THEMED ARTICLE y Epilepsy
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Devender Bhalla1,
Bertrand Godet1,
Michel Druet-Cabanac1
and Pierre-Marie
Preux†1
1
Université 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
preux@unilim.fr
www.expert-reviews.com
Review
Etiologies of epilepsy:
a comprehensive review
Expert Rev. Neurother. 11(6), 861–876 (2011)
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 and language; chosen based on novelty and 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 gain knowledge.
Keywords : epidemiology • epilepsy • etiology • genetic • metabolic • risk factors • seizure • structural
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

Stroke

Cavernomas and arteriovenous

malformations
Cerebral immunological disorder

Hippocampal sclerosis

Malformations of cortical development

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

Neurocutaneous
Parasitic brain infection
syndrome

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-
tionship between the clinical syndrome and the genetic mecha-
nism may either involve locus heterogeneity (e.g., benign familial
neonatal convulsions) or variable expressivity (e.g., generalized
epilepsy with febrile seizures plus). Various genetic epilepsy forms
are described in Table 1. Various metabolic causes of genetically
determined epilepsy (early in life) by age are descibed in 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% show
EEG abnormalities. Epilepsy tends to begin 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 appear to be valproic acid and clon-
azepam [8] . Ring chromosome 20 syndrome is characteristically
associated with drug-resistant epilepsy. Children present noncon-
vulsive status 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 & epilepsy
Brain tumors, benign or malignant, are a common cause of epilepsy
and yield an epilepsy incidence of nearly 30% [10] . On the other
hand, almost 4% of epilepsy patients have brain tumors [11] . The
risk for developing epilepsy is higher among adults than children [11]
and this epilepsy risk depends upon many factors including tumor
type, tumor grade or location, presence of cerebral hemispheric
dysfunction or incomplete tumor resection [10,12] . The factors that
are mostly associated with adult epilepsy include melanoma, hem-
orrhagic lesions, multiple metastases and slowly growing primary
tumors. Factors among children include gangliogliomas, low grade
astrocytomas, dysembryoplastic neuroepithelial tumor and oligo-
dendrogliomas [12] . WHO grade I tumors (such as ganglio­gliomas
and pilocytic astrocytomas) may be the most significant epilepsy
predictor since they are most commonly seen (70% of cases) among
patients with primary brain tumor and drug-resistant epilepsy [13] .
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
supplementary areas [14] . A study showed that the 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
progression may allow more time for epileptogenesis to develop,
whereas high grade tumors (e.g., glioblastomas) are malignant,
grow rapidly and most likely destroy nearby neurons instead of
stimulating 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, as follows:
• Altered BBB function may lead to the generation of seizure
foci [18] ;
• Enzymatic changes in lactate dehydrogenase and cAMP
phosphodiesterase may lead to metabolic imbalance [19] ;
• Impaired cellular connections and altered expression of connex-
ins 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 play a role in epileptogenesis. Marked perilesional
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 neuro­
transmitters 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 GABA
immunoreactivity [22] , as well as its potential to depolarize neu-
rons (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 trauma against the head
and characterized by changes in brain function, that is, loss of
consciousness, amnesia, confusion and focal temporary neurologi-
cal 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 as in people without BI (relative risk [RR]: 2.22; 95% CI:
2.07–2.38), whereas it was sevenfold higher among cases with
SBI (RR: 7.40; 95% CI: 6.16–8.89)  [25] . The epilepsy risk also

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 Review Bhalla, Godet, Druet-Cabanac & Preux

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 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
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/adolescence
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
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 studies on soldiers who were exposed to craniocerebral missile
wounds in armed conflicts has been estimated to be 50% even 10
or more years after the injury [24] . Other factors may have a role
in yielding an increased risk for epilepsy, including: acute seizure
in the first week after BI, necessity of neurosurgical procedures,
prolonged post-traumatic amnesia, missile injuries [27] , being older
than 15 years of age at the time of injury, and 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
epilepsy 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
considerable 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
deposition from extravasated blood, increased excitotoxicity due
to accumulation of glutamate, diffuse axonal injury, edema or
ischemia [27] . Evidence for cortical damage, presence of hemo-
siderin deposits and gliotic scarring on MRI could be important
predictor for epilepsy.
Infectious epilepsy
Bacterial or viral meningitis/viral encephalitis
Meningitis 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 hear-
ing loss) are at an increased risk of having at least one late unpro-
voked 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 proinflamma-
tory cytokines, such as TNF, in response to chronic inflam-
mation or activation of immune system agents in response to
endotoxemia [32,33] , suggesting their role in mechanisms that
induce an increase in seizure susceptibility during brain infec-
tion. Furthermore, activation of host pattern-recognition recep-
tors such as Toll-like receptor (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 enceph-
alitis (HSE) is most commonly associated with epilepsy  [35] .
Hospital-based studies suggest seizures occur in 40–65% of
cases  [36] . The risk for epilepsy is high in those patients who

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 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-
cant 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 basifron-
tal cortices. Several autopsy-based and postsurgical examinations
of brain tissues reveal chronic inflammation within the mesial
temporal lobe structures in addition 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 facilitating the development of
acute seizures and subsequent epilepsy [41] . In general, following
any viral encephalitis, there is a 16-fold increased risk of devel-
oping 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% and for cases of acute nipah virus encephalitis, the
incidence rate is 2.2% over 8 years.
Bacterial brain abscesses
Bacterial brain abscesses are usually related to head trauma, con-
tiguous suppurating process, blood-bourne infection or compli-
cations 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 (endocar-
ditis) [42] . In this study, 4.3% of surviving 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 neuro­logical manifestations, particularly in endemic
tuberculosis regions [44,45] .
Neurocysticercosis
Neurocysticercosis (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 community-
based surveys demonstrated high seroprevalence (determined by
enzyme-linked immunoelectrotransfer blot techniques) in various
countries of Latin America (10–23%) and Asia (20–47%) [47] .
A relationship between seroprevalence and epilepsy as demon-
strated in case–control studies, reflected by high odds ratio (OR)
of 1.8–4.6 [48–51] which, as suggested in a large meta-ana­lysis, is
even higher in various African populations (mean OR: 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 degenera-
tion (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 resistance, 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 fron-
tal and temporal lobes [55] . The host response to degenerating cysts
may also play an important role in epileptogenesis that could vary
significantly; for instance, a more profound response is observed
among women or children and secondly, within the same subject,
a varying degree of pericystic inflammation (profound or even
absent) is observed [53,55] .

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 Review Bhalla, Godet, Druet-Cabanac & Preux
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 epi-
lepsy 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 show vascular ischemic lesions
resulting from sequestration of parasitic erythrocytes and are
confirmed in autopsy studies [60] . Durck’s malarial granuloma
comprising of reactive astrocytes is also reported to have epilep-
togenic 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] .
Onchocerciasis
The nature of onchocerciasis’ relationship with epilepsy is con-
troversial. A few population-based African studies reported a
significant correlation between prevalence of epilepsy, oncho-
cerciasis and its microfilarial load [64,65] . A large meta-ana­lysis
showed that overall risk increased [66] and epilepsy prevalence
increased by 0.4% with every 10% increase in Onchocerca vol-
vulus prevalence [64] . On the other hand, some studies 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 nee-
dles. Cytokine levels, such as IL-1, in immunologic response
to Onchocerca volvulus, are increased in animal models [70] and
studies of the hippocampus have shown that IL-1b inhibits the
function of the GABA-A receptor [71] and increases the intra-
cellular calcium concentration [72] , which may in turn cause an
increase in neuronal excitability.
Toxoplasmosis
Toxoplasmosis 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, toxo-
plasmosis is a frequent etiological factor for acute seizures and
epilepsy, as are progressive multifocal leukoencephalopathy
and other acute cerebral infections [73] . Moreover, high levels
of Toxoplasma gondii IgG among the general populations, in
the USA (20%), France (80%) and Turkey (36%) have been
reported [74] . A meta-ana­lysis showed a higher epilepsy rate in
concordance with high toxoplasmosis prevalence [75] , which
could indicate that some cases of cryptogenic epilepsy may be
a consequence of latent toxoplasmosis. The rupture of some
cysts may cause a marked inflammation leading to a microglial
reaction and scar tissue formation, which is reported to be an
epileptogenic factor [76] .
866
Toxocariasis
Toxocariasis is one of the most common zoonotic helminthic
infections predominantly seen in children (aged <5 years) in rural
and non-Western tropical general populations (63.2–93% sero-
prevalence). Western seroprevalence varies from 2–5% in urban
zones to 14.2–37.0% in rural ones. The human form is caused
by the larvae of Toxocara canis, which has long been known to
have a tendency to lodge in the brain. A high seroprevalence is
observed among people with intellectual difficulties. Some studies
have demonstrated 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 sero-
positivity 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 com-
pletely mature in humans and most infections remain asymptom-
atic or latent. The host immune response may lead to generalized
seizures while granulomas may lead to focal seizures  [78] . There
is also a possibility that migrating larvae carry other infectious
epilepsy trigger agents since eosinophilic meningitis, encephalitis
or meningo-encephalitis [79] are observed. Those showing patho-
logical indicators on a CT or MRI scan with solitary mass lesions
should be screened for such infection.
Stroke & epilepsy
Stroke is a major risk factor for epilepsies. It may explain a 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 it was 3.8% in a UK popula-
tion 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 popula-
tion [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 sig-
nificantly 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 includ-
ing Wernicke’s aphasia, isolated hemianopsia, hemineglect and
Expert Rev. Neurother. 11(6), (2011)
 Etiologies of epilepsy: a comprehensive review
apraxia were predictors of epilepsy [85] , whereas in a prospective
multicenter study of 1897 patients, cortical location of stroke was
not an independent risk factor [83] . The magnitude of stroke (i.e.,
extended to a half hemisphere or more) seems to be associated
with PSE in some studies [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 neurotransmit-
ter 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 excito-
toxic glutamate, ionic imbalances, breakdown of membrane
phospholipids and release of free fatty acids promote epilepto-
genic processes. In hemorrhagic stroke, a combination of focal
ischemia, blood products (hemosiderin) and the sudden devel-
opment 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 associ-
ated 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 mal-
formations can be associated with cavernomas but are frequent
abnormalities (3% of population) and do not seem to be associ-
ated with cerebral hemorrhage or epilepsy. Temporal cavernomas
show a tendency to be associated with intractable epilepsy [93] .
When cavernomas are responsible for intractable epilepsy, surgi-
cal resection has shown good results, with seizure remission in
94% of cases [88] .
Cavernomas have no capsule separating the lesion from the
surrounding brain parenchyma. Glial changes and hemosid-
erin deposition can be found in surrounding neuronal paren-
chyma  [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 malforma-
tions 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 fre-
quency than other mass lesions such as arteriovenous malforma-
tions (AVMs; 20–40%) or gliomas (10–30%) [96] . More than
its effect as a 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] .
www.expert-reviews.com
Review
AVM & epilepsy
Epilepsy risk with 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 sclerosis
No 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-resis-
tant patients. MTLE may occur many years after the occurence of
febrile seizures. Seizures have a gradual onset, are drug-refractory,
and begin with subjective symptoms before frequent secondary
loss of contact [103] . Secondary generalized tonic–clonic (GTC)
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 epilepsy  [107,108] . Dual
pathology associating HS and cortical dysplasia 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 tem-
poral lobe. However, it is not yet elucidated whether HS is a con-
sequence of repeated seizures due to cortical dysplasia or whether
a congenital pathology can be responsible for this dual pathol-
ogy. 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.
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
Anti-GAD
(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
in the temporal regions) are present on encephalogram and MRI
sometimes 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 syn-
drome [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 WHO ruled that pertussis vaccines,
often blamed, do not cause brain damage or encephalopathy.
Multiple sclerosis
It is unclear whether a relationship between epilepsy and multiple
sclerosis (MS) is either symptomatic or coincidental. Epileptic sei-
zures can be the first observable symptom in 10% of cases [134] and
could be of significance since many MS lesions, even when evalu-
ated by MRI, remain silent [135] . Epilepsy rates are particularly high
in some studies in the MS population. One study found a threefold
higher rate (over a period of 25 years) [136] 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 vs 30%)
[137,138] . Evidence suggests that cortical and subcortical demyelin-
ating 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 disorders
A large meta-ana­lysis 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 & epilepsy
There is a significant relative risk for epilepsy in chronic alco-
hol users (RR: 2.19; 95% CI: 1.83–2.63) [142] and those with
presumed alcohol-related first seizure may experience recurrence
within 3 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 generalized
and especially tonic–clonic [144] and those with GTC are more
often regular alcohol drinkers with a high daily consumption
rate [144] . There is a low rate (5–16%) of partial seizures [145] .
Owing to alcohol, there may also be increased risk for neural or
metabolic complications that may further lead to repeated sei-
zures [143] . Acute consumption may raise the convulsive threshold
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Review
and delays the occurrence of kindling effect [146] , whereas chronic
consumption may facilitate neurobiological modulations (excita-
tion 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 hyperexcitatory pathogenesis [148] .
Moreover, the potential for cerebrovascular infarctions and trau-
mas is augmented in heavy alcohol users and could therefore
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
damage (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 heteroto-
pias (LIS1, TUBA1A and 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 a hemisphere (such as focal cortical dysplasias,
polymicrogyria [151] with or without schizencephaly or nodular
heterotopia of gray matter). Surgery provides a seizure-free out-
come in ≥50% (range: 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 & epilepsy
Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is an autosomal dominant
disorder with an incidence at birth of one in 6000. This dis-
order 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 manifesta-
tion and 60–90% of 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 regula-
tors of the pathway of mTOR, which regulates cell growth and
proliferation [156] .
869
 Review Bhalla, Godet, Druet-Cabanac & Preux
Modifications in glutamate receptor expression, such as AMPA
or NMDA subunits, on neuronal or glial cells in and around the
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 1
Despite being one of the most common neurocutaneous disor-
ders, studies of 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 neuro­imaging abnormalities that are relevant to epilepsy
[159,160] . Similar to other phacomatoses with subcortical focal
brain lesions, an evolution from generalized to focal-onset epi-
lepsy is observed and this might be related to glioma or cortical
dysplasia, although it is infrequently found in neurofibromatosis
1 cases [161] . The epileptogenesis may follow similar patterns, as
observed in TSC cases, with alteration in cytoarchitecture, neu-
rotransmitter receptor expression (such as for glutamate recep-
tors), which may have a role in epileptogenicity. Since hydro-
cephalus is quite common among these cases, cerebral insults
due to ventricular catheterization or any associated infection,
may also be relevant in epileptogenesis.
Perinatal adverse events & epilepsy
Injury 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. The pre-term brain exhibits particular susceptibility
of the white matter whereas the at-term brain rather exhibits
fragility of gray matter 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 incidence of recurrent seizures after perinatal
stroke ranges from 0 to 40%  [164] . In a recent study, perinatal
stroke was shown to be associated with a very high rate of epi-
lepsy (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 peri-
natal complications, especially epilepsy. However, this epilepsy
risk is only significant during the first year of life. One large
cohort of children (born ≥39 gestational weeks) demonstrated a
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
cesarean deliveries (1.4–4.9) [168] . Epileptogenesis may result, as
in adults, from many factors, but comparatively greater excitation
870
than inhibition is observed in neuronal networks of the develop-
ing brain [169] . Moreover, animal models have shown that chlo-
ride transporters (NKCC1) in the immature brain may promote
neuronal excitability through modulation of the activation effect
of GABA that become depolarizing in the developing brain [170] .
Conclusion
It is evident that epilepsy is a complex and heterogeneous dis-
order with a long list of risk factors. We reviewed epilepsy eti-
ologies and highlighted the main risk-defining parameters as
far as possible (injury severity, low grade tumors especially of
temporal or rolandic localization, early onset, genetic origin of
AD and so on), which might promote timely identification of a
suitable target population (people at risk of developing epilepsy).
Variable significance of individual etiologies (stroke, perinatal
trauma, infections in low–middle income countries [LMIC])
and presence 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 oncho-
cerciasis 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 fac-
tors and infections do represent significant causes of epilepsy
in many pockets 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 pres-
ence 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 avail-
able to develop epileptogenic drugs, for instance inhibitors of the
mTOR pathway, may modify the course of tuberous sclerosis and
consequentially the risk of epilepsy onset. Most drugs of today are
seizure-controllers. This should go hand-in-hand with the need to
develop specific epilepsy prevention methods that may constitute
newer research avenues. Finally, there is a need to develop LMIC-
specific ‘ideal epilepsy epidemiology 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 in these countries are different and may need
different solutions.
Expert commentary
Seizure and syndromic classifications are always controversial.
Unlike newer classification schemes, in this article 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
Expert Rev. Neurother. 11(6), (2011)
 Etiologies of epilepsy: a comprehensive review Review

of onset) but is of limited use for idiopathic or electroclinical
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 view
First, 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
developing countries. However, this may 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 antiepileptogenic drugs in order to prevent epilepsy onset
but current drugs are only seizure-controllers. This article has
discussed all known causes of epilepsy and where possible high-
lighted 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-epileptogenic drug development and designate
suitable targets (people at higher risk to develop epilepsy) to test
for such molecules.
Financial & competing interests disclosure
The 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.

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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