Q Seminar of Epileptology Epileptic Disord 2021; 23 (1): 1-16 The aetiologies of epilepsy Simona Balestrini 1,2, Alexis Arzimanoglou 3,4, Ingmar Blümcke 5, Ingrid E. Scheffer 6, Samuel Wiebe 7, Johan Zelano 8,9, Matthew C. Walker 1 1 UCL Queen Square Institute of Neurology, Member of the ERN ABSTRACT – The identification of the aetiology of a patient’s epilepsy is instrumen- EpiCARE, London, UK tal in the diagnosis, prognostic counselling and management of the epilepsies. 2 Chalfont Centre for Epilepsy, Bucks, UK Indeed, the aetiology can be important for determining the recurrence risk of single 3 Department of Paediatric Clinical seizures and so for making a diagnosis of epilepsy. Here, we divide the aetiologies Epileptology and Functional into six categories: structural, genetic, infectious, metabolic, immune (all of which Neurology, University Hospitals of Lyon (HCL), Member of the ERN are part of the International League Against Epilepsy [ILAE] classification system) EpiCARE, Lyon, France and neurodegenerative (which we have considered separately because of its grow- 4 Epilepsy Research Program, ing importance in epilepsy). These are not mutually exclusive categories and many Epilepsy Unit, San Juan de Dios Paediatric Hospital, Member of the aetiologies fall into more than one category. Indeed, genetic factors probably play a ERN EpiCARE, Barcelona, Spain role, to varying degrees, in the risk of seizures in all people with epilepsy. In each of 5 Institute of Neuropathology, University Hospitals Erlangen, the categories, we discuss what we regard as the most important aetiologies; impor- Collaborating Partner of the ERN tance being determined not only by prevalence but also by clinical significance. EpiCARE, Erlangen, Germany The introduction contains information suitable for level 1 competency (entry level), 6 University of Melbourne, Austin Health and Royal Children’s whilst the subsequent sections contain information aimed at level 2 competency Hospital, Florey and Murdoch (proficiency level) as part of the new ILAE competency-based curriculum. As we Children’s Research Institutes, move towards precision medicine and targeted therapies, so aetiologies will play an Melbourne, Australia 7 Cumming School of Medicine, even greater role in the management of epilepsy. University of Calgary, Canada 8 Sahlgrenska Academy and Key words: structural; genetic; infectious; metabolic; immune; neurodegenerative University Hospital, Member of the ERN EpiCARE, Gothenburg, Sweden 9 Wallenberg Center for Molecular and Translational Medicine, Gotenburg, Sweden Received August 13, 2020; Accepted October 14, 2020 Learning objectives [1] • Describe the major aetiologies for epilepsy (i.e. structural, genetic, infectious, metabolic, immune, and neurodegenerative) (L1). CC = BYNC SA ND • Describe the common structural aetiologies (e.g. hippocampal sclerosis, tumours, malformations, vascular lesions, traumatic brain injury, etc.) (L2). • Describe the common genetic causes of epilepsy (e.g. monogenic or polygenic • Correspondence: Simona Balestrini inheritance, germline or somatic mutations) (L2). UCL Queen Square Institute • Describe the common infectious causes of epilepsy, including geographical of Neurology, impacts (e.g. bacterial, fungal, viral, parasites) (L2). Queen Square • Describe the common metabolic causes of epilepsy (e.g. inborn errors of metab- London WC1N 3BG, UK olism, glucose transport defects, pyridoxine dependent seizures, mitochondrial Matthew Walker UCL Queen Square Institute pathologies) (L2). of Neurology, • Describe the common immune causes of epilepsy (e.g. Rasmussen encephalitis, Queen Square LGI1 antibodies, NMDA antibodies, etc.) (L2). London WC1N 3BG, UK • Describe the common neurodegenerative causes of epilepsy (e.g. Alzheimer’s <[email protected]> disease, Down syndrome, progressive myoclonic epilepsies) (L2). doi:10.1684/epd.2021.1255 <[email protected]> Epileptic Disord, Vol. 23, No. 1, February 2021 • 1 S. Balestrini, et al. Major aetiologies of epilepsy Although many epidemiological studies investigate the prevalence of each of the aetiological categories (figure 1), they are often performed in resource-rich Any brain has the propensity to have seizures, which countries and do not represent the spectrum and occur when excitability of an area or areas of the brain prevalence of epilepsy aetiologies globally. Time and exceed a certain threshold. The epilepsies are a group place have a considerable impact on the spectrum of heterogenous neurological conditions whereby an of aetiologies seen clinically. For example, infectious underlying brain disorder leads to a reduction of the causes, in particular parasitic infections, are com- intrinsic seizure threshold, so increasing the propen- moner in resource-poor countries. In some endemic sity for spontaneous recurrent seizures. communities, neurocysticercosis is the cause of The clinician’s first diagnostic step is to determine that approximately a third of all active epilepsy [8]. Over an event is most likely an epileptic seizure and not one time, public health measures reduce the incidence of a range of possible differential diagnoses including of perinatal insults, infectious causes and traumatic dissociative seizures, syncope, parasomnias, movement brain injury, whilst an ageing population results in an disorders and other non-epileptic events. The iden- increase in the frequency of stroke and dementia. tification of an underlying aetiology is a fundamental Because aetiology plays a central role in the diagnosis subsequent step for the diagnosis and management of and management of people with epilepsy, investiga- the epilepsies. Indeed, since aetiology influences the tions into cause should be instigated from the outset; recurrence risk following a single seizure [2, 3], it can be for example, neuroimaging, ideally MRI (where availa- important in making the diagnosis of epilepsy, for which ble) should be undertaken in all people with a first sei- a seizure recurrence risk of 60% is an accepted criterion zure when a structural aetiology is suspected [2]. The [4]. The most recent classification of the epilepsies pro- presence of a structural abnormality together with an vides a new framework at three levels and highlights electro-clinical assessment help to determine prog- the importance of considering aetiology at each level: nosis and allow earlier recognition of surgical can- seizure type, epilepsy type, and epilepsy syndrome didates in those who do not respond to appropriate [5]. Aetiological categories in the International League Against Epilepsy (ILAE) classification include structural, genetic, infectious, metabolic, immune, and unknown [5]. In the ILAE curriculum, there is an additional cate- gory, neurodegenerative. The aetiologies within neu- rodegenerative can be placed in other aetiological 20% categories, but, because of the growing clinical impor- tance of neurodegenerative disease, here it is consid- ered separately [6]. These categories are not mutually 36% exclusive; for example, some genetic conditions, such as tuberous sclerosis, cause structural lesions, or inborn errors of metabolism can often be included in both genetic and metabolic aetiological categories. Moreo- ver, there may be multiple risk factors that contribute to the development of epilepsy (e.g. people with a family history of epilepsy have a higher chance of developing epilepsy following a traumatic brain injury). 37% The unknown category rather speaks to our lack of 2% knowledge, or perhaps lack of suitable diagnostic tools, and remains one of the largest categories [7]. 3% 2% As science advances and as diagnostic tools become more widely available, fewer epilepsies will fall into the unknown category, and the aetiological catego- Genetic/presumed genetic Structural risation of certain epilepsies will change. Indeed, Metabolic Infectious recent advances in high-resolution neuroimaging, testing for autoimmune antibodies, and next-genera- Neurodegenerative Unknown tion sequencing (NGS) have revolutionised our ability to identify the aetiology of many epilepsies. There- fore, every patient with epilepsy, in whom the aetiol- Q Figure 1. Aetiologies of epilepsies in a resource-rich ogy is unknown, deserves regular review with regard European region (after Syvertsen et al. 2015). to their underlying aetiology. 2 • Epileptic Disord, Vol. 23, No. 1, February 2021 The aetiologies of epilepsy antiseizure medications [9]. Equally, identification of systemic comorbidities, and can increase the risk of a genetic cause carries several clinical implications, premature mortality. Understanding the breadth of including focusing further investigations, informing phenotypic manifestations informs the need for com- long-term prognosis, and counselling the patient prehensive management strategies [16]. about family risk and prenatal testing options. More- over, discovering a specific pathogenic gene variant as a cause for epilepsy increasingly allows tailoring of Common structural aetiologies treatment strategies, and targeting of the underlying pathophysiological mechanisms [10]. Infectious aeti- ologies are the commonest group worldwide and are Any structural lesion affecting the cortex can result often associated with structural abnormalities. They in seizures and epilepsy. However, seizure semiology also carry specific treatment implications, including will depend on lesion location and not on the type surgical treatment [11, 12]. Metabolic causes can refer of lesion. Although neuroimaging can give