EPILEPSY “AND/IN” DEMENTIA(s)

Mirko Avesani (1,2,3,4), Agnese Tonon (2), Maria Giovanna Bon (1), Cristina Accordini (1), Gloria Massironi (1), Salvatore Bazzano (1), Riccardo Checchetto (2), Isabella Silvestri (2, +), Lorella Marastoni (1), Raffaela Marchetto (1), Lucilla Franchi (2), Camilla Vianello (2), Martina Boscolo (2), Roberta Gobbato (2), Maria Grazia Passarin (3), Francesco Paladin (2)

  1. AULSS 9 Scaligera (ex ULSS 20 of Verona), Cognitive Impairment and Dementias Center – Verona
  2. AULSS 3 Serenissima (ex ULSS 12 Veneziana), Civil Hospital of Venice “SS. Giovanni e Paolo”, Division of Neurology
  3. AULSS 9 Scaligera (ex ULSS 22 of Bussolengo), Civil Hospital of Bussolengo “Orlandi”, Division of Neurology, Cognitive Impairment and Dementias Center – Bussolengo (VR)
  4. Cheaf of the project and corresponding author: mirko.avesani@gmail.com

In memory of Isabella Silvestri

INTRODUCTION

Epilepsy is an increasingly recognized comorbidity in Alzheimer’s disease (AD). First described as generalized in dementia patients, epileptic AD patients are nowadays fully described in earlier stages of the disease (with mild or subjective cognitive impairment). At such early stages, patients may present not only with generalized seizures, but also with focal seizures (commonly localized in the frontal or temporal lobe). Thus, focal or generalized epilepsy is part of the semiological spectrum of AD that should be borne in mind at all stages of disease to ensure early identification and prevent the risk of repeated seizures (such as accidents, injury, progression of cognitive impairment).

Not only: Interictal epileptiform discharge (IED) effects on neuropsychological assessment and epilepsy surgical planning. Both animal research and human research suggest that interictal epileptiform discharges (IEDs) may affect cognition, although the significance of such findings remains controversial. A recent review (Drane, 2016), analyzed a wide range of literature with bearing on this topic and present relevant epilepsy surgery cases, which suggest that the effects of IEDs may be substantial and informative for surgical planning. In the first case, a patient with epilepsy with left anterior temporal lobe (TL) seizure onset who experienced frequent IEDs during preoperative neuropsychological assessment was presented. Cognitive results strongly lateralized to the left TL. Because the patient failed performance validity tests and appeared amnestic for verbal materials inconsistent with his work history, selected neuropsychological tests were repeated 6 weeks later. Scores improved one to two standard deviations over the initial evaluation and because of this improvement, were only mildly suggestive of left TL impairment. The second case involved another patient with documented left TL epilepsy who experienced epileptiform activity while undergoing neurocognitive testing and simultaneous ambulatory EEG recording. This patient’s verbal memory performance was impaired during the period that IEDs were present but near normal when such activity was absent. Overall, although the presence of IEDs may be helpful in confirming laterality of seizure onset, frequent IEDs might disrupt focal cognitive functions and distort accurate measurement of neuropsychological ability, interfering with accurate characterization of surgical risks and benefits. Such transient effects on daily performance may also contribute to significant functional compromise. It was concluded that IED effects during presurgical assessment can hinder individual patient presurgical planning as well as distort outcome research (e.g., IEDs occurring during presurgical assessment may lead to an underestimation of postoperative neuropsychological decline).

EPIDEMIOLOGY

Many studies have shown that patients with Alzheimer’s disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. A literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD (Friedman, 2012), reviewed seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, limitations and methodological issues were considered. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. It was concluded that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.

Another study (Nicastro, 2016) described the association between Alzheimer’s disease and seizures by reviewing epidemiological data from available literature and to assess the putative pathophysiological links between neurodegeneration and altered cortical excitability. This study also discussed specific antiepileptic treatment strategies in patients with Alzheimer’s disease, as well as transient epileptic amnesia as a possible crossroads between degeneration and epilepsy. Regarding epidemiology, the authors searched publications in Pubmed, Medline, Scopus and Web of Science (until September 2015) using the keywords “incidence”, “prevalence” and “frequency”, as well as “Alzheimer’s disease” and “seizures”. In addition, therapeutic aspects for seizures in Alzheimer’s disease were searched using the key words “antiepileptic drugs”, “seizure treatment” and “Alzheimer”. The prevalence and incidence rates of seizures were found to be increased 2 to 6-fold in patients with Alzheimer’s disease compared to age-adjusted control patients. Treatment strategies have mainly been extrapolated from elderly patients without dementia, except for one single randomized trial, in which levetiracetam, lamotrigine and phenobarbital efficacy and tolerance were investigated in patients with Alzheimer’s disease. Mouse models appear to show a major role of amyloid precursor protein and its cleavage products in the generation of cortical hyperexcitability. A link between Alzheimer’s disease and epilepsy has long been described and recent cohort studies have more clearly delineated risk factors associated with the genesis of seizures, such as early onset and possibly severity of dementia. As genetic forms of Alzheimer’s disease and experimental mouse models suggest, beta-amyloid may play a prominent role in the propagation of synchronised abnormal discharges, perhaps more via an excitatory mode than a direct neurodegenerative effect.

PATHOPHYSIOLOGY

Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Several relationships have been obtained between cognitive impairment and epilepsy-related or treatment-related factors (Aldenkamp, 1997). One of these factors is treatment-related: the central cognitive side effects of the antiepileptic drugs (AEDs). The second and third factors are disease-related factors, i.e., the effect of the seizures and underlying epileptiform discharges in the brain and the localization of the epileptogenic focus in specific areas of the brain. Although most cognitive problems have a multifactorial origin and often several factors combined are responsible for the “make-up” of a cognitive problem, we have attempted to isolate one factor: the effect of seizures and epileptiform EEG discharges on cognitive function. Several studies show the impact of ictal activity, but special attention is required for the postictal and interictal effects of epilepsy on cognitive functions. This may explain substantial cognitive impairments in children with subclinical epileptiform discharges or with infrequent subtle seizures.

A dated, but still valid, review (Aldenkamp, 2004) analyzed the existing evidence on the cognitive impact of interictal epileptiform EEG discharges. Such cognitive impairment occurs exclusively in direct relation to episodes of epileptiform EEG discharges and must be distinguished from (post) ictal seizure effects and from the nonperiodic long-term “stable” interictal effects caused by the clinical syndrome or the underlying etiology. Especially in patients with short nonconvulsive seizures, characterized often by difficult-to-detect symptoms, the ictal or postictal effects may be overlooked and the resulting cognitive effects may be erroneously related to the epileptiform EEG discharges. The existing epidemiological data showed that the prevalence of cognitive impairment during epileptiform EEG discharges is low. In one study 2.2% of the patients referred to a specialized epilepsy center for EEG recording showed a definite relationship between epileptiform EEG discharges and cognitive impairments (“transient cognitive impairment”). Several studies have sought to analyze to what extent cognitive impairment can be attributed to epileptiform EEG discharges among the other epilepsy factors (such as the effect of the clinical syndrome). These studies show that epileptiform EEG discharges have an additional and independent effect, but this effect is mild and limited to transient mechanistic cognitive processes (alertness, mental speed). This finding concurs with clinical studies that also reported only mild effects. In only exceptional cases were epileptiform EEG discharges the dominant factor explaining cognitive impairment. In addition, some studies have indicated that such mild effects may accumulate over time (when frequent epileptiform EEG discharges persist over years) and consequently result in effects on stable aspects of cognitive function such as educational achievement and intelligence. Hence, the clinical relevance was that early detection of cognitive effects of epileptiform EEG discharges and subsequent treatment may prevent a definite impact on cognitive and educational development. The disruptive effects of epileptiform EEG discharges on long-term potentiation, as established in animal experiments, may be one of the neurophysiological mechanisms underlying this accumulation. In conclusion the concept of “transient cognitive impairment” was still valid, but refinement of methodology has shown that a large proportion of presumed transient cognitive impairment could be attributed to subtle seizures, while interictal epileptic activity accounted for a much smaller part of the cognitive effects than previously thought. In particular cryptogenic focal epilepsies are associated with the risk of cognitive impairment. The authors concluded hoping that increased clinical awareness of this need for early detection would have stimulated longitudinal and prospective research that eventually also would provide an answer to the questions of when and how epileptiform discharges that were not part of a seizure need to be treated.

See comment in PubMed Commons belowEpileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness (Vossel, 2013).

Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD (Palop, 2009) have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models.

The first conclusion of Palop is that high levels of Aβ cause epilepsy and cognitive deficits The brain is characterized by multiple levels of complexity, ranging from molecules and individual synapses to circuits and interconnected networks. Activities in lower levels determine activities in higher levels and vice versa. Consequently, molecular and synaptic alterations can affect the function of networks and, in turn, alterations in network functions can affect individual synapses and molecules. It is well known that Aβ causes depression of excitatory neurotransmission at specific synaptic connections (Figure 1), (Palop, 2007; Hsia AY, 1999; Walsh DM, 2002; Shankar GM, 2007) but the net effect of Aβ on the activity of microcircuits and broader neural networks had been unknown.

High lefels of A depress excitatory synaptic transmission and impair plasticity at the levels of specific synapses (A) but elicit epileptiform activity and seizures at the network level (B). Whether there is a casual relationship between these AB effects is unknown.

F indicates frontal; fEPSP, field excitatory postsynaptic potential; H: Hippocampal; hAPPJ20, human amyloid precursor protein transgenic mice; L: left; NTG: non transgenic mice; O: posterior-parietal; P: parietal; R: right; T: temporal; TBS: theta-burst stimulation.

Adapted from Palop 2006 (Nature) and Palop 2007 (Neuron)

Fig. 1 (Palop, 2009)- Amyloid (A) can affect neuronal activity at multiple levels of complexity

To shed light on this issue, Palop (2009) continually monitored neuronal activity in cortical and hippocampal networks by video electroencephalography (EEG) recordings in hAPP mice (J20 line; hAPPJ20), which have behavioral and synaptic deficits but no obvious neuronal loss (Palop, 2007) These recordings revealed frequent epileptiform activity including spikes and sharp waves (Figure 1). The hAPPJ20 mice also had intermittent unprovoked seizures involving diverse regions of the neocortex and hippocampus that were not accompanied by tonic or clonic motor activity (Figure 1). These results suggested that high levels of Aβ are sufficient to elicit epileptiform activity in vivo in the absence of frank neurodegeneration. Therefore, aberrant network synchronization appears to be a primary effect of high Aβ levels rather than a secondary consequence of extensive neurodegeneration. Electroencephalographic epileptiform activity has subsequently been identified in independent transgenic mouse models of AD, including hAPPJ9/FYN mice (unpublished data), Tg2576 mice (Chin, 2008) and hAPP/PS1 mice (Tanila, 2008) underlining the robustness of this Aβ effect.

Several lines of evidence suggest that Aβ-induced aberrant neuronal activity could contribute to cognitive deficits in hAPP mice and in AD. Epileptic activity triggers a variety of inhibitory compensatory responses in hippocampal circuits to counteract imbalances in network activity (Figure 2) – (Palop, 2007). Although these compensatory inhibitory mechanisms may dampen aberrant increases in network activity, they may also interfere with normal neuronal and synaptic functions required for learning and memory (Palop, 2006). In hAPP mice, Aβ-induced epileptic activity was associated with sprouting of inhibitory axonal terminals in the molecular layer of the dentate gyrus, enhanced synaptic inhibition, and alterations in several calcium- and activity-regulated proteins in granule cells including calbindin, Fos, and Arc (Figure 2B) – (Palop, 2007; Palop, 2003; Palop, 2005; Cheng, 2007)

Importantly, these alterations correlated tightly with each other and with deficits in learning and memory (Palop, 2003) suggesting that Aβ-induced aberrant neuronal activity and associated compensatory inhibitory responses may be causally linked to cognitive decline (Figure 2A). Palop (2009) further assessed this possibility by crossing hAPP mice onto a tau-deficient (tau−/−) background, a genetic manipulation that blocks Aβ– and excitotoxin-induced overexcitation (Palop, 2007; Roberson, 2007). Reducing tau levels in hAPP mice prevented learning and memory deficits, compensatory inhibitory responses, premature mortality, and most evidence for aberrant network activity without affecting either hAPP or Aβ (Figure 3) – (Palop, 2007; Roberson, 2007). These results were consistent with Palop (2009) hypothesis that Aβ-induced aberrant neuronal activity contributes causally to learning and memory deficits in hAPP mice and possibly in AD.

Fig. 2 (Palop, 2009) – latest view of the β-amyloid (Aβ) cascade hypothesis and resultant hippocampal remodeling

A, High levels of Aβ induce epileptiform activity, which triggers compensatory inhibitory responses to counteract overexcitation. Both aberrant excitatory neuronal activity and compensatory inhibitory responses may contribute to Alzheimer disease–related cognitive deficits. B, Aβ-dependent circuit remodeling in the dentate gyrus of human amyloid precursor protein transgenic mice (hAPPJ20). In contrast to nontransgenic mice (NTG), hAPPJ20 mice show increased sprouting of inhibitory axonal terminals in the molecular layer, enhanced synaptic inhibition, ectopic neuropeptide Y (NPY) expression in granule cells, and depletion of activity-dependent proteins such as calbindin, Arc, and Fos. These alterations likely reflect compensatory inhibitory responses to aberrant excitatory neuronal activity. CB indicates calbindin; GABA, {gamma}-aminobutyric acid; Glu, glutamate; PV, parvalbumin; and SOM, somatostatin. Adapted from Palop 2007 (Neuron).

The incidence of unprovoked seizures is clearly higher in sporadic AD than in reference populations, and the increase appears to be independent of disease stage (Amatniek, 2006; Hauser, 1986; Mendez, 2003). However, just as in hAPP mice, frank convulsive seizures are rather infrequent in AD. Nonetheless, 7% to 21% of patients with sporadic AD are estimated to have at least 1 unprovoked clinically apparent seizure during their illness (Amatniek, 2006; Hauser, 1986; Volicer, 1995).. The relative risk of unprovoked seizures markedly increases in patients with early-onset AD, reaching 3-, 20-, and 87-fold with dementia onset when aged 70–79, 60–69, or 50–59 years, respectively (Amatniek, 2006)

Thioflavin-S staining (A) and anti-Aβ immunostaining (B) of hippocampal amyloid plaques in mice with human amyloid precursor protein transgenic mice (hAPPJ20) with 2 (tau+/+) or no (tau−/−) functional tau alleles revealed that tau reduction did not alter plaque loads in hAPP mice. However, tau reduction effectively prevented Aβ-induced depletion of calbindin (CB) (C) and increases in neuropeptide Y (NPY) (D) in the dentate gyrus as well as spatial memory deficits in the Morris water maze (E). The representative path tracings in (E) were obtained in a probe trial (platform removed) 24 hours after 3 days of hidden platform training. Tau reduction markedly increased focused search activity in the target quadrant (light gray) and over the platform location (dark gray), suggesting improved spatial memory retention. Adapted from Palop 2007 (Neuron) and Roberson 2007 (Science)

Fig. 3 (Palop, 2009) – Tau reduction prevents β-amyloid (Aβ) toxicity in vivo

The relationship between clinically apparent seizures and AD is even stronger in autosomal dominant early-onset AD, which can be caused by mutations in hAPP (≥23 mutations), presenilin-1 (≥174 mutations), or presenilin-2 (≥14 mutations) and by duplications of wild-type hAPP (≥7 duplications) – (The Alzheimer disease and frontotemporal dementia mutation database. Flanders Interuniversity Institute for Biotechnology Department of Molecular Genetics Web site; 2008. http://www.molgen.ua.ac.be. Accessed September 6). These genetic alterations either increase Aβ42 production or the Aβ42:Aβ40 ratio or promote Aβ aggregation, providing strong evidence for a causal role of Aβ in AD. Notably, more than 30 mutations in presenilin-1 are associated with epilepsy (Larner, 2006), and 56% of patients with early-onset AD with APP duplications have seizures (Cabrejo, 2006). Around 83% of pedigrees with very early onset of dementia (<40 years of age) show frank seizures or epilepsy (Snider, 2005). Most cases of Down syndrome have an extra copy of the hAPP gene and develop early-onset AD; notably, 84% of those cases also have frank seizures (Lai, 1989).

These clinical observations were consistent with Palop’s hypothesis that Aβ is an important cause of aberrant neural network synchronization in AD.

The second conclusion of Palop (2009) is that Apolipoprotein E4 is Associated with Subclinical Epileptiform Activity in Carriers without Dementia. Apolipoprotein is the most important known genetic risk factor for sporadic AD. Although the mechanisms underlying this link remain to be fully elucidated, much evidence suggests that ApoE4 contributes to AD pathogenesis through both Aβ-dependent and Aβ-independent pathways (Mahley, 2006). Aberrant increases in network excitability may represent a critical convergence point for the adverse effects of ApoE4 and Aβ in the pathogenesis of AD. In contrast to noncarriers, ApoE4 carriers without dementia showed signs of epileptiform activity and sharp waves on their EEGs after hyperventilation, although their EEGs were normal under resting conditions (Ponomareva, 2008). Similar changes have been found in subjects with high familial risk of developing AD, such as first-order relatives of patients with early-onset AD (Ponomareva, 2003). Apolipoprotein E4 also exacerbates epilepsy and promotes memory impairment in patients with long-standing intractable temporal lobe epilepsy (Busch, 2007). These data indicated that major genetic risk factors for developing AD are associated with increased network excitability in individuals without dementia, suggesting that this type of network dysfunction might play an early role in the establishment of pathogenic cascades leading to AD. The third conclusion of Palop (2009) is that Amnestic Wandering and Disorientation in AD can be Associated with Epileptiform Activity. Many patients with AD experience fluctuations in cognitive functions such as transient episodes of amnestic wandering and disorientation (Palop, 2006; Bradshaw, 2004) . The intermittent inability to retrieve memories cannot be easily explained by relatively protracted processes such as neuronal loss, plaque deposition, or tangle formation. It seems more likely that abnormal neuronal network activity is to blame. Interestingly, amnestic episodes in patients with AD have been associated with epileptiform EEG discharges such as spikes and sharp waves (Rabinowicz, 2000). What is more, these specific cognitive disturbances and the associated epileptiform EEG discharges could be prevented by antiepileptic treatment (Rabinowicz, 2000). Epileptiform discharges in patients with temporal lobe epilepsy can also lead to transient amnesia and even simulate AD-like memory disturbances (Sinforiani, 2003).Therefore, nonconvulsive epileptiform activity could underlie at least some of the cognitive impairments observed in AD. Prospective clinical investigations focusing on hard-to-detect forms of epileptic activity are needed to further test this hypothesis in the clinic.

Palop (2009) concluded that all these observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Recent experimental data demonstrated that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. So, beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis (Palop, 2009).

Recent evidence (Born, 2015) suggests that nonconvulsive network abnormalities, including seizures and other electroencephalographic abnormalities, may be more commonly found in patients than previously thought. Patients with familial AD are at an even greater risk for seizures, which have been found in patients with mutations in PSEN1, PSEN2, or APP, as well as with APP duplication. A recent review (Born, 2015) also provides an overview of seizure and electroencephalography studies in AD mouse models. The amyloid-β (Aβ) peptide has been identified as a possible link between AD and seizures, and while Aβ is known to affect neuronal activity, the full-length amyloid precursor protein (APP) and other APP cleavage products may be important for the development and maintenance of cortical network hyperexcitability. Nonconvulsive epileptiform activity, such as seizures or network abnormalities that are shorter in duration but may occur with higher frequency, may contribute to cognitive impairments characteristic of AD, such as amnestic wandering. Finally, the review discusses recent studies using antiepileptic drugs to rescue cognitive deficits in AD mouse models and human patients. Understanding the mechanistic link between epileptiform activity and AD is a research area of growing interest. Further understanding of the connection between neuronal hyperexcitability and Alzheimer’s as well as the potential role of epileptiform activity in the progression of AD will be beneficial for improving treatment strategies.

SEIZURE SEMIOLOGY

Seizures occur at a higher frequency in people with Alzheimer’s disease (AD), and See comment in PubMed Commons belowepileptic activity is frequently associated with Alzheimer’s disease and any type of seizure can be observed in Alzheimer’s disease, so overt, clinically obvious events are infrequent See comment in PubMed Commons below(Liu, 2016; Musaeus, 2017).

A retrospective observational study from 2007 to 2012 (Vossel, 2013) was performed by SETTING Memory and Aging Center, University of California, San Francisco. 54 patients were studied with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7). This to describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity.

Main Outcomes and measures were: Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications. As results, patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02), patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001), patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%).

Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin. In conclusion, the common clinical features of patients with aMCI- or AD-associated epilepsy at that center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

A recent review (Cretin B, 2017) of the available (and still growing) literature shows that there are already sufficient data to inform physicians on seizure semiology, and on the diagnostic value of electroencephalography and brain imaging. Taken together, these tools can help to rapidly identify epilepsy in AD patients. Nevertheless, epilepsy diagnosis can be challenging, and test medication is sometimes necessary. Some cerebrospinal fluid biomarkers (or their ratios) may also prove to be good predictors of seizures in AD, but further studies are needed. Epilepsy in AD patients is frequently pharmacosensitive, and a good response can be obtained with standard doses of antiepileptic drugs. For all these reasons and based on this review of the literature, it appears that, at present, the diagnosis of epilepsy in AD is not only possible at any stage of the disease, but also to be recommended to improve the patient’s prognosis.

NEUROPHYSIOLOGICAL ASSESSMENT OF EPILEPSIES IN DEMENTIAS

Several studies have suggested that the default mode network (DMN) plays an important role in the pathological mechanisms of Alzheimer’s disease (AD). To examine whether the cortical activities in DMN regions show significant difference between mild AD from mild cognitive impairment (MCI), electrophysiological responses Hsiao (2013) analyzed from 21 mild Alzheimer’s disease (AD) and 21 mild cognitive impairment (MCI) patients during an eyes closed, resting-state condition. The spectral power and functional connectivity of the DMN were estimated using a minimum norm estimate (MNE) combined with fast Fourier transform and imaginary coherence analysis. These results indicated that source-based EEG maps of resting-state activity showed alterations of cortical spectral power in mild AD when compared to MCI. These alterations were characteristic of attenuated alpha or beta activities in the DMN, as were enhanced delta or theta activities in the medial temporal, inferior parietal, posterior cingulate cortex and precuneus. With regard to altered synchronization in AD, altered functional interconnections were observed as specific connectivity patterns of connection hubs in the precuneus, posterior cingulate cortex, anterior cingulate cortex and medial temporal regions. Moreover, posterior theta and alpha power and altered connectivity in the medial temporal lobe correlated significantly with scores obtained on the Mini-Mental State Examination (MMSE). In conclusion, EEG was demonstrated a useful tool for investigating the DMN in the brain and differentiating early stage AD and MCI patients.

A relatively new approach to brain function in neuroscience is the “functional connectivity”, namely the synchrony in time of activity in anatomically-distinct but functionally-collaborating brain regions. On the other hand, diffusion tensor imaging (DTI) is a recently developed magnetic resonance imaging (MRI)-based technique with the capability to detect brain structural connection with fractional anisotropy (FA) identification. FA decrease has been observed in the corpus callosum of subjects with Alzheimer’s disease (AD) and mild cognitive impairment (MCI, an AD prodromal stage). Corpus callosum splenium DTI abnormalities are thought to be associated with functional disconnections among cortical areas. Recently it was investigated (Vecchio, 2015) possible correlations between structural damage, measured by MRI-DTI, and functional abnormalities of brain integration, measured by characteristic path length detected in resting state EEG source activity (40 participants: 9 healthy controls, 10 MCI, 10 mild AD, 11 moderate AD). For each subject, undirected and weighted brain network was built to evaluate graph core measures. eLORETA lagged linear connectivity values were used as weight of the edges of the network. Results showed that callosal FA reduction is associated to a loss of brain interhemispheric functional connectivity characterized by increased delta and decreased alpha path length. These findings suggested that “global” (average network shortest path length representing an index of how efficient is the information transfer between two parts of the network) functional measure can reflect the reduction of fiber connecting the two hemispheres as revealed by DTI analysis and also anticipate in time this structural loss.

Several other studies (Vecchio 2013) on resting state eyes-closed EEG rhythms recorded in amnesic mild cognitive impairment (MCI) and AD subjects support the idea that spectral markers of these EEG rhythms, such as power density, spectral coherence, and other quantitative features, differ among normal elderly, MCI, and AD subjects, at least at group level. Regarding the classification of these subjects at individual level, the most previous studies showed a moderate accuracy (70-80%) in the classification of EEG markers relative to normal and AD subjects. Resting state EEG makers are promising for large-scale, low-cost, fully noninvasive screening of elderly subjects at risk of AD. Babiloni (2013) observed that cortical gray matter volume and resting state cortical electroencephalographic rhythms are typically abnormal in subjects with amnesic mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Here he tested the hypothesis that in amnesic MCI and AD subjects, abnormalities of EEG rhythms are a functional reflection of cortical atrophy across the disease. Eyes-closed resting state EEG data were recorded in 57 healthy elderly (Nold), 102 amnesic MCI, and 108 AD patients. Cortical gray matter volume was indexed by magnetic resonance imaging recorded in the MCI and AD subjects according to Alzheimer’s disease neuroimaging initiative project (http://www.adni-info.org/). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). These rhythms were indexed by LORETA. Compared with the Nold, the MCI showed a decrease in amplitude of alpha 1 sources. With respect to the Nold and MCI, the AD showed an amplitude increase of delta sources, along with a strong amplitude reduction of alpha 1 sources. In the MCI and AD subjects as a whole group, the lower the cortical gray matter volume, the higher the delta sources, the lower the alpha 1 sources. The better the score to cognitive tests the higher the gray matter volume, the lower the pathological delta sources, and the higher the alpha sources. These results suggested that in amnesic MCI and AD subjects, abnormalities of resting state cortical EEG rhythms are not epiphenomena but are strictly related to neurodegeneration (atrophy of cortical gray matter) and cognition.

Another study (Vecchio, 2014) was performed to investigate the neuronal network characteristics in physiological and pathological brain aging. A database of 378 participants divided in three groups was analyzed: Alzheimer’s disease (AD), mild cognitive impairment (MCI), and normal elderly (Nold) subjects. Through EEG recordings, cortical sources were evaluated by sLORETA software, while graph theory parameters (Characteristic Path Length λ, Clustering coefficient γ, and small-world network σ) were computed to the undirected and weighted networks, obtained by the lagged linear coherence evaluated by eLORETA software. EEG cortical sources from spectral analysis showed significant differences in delta, theta, and alpha 1 bands. Furthermore, the analysis of eLORETA cortical connectivity suggested that for the normalized Characteristic Path Length (λ) the pattern differences between normal cognition and dementia were observed in the theta band (MCI subjects are find similar to healthy subjects), while for the normalized Clustering coefficient (γ) a significant increment was found for AD group in delta, theta, and alpha 1 bands; finally, the small world (σ) parameter presented a significant interaction between AD and MCI groups showing a theta increase in MCI. The fact that AD patients respect the MCI subjects were significantly impaired in theta but not in alpha bands connectivity were in line with the hypothesis of an intermediate status of MCI between normal condition and overt dementia.

A review (Babiloni 2016) reported literature results concerning EEG studies in condition of resting state in AD and mild cognitive impairment (MCI) subjects as a window on abnormalities of the cortical neural synchronization and functional and effective connectivity. Results showed abnormalities of the EEG power density at specific frequency bands (<12Hz) in the MCI and AD populations, associated with an altered functional and effective EEG connectivity among long range cortical networks (i.e. fronto-parietal and fronto-temporal). The results suggested that resting state EEG rhythms reflect the abnormal cortical neural synchronization and coupling in the brain of prodromal and overt AD subjects, possibly reflecting dysfunctional neuroplasticity of the neural transmission in long range cortical networks.

Although the altered coherence between cortical areas in Alzheimer’s disease (AD) has been widely studied, it remains unclear whether the source-based coherence measures within sensorimotor network show significant difference between mild cognitive impairment (MCI) and AD.

Hsiao (2014), for first time, studied resting-state electroencephalographic signals from 21 MCI and 21 mild AD patients. The spectral power and coherence in the sensorimotor areas were analyzed using the minimum norm estimate (MNE) combined with fast Fourier transform and coherence analysis in delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-25 Hz), and gamma (25-40 Hz) bands. The results indicated that source-based coherence in AD showed increased delta coherences between the bilateral precentral, left supplementary motor area (SMA) and right precentral, and left SMA and right postcentral areas. However, no significant difference of spectral powers was observed between AD and MCI. In conclusion, it was suggested that the phenotype conversion from MCI to AD may be associated with an altered connectivity of the sensorimotor cortical network. This was a promising finding; however, further large-scale studies were needed.

TREATMENT

This association between AD (and other cognitive impairments) and epilepsy (and epileptic activities during seizures) has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis (Vossel, 2017).

Evidence from animal models and studies in mild cognitive impairment suggest that subclinical epileptic discharges may play a role in the clinical and pathophysiological manifestations of AD (Musaeus, 2017).

Palop (2009) considered interesting Therapeutic Implications. Many drugs for AD currently in clinical trials aim to reduce Aβ levels. However, the efficacy and long-term safety of these drugs have not yet been established. The studies discussed above suggest that reducing aberrant synchronization of neuronal activity may effectively protect the brain against Aβ‘s adverse effects on cognitive functions and thus could provide a complementary or alternative therapeutic strategy. We specifically hypothesize that cognitive deficits in hAPP mice, and perhaps in humans with AD, result from the combination of aberrant excitatory neuronal activity and of compensatory inhibitory responses that reduce overexcitation but end up constraining the functional agility of processes required for learning and memory (Figure 2A). Combination treatments may be required to block the contributions of overexcitation and overinhibition to AD-related cognitive deficits, although it seems reasonable to speculate that blocking the former should prevent, and might reverse, the latter.

Low doses of the {gamma}-aminobutyric acid A (GABAA) receptor antagonist picrotoxin prevented long-term potentiation deficits in the dentate gyrus and cognitive impairments in hAPP/presenilin 1 mice (Yoshiike, 2008) as well as in Ts65Dn mice, a mouse model of Down syndrome (Fernandez, 2007).These results indicate that inhibition in the dentate gyrus may critically contribute to cognitive impairments in these overlapping disorders. However, blocking inhibition with GABAA receptor antagonists can also exacerbate or precipitate seizures in hAPP mice (Palop, 2007; Del Vecchio, 2004) making this therapeutic intervention risky, at least as a monotherapy. Blocking overexcitation might provide a more effective upstream approach. A key question is whether any of the available Food and Drug administration–approved antiepileptic drugs could prevent or ameliorate Aβ-induced aberrant network excitation. Notably, some of the most commonly used antiepileptic drugs actually worsened seizure activity in hAPPJ20 mice (Palop, 2008), underlining the need to carefully evaluate these agents at the preclinical level before designing clinical trials for people with AD or mild cognitive impairment. Consistent with this notion, the few clinical trials of antiepileptic drugs that have been conducted in AD so far have yielded disappointing results, but they were small and focused mostly on behavioral abnormalities in late stages of the disease (Herrmann, 2007).

Up to one-third of patients with seizures without AD do not respond satisfactorily to medication and develop refractory epilepsy (French, 2007). Antiepileptic drugs can also aggravate or precipitate certain types of seizures (Thomas, 2006).Thus, the efficacy of antiepileptic drugs in AD will likely depend on the exact mechanisms of Aβ-induced dysrhythmias, which are currently unknown. Some antiepileptic drugs may elicit beneficial effects, whereas others may exacerbate aberrant network activity and cognitive decline. It is also possible that novel drugs may have to be developed to specifically block Aβ-induced dysrhythmias in AD. Our experimental data suggest that reducing tau levels is highly effective in preventing Aβ-induced network dysfunction and cognitive deficits in vivo (Figure 3) – (Palop, 2007; Roberson, 2007). However, for Palop (2009), much more research was needed to further assess the efficacy and safety of this novel therapeutic strategy.

In clinical practice, seizures in patients with Alzheimer’s disease (AD) can easily go unrecognized (Vossel, 2017; Musaeus, 2017) because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer’s disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer’s disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer’s disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer’s disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer’s disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with AD. There are pharmacological and non-pharmacological treatments for epilepsy in people with AD. There are no current systematic reviews to evaluate the efficacy and tolerability of the treatment. A Cochrane database study (Liu, 2016) aimed to review those different modalities, and to assess the efficacy and tolerability of the treatment of epilepsy for people with Alzheimer’s disease (AD) (including sporadic AD and dominantly inherited AD). The authors searched the Cochrane Epilepsy Group Specialized Register (1 February 2016), the Cochrane Central Register of Controlled Trials (1 February 2016), MEDLINE (Ovid, 1 February 2016) and ClinicalTrials.gov (1 February 2016). In an effort to identify further published, unpublished and ongoing trials, authors searched ongoing trials’ registers, reference lists and relevant conference proceedings, and authors and pharmaceutical companies were contacted. As selection criteria, randomized and quasi-randomized controlled trials investigating treatment for epilepsy in people with AD were included, with the outcomes of proportion of seizure freedom or experiencing adverse events. Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. It was performed no meta-analyses due to the limited available data. The authors included one randomized controlled trial with 95 participants. Concerning the proportion of participants with seizure freedom, no significant differences were found in levetiracetam (LEV) versus lamotrigine (LTG) (risk ratio (RR) 1.20, 95% confidence interval (CI) 0.53 to 2.71), in levetiracetam versus phenobarbital (PB) (RR 1.01, 95% CI 0.47 to 2.19), or in LTG versus PB (RR 0.84, 95% CI 0.35 to 2.02). It seemed that LEV could improve cognition and LTG could relieve depression; while PB and LTG could worsen cognition, and LEV and PB could worsen mood. Authors judged the quality of the evidence to be very low. As author’s conclusions, this review does not provide sufficient evidence to support LEV, PB and LTG for the treatment of epilepsy in people with AD. Regarding the efficacy and tolerability, no significant differences were found between LEV, PB and LTG. In the future, large randomized, double-blind, controlled, parallel-group clinical trials are required to determine the efficacy and tolerability of treatment for epilepsy in people with AD.

In a feasibility study (Musaeus, 2017), the neurophysiological and cognitive effects of acute administration of levetiracetam (LEV) were measured in patients with mild AD to test whether it could have a therapeutic benefit. AD participants were administered low dose LEV (2.5 mg/kg), higher dose LEV (7.5 mg/kg), or placebo in a double-blind, within-subject repeated measures study with EEG recorded at rest before and after administration. After administration of higher dose of LEV, we found significant decreases in coherence in the delta band (1-3.99 Hz) and increases in the low beta (13-17.99 Hz) and the high beta band (24-29.99 Hz). Furthermore, trends toward increased power in the frontal and central regions in the high beta band (24-29.99 Hz) were founded. However, there were no significant changes in cognitive performance after this single dose administration. The pattern of decreased coherence in the lower frequency bands and increased coherence in the higher frequency bands suggests a beneficial effect of LEV for patients with AD. Larger longitudinal studies and studies with healthy age-matched controls are needed to determine whether this represents a relative normalization of EEG patterns, whether it is unique to AD as compared to normal aging, and whether longer term administration is associated with a beneficial clinical effect.

OUR EXPERIENCE

The corresponding author works as neurologist, firstly co-cheaf of Dementia Center of Neurological Division of Civil Hospital of Bussolengo, Verona (from 2009 to 2011), then chef of Dementia Center of Neurologica Division of Civil Hospital of Venice (from 2011 to 2015) and finally co-chief of Dementia Center of Verona (from 2015 to present day).

These are three great centers (in North East of Italy) of praecox diagnosis and treatment of cognitive impairment and dementias, in order to make the progression slower.

In all these centers, the problem of comorbidity of Epilepsia in Dementia is very diffused and create several problems of treatment, as before reported. Epilepsy may worsen Dementia but also Dementia may worsen Epilepsy.

The future, for us, will be a real pathogenetic (and not only symptomatic) treatment of Dementia, because only disrupting the -amiloyd cascade and, so, blocking neurodegeneration (figg. 1, 2 and 3) will let us to keep intact the different inhibitory networks whose damage, nowadays, causes epilepsy.

At the moment, unfortunately, these therapeutic approaches are not disposable but in a next future we hope to treat dementia (and, so, also epilepsy) in this way.

AKNOWLEDGMENTS

A special thanks to Doctor Michele Avesani, Doctor Alessandro Favazza, and Lawyer Stefano Casali. Their presence, in this moment, let this chapter be written.

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