1. Context
Alzheimer ‘s disease (AD) and isolated or recurrent seizures, i.e. epilepsy, are two common neurologic disorders whose incidence increases with age. It is possible that they appear concurrently in the same subject causing at times serious difficulties in diagnosis and illness management, and also raising questions as to the nature of their association, e.g. fortuitous or causally interlinked. The aim of this research was to review the literature in search of a possible link between these two diseases.
2. Evidence Acquisition
Medline literature until July 2016 was scanned using epilepsy, seizures, Alzheimer’s disease, dementia and mild cognitive impairment, as key-words. When epilepsy was identified, the search was narrowed using electroencephalographic discharges, epileptiform activity and models of Alzheimer’s disease. Other studies were identified by reviewing relevant bibliography quoted in the original papers. Clinical studies were included if they could meet these fundamental criteria: 1, AD diagnosis according to the NINCDS- ADRDA criteria (1); including patients with dementias other than AD when sufficient data on the AD were provided; 2, minimum sample of twenty subjects; and 3, use of standardized instruments of evaluation.
3. Results
3.1. Clinical and Electroencephalographic Findings
Alzheimer himself reported seizures in the late course of the disease of his second patient (2). However, it was only in the 1950s when a few small series drew attention to the high frequency of seizures in patients affected by AD (3, 4); from the 1980s, researches on the subject became relatively more frequent and the series became larger. Except for a few cases (5), early work on seizures only considered the later stages of the disease (6-11). However, from the 1990s, seizures were also referred in the early stages (12-18), in mild cognitive impairment (MCI) (17) and as early symptoms of AD (19, 20). Irizarry and Coll (21) examined 3078 subjects with AD and without history of seizures: the overall incidence of seizures was 484 per 100000 individuals/year; a higher percentage than the incidence found in other elderly population samples. Sherzai and Coll (22) claimed that AD patients were about three times more likely to have seizures and patients in younger age groups tend to have higher odds of having seizures. Also Cheng and Coll (23) reported that the incidence of seizures was doubled in AD patients compared to non-demented subjects and in their series the increment of age was significantly associated with higher occurrence of seizures. In the dominantly inherited AD, Zarea and Coll (24) reported seizures in the 47.7 of the patients after a mean follow-up of 8.4 years. The average time between the onset of the cognitive decline and the first seizure was 5.8 years but in four patients the seizure was the first sign of the disease. In summary, today all authors agree that seizures can appear at any stage of the disease and that greater frequencies are found in the later stages or in younger subjects with familial AD. Also the seizure’ frequency varies between series, ranging from a minimum of 3.5% of the patients (17) to a maximum of 64% (7). These disparities are likely related to the different populations examined: in older studies the patients were in advanced stages of dementia whereas in more recent studies the patients were chosen from all stages of the disease. The typology of reported seizures also changes with time: older studies mainly report tonic-clonic seizures (8-10, 14) whereas more recent studies consider focal seizures with or without impairment of consciousness with similar or even greater frequency, ranging from 47% to 92% (16, 17, 25). Inconsistencies between different series are also related to methodological problems: most studies are retrospective and it is sometimes difficult to distinguish an epileptic seizure from a convulsive syncope on the basis of medical records. Focal seizures without impairment of consciousness are even more difficult to recognize because aggression, wandering or inattentiveness can be easily misdiagnosed as signs of dementia. The epileptic amnesic syndrome is very difficult to recognize because the syndrome typically begins in the late-middle or old age and AD can coexist (19, 20) (see later). The routine Electroencephalograms (EEG) are seldom more useful: they usually register focal or generalized slowing whereas epileptiform activity is infrequent. In 21 patients with epileptic events, Scarmeas et al. (14) observed epileptiform activity in 16% of the EEG and Rao (15) in 38% while Bernardi et al. (16) observed spike-waves in 35.7% of their epileptic patients. Vossel et al. (17) refer instead a greater frequency of epileptic foci defined as regions of maximum electronegativity: in 62% of the patients evaluated for seizures and in 6% of those without known seizures they were predominantly unilateral and most commonly temporal. This greater frequency is due to the use of serial EEG or long-term video EEG. In some subjects epileptiform discharges are recorded in absence of clinical seizures. In the series of Amatniek et al. (12) focal epileptiform activity was found to be predictive of seizures; in a wide series (26) including 510 patients with AD and 225 with MCI focal epileptiform activity mainly temporal was recorded in 2% of the patients respectively; the same percentage of electroencephalographic anomalies was found in patients with other dementias or with subjective complaints; one AD patient and one with vascular dementia developed seizures after two years. In Vossel et al.’s series (17) epileptiform foci were recorded in 6% of patients without know seizures; however the Authors do not indicate whether some patients displayed seizure over time.
3.2. Possible Risk Factors for Seizures, Therapy, and Prognosis
Typically, the AD is a disease of the old age so it is not unusual to be associated with diseases or therapies that can help the appearance of seizures. Cerebral vascular lesions are common in the AD with frequency of seizures found to be 5.6/1.000 person-years in the AD and 7.5/1.000 person-years in vascular dementia (18). When availables, pathology (3-5, 7-11, 14) or neuroimaging (16, 17) ruled-out vascular lesions serious enough to cause seizures. The importance of the microbleeds is still under debate: they are encountered in the 4.8% of the AD patients (25, 27-29) and only in the 0.7% of the general population (30) and are related to transient focal neurological episodes that can resemble transient ischemic attacks, seizures or migraine crisis. Some Authors understand the Apolipoprotein ε4 as a risk factor for seizures: Ponomareva et al. (31) show epileptiform activity during hyperventilation in first-order relatives of patients with early-onset AD. The same Authors refer the appearance under hyperventilation of synchronous high-voltage delta, theta activity and sharp-waves together with decrease in alpha and increase in delta and theta activity in Apolipoprotein ε4 carriers without signs of dementia (32). Even if Lhetovirta et al. (33) did not find any difference in the seizures’ frequency according to the Apolipoprotein ε4 genotype, some Authors related Apolipoprotein ε4 to refractory seizures (34). Some Authors claimed a drop in the epileptic threshold due to use of acetylcholinesterase inhibitors, memantine, antidepressants or neuroleptic drugs (35-38). In the study of Fisher et al. (39) donepezil was administered to epileptic patients complaining about their memory: two patients experienced an increase in the frequency of the seizures. But in a similar work (40) the use of donepezil was not associated with increased seizure frequency or severity. In the wide series of Irizarry and Coll. (21) the use of antipsychotic drugs was a risk factor for new-onset seizures whereas this finding is not confirmed in other series (14, 16). In the population study of Bell et al. (41) the annual prevalence of antiepileptic drugs use was 5% among persons with AD compared to 3.4% among persons without AD; these data indirectly confirm the high prevalence of seizures in the AD and particularly in younger patients. The main finding of this study was the prevalent use of the older antiepileptic drugs, mainly valproic acid and carbamazepine. There are only few series reporting therapies and their efficacy. In the series of Rao et al. (15) the most commonly used drugs are phenytoin and valproic acid causing at least a 95% reduction of seizures frequency in 79% of the patients. However, Fleischer et al. reported that chronic use of valproate enhances cognitive decline (42). In the series of Vossel et al. (17) the mostly used drugs are lamotrigine and levetiracetam; the Authors underline their greater efficacy and lighter side-effects. The efficacy of levetiracetam is confirmed in a prospectic study of 25 patients with advanced AD and new-onset seizures: 72% of patients were seizure-free for at least one year but 16% discontinued the drug because of the side-effects and 4% were unresponsive (43). Cumbo and Ligori (44) compared leviteracetam, phenobarbital and lamotrigine in 95 AD patients. There were no significant differences in efficacy but phenobarbital produced persistent negative cognitive effects whereas levetiracetam was associated with improved cognitive performance and lamotrigine with a better effect on mood. Few Authors tried to evaluate whether the appearance of seizures could have a prognostic value, obtaining contradictory results. According to Volicer et al. (11), the patients’ condition suddenly worsened after seizures; however according to Samson et al. (45) seizures could not be associated with mortality.
3.3. Putative Links between AD and Epilepsy
Clinically the clearest link between the AD and epilepsy shows in the familial AD mainly if due to a mutation in the presenilin 1 gene. The phenotype is variable: pyramidal and extrapyramidal signs, cerebellar ataxia, myoclonus and seizures may add to dementia (www. Molgen.vib-na.be/ADmutations). The seizures sometimes appear in the late curse of the disease but can also precede cognitive symptoms for several years (24, 46). The data of Vossel et al. (17) confirm seizures’ frequency also in the early stages of sporadic AD and even in the MCI. Researchers’ attention was directed to the temporal lobe epilepsy (TLE) because these patients often refer of memory impairments (47) or depression (48) similarly to patients with AD and because experimental works in animals (see later). A link between the AD and epilepsy was also confirmed in pathological studies: Thom et al. (49) showed a significant increase in Braak stages III and IV in middle-aged subjects with chronic drug-resistant epilepsy. However, the same authors noticed that the Braak stage was low in over half of the patients with cognitive decline, thus suggesting that other factors contribute to such cognitive decline. Animal models of the AD confirm the link with seizures; in this field the most important work is that of Palop et al. (50), which found spontaneous non-convulsive seizure activity in cortical and hippocampal networks in all transgenic mice with high levels of amyloid-β peptide. The authors believe that the amyloid-β peptide triggers intermittent aberrant excitatory neuronal activity in the cortex and hippocampus resulting in a remodelling of inhibitory circuits and increased inhibition of the granule cells. In their view the cognitive deficit results from the combination of neuronal over-excitation and the subsequent development of compensatory inhibitory mechanisms. Such results were confirmed by several authors (51-53). For a long time, it has been know that interictal spikes cause cognitive impairments (54); using a rodent model in a behaviour task, Kleen et al. (55) showed that hippocampal spikes were also associated with dramatic alterations in both response latency and accuracy. It is possible that modification of neuronal excitability is not directly related to amyloid-β but instead it is related to certain metabolites, for example, high levels of amyloid precursor protein intracellular domain alters membrane stability (52). Another example is the observation that altered processing of voltage-gated sodium channels may contribute to aberrant neuronal activity and cognitive deficits in mice (56). Also the tau protein exerts important effects on the neuronal excitability: in transgenic mice reduction of the tau increased resistance to pentylenetetrazole-induced seizures (57). The AD and TLE are similar yet they also have some differences: preeminent deficit in the remote memory and in the long-term forgetting and temporal sclerosis are frequently are different in TLE when compared to AD (58). In AD the GABAergic neurons are spared and no recurrent sprouting of excitatory collateral mossy fibers onto GABAergic basket cells is found (50). Another difference is that in AD the more damaged neurons are in the layer II of the entorhinal cortex (59) whereas in TLE the more damaged neurons are in layer III (60). However, according to Scharfman (61), AD and TLE likely show similarities in the neurobiological mechanisms and the comparison of these two diseases may identify novel opportunities for mechanistic insight and therapeutic strategies. According to the hypothesis that seizures can worsen cognitive deficits, the use of antiepileptic drugs was suggested. Valproic acid administered to subjects with moderate AD for 24 months was ineffective in slowing cognitive and functional impairment or in slowing the emergence of agitation (62). Sodium valproate and levetiracetam at low doses improved memory in aged rats (63) and also potentiators of γ-amino-butyric acid and GABAa α5 receptors improved performances in aged rats (64). Devi et al. (65) confirmed that pre-training administration of levetiracetam ameliorates memory impairment in aged mice, but not in transgenic mice, whereas Cumbo and Ligori (44) observed improved cognitive performances in AD subjects treated with levetiracetam and better mood in those treated whit lamotrigine whereas patients treated with phenobarbital showed cognitive side effects.
4. Discussion
For a long time, seizures in AD were thought to be due to neuronal damage and gliosis and typical of the late stages of the disease. Only recently, was reported their appearance in the early stages of AD or even before the appearance of cognitive impairments. Because seizures are often focal and because there are some similarities between patients affected by AD and patients affected by TLE, attention has been drawn to the temporal lobe and relevant questions have been put forward. First of all, the true frequency of the seizures was investigated. Actually non-convulsive seizures seem more frequent in AD but are difficult to recognize clinically especially in confused patients and it is well-know that temporal seizures are often unrecognised by the standard Electroencephalogram (EEG). Interestingly, both Minkiviciene in mice (51) and Vossel in humans (17) recorded anomalies in more than 60% of their subjects using prolonged recording, a much greater percentage than that reported using standard recording techniques. According to the data of Palop et al. (50) the epileptiform discharges are the rule, at least in mice. The question is of practical importance because some authors (21, 24) have reported an association between seizures and rapid progression of cognitive decline; this is a matter for future studies. The second question is why seizures appear. It seems reasonable to suppose that these two diseases have a common mechanism responsible for similar symptoms such as depression, seizures and cognitive impairment. To a certain extent, AD and TLE remain different both clinically and pathologically; at this stage, it is therefore not possible to refuse the alternative hypothesis that similar symptoms appear simply because the same cerebral region is affected by both diseases. In support of this hypothesis, it must be noted that seizures were recorded also in other dementias and particularly in vascular dementia (18). It remains well-recognized that seizures cause cognitive impairment; it is therefore logical to investigate whether antiepileptic drugs can slow the process. Works in this direction are very few: in old animals antiepileptic drugs seem to improve the cognitive performances; however in general animal models of AD and in humans these drugs are ineffective. The improved knowledge of the mechanisms responsible for neuronal hyperexcitability may lead to more selective and effective drugs. Finally, it should be noted that the NINCS-ADRDA criteria (1) take into account only cognitive impairments, thus leaving out several non-cognitive symptoms that can also appear in the early stages and can be precocious signs of the disease (66). According to the NINCS-ADRDA criteria seizures at the onset or very early in the course of the illness make the diagnosis uncertain or unlikely. However, this statement dates back to 1984 whereas more recent studies both in animals (Palop 2007, Minkieviciene 2009, Vog 2011, Yan 2012) and humans (Vossel 2013, Zarea 2016) showed a greater frequency. Studies on humans are few but if confirmed this statement needs to be modified.
