Simona Balestrini and Sanjay M. Sisodiya A risk factor increases the likelihood of disease but does not fully explain its occurrence, while a cause fully explains the occurrence of a condition. Here, we refer to ‘risk factor’ to encompass all contributing variables. Epilepsy risk factors encompass genetic, structural, infectious, metabolic, immune, and other, as well as still unknown, origins.1 Neurodegenerative conditions are increasingly recognised as epilepsy risk factors.2 Several factors may jointly contribute to an individual’s epilepsy. For instance, a person with traumatic brain injury may have a genetic predisposition to epilepsy, or various environmental risk factors may affect the manifestation of monogenic familial epilepsy. Age and geographical location considerably impact the relative prevalence and importance of risk factors.3 Ischaemic lesions due to cerebrovascular disease or neurodegeneration associated with dementia are the most typical risk factors for seizures in older age. Next‐generation sequencing (NGS) has shown numerous genetic variants – coding and non‐coding, common and rare – associated with epilepsy. Common variants occur in ≥1% of individuals, contributing small and additive effects, while rare variants are present in <1%, and often exert greater effects on disease development. Monogenic epilepsies result from pathogenic variants in single genes, frequently following an autosomal dominant inheritance pattern, although some have an autosomal recessive or X‐linked inheritance. Pathogenic variants are commonly found in the protein‐coding sequence, leading to amino acid substitutions (missense variants) or protein truncation (such as nonsense, frameshift, insertion–deletion, or splicing variants). Demonstrating that a variant disrupts the function of the encoded protein (e.g. directly affecting brain activity or development) strengthens its association with pathogenicity. Many genes linked to epilepsy encode ion channels. Causative epilepsy genes also encode proteins involved in various other biological processes, including enzyme activity, cytoskeletal structure, transport, receptor modulation, nucleic acid binding, cell adhesion, signal transduction and membrane trafficking. Phenotype–genotype correlations in monogenic conditions are often complex, characterised by a broad phenotypic spectrum for many implicated genes, and incomplete penetrance, as not everyone with the pathogenic variants develops epilepsy. Variable expression and phenotypes may also occur even within the same family carrying the same genotype. Developmental and epileptic encephalopathies (DEE) represent the most severe epilepsy syndromes, caused by monogenic de novo (ie arising spontaneously during cell division in the individual) autosomal dominant variants, and more rarely by X‐linked and autosomal recessive variants. Some pathogenic variants may influence treatment; for example, presurgical evaluation is often terminated if a pathogenic SCN1A variant is identified. The choice of antiseizure medication (ASM) may be directly affected (e.g. sodium channel blockers are typically avoided in seizure disorders caused by loss‐of‐function SCN1A variants as they may aggravate seizures). Common epilepsies, including most generalised and focal epilepsies, have a complex polygenic basis involving multiple small‐effect risk variants and potential environmental contributions. Rarely, some common epilepsy phenotypes may be caused by single‐gene variants with a large effect size, e.g. generalised epilepsies caused by pathogenic variants in SLC2A1, GABRA1, or GABRAG2, or autosomal dominant sleep‐related hypermotor epilepsy (ADSHE), caused by pathogenic variants in CHRNA4, CHRNA2, CHRNB2, DEPDC5, KCNT1, NPRL2, or NPRL3.4 Mosaicism occurs when an individual harbours two distinct cell populations: one with a pathogenic variant and one without. Somatic mosaicism affects only specific tissues, while variants seen in germline mosaicism can be transmitted to offspring. De novo variants cause most DEE, but a minority of people with them have a parent with mosaicism, with increased recurrence risk in the family.5 Somatic mosaicism also underlies some malformations of cortical development (MCD).6 The genetics of the epilepsies are considered in more detail in Chapter 5. Malformations of cortical development (MCD) result from abnormal prenatal brain development, and frequently cause drug‐resistant epilepsy (DRE), developmental delay and motor impairment. Advances in genetics and neuroimaging have led to the identification of additional MCD forms and their underlying genetic causes.7 MCD can be isolated or associated with various neurological and extra‐neurological features, including other congenital disabilities and facial dysmorphisms. The clinical presentation varies significantly based on the specific malformation type, as outlined in Table 4.1. Table 4.1 Main types and description of malformation of cortical development (MCD). Up to half of people with brain tumours present with seizures, and up to a third will develop seizures during disease progression. The 2016 World Health Organisation Classification of Tumours of the Central Nervous System uses molecular parameters and histology to define tumour entities.8 The pathophysiology of brain tumour‐related epilepsy is likely multifactorial, including tumour burden, type, location, growth rate, altered neurotransmitter homeostasis and gap junction alterations. Glioneuronal tumours often present with seizures in childhood, with the prevalence of epilepsy being inversely proportional to tumour growth rate. Hypothalamic hamartoma is a rare benign tumour with an estimated prevalence of 1 in 200,000 children, often associated with DRE, including gelastic seizures that may typically be unrecognised in the early years. Age at onset is typically in the first year of life for gelastic seizures and between 2 and 7 years for additional focal seizure types.9 Ischaemic and haemorrhagic strokes are risk factors for epilepsy, accounting for almost half of cases in adults over age 60 years.10 Acute symptomatic seizures occur within the first seven days after stroke,11 resulting from acute neuronal injury with subsequent glutamate‐mediated excitotoxicity, ion channel dysfunction and blood–brain barrier disruption. Late unprovoked seizures occur from seven days to years after the stroke. It is hypothesised that these arise due to gliotic scarring accompanied by changes in membrane properties, deafferentation, selective neuronal loss, and collateral sprouting. These processes collectively contribute to neuronal hyperexcitability and increased synchronisation of neuronal activity.12 According to the most recent ILAE definition, epilepsy can be diagnosed after one late post‐stroke seizure, because there is a > 60% recurrence probability over the next ten years.13 Risk factors for post‐stroke epilepsy include cortical involvement, haemorrhagic stroke, younger age at stroke, lesion size, family history of seizures, and early symptomatic seizures.14 Even in the absence of a definite stroke, cerebrovascular disease such as leukoaraiosis (ie white matter rarefaction due to small vessel disease‐causing small deep infarcts) is an epilepsy risk factor, although the mechanisms are unclear.14
CHAPTER 4
Risk Factors for Epilepsy
GENETIC FACTORS
STRUCTURAL FACTORS
MALFORMATIONS OF CORTICAL DEVELOPMENT
Phenotype
Description
Microcephaly
Most common MCD characterised by a reduction in the occipito‐frontal circumference by ≥2SD compared to controls. Microcephaly is classed as congenital if present at birth, primary microcephaly, or postnatal if it develops after birth, secondary microcephaly. The final brain size results from a complex process involving neural stem cell proliferation, migration, ongoing organisation, synaptogenesis, and apoptosis. Genetic and non‐genetic factors can lead to a small brain. Genetic causes include a growing list of single‐gene disorders, copy number variations, and large chromosomal rearrangements. Non‐genetic or environmental insults include in utero infections, teratogenic exposures and vascular insults.
Megalencephaly
Significant increase in the occipito‐frontal circumference and brain size by ≥3SD compared with controls. There are focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly, in which the affected hemisphere is enlarged, and the lesion can extend to non‐brain tissue (e.g. skin abnormalities and localised overgrowth of one or several body parts).
Focal cortical dysplasia
Commonest epilepsy‐associated MCD. There are three subtypes: type I with cortical dyslamination, type II with cortical dyslamination and dysplastic, megalocytic neurons, without or with balloon cells, and type III, associated with another principal lesion. It is identified on imaging by focal irregularities of cortical morphology and thickness, blurring of the grey‐white matter boundary, and white matter T2 hyperintensity.
Lissencephaly
Includes agyria (absent gyri), pachygyria (or broad gyri), in combination with an abnormally thick cortex, and subcortical band heterotopia (a band of grey matter separated from the cortex and lateral ventricles by zones of white matter)
Grey matter heterotopia
Groups of neurons in an abnormal location include periventricular nodular heterotopia (i.e, grey matter nodules along the ventricular walls). Periventricular nodular heterotopia can be associated with various copy number variants and single‐gene variants, and may be part of a complex syndromic disorder.
Cobblestone malformation
Irregular and “pebbled” cerebral surface with moderately thick cortex and jagged grey–white matter border with frequent vertical striations. Caused by defects of the pial limiting membrane, with resulting neuronal overmigration from the cortical plate into the leptomeninges. Cobblestone malformation often co‐occurs with eye, muscle and additional brain malformations within the spectrum of the α‐dystroglycanopathies.
Polymicrogyria
Excessive number of abnormally small cerebral gyri with cortical overfolding, irregular “pebbled” cortical surface and a “stippled” grey‐white matter boundary. This affects the Sylvian fissures preferentially, is one of the most frequent types of malformation of cortical development, is frequently seen in association with other brain malformations and has a heterogeneous aetiology.
Schizencephaly
A full‐thickness cerebral cleft lined with grey matter extends from the ventricular surface to the pial surface.
CEREBRAL TUMOURS
STROKE
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