletely mature in humans and most infections remain asymptom-
atic or latent. The host immune response may lead to generalized
Onchocerciasis seizures while granulomas may lead to focal seizures  [78] . There
The nature of onchocerciasis’ relationship with epilepsy is con- is also a possibility that migrating larvae carry other infectious
troversial. A few population-based African studies reported a epilepsy trigger agents since eosinophilic meningitis, encephalitis
significant correlation between prevalence of epilepsy, oncho- or meningo-encephalitis [79] are observed. Those showing patho-
cerciasis and its microfilarial load [64,65] . A large meta-ana­lysis logical indicators on a CT or MRI scan with solitary mass lesions
showed that overall risk increased [66] and epilepsy prevalence should be screened for such infection.
increased by 0.4% with every 10% increase in Onchocerca vol-
vulus prevalence [64] . On the other hand, some studies show lack Stroke & epilepsy
of any association, especially in regions where onchocerciasis Stroke is a major risk factor for epilepsies. It may explain a third
prevalence is low [67] . Microfilaria, usually intradermal, have of those that occur in the elderly population and there is probably
been found in the CSF of onchocerciasis patients, either after a relationship between epilepsy and stroke risk in later life [80,81] .
treatment with a filaricidal drug [68] or in untreated patients [69] , In several large and well-designed prospective studies, 2–4% of
but they may have also been introduced to the CSF by nee- stroke cases were shown to experience epilepsy during their life-
dles. Cytokine levels, such as IL-1, in immunologic response time. These rates are much higher in smaller (e.g., 6–9%) or
to Onchocerca volvulus, are increased in animal models [70] and retrospective studies (e.g., 39% over 30 months) [82] . These rates
studies of the hippocampus have shown that IL-1b inhibits the also vary from population to population and between different
function of the GABA-A receptor [71] and increases the intra- periods of follow-up, for instance it was 3.8% in a UK popula-
cellular calcium concentration [72] , which may in turn cause an tion over 5 years. The risk of epilepsy associated with stroke has
increase in neuronal excitability. 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
Toxoplasmosis had early onset of seizures) over 26 months in Australian popula-
Toxoplasmosis is an opportunistic infection among immuno- tion [82] . The diagnosis of a post-stroke seizure is difficult because
compromised individuals, such as those with AIDS and those seizure can be characterized by negative motor symptoms and may
who have a low (<200) CD4 cell count. In these patients, toxo- resemble transient ischemic attacks.
plasmosis is a frequent etiological factor for acute seizures and Risk factors for epilepsy or early seizure are dependent on stroke
epilepsy, as are progressive multifocal leukoencephalopathy subtype, stroke location and stroke disability. Hemorrhagic stroke
and other acute cerebral infections [73] . Moreover, high levels is often reported in patients affected with early seizures in recent
of Toxoplasma gondii IgG among the general populations, in cohorts [83] , while it was also associated with post-stroke epilepsy
the USA (20%), France (80%) and Turkey (36%) have been (PSE) in older works [84] . Atherothrombotic and cardioembolic
reported [74] . A meta-ana­lysis showed a higher epilepsy rate in stroke types are together responsible for almost 74% of cases, but
concordance with high toxoplasmosis prevalence [75] , which contrary to previous understanding, lacunar infarct is also sig-
could indicate that some cases of cryptogenic epilepsy may be nificantly associated with PSE [83,85] . Cortical location is reported
a consequence of latent toxoplasmosis. The rupture of some to be an independent predictor of early seizure, but its role as
cysts may cause a marked inflammation leading to a microglial a risk factor for epilepsy is less clear. In a French prospective
reaction and scar tissue formation, which is reported to be an cohort of 581 patients, the presence of cortical deficits includ-
epileptogenic factor [76] . ing Wernicke’s aphasia, isolated hemianopsia, hemineglect and

866 Expert Rev. Neurother. 11(6), (2011)

Etiologies of epilepsy: a comprehensive review Review

apraxia were predictors of epilepsy [85] , whereas in a prospective AVM & epilepsy
multicenter study of 1897 patients, cortical location of stroke was Epilepsy risk with AVM can be as high as 40% with higher rates
not an independent risk factor [83] . The magnitude of stroke (i.e., in older people [99] . Epileptogenicity increases particularly with
extended to a half hemisphere or more) seems to be associated temporal and rolandic locations, which constitute 40–45% of
with PSE in some studies [85] . There may also be a specific greater AVM-related epilepsy. Seizures are the first symptom in 17–36%
risk for epilepsy among those who develop an initial seizure as of cases, while in 40% of cases it is bleeding that reveals AVM.
late onset (>2 weeks) after ischemic stroke [83] . Severity of the The majority of patients show improvement in their epilepsy after
initial and later disability (Rankin Scale) is associated with early respective surgery or radiosurgery of the AVM [100] .
epileptic seizures but not PSE [82,85] .
Epileptogenic mechanisms are poorly understood. The Mesial temporal lobe epilepsy with
regional metabolic dysfunction and excitotoxic neurotransmit- hippocampal sclerosis
ter release secondary to neuronal death and ischemic penumbra No precise epidemiological information is available but accord-
surrounding the infarct is probably the substrate of early onset ing to one estimate, mesial temporal lobe epilepsy (MTLE) with
seizures. Brain damage involving enhanced release of excito- hippocampal sclerosis (HS) may account for 20% of all epilepsy
toxic glutamate, ionic imbalances, breakdown of membrane and 65% of all MTLE [101] . One study reported HS in 36% of
phospholipids and release of free fatty acids promote epilepto- new onset temporal lobe epilepsy [102] . These estimates could, in
genic processes. In hemorrhagic stroke, a combination of focal fact, be higher owing to the increasing use of MRI scans leading
ischemia, blood products (hemosiderin) and the sudden devel- to increased identification and bias towards selection of drug-resis-
opment of a space-occupying lesion may elicit seizure activity. tant patients. MTLE may occur many years after the occurence of
The cause of PSE is thought to be an epileptogenic effect of febrile seizures. Seizures have a gradual onset, are drug-refractory,
gliotic scarring [86] . and begin with subjective symptoms before frequent secondary
loss of contact [103] . Secondary generalized tonic–clonic (GTC)
Cerebral cavernous malformations & epilepsy seizures are unusual. A randomized controlled trial showed sig-
Cerebral cavernous malformations are benign and rare vascular nificant chances for seizure freedom post-surgery as compared
malformations affecting 0.02–0.5% of the population [87] and are with drug treatment [104] . Anterior temporal lobectomy is associ-
supratentorial in 65–90% of cases [88] . Seizures are often associ- ated with a high rate of seizure-free patients according to Engel’s
ated with them and can be a sole presenting feature in 40–79% class I (seizure-free group included those who experienced auras
of cases  [89] . The risk of epilepsy is variable (30–64%) [90] and [simple partial seizures only]) of 97.6, 95 and 71.1% at 1, 2 and
is higher in children (perhaps owing to a greater propensity to 10 years after surgery, respectively [105] .
hemorrhage) [91] and in those with multiple lesions (1.51% per Epileptogenesis is accompanied by numerous changes: extensive
person/year for those with a single lesion or 2.48% per lesion/ hilar and pyramidal layer neuron loss from Ammon’s horn (CA1,
year for those with multiple lesions) [92] . Congenital venous mal- CA3) with partial or majority survival of dentate granule cells
formations can be associated with cavernomas but are frequent and CA2 pyramidal cells, synaptic reorganization with sprouting
abnormalities (3% of population) and do not seem to be associ- of glutamatergic granule cells in dentate gyrus (mossy fibers) and
ated with cerebral hemorrhage or epilepsy. Temporal cavernomas neurogenesis [106] causing hypersynchronization and excitability.
show a tendency to be associated with intractable epilepsy [93] . The question remains of the determinants of epileptogenesis
When cavernomas are responsible for intractable epilepsy, surgi- leading to HS. The preferred hypothesis is that HS results from
cal resection has shown good results, with seizure remission in damage following prolonged febrile convulsions frequently found
94% of cases [88] . in patients’ medical histories [106] . Febrile seizure, particularly in an
Cavernomas have no capsule separating the lesion from the age-specific time window, could explain hippocampic insult, but
surrounding brain parenchyma. Glial changes and hemosid- why unilateral injury? Current evidence suggests that pre-existing
erin deposition can be found in surrounding neuronal paren- cortical dysplasia, especially in the temporal lobe, may increase
chyma  [94] . Cavernomas are dynamic lesions and follow-up the pro-epileptogenic effect of prolonged febrile seizures and thus
MRI studies reveal changes in size and signal characteristics. ensure the later development of temporal epilepsy  [107,108] . Dual
Mechanisms underlying epilepsy are complex. Studies have pathology associating HS and cortical dysplasia is more frequent
reported that neurons adjacent to cerebral cavernous malforma- in patients with a history of febrile seizures  [108] , and in those
tions are twice as excitatory than neurons adjacent to similar patients with HS, focal cortical dysplasia is located in the tem-
intracellular mass lesions [95] , while in another study, cerebral poral lobe. However, it is not yet elucidated whether HS is a con-
cavernous malformations yielded twice as high a seizure fre- sequence of repeated seizures due to cortical dysplasia or whether
quency than other mass lesions such as arteriovenous malforma- a congenital pathology can be responsible for this dual pathol-
tions (AVMs; 20–40%) or gliomas (10–30%) [96] . More than ogy. Other developmental lesions such as microdysgenesis of the
its effect as a space-occupying lesion, microhemorrhages and temporal lobe are associated with HS and MTLE [109] . In the
deposits of hemosiderin surrounding the cavernoma appear to past, perinatal damages were suspected of being able to provoke
induce epileptic activities [97] via neuronal excitotoxicity and HS but such medical histories are extremely rare in MTLE–HS
reactive glial proliferation [98] . patients. Finally, the question of a genetic contribution remains. 867
Review Bhalla, Godet, Druet-Cabanac & Preux

An association of a polymorphism in the IL-1b gene in patients Epilepsy of inflammatory origin

with HS and MTLE has been reported. This polymorphism may Autoimmune encephalitis
result in increased production of the proinflammatory IL-1b and Rasmussen encephalitis is a rare childhood syndrome [122] ini-
promote hippocampic damage after febrile seizure [110] . However, tially described by Rasmussen as ‘focal seizures due to chronic
another study disproves this association [111] . Several forms of localized encephalitis’. A typical disease course involves a pro-
familial mesial temporal lobe epilepsy have been described, but gressive decline in functions associated with the affected hemi-
HS is unusual in these forms [112] . sphere along with frequent intractable unilateral focal motor
seizures or secondarily generalized seizures. Epilepsia partialis
Alzheimer’s disease & epilepsy continua is frequent. After an acute period of 8–12 months,
Neurodegenerative disorders such as Alzheimer’s disease (AD) the patient passes into a residual stage with stable neurologi-
are progressively recognized as a cause of epilepsy onset. A high cal deficit but persistent drug-resistant seizures. The role of
prevalence rate of epilepsy, with at least one unprovoked late some antibody-mediated immune responses such as AMPA
onset GTC seizure, is found in 16% of sporadic advanced AD receptor antibodies (GLuR3), acetylcholine receptor antibod-
cases  [113] and similar rates are observed in retrospective stud- ies (a7  AChR) and synaptic protein Munc18–1 antibodies
ies [114] . Nonetheless, another study reported equally high risk for or cytotoxic T cells, causing apoptotic death of neurons and
epilepsy early (within 6 months) in the course of AD onset [115] . In astrocytes [123] , has been suggested.
fact, the incidence of seizures appears to be independent of disease Systemic lupus erythematosus (SLE) is the most common rheu-
stage. Retrospective studies have suggested a greater epilepsy risk matic disease of greater significance in children. Epilepsy preva-
of nearly tenfold for AD patients [116] . Seizures are mostly GTC, lence is eightfold higher in these cases than in the general popula-
both in prospective and retrospective studies [113,114] . Seizure in tion and varies between 10 and 20%. Quite significantly, seizures
AD has been widely interpreted as a secondary process. Indeed, precede the clinical onset of SLE in a considerable number of cases
aging-related cofactors and neurodegeneration may contribute to (up to 10%) and may suggest some role of antiepileptic drugs in
the development of seizures in AD. Several observations support precipitating SLE. The autoimmune mechanism in these cases
a direct relationship including those collected from one of the primarily involves antiphospholipid or anticardiolipin antibodies
principal animal models of AD: hAPP mice. The brains of these (later present in up to 60% of cases). There is threefold greater
transgenic mice are exposed to high levels of human b-amyloid epilepsy risk among those who have anticardiolipin antibodies
peptides (Ab), which is suspected to have a pathogenic role in AD. compared with those who do not [124,125] .
Electroencephalograms of these mouse models reveal epileptiform In Behcet’s disease (BD), the brain is frequently involved in
activity and intermittent seizures involving the neocortex and 2.5–49% of cases. Epilepsy risk is not known; however, seizures
hippocampus without any overt neuronal loss. This makes it pos- are frequently reported and frequency varies from 2.2–27% in
sible to assume that Ab is an important cause of aberrant neural neurological forms of BD [126,127] . This risk may vary with eth-
network activities, thus being able to lead to epilepsy [115,117] . nicity and environmental factors (seizure-provoking factors or
Moreover, in autosomal dominant early onset AD, including exacerbation of disease). Epilepsy may have a direct causative
those with mutations in presenilin-1, presenilin-2 or the amy- relationship with BD or may be secondary to parenchymal
loid precursor protein (APP), the relationship between clinically lesions [128] .
apparent seizures and AD is stronger. More than 30 mutations in In the rarer Hashimoto’s encephalopathy, epileptic seizures
presenilin-1 are associated with epilepsy [118] and 56% of patients are often present, although these could be provoked in nature.
with early onset AD with APP duplications have seizures [119] . The pathogenesis depends upon the anti-thyroid antibodies and
Finally, apolipoprotein E4 also exacerbates epilepsy or epilepti- a response to corticosteroids is consistently found [129] . Within a
form activity [120] and contributes to AD pathogenesis through series of seven such patients, one had complex partial epilepsy and
both Ab-dependent and Ab-independent pathways [121] . recurrent status epilepticus without other clinical features [130] .
Autoimmune limbic encephalitis is of
Table 4. Antibodies in autoimmune epilepsy. paraneoplastic or non-paraneoplastic ori-
Encephalitis Antibody (associated main tumors) gin. Several antineuronal antibodies have
been associated with this disease (Table 4) .
Rasmussen Anti-GluR3, Anti-7 AChR, Anti-Munc18–1
Voltage-gated potassium channel antibod-
Paraneoplastic Anti-Hu (small cell lung cancer) ies are most frequently coupled with epi-
Anti-Ma-1 (testicular) lepsy [131] . Voltage-gated potassium chan-
Anti-Ma-2 (testicular)
nel antibodies-encephalitis often involves
Anti-Yo (ovarian)
Anti-NMDAR (ovarian teratomas) complex partial and generalized seizures,
sleep behavior disorder and confusion.
Nonparaneoplastic Anti-VGKC
Characteristic epileptiform abnormalities
(such as focal or generalized slow wave
Hashimoto Anti-thyroid peroxidase (anti-TPO) antibodies abnormalities, electrographic seizures or
Data taken from [124,130,131]. periodic lateralized epileptiform discharges

868 Expert Rev. Neurother. 11(6), (2011)

Etiologies of epilepsy: a comprehensive review Review

in the temporal regions) are present on encephalogram and MRI and delays the occurrence of kindling effect [146] , whereas chronic
sometimes shows abnormalities of medial temporal areas. In the consumption may facilitate neurobiological modulations (excita-
later stages of the disease, a relapse involving HS and chronic tion of R-NMDA or increase in glutamate levels in the limbic and
epilepsy may evolve as sequelae. cortical areas and inhibition of GABA-A) that in turn facilitate
neuronal hyperexcitability [147] . Nearly 74% of chronic alcohol
Post-vaccination encephalopathy & epilepsy drinkers with epilepsy have a consequential cerebral atrophy
There is no evidence that vaccination causes epilepsy. The term of and so this may have a role in hyperexcitatory pathogenesis [148] .
‘vaccine encephalopathy’ used to describe seizures and encepha- Moreover, the potential for cerebrovascular infarctions and trau-
lopathy following a vaccination is linked by several studies to the mas is augmented in heavy alcohol users and could therefore
beginning of myoclonic severe epilepsy of infancy or Dravet syn- mediate epilepsy [148] .
drome [132,133] . In this epileptic encephalopathy, prolonged febrile
seizures in the first 6 months of life are frequently provoked by Malformations of cortical development & epilepsy
a vaccination. In 2005, the WHO ruled that pertussis vaccines, Malformations of cortical development (MCD) are the second
often blamed, do not cause brain damage or encephalopathy. leading cause of symptomatic focal epilepsy in children (13.1%)
after nervous system infections (15.1%) and before perinatal brain
Multiple sclerosis damage (12.6%). Cerebral malformations are the first etiology of
It is unclear whether a relationship between epilepsy and multiple intractable epilepsy [149] .
sclerosis (MS) is either symptomatic or coincidental. Epileptic sei- Epilepsy begins mostly in childhood and adolescence and is
zures can be the first observable symptom in 10% of cases [134] and often associated with mild or severe cognitive impairment and
could be of significance since many MS lesions, even when evalu- other neurologic disabilities. A family history of epilepsy should
ated by MRI, remain silent [135] . Epilepsy rates are particularly high always be sought in order to take into account the presence of
in some studies in the MS population. One study found a threefold genetic MCD forms, such as those associated with nodular hetero-
higher rate (over a period of 25 years) [136] or tenfold higher age- topia (filamin A), with lissencephaly or subcortical band heteroto-
adjusted prevalence [137] . Seizures are particularly partial (simple pias (LIS1, TUBA1A and DCX ) or with polymicrogyria (GPR56,
and complex) and occur in a greater proportion in patients with MS SRPX2) and schizencephaly (EMX2) [150] . Resective surgery is the
than that observed in a general epilepsy population (50 vs 30%) only available treatment and is indicated for those with MCDs
[137,138] . Evidence suggests that cortical and subcortical demyelin- restricted to part of a hemisphere (such as focal cortical dysplasias,
ating lesions are themselves irritative foci [137] . MRI studies have polymicrogyria [151] with or without schizencephaly or nodular
shown a higher frequency of MS lesions that extend into the cortex heterotopia of gray matter). Surgery provides a seizure-free out-
when epilepsy was present [139] . Frontal atrophy in epilepsy cases come in ≥50% (range: 49–76%) cases over 5–8 years [152,153]
may also have a role in epileptogenesis [137,138] . but the proportion of patients with satisfactory outcome tends to
decrease during the first 3 years.
Gastrointestinal inflammatory disorders
A large meta-ana­lysis has shown that the relative risk of epilepsy Neurocutaneous syndromes & epilepsy
among celiac disease cases is 2.1 and that of celiac disease in Tuberous sclerosis complex
epilepsy cases is 1.7 but the overall risk difference was close to Tuberous sclerosis complex (TSC) is an autosomal dominant
zero, thus suggesting a low possibility for epilepsy among these disorder with an incidence at birth of one in 6000. This dis-
cases. Another Italian study also yielded a similar prevalence of order is characterized by the development of benign tumors
antibodies related to celiac disease in those with epilepsy and in multiple organ systems, including the brain. Neurological
controls [140,141] . manifestations of TSC are epilepsy, mental retardation and
autism. Epilepsy is the most commonly associated manifesta-
Alcohol & epilepsy tion and 60–90% of cases may develop epilepsy during their
There is a significant relative risk for epilepsy in chronic alco- lifetime [154] . These rates are even higher in retrospective studies
hol users (RR: 2.19; 95% CI: 1.83–2.63) [142] and those with (93.2%) [155] . Seizures often begin early in life as partial seizures
presumed alcohol-related first seizure may experience recurrence and infantile spasms and then evolve into severe multifocal
within 3 years [143] . Epilepsy risk is dose dependent and increases epilepsy with mixed seizure types, often characterized by a low
after four or more drinks per day (RR: 4/6/8 drinks/day: [1.81; remission rate.
95% CI: 1.59–2.07]; [2.44; 95% CI: 2.00–2.97]; [3.27; 95% Cortical and subcortical tubers and their surrounding tissue
CI: 2.52–4.26], respectively). The seizures are mostly generalized are responsible for the seizures. These tubers are characterized
and especially tonic–clonic [144] and those with GTC are more by proliferation of glial and neuronal cells, and loss of the six-
often regular alcohol drinkers with a high daily consumption layered cortical structure. This disorder is caused by mutations
rate [144] . There is a low rate (5–16%) of partial seizures [145] . in tumor suppressor genes TSC1 or TSC2. The protein products
Owing to alcohol, there may also be increased risk for neural or of these genes, hamartin and tuberin, act as negative regula-
metabolic complications that may further lead to repeated sei- tors of the pathway of mTOR, which regulates cell growth and
zures [143] . Acute consumption may raise the convulsive threshold proliferation [156] . 869
Review Bhalla, Godet, Druet-Cabanac & Preux

Modifications in glutamate receptor expression, such as AMPA than inhibition is observed in neuronal networks of the develop-
or NMDA subunits, on neuronal or glial cells in and around the ing brain [169] . Moreover, animal models have shown that chlo-
tuber may also have a role in epileptogenicity [157] . At the same ride transporters (NKCC1) in the immature brain may promote
time, neuronal inhibition seems to be deficient because of the neuronal excitability through modulation of the activation effect
molecular changes in GABA receptors [158] , which may explain of GABA that become depolarizing in the developing brain [170] .
the high efficacy of vigabatrin, a GABAergic antiepileptic drug,
in this disorder. Conclusion
It is evident that epilepsy is a complex and heterogeneous dis-
Neurofibromatosis 1 order with a long list of risk factors. We reviewed epilepsy eti-
Despite being one of the most common neurocutaneous disor- ologies and highlighted the main risk-defining parameters as
ders, studies of neurofibromatosis are limited in number and fail far as possible (injury severity, low grade tumors especially of
to provide any detailed perspective on epilepsy risk. However, temporal or rolandic localization, early onset, genetic origin of
based on available studies, the prevalence of epilepsy varies AD and so on), which might promote timely identification of a
between 3 and 12%, where a significant proportion of cases suitable target population (people at risk of developing epilepsy).
show neuro­imaging abnormalities that are relevant to epilepsy Variable significance of individual etiologies (stroke, perinatal
[159,160] . Similar to other phacomatoses with subcortical focal trauma, infections in low–middle income countries [LMIC])
brain lesions, an evolution from generalized to focal-onset epi- and presence of cofactors (other diseases or clinical symptoms)
lepsy is observed and this might be related to glioma or cortical may lead to region-specific epilepsy frequencies. A direct role of
dysplasia, although it is infrequently found in neurofibromatosis alcohol in epilepsy onset is less convincing. The role of oncho-
1 cases [161] . The epileptogenesis may follow similar patterns, as cerciasis in epilepsy onset remains possible but subject to further
observed in TSC cases, with alteration in cytoarchitecture, neu- research. Many gene mutations representing rarer epilepsy forms
rotransmitter receptor expression (such as for glutamate recep- have been discovered but are of limited day-to-day clinical value.
tors), which may have a role in epileptogenicity. Since hydro- Particular attention should be paid to cerebral malaria, AD and
cephalus is quite common among these cases, cerebral insults limbic encephalitis. Populations in many countries (e.g., North
due to ventricular catheterization or any associated infection, Europe) are aged/aging and this may lead to a consequential
may also be relevant in epileptogenesis. increase in AD-related epilepsy in the near future. Perinatal fac-
tors and infections do represent significant causes of epilepsy
Perinatal adverse events & epilepsy in many pockets of LMICs but these conclusions are drawn
Injury during the perinatal period is generally the result of in the absence of sufficient population-based studies and their
hypoxia or ischemia related to stroke, sepsis or cardiovascular independent effect as epilepsy triggers has most probably been
insufficiency. This injury risk varies depending upon the birth overhighlighted; for example, the independent significance of
term. The pre-term brain exhibits particular susceptibility perinatal trauma as a causal factor may get diluted by the pres-
of the white matter whereas the at-term brain rather exhibits ence of family history of epilepsy. They also overshadow other
fragility of gray matter and thus an augmented risk towards more relevant etiologies such as stroke and cerebral malaria in
epilepsy  [162] . Epilepsy is a common additional disability that these populations. Moreover, the wealth of information avail-
may affect children with cerebral palsy who have suffered severe able to develop epileptogenic drugs, for instance inhibitors of the
hypoxia/ischemia at-term, affecting up to 50% of children with mTOR pathway, may modify the course of tuberous sclerosis and
spastic quadriplegia [163] . While most neonates with stroke would consequentially the risk of epilepsy onset. Most drugs of today are
present with seizures, the majority do not develop epilepsy in seizure-controllers. This should go hand-in-hand with the need to
childhood. The incidence of recurrent seizures after perinatal develop specific epilepsy prevention methods that may constitute
stroke ranges from 0 to 40%  [164] . In a recent study, perinatal newer research avenues. Finally, there is a need to develop LMIC-
stroke was shown to be associated with a very high rate of epi- specific ‘ideal epilepsy epidemiology monitoring criteria’ since
lepsy (67%) [165] . Some studies suggest that pre-term birth may the guidelines that currently exist do not fit the challenges that
be an independent risk factor for epilepsy that increases with an epidemiological investigation on epilepsy in these countries
decreasing gestational age [166] . A later life epilepsy risk increases may have. Problems in these countries are different and may need
with decreasing Apgar scores, with a relative risk of 7.1 (95% CI: different solutions.
5.8–8.8) [167] . Similarly, prolonged gestation could lead to peri-
natal complications, especially epilepsy. However, this epilepsy Expert commentary
risk is only significant during the first year of life. One large Seizure and syndromic classifications are always controversial.
cohort of children (born ≥39 gestational weeks) demonstrated a Unlike newer classification schemes, in this article we addressed
high incidence ratio of epilepsy for birth at 42 weeks (1.3) , and epilepsy etiologically, which views epilepsy as due to different
for birth at ≥43 weeks (2.0) versus birth at 39–41 weeks (1) [168] . causes, having various localizations and occuring in conjunc-
Finally, this epilepsy risk increased for instrument-assisted and tion with other diseases, thus occuring at varying frequencies.
cesarean deliveries (1.4–4.9) [168] . Epileptogenesis may result, as This classification provides more biological significance, limited
in adults, from many factors, but comparatively greater excitation syndromic overlap and greater precision (e.g., with regard to age

870 Expert Rev. Neurother. 11(6), (2011)

Etiologies of epilepsy: a comprehensive review Review

of onset) but is of limited use for idiopathic or electroclinical childbirth and infections. Suitable strategies may thus emerge
syndromes. An underlying cause can only be identified in 30% in the coming years. Third, there has been a continuous search
of cases. Future research may answer some pertinent questions: for antiepileptogenic drugs in order to prevent epilepsy onset
for instance, occurrence of differing epilepsy forms with the same but current drugs are only seizure-controllers. This article has
SCN1A mutation (generalized febrile seizures in some and severe discussed all known causes of epilepsy and where possible high-
myoclonic epilepsy in others) or how gain or loss of function in lighted the highest risk-defining parameters (injury severity, low
SCN1A channel could lead to the same Dravet syndrome. grade tumors, temporal versus rolandic, early onset, genetic origin
of AD and so on). Thus, we expect that many valuable works
Five-year view would lead to anti-epileptogenic drug development and designate
First, populations in many countries are aged/aging (e.g., North suitable targets (people at higher risk to develop epilepsy) to test
Europe), which may redirect the focus on etiologies such as AD for such molecules.
with consequential increase in epilepsy incidence in such coun-
tries. In addition, there is a need to develop specific prevention Financial & competing interests disclosure
methods, for instance those based on b-amyloid, could constitute The authors have no relevant affiliations or financial involvement with any
newer research avenues in the coming years. Second, perinatal organization or entity with a financial interest in or financial conflict with
and infection-related epilepsies are most likely over-represented the subject matter or materials discussed in the manuscript. This includes
in the absence of sufficient population-based studies in many employment, consultancies, honoraria, stock ownership or options, expert
developing countries. However, this may not undermine the testimony, grants or patents received or pending, or royalties.
need to develop and implement better public management of No writing assistance was utilized in the production of this manuscript.

Key issues
• Many past reviews have addressed sole etiologies. In this article, we aimed to comprehensively discuss all etiologies significant for both
the developing and developed world and routine clinical-epidemiological practice.
• Differing etiological significances (e.g., stroke, perinatal trauma, infections in low–middle income countries [LMIC]) and presence of
cofactors (other disease/symptoms) are the main reasons for differing (region-specific) epilepsy frequencies.
• Some risk factors are age-specific. In those over 40 years of age, trauma, tumor and stroke are pertinent risk factors. In early age,
metabolic, cerebral anoxia, infection and developmental abnormalities are significant risk factors. In adolescents, hippocampal sclerosis,
vascular malformations and trauma are the main etiological factors.
• The chief risk factors 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 and so on.
• New information has emerged in recent years: epilepsy risk is associated with limbic encephalitis, there is a genetic basis of Alzheimer’s-
related epilepsy, a genetic basis of cortical malformations, and the discovery of several genes/mutations for rarer epilepsy forms of
limited clinical interest.
• There is a 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 a consequential increase in epilepsy may occur in the near future.
• 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 overhighlighted and they overshadow other more relevant etiologies in
these populations.
• We need to utilize the existing wealth of information to develop epileptogenic drugs, for instance inhibitors of the mTOR pathway,
which may modify the course of tuberous sclerosis and hence epilepsy onset.
• Specific epilepsy prevention methods may constitute newer research avenues.
• There is a need to develop LMIC-specific ‘ideal epilepsy epidemiology monitoring criteria’, since existing guidelines do not fit the
current 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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