Abstract and Introduction
With advances in healthcare and the aging population, the number of older adults with epilepsy worldwide will increase significantly. In developed countries, epilepsy is most prevalent in people over the age of 65, and as life expectancy increases, people who develop epilepsy at an early age also live longer. Recent findings show that older people with epilepsy are more likely to suffer from cognitive dysfunction and that there may be an important bi-directional relationship between epilepsy and dementia. For example, some people with epilepsy may be at a higher risk of developing dementia, while people with certain forms of dementia, especially Alzheimer's disease and vascular dementia, are at significantly higher risk of developing epilepsy. Consistent with this emerging picture, epidemiological findings show that people with epilepsy and those with Alzheimer's disease have common risk factors. Recent studies on Alzheimer's disease and late onset epilepsy also indicate common pathological links mediated by underlying vascular changes and / or tau pathology. Meanwhile, electrophysiological and imaging studies in epilepsy, Alzheimer's disease and vascular dementia have focused attention on network dysfunction, which could be important in mediating cognitive dysfunction in all three cases. In this review, we examine whether seizures promote dementia, whether dementia causes seizures, or whether common underlying pathophysiological mechanisms cause both. We investigate the evidence that cognitive impairment is associated with epilepsy in the elderly (over 65 years) and the prognosis for patients with dementia epilepsy, with a particular focus on common mechanisms that may underlie the cognitive deficits in epilepsy and Alzheimer's disease , Our analysis suggests that epilepsy, Alzheimer's disease and cerebrovascular disease are highly interdependent, so a better understanding of common mechanisms under these conditions could help relieve not only seizures but also epileptogenesis and cognitive dysfunction.
About 65 million people worldwide suffer from epilepsy, with about 80% living in developing countries (Birbeck, 201
The population of older adults with epilepsy (defined here as> 65 years of age) consists of two main groups: those who have been suffering from epilepsy for many years and now live in old age due to improvements in health care and those who have epilepsy de novo in later life. While some of the underlying causes may contribute to emerging epilepsy in the elderly (Stefan, 2011), cerebrovascular disease accounts for 50-70% of cases and is the leading cause (Brodie et al. 2009; Choi et al. 2017). Recent work from the United States reports that the risk of epilepsy is highest in people with cerebrovascular disease aged 75-79 years, with African Americans particularly at risk (Choi et al. 2017). The incidence of epilepsy was highest in elderly patients who had a stroke. Others have shown that in the first year after a stroke, the risk of developing epilepsy can be increased 20-fold (Brodie et al. 2009). The exact pathophysiology of stroke epilepsy has not been established, but intracerebral hemorrhage, haemorrhagic transformation of ischemic stroke, greater stroke severity, cortical involvement, and venous sinus thrombosis increase seizure risk (Conrad et al. 2013; Zhang et al. 2014).
Older people who have cranial trauma are at least 2.5 times more likely to develop post-traumatic epilepsy than their younger counterparts, and up to 20% epilepsy can be attributed to head injury (Annegers et al. ] 1998, Bruns and Hauser, 2003). Dementia and neurodegenerative disorders make up another 10-20% of late-onset epilepsy cases (Stefan, 2011), with much of the current research focusing on Alzheimer's disease. Patients with Alzheimer's disease ≥65 years have an up to 10-fold increased risk of epilepsy (Hommet et al. 2008; Pandis and Scarmeas, 2012). Other causes of dementia have received much less attention, but a large UK study reports that people over 65 who were classified as having vascular dementia had a similar likelihood of developing seizures or epilepsy as those with Alzheimer's disease (Imfeld et 2013).
Some findings suggest that older patients with epilepsy have a higher risk of developing cognitive disorders and eventually dementia (van Duijn et al. 1991; Breteler et al. 1995). Why should that be the case? In this review, we examine whether seizures promote dementia, whether dementia causes seizures, or whether common underlying pathophysiological mechanisms are responsible for both. First, we review the evidence for cognitive function and the potential for higher dementia risk in older patients (age> 65 years) with epilepsy. We then turn to the findings suggesting that there is a bi-directional link between epilepsy and dementia, so that patients with dementia are also at an increased 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 possible joint molecular links, including new evidence for tau pathology in elderly patients with epilepsy (Sen et al. 2007 [19459008a Thom et al. 2011; Tai et al. 2016). Finally, we investigate new evidence suggesting that widespread brain changes in Alzheimer's disease (without concomitant vascular pathology) and epilepsy may contribute to cognitive impairment under these conditions (Wandschneider et al. 2014 Canter et al. 2016; Palop and Mücke, 2016; Chong et al. 2017), including the Remote Effects of Interictal Epileptiform Discharge (IEDs) (Kleen et al 2013 ; Gelinas et al. 2016; Ung et al. 2017).
Our review of these different findings leads to the conclusion that, although current data do not allow definitive mechanistic conclusions, they do show that this is an important area for investigations that can be applied to both epileptics and dementia patients , It is now well known that many patients clinically diagnosed with Alzheimer's disease have mixed pathology with concomitant cerebrovascular changes at postmortem and vice versa (Rahimi and Kovacs, 2014) . Therefore, targeted lifestyle and vascular risk factors could offer important therapeutic options for modifying the underlying disease processes and the progression of cognitive decline in people with epilepsy