Adult-Onset Epilepsy in Presymptomatic Alzheimer’s Disease: A Retrospective Study

Abstract

Background:

The prevalence of epilepsy with onset in adulthood increases with age, mainly due to the accumulation of brain damage. However, a significant proportion of patients experience seizures of unknown cause. Alzheimer’s disease (AD) is associated with an increased risk of seizures. Seizure activity is interpreted as a secondary event related to hyperexcitability caused by amyloid-β aggregation.

Objective:

Since neurodegenerative processes begin several years before clinical symptoms, epilepsy could be more frequent in the presymptomatic stages of dementia.

Methods:

We retrospectively reviewed the prevalence of epilepsy of unknown origin with adult onset before cognitive decline in a large cohort of AD patients (EPS-AD) recruited based on clinical and neuropsychological data. Data of patients with epilepsy followed by AD were compared with two control groups: patients with AD without seizures (no EPS-AD) and a large reference population (RP).

Results:

In AD patients, the prevalence of epilepsy of unknown origin, with onset in the adulthood before cognitive decline is 17.1 times higher compared with the RP (95% CI: 10.3–28.3). In EPS-AD, seizures begin on average 4.6 years (median 2.0) before the onset of cognitive symptoms and cognitive decline starts 3.6 years earlier compared with noEPS-AD.

Conclusions:

Neurodegenerative processes of dementia could play a key role in the pathogenesis of epilepsy in a subgroup of individuals intended to develop cognitive decline. Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia.

Keywords

Alzheimer’s disease disease modifying therapies epilepsy neurodegeneration prevalence seizure

INTRODUCTION

Epilepsy is the third most common neurological disease affecting the elderly population, following stroke and neurodegenerative disorders [1, 2]. Several epidemiological studies confirm that epilepsy increases with age and is most common among persons aged 75 and older [3 –6]. These observations have been recently confirmed in a large population of Northern Italy. Considering subjects older than 55, the authors report a progressive increase of epilepsy with the age, especially for the older classes [6, 7].

Epilepsy with onset in the elderly is considered as the expression of a structural disease of the central nervous system (CNS). The majority of causes are linked to an accumulation of brain damage, mainly represented by cerebrovascular disease, tumor, trauma, medications, metabolic and toxic conditions. However, although any disease of the CNS can virtually cause epileptic seizures, in up to one-third of all elderly patients, the etiology of adult-onset epilepsy remains unclear [3, 8].

Neurodegenerative diseases are associated with a significant increase of epilepsy [9, 10]. Particularly, patients with Alzheimer’s disease (AD) are up to ten times more prone to develop seizures, compared with age-matched healthy controls. The prevalence of one or more unprovoked seizures in AD varies significantly, from 0.5 to 64% according to different studies [9 , 11–18], and the incidence rate ranges between 4.8 and 11.9/1,000 person-years, which is 2–6 fold higher than in subjects of similar age without dementia [19, 20]. This huge variability of results strongly indicates the need for more detailed epidemiological studies, in order to clarify these important aspects. The “epileptic variant” of AD has also been described in few cases, characterized by a non-convulsive epileptic syndrome [17 , 22]. Recently, an elegant study with prolonged EEG and MEG monitoring discovered that a subclinical epileptiform activity is more frequent in AD subjects and is linked to a faster cognitive decline [23, 24]. Even if not yet validated in clinical practice, EEG recording could be a useful tool to monitor the progression of cognitive decline in AD patients. In these patients, the increase of epileptiform activity could thus be considered a marker of the progression of the ongoing neurodegenerative process [25, 26]. In fact, there is an increasing evidence that the pathogenesis of amyloid-β (Aβ) plaque deposition and epilepsy partially overlap, suggesting common underlying mechanisms for both conditions. The mechanism of seizure generation in AD could involve the increased production of Aβ and the subsequent deposition of plaques, supporting the hypothesis that Aβ causes an increase in excitatory synaptic transmission, at least at low concentrations [27]. Notably, plaques are more frequent in patients with epilepsy compared to age-matched healthy controls [28]. Moreover, the risk for AD subjects of developing epilepsy seems even higher than in other types of non-AD dementias [9 , 29].

Since the neurodegenerative processes leading to dementia begin several years before the onset of clinical symptoms, we hypothesized that epilepsy could be more frequent in the presymptomatic stages of AD, compared to the general population. Thus, in this study we retrospectively evaluated the prevalence and characteristics of adult-onset epilepsy of unknown cause with onset before and after cognitive symptoms in a large cohort of AD patients, comparing these data with the general population.

MATERIALS AND METHODS

Patient recruitment and data collection

This retrospective observational study has been approved by the ethical committee of the San GerardoHospital, Monza (Italy). We recruited all the patients referred to the Unit for Alzheimer’s disease Assessment (UVA center) of the San Gerardo Hospital, Monza (Italy) from May 2000 to July 2016. We collected information about gender, date of birth, medical history, type of dementia, age at onset of cognitive symptoms, pharmacological therapy (cholinesterase inhibitors and NMDA receptor antagonist). We also evaluated the type of dementia and identified patients affected by AD according toMcKhann’s diagnostic criteria [30]. The other forms of non-AD neurodegenerative dementia have been diagnosed based on clinical and neuropsychological data, in accordance with the specific diagnostic criteria. The diagnosis of AD was based on clinical criteria and confirmed by neuropsychological data. The diagnostic process to define the type of dementia was obtained through clinical evaluations of increasing complexity. A young trainee medical doctor (VP) made the first evaluation. A senior neurologist (LT), expert in the field of neurodegenerative diseases, subsequently reviewed all the medical records. If the diagnosis was uncertain or there was disagreement between the first two investigators, a third opinion was required to the senior neurologist, chief of the UVA center (IA).

Among AD patients, we identified those with a history of epilepsy, defined by the occurrence of one or more unprovoked seizures [31] with onset after age 55, before the occurrence of cognitive symptoms (EPS-AD) or without seizures in anamnesis (noEPS-AD). In the first group, we collected data on the age at onset of seizures, etiology, epilepsy syndrome [32], and antiepileptic drug therapy. For the diagnosis of epilepsy and the characterization of patients, a young trainee medical doctor (VP) made the first evaluation. A senior neurologist (JCD), expert in the field of epilepsy, subsequently reviewed all the medical records. In order to identify a possible symptomatic etiology of seizures, clinical and instrumental data of patients with epilepsy were deeply reviewed. Structural causes, such as cerebrovascular disease, tumor, or trauma, were investigated in all the patients with brain neuroimaging studies (MRI or, when not possible, CT scan); biochemical and hematological tests were performed to exclude metabolic causes. Other seizure provoking factors like ongoing antipsychotic or antidepressant therapy, alcohol or drug dependency, infection of the central nervous system, and history of electroconvulsive therapy were excluded. EEG was used to characterize features of epilepsy. EEG recording was carried out using a minimum of eight channels, placed according to the International 10–20 system. The duration of tracings was at least 15 min. The low filter was set at 1.6 Hz and the high filter at 70 Hz; the sensitivity was switched between 50 and 100 μV/cm, according to signal amplitude. Tracings were classified as normal, with focal or generalized epileptiform abnormalities (EAs) and/or with unspecific (non-epileptiform) baseline abnormalities. We calculated the prevalence of adult-onset epilepsy of undetermined nature in the presymptomatic phase of dementia in the AD population and compared this to a large reference population (RP) from a well-defined adjacent geographic area [6]. Moreover, in order to compare our results with previous studies, we calculated the prevalence of epilepsy with onset following the diagnosis of AD in our cohort.

Statistical analyses

The main demographic and clinical characteristics of AD and EPS-AD patients were reported using counts, percentages, means, and standard deviations, as appropriate. The prevalence of adult-onset epilepsy of unknown cause was calculated in AD patients, for both epilepsy with onset before cognitive symptoms and after the diagnosis of AD, separately. In the reference population, prevalence was calculated among subjects older than 55 years: prevalent cases of adult-onset epilepsy of unknown nature were subjects who received a diagnosis of partial idiopathic, partial cryptogenic, generalized idiopathic, or undetermined epilepsy, after age 55 years. The prevalence of adult-onset epilepsy with onset before cognitive symptoms in AD patients, was then compared with the prevalence of adult-onset epilepsy in the reference population. The comparison was expressed as prevalence ratio with the corresponding 95% confidence interval. The mean age of onset of cognitive decline was calculated and compared between EPS-AD and noEPS-AD patients using the Student’s t-test. All tests were two-tailed with a 5% level of significance. Analyses were performed using SAS statistical package (version 9.4, SAS Institute Inc., Cary, NC, USA) and GraphPad Prism 4.

RESULTS

Study population

The population referred to the UVA center from May 2000 to July 2016 consisted of 2,250 patients. All the subjects considered for the analyzes were from the neighboring areas (Lombardy, Northern Italy). We identified 1,371 patients affected by AD. Of these, 62% were female; the mean age at onset of cognitive symptoms was 75 years. The mean educational level was 7 years. 26% of AD patients was treated with acetylcholinesterase inhibitor (AChEI) or N-methyl D-aspartate (NMDA) receptor antagonists (Table 1). 547 additional subjects resulted affected by different types of neurodegenerative (ND) diseases, including mild cognitive impairment, dementia with Lewy bodies (DLB), corticobasal syndrome, frontotemporal dementia, and Parkinson’s disease dementia. The remaining 332 cases were affected by other diseases variably linked to dementia, mainly represented by vascular encephalopathy, psychiatric illness, major depressive disorder and subjective cognitive impairment. All the subjects with a cognitive decline not attributable to AD were excluded from subsequent analyses (Fig. 1).

Table 1

Characteristics of AD patients

Gender (% F/M)	62/38
Age of cognitive decline (mean±SD)	75±7
Years of education (mean±SD)	7±4
AChEI/NMDA rec treatment (%)	26

Fig.1

Flowchart of patient recruitment.

Adult-onset epilepsy of undetermined cause in presymptomatic AD

Among the 1,371 AD patients, we identified 23 subjects experiencing epilepsy of unknown cause with adult onset, preceding the diagnosis of dementia (EPS-AD). The majority were females (16); the mean age at the first seizure was 68.2 years. Epilepsy was classified as generalized in 11 patients, partial in five, and undetermined in seven. Detailed information about the antiepileptic treatment was missing. However, the revision of clinical records showed that all patients had a good control of seizures with a single drug and none resulted pharmacoresistant. EEG recordings were available for eight patients, resulting normal in two, with focal or generalized EAs in four, and with unspecific (non-epileptiform) interictal abnormalities in the remaining two subjects (Table 2). Although these patients were not specifically analyzed with dedicated neuropsychological tests, none of them reported signs of cognitive decline before the onset of the first epileptic seizure and at the time of the neurological examination.

Table 2

Features of the EPS-AD group

Number of cases	23
Gender (F/M)	16/7
Age of first seizure (mean±SD)	68.2±13
Age of cognitive decline (mean±SD)	71.4±10
Prevalence of epilepsy	16.8 per 1000
Years of education (mean±SD)	6±2
Type of seizure
Generalized	11
Partial	5
Undetermined	7
EEG recording
Normal	2
Focal/generalized EAs	4
Non-epileptiform abnormalities	2

AChEI, acetylcholinesterase inhibitors; NMDA, N-methylD-aspartate receptor antagonists; EAs, epileptiform abnormalities.

In this group, the prevalence of epilepsy resulted 16.8 per 1,000. We compared this data with the prevalence of epilepsy in the RP [6] where, in the year 2008, in patients older than 55 years (globally 42,739 individuals), the prevalence of epilepsy of unknown nature resulted 0.98 per 1,000. This corresponded to a 17.1-fold increased risk of epilepsy in the AD group (95% CI: 10.3–28.3).

The mean age of onset of cognitive decline was 71.4 and 75 years, respectively in the EPS-AD and noEPS-AD cohorts. Cognitive impairment occurred 3.6 years earlier in patients who experienced epilepsy in the presymptomatic stage of AD, compared to subjects without a history of seizures (p value = 0.01; Fig. 2; Cohen’s d = 0.48). In the EPS-AD cohort, the onset of seizures preceded symptoms of cognitive decline by 4.6 years (median 2.0, IQR 0.5–6.0, range 0.5–29.0). For all the other variables analyzed (gender and AD treatment), we did not identify significant differences between the two groups.

Fig.2

Age at onset of cognitive decline in AD patients with and without epilepsy. Graph showing that in EPS-AD, symptoms of cognitive decline occur 3.6 years earlier compared to noEPS-AD (p value = 0.01).

Epilepsy following the diagnosis of AD

Sixteen AD patients presented seizures after the diagnosis of AD, giving a prevalence of 11.6 per 1,000. In this group, we observed a mean interval of 5 years between the onset of cognitive decline and seizures.

DISCUSSION

This retrospective, observational, single-center study demonstrates that the prevalence of epilepsy of unknown origin with adult-onset is increased during the presymptomatic stages of AD, as compared to the general population. Moreover, AD patients with presymptomatic epilepsy anticipate their cognitive decline, as compared to AD without clinical seizures. Our observations are consistent with previous data showing an increased number of patients with new-onset seizures few years before the diagnosis of AD, coupled with an anticipated onset of cognitive decline when compared to non-epileptic subjects[17, 24].

The reasons for the anticipation of cognitive symptoms in patients with presymptomatic epilepsy are not clear yet. Since the causes of epilepsy remain unknown in these patients, we could speculate that seizures defined as of “undetermined” nature are actually secondary to the ongoing ND process. In fact, due to the relationship between the deposition of Aβ plaques in the brain and the altered neuronal excitability [26 , 33–37], seizures might accelerate the ND process, leading to an anticipation of cognitive symptoms. This could generate a “vicious cycle” where seizures increase Aβ deposition, leading to an increase of neuronal excitability and a further predisposition to develop epilepsy [38]. Our data support a link between epileptogenesis and neurodegeneration, leading to the generation of a stable epileptogenic circuitry. Nevertheless, it remains unclear why only some AD patients develop seizures during the presymptomatic stages of dementia. We postulate the presence of a threshold effect, determined by genetic and/or environmental factors, although these aspects remain to beclarified.

In this scenario, the onset of epilepsy of unknown origin in the adulthood could thus represent an early risk factor for dementia occurring during the presymptomatic stages of the disease. Seizures may indeed act as the clinical expression of the ongoing ND process. This is also supported by experimental data showing an increased epileptic activity in animal models of AD, compared to controls [37]. These observations require some further reflections. First, the onset of undetermined seizures in adulthood could be proposed as a novel risk factor for the early identification of subjects developing dementia. As already reported by Costa and colleagues, measuring Aβ and tau levels in the cerebrospinal fluid (CSF) and PET brain imaging studies would allow the early identification of patients leading to cognitive decline few years later [37]. A detailed and thorough neuropsychological characterization of these subjects seems therefore mandatory, in order to highlight any possible symptoms of subclinical cognitive impairment, not evident at the routine neurological evaluation. Another potentially relevant aspect relates to the ongoing disease modifying therapies for the treatment of AD. This approach has proved unsuccessful when applied to patients already in the active phase of the disease [39], while positive effects on cognition have been reported in an early or prodromal stage of the disease [40]. In this context, many ongoing studies now aim at the identification and treatment of subjects as early as possible or even in the presymptomatic phase of AD [41, 42]. We can thus hypothesize that individuals with adulthood-onset epilepsy in the presymptomatic phase of de-mentia could represent good candidates for disease modifying therapies. Moreover, in line with ongoing pioneering pharmacological trials (Levetiracetam for Alzheimer’s Disease-Associated Network Hyperexcitability; NCT02002819), the antiepileptic treatment of these subjects could interrupt the vicious circle between epilepsy and neurodegeneration, thus reducing or at least delaying the onset of cognitive symptoms.

The first limitation of this study is the retrospective design. A second limitation is represented by the population that was referred from a single UVA center, a structure highly specialized in the treatment of dementia. In our experience, patients referring to in these structures usually represent advanced or the most complicated cases, while others are institutionalized or, conversely, managed directly by their general practitioners. Moreover, despite having ruled out dementia at the onset of epilepsy, we cannot definitely exclude subclinical signs of cognitive impairment already present at the time of the first seizure. Furthermore, being a retrospective study on patients referred to our UVA Center since 2000, in all patients the diagnosis of AD was based on clinical criteria and confirmed by neuropsychological data. In the retrospective revision of the clinical records, all included AD subjects fulfilled the McKhann’s diagnostic criteria, while only a minority of them underwent adjunctive analyses like CSF and brain neuroimaging (PET techniques). It should be considered that clinical and neuropsychological data alone could not exclude some misdiagnoses, such as of AD in DLB patients or DLB in AD with the extrapyramidal variant [43]. However, the examination of the follow-up in the medical records could confirm the diagnosis of AD, based on the progression of symptoms and the evolution of the patient’s clinical picture. Considering the above limitations, the data resulting from the present study should be considered as a proof of concept, since the diagnosis of AD is limited to clinical and neuropsychological data, without direct pathophysiological disease biomarkers (CSF and brain amyloid/tau PET data) or topographic markers of hypometabolism (FDG-PET) and atrophy of medial temporal lobe (structural MRI). Future studies will be necessary in order to confirm the data here reported, using modern criteria for the diagnosis of AD. Another limitation is represented by the difference, in space and in time, between the AD cohort and the RP. The AD cohort and the RP came from different, but adjacent geographic areas (both in the same region of Northern Italy). The prevalence of epilepsy (with onset preceding the diagnosis of dementia) in AD patients was obtained in a cohort recruited during a 17-year period (2000–2016), while the prevalence in the RP was calculated in the year 2008. However, we can reasonably assume that the probability of having seizures before the onset of dementia remained approximately the same over the period 2000–2016. Moreover, there is no reason to consider that the RP and the population from which the AD cohort originated have different structure and socio-cultural and economic characteristics. However, given the potential significance of this work, our results should be confirmed in larger cohorts and more heterogeneous populations, mainly through multi-center studies. As a consequence, the importance of a thorough evaluation of cognition in subjects with single or recurrent unprovoked seizures with onset in adulthood should be considered, in order to identify the presymptomatic stage ofdementia.

Conclusions

The pathogenic mechanisms underlying the epileptogenic processes are partly understood. In the majority of cases, these are secondary to abnormalities in ion transporters (channelopathies) or other neuronal proteins, genetically determined or acquired [44 –46]. Conversely, the mechanisms leading to the generation of the epileptogenic potential in the context of neurodegeneration are still largely unknown. The present findings represent a proof concept that pathophysiological processes underlying dementia might play a role in the pathogenesis of epilepsy in a fraction of individuals who will develop major cognitive disorders across aging. Adult-onset epilepsy of undefined cause might thus represent a risk factor for later dementia, even preceding by years the onset of cognitive impairment. It will be important to clarify these aspects, to identify possible innovative strategies for the treatment of epilepsy and neurodegenerative diseases.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/17-0392r4).

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