Abstract and Introduction

Abstract

With advances in healthcare and an ageing population, the number of older adults with epilepsy is set to rise substantially across the world. In developed countries the highest incidence of epilepsy is already in people over 65 and, as life expectancy increases, individuals who developed epilepsy at a young age are also living longer. Recent findings show that older persons with epilepsy are more likely to suffer from cognitive dysfunction and that there might be an important bidirectional relationship between epilepsy and dementia. Thus some people with epilepsy may be at a higher risk of developing dementia, while individuals with some forms of dementia, particularly Alzheimer's disease and vascular dementia, are at significantly higher risk of developing epilepsy. Consistent with this emerging view, epidemiological findings reveal that people with epilepsy and individuals with Alzheimer's disease share common risk factors. Recent studies in Alzheimer's disease and late-onset epilepsy also suggest common pathological links mediated by underlying vascular changes and/or tau pathology. Meanwhile electrophysiological and neuroimaging investigations in epilepsy, Alzheimer's disease, and vascular dementia have focused interest on network level dysfunction, which might be important in mediating cognitive dysfunction across all three of these conditions. In this review we consider whether seizures promote dementia, whether dementia causes seizures, or if common underlying pathophysiological mechanisms cause both. We examine the evidence that cognitive impairment is associated with epilepsy in older people (aged over 65) and the prognosis for patients with epilepsy developing dementia, with a specific emphasis on common mechanisms that might underlie the cognitive deficits observed in epilepsy and Alzheimer's disease. Our analyses suggest that there is considerable intersection between epilepsy, Alzheimer's disease and cerebrovascular disease raising the possibility that better understanding of shared mechanisms in these conditions might help to ameliorate not just seizures, but also epileptogenesis and cognitive dysfunction.

Introduction

Around 65 million people worldwide have epilepsy

, with ~80% living in developing regions (Birbeck, 2010; Ngugi et al., 2010). In the UK >600 000 people, i.e. almost 1 in 100 (Joint Epilepsy Council, 2011) and in the USA >3 million people or 0.84 in 100 (Helmers et al., 2015) have the disorder. Several studies have consistently shown that the peak incidence is higher in the older population, rising from the age of 65 (Annegers et al., 1999; Hussain et al., 2006). In fact ~25% of new-onset epilepsies are diagnosed after this age (Joint Epilepsy Council, 2011). Given that the global population aged >65 will increase by ~400 million to reach almost 1 billion by 2030, the number of older adults with epilepsy is expected to rise substantially.

The population of older adults with epilepsy (defined here as >65 years) consists of two main groups: those who have had epilepsy for many years and, owing to improvements in healthcare, are now living to older age, and those who develop epilepsy de novo in later life. While several underlying causes may contribute to new-onset epilepsy in the elderly (Stefan, 2011) cerebrovascular disease accounts for 50–70% of cases and is the single most common cause (Brodie et al., 2009; Choi et al., 2017). Recent work from the USA has reported that the incident risk for epilepsy is highest in people with cerebrovascular disease aged 75–79, with African Americans at particularly high risk (Choi et al., 2017). The incidence of epilepsy was highest of all in older patients who had experienced a stroke. Others have shown that in the first year after a stroke the risk of developing epilepsy can increase 20-fold (Brodie et al., 2009). The exact pathophysiology of stroke-related epilepsy is not established, but intracerebral haemorrhage, haemorrhagic transformation of ischaemic stroke, greater stroke severity, cortical involvement and venous sinus thrombosis all increase the risk of seizures (Conrad et al., 2013; Zhang et al., 2014).

Older people who experience head trauma are also around 2.5 times more likely to develop post-traumatic epilepsy than their younger counterparts

and up to 20% of epilepsy in the elderly may be attributable to head injury (Annegers et al., 1998; Bruns and Hauser, 2003). Dementia and neurodegenerative disorders account for a further 10–20% of late-onset cases of epilepsy (Stefan, 2011), with much of the research to date focusing on Alzheimer's disease. Patients with Alzheimer's disease aged ≥65 years have up to a 10-fold higher risk of epilepsy (Hommet et al., 2008; Pandis and Scarmeas, 2012). Other causes of dementia have received far less attention, but one large study in the UK reported that in people over 65, individuals classified as having vascular dementia had a similar likelihood of developing seizures or epilepsy as those with Alzheimer's disease (Imfeld et al., 2013).

Importantly, some findings also suggest that older patients with epilepsy are at a higher risk of developing cognitive impairment and ultimately dementia (van Duijn et al., 1991; Breteler et al., 1995). Why should that be the case? In this review we consider whether seizures promote dementia, whether dementia causes seizures, or if common underlying pathophysiological mechanisms are responsible for both. First, we consider the evidence regarding cognitive function and the potential higher risk of dementia in older patients (aged >65 years) with epilepsy. We then turn to findings that suggest there might be a bidirectional link between epilepsy and dementia such that patients with dementia also seem to be at greater risk of developing seizures (Subota et al., 2017). We discuss the evidence for common lifestyle and vascular risk factors in epilepsy and dementia, and then consider potential shared molecular links, including new evidence for tau pathology in older patients with epilepsy (Sen et al., 2007a; Thom et al., 2011; Tai et al., 2016). Finally, we examine emerging evidence which suggests that widespread, brain network changes in Alzheimer's disease (with our without concomitant vascular pathology) and epilepsy might contribute to cognitive dysfunction in these conditions (Wandschneider et al., 2014; Canter et al., 2016; Palop and Mucke, 2016; Chong et al., 2017), including the remote effects of interictal epileptiform discharges (IEDs) (Kleen et al., 2013; Gelinas et al., 2016; Ung et al., 2017).

Our review of these disparate findings leads to the conclusion that although current data do not allow us to make definitive mechanistic inferences, they do show that this is an important area for investigation that has potential application to both patients with epilepsy and dementia. It is now well established that many patients who are diagnosed clinically to have Alzheimer's disease have mixed pathology with concurrent cerebrovascular changes at post-mortem, and vice versa (Rahimi and Kovacs, 2014). Thus, targeting lifestyle and vascular risk factors might offer important therapeutic opportunities to modify the disease processes underlying these conditions as well as the progression of cognitive decline in people with epilepsy