Effect of late-onset epilepsy on cognitive functioning in patients with small vessel disease

Highlights

• Patients with cSVD-LOE showed poorer cognitive performance compared with patients with cSVD.

• Cognitive profile in cSVD-LOE is different from that typically observed in cSVD.

• Epilepsy was the major contributor to the decrease in verbal memory.

• Seizure localization and vascular burden were not related with cognitive performance.

• Epilepsy could be an early sign of incipient neurodegenerative disease in these patients.

Abstract

Rationale

Late-onset epilepsy (LOE) often has underlying cerebrovascular cause and has been associated with neurocognitive deficits and dementia. Nevertheless, the interplay between these factors has not been studied thus far. Hence, we conducted a retrospective cross-sectional study aimed to explore how unprovoked epileptic seizures along with vascular-related factors contribute to neurocognitive impairments in patients with cerebral small vessel disease.

Methods

Twenty-seven patients with LOE aged > 60 years with concomitant cerebral small vessel disease (cSVD) and a matched group of cSVD without epilepsy were cognitively assessed. Demographic, clinical, and vascular information were obtained and vascular burden score was calculated for each patient. Multiple linear regression models were used to explore the relationship between epilepsy and cognitive measures adjusting for demographic and vascular risk factors.

Results

Compared with cSVD, cSVD-LOE group showed a poorer performance on verbal memory measures, visuomotor tracking and speed processing and phonetic fluency. In the multiple regression analysis, the presence of epilepsy was found to be the major predictor for verbal memory dysfunction, specifically in verbal short recall (p = 0.008) and verbal learning (p < 0.001). No interactions between vascular burden and epilepsy were found.

Conclusion

Patients who had cSVD with concurrent LOE showed poorer performance on memory function compared with patients with cSVD without epilepsy, and they showed a different cognitive profile from that typically manifested by patients with cSVD. The presence of epilepsy, but not seizure localization nor vascular burden, was the major contributor to the decrease in verbal memory.

Introduction

Late-onset Epilepsy (LOE), defined as epilepsy starting after 60 years of age, is an increasingly common problem in older population that accounts up to 25% of all incident cases with epilepsy [1], [2]. As life expectancy increases, with the population older than 65 years expecting to represent one in four people in Europe and Northern America by 2050, the prevalence of LOE is also expected to increase [3]. Causes of LOE include overt cerebrovascular disease, neurodegenerative disorders and dementia, traumatic brain injury, structural injury, metabolic disorders, and autoimmune diseases. However, almost 40% of patients may present LOE of an unknown etiology [3], [4].

Among several etiological hypotheses, subclinical cerebrovascular disease has been proposed to contribute to the development of a first unprovoked seizure in later life. Although it is well known that cortical vascular lesions after stroke predispose to epilepsy, cerebral small-vessel disease (cSVD) which manifests on brain parenchyma by the appearance of white matter hyperintensities, brain atrophy, and cerebral microbleeds, might also be a cause of LOE [5], [6], [7]. Moreover, the increase in blood–brain barrier permeability might trigger cSVD, resulting in structural and perivascular changes in the small vessels of the brain [8], which may in turn contribute to enhance excitability and epileptogenesis in these patients [9].

In addition, cSVD constitutes a major source of cognitive decline and neurological disability in the elderly [10]. Brain atrophy, cerebral microbleeds, lacunar infarcts, and burden of periventricular white matter lesions have been associated with steeper decline in cognitive function, specifically in executive function, attention, and information speed processing, observing a relative preservation of episodic memory encoding [11], [12]. A bidirectional association between cognitive decline and epilepsy in later life also has been established, with higher rates of prevalence of dementia in people who develop LOE and vice versa [13], [14] Although the mechanisms of this association are poorly understood, evidence suggests that patients with epilepsy present an increased relative risk (RR) of being diagnosed of Alzheimer Disease (AD) within 1 year after epilepsy onset. Interestingly, this risk is greater in those patients who had epilepsy for few years (RR of 2.5) comparing with patients who had epilepsy for more than 10 years (RR of 1.4), underpinning the idea that this increased risk is not caused by a cumulative effect of longstanding seizures [15].

All these considerations raise questions about whether epilepsy triggers pathological changes in the brain that may increase the likelihood of dementia; or if epilepsy and cognitive decline may be the expression of shared pathological mechanisms [16], as cerebrovascular disease may be the shared contributor to both dementia and epilepsy [17], [18].

Although increasing evidence associates cSVD, vascular risk factors, LOE and neurocognitive decline, no group studied the interplay between these factors thus far. Hence, we have set a retrospective cross-sectional study aimed to explore how unprovoked epileptic seizures along with vascular-related factors contribute to neurocognitive impairments in patients with cSVD.