Epilepsy And Early Onset Dementia

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Gallagher has been putting this theory to the test in clinical trials. A short phase 2 trial completed in 2017 used a common anti-seizure drug called levetiracetam and measured reduced activity in the hippocampus of test subjects coupled with improved performance on memory tests.

Gallagher started a company, AgeneBio, that is now recruiting 830 subjects for a phase 3 clinical trial using a specially formulated low-dose version of the drug. Patients with the type of mild cognitive impairment that precedes Alzheimers will take the drug for a year and a half to crank down the neural activity, said Gallagher, and see whether the disease progresses more slowly. Three smaller phase 2 trials using a similar strategy are also underway, sponsored by the Medical College of Wisconsin, University of Minnesota, University of San Francisco, and Oxford University Hospitals.

Mucke, like Gallagher and many other neuroscientists, believes that the phenomenon of hyperactivity is ripe for the discovery of additional therapeutic entry points that might not only be symptomatically beneficial but also have the potential to be disease-modifying. He points out that brain rhythms have a strong impact on immune system function in the brain, which is increasingly implicated in the pathogenesis of Alzheimers disease.

So, if we do establish that this is an early sign, one thing that I would be very interested in evaluating, said Keret, is whether interventions at this stage are successful.

What Is The Link Between Seizures And Dementiablog

There are some symptoms of dementia that are more commonly known, such as memory loss. Seizures are a less common symptom of dementia that are not as understood. Hear from one of our dementia researchers who has been studying seizures in people with the condition.

This article was first published in 2019 and most recently updated in September 2022.

How common are epileptic seizures in dementia? Who is most at risk of having them? What do these seizures look like? What effect do they have on how someones memory changes over time?

These are the questions that I have been researching since starting my PhD in 2016. I’m a student funded by Alzheimers Society as part of the University of Exeter doctoral training centre.

Clinical Efficacy Of Antiseizure Drugs In Patients With Alzheimers Disease

The focal seizures in AD may be difficult to recognize and may even go undetected by surface EEG electrodes that only detect cortical activity . Undetected seizures are untreated seizures. Whether the onset or severity of behavioral sequelae of AD is exacerbated by uncontrolled focal seizures is presently unclear. Synaptic activity itself can drive the release of A . It is therefore reasonable to presume that administration of ASDs could reduce the accumulation of A through the direct suppression of seizures and hyperexcitability .

Table 1 Clinical studies of ASD efficacy and tolerability in patients with Alzheimers disease

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Seizure In Alzheimers Disease: An Underestimated Phenomenon

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Multivariable Analysis For Risk Factors Of Having Epilepsy In People With Ncds

The multivariable logistic regression identified NCD subtype, age at onset of cognitive decline, and current smoking status as risk factors for having epilepsy . People with FTD and MDD showed significantly lower risk of developing epilepsy compared to unspecified NCD , while the risk did not significantly differ for other NCD subtypes. People whose cognitive decline began at age 50 or less had a significantly higher risk of having epilepsy compared to those with cognitive decline starting after age 50 years . Current smoking status also increased the risk of epilepsy compared to non- or ex-smokers .

Table 4. Multivariable logistic regression in the whole cohort and the young-onset cohort.

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What Causes Epileptic Episodes In People With Dementia

Naturally, anything that contributes to changing the brain structure can result in seizures. Mostly, people suffer from epilepsy after a head injury, stroke or brain infection.

In line with this, it is safe to say that something similar happens in the brain of those with dementia. The brain shrinks in size as some of its cells die off, leading to epilepsy.

Tau and amyloid are two proteins that can build up in the brain of individuals with dementia. This affects how the nerve cells in the brain communicate with each other.

At times, the cells can behave uncontrollably resulting in epileptic seizures.

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Lennart Mucke, director of the Gladstone Institute of Neurological Disease and a professor at UC San Francisco, has been examining the relationship between epilepsy and Alzheimers in both animal models and people since the early 2000s. He noted in an interview that one reason study results may differ is that some types of seizures are easy to miss. When we looked at patients who had come to UCSF with both epilepsy and Alzheimers disease, it became clear that a lot of the epilepsy they had was non-convulsive, said Mucke.

Patients with these so-called partial seizures might stop and stare, or experience psychic phenomena like deja vu. Seizures that can be detected on EEG during an overnight testing session are often missed during standard daytime tests that may be as short as 20 minutes.

In a 2016 paper, Mucke, who was not involved in the research presented this week, reported that more than 40 percent of the patients with Alzheimers he studied had epileptic activity. Mucke said that he and his colleagues also found in an earlier study that the onset of the seizures wasnt late in the game but could happen shortly before the cognitive decline became manifest.

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Epilepsy In Early Onset Alzheimers Disease

Article type: Research Article

Authors: Haoudy, Saraha | Jonveaux, Thérèsea d e | Puisieux, Saloméa | Epstein, Jonathanf | Hopes, Luciea | Maillard, Louisa b c | Aron, Oliviera b | Tyvaert, Louisea b c *

Affiliations: Department of Neurology, University Hospital Nancy, Nancy, France | UMR 7039 CRAN Nancy, Nancy, France | University of Lorraine, Nancy, France | CMRR, University Hospital Nancy, Nancy, France | Laboratoire Lorrain de Psychologie et de Neurosciences de la Dynamique des Comportements 2LPN EA 7489, University of Lorraine, Nancy, France | Department of Clinical Epidemiology, INSERM, University of Lorraine and University Hospital Nancy, Nancy, France

Correspondence: Correspondence to: Louise Tyvaert, MD, PhD, University of Lorraine, UMR 7039, CRAN, Department of Neurology, CHRU Nancy, hôpital Central, 29 Avenue du Maréchal de Lattre de Tassigny, 54000 Nancy, France. Tel.: +33 3.83.85.12.75 E-mail: .

Keywords: Cognitive decline, early onset Alzheimers disease, epilepsy, seizures

DOI: 10.3233/JAD-210681

Journal: Journal of Alzheimer’s Disease, vol. 85, no. 2, pp. 615-626, 2022

Assessment Of Seizures And Ad Stage

In the UDS , occurrence of seizures is assessed by information obtained from the study participant and a mandatory co-participant interview, from medical records and from observation. Four options are at choice: Absent , Recent/Active , Remote/Inactive , or Unknown . From now on, if Seizures are stated Recent/Active, they are referred to as active seizures.

The cognitive status is categorized in the NACC-UDS according to the four mutually exclusive options normal cognition, MCI , impaired-not-MCI or dementia. In subjects with any cognitive impairment , the presumptive etiologic diagnosis is stated by the respective trained rater. For an etiologic diagnosis of AD, either the NINCDS/ADRDA criteria or the NIA-AA criteria for AD dementia were applied.

Fig. 1

Flow chart depicting the study population at baseline and separation into subgroups. For pre-symptomatic Alzheimers disease, a normal cognitive status at baseline and a diagnosis of Alzheimers disease dementia at follow-up was required. For impaired-not-MCI due to Alzheimers disease and MCI due to Alzheimers disease, both a presumptive etiologic diagnosis of Alzheimers disease at baseline and a diagnosis of Alzheimers disease dementia at follow-up were required. Groups that were included in analyses are shown in bold. MCImild cognitive impairment

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Definition Of Incidence Of Dementia

For the epilepsy and comparison cohorts, the dementia incidence rate was expressed as the number of events per 1,000 person-years. In the present study, the primary outcome measure was new cases of dementia diagnosis throughout the period of the study based on ICD-9-CM codes 290, 294.1, and 331.0 defined in at least three separate medical claims released in an outpatient situation or in one claim issued in an inpatient setting. The very first hospitalization or an outpatient clinic visitation date, with dementia diagnosis, was defined as the date of diagnosis and also regarded as the date of recently diagnosed dementia for all successive analyses. We used dementia diagnosis, death, or December 31, 2013, of the final date of observation, whichever occurred first, as the endpoint from the index date.

Eeg And Other Diagnostic Tools

While an imaging study known as an electroencephalogram can be used to confirm seizure activity, it has its limitations. An EEG measures electrical activity in the brain and, as such, can only definitively diagnose seizures if abnormalities occur during the test. As a result, only between 3 percent and 10 percent of Alzheimer’s-related seizures are diagnosed with EEG alone .

With that being said, an EEG can sometimes detect abnormal electrical activity, known as epileptiform discharges, 24 to 48 hours after a seizure. If recurrent seizures are suspected, the healthcare provider may recommend a wireless EEG in which a headset is worn for 24 to 72 hours to provide ongoing monitoring of brain activity.

While neuroimaging studies, such as computed tomography and magnetic resonance imaging , can detect changes in the brain consistent with Alzheimer’s, they cannot tell us whether those changes are consistent with seizures. The same applies to genetic blood tests, which are more useful in supporting a diagnosis rather than making one.

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We had to design a very conservative study that takes these participants out, said Ophir Keret, a neurologist at the University of California, San Francisco who was a researcher on both studies, because we wanted to isolate the effect that epilepsy would have.

Michela Gallagher, a professor of psychology and neuroscience at Johns Hopkins University, said the researchers used good criteria for defining unprovoked seizures independent of things that could be causing , and pointed to the large sample size and long time period for tracking each veterans health trajectory as two of the studys strengths. One weakness she noted is that the Veterans Affairs health data used in the study did not allow researchers to differentiate between Alzheimers or other types of dementia. Neither the veterans study or the smaller one has been published yet in a peer-reviewed journal.

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Research with mouse models supports the hypothesis that seizures or other epileptic events may sometimes be an early feature of Alzheimers disease. Scientists have recorded such abnormal electrical activity in the brains of mice before they went on to accumulate amyloid plaques or tau tangles, both hallmarks of Alzheimers. Many of these events had no outward manifestation, suggesting again that the prevalence of epileptic activity may be going unrecognized and therefore underestimated.

Seizures are an extreme example of an imbalance in brain function. Normally, a class of cells called inhibitory neurons, which have received scant attention until recently, act much like the bouncers at a night club. Their job is to manage the timing and flow of brain signals and keep excitatory neurons under control. As we age, inhibitory neurons appear to become less effective, resulting in chronic hyperactivity. Low-level hyperactivity has been detected in the hippocampus a brain region critical to memory of both rodents and older people with mild cognitive impairment.

Researchers once assumed that hyperactivity was a compensatory mechanism to make up for a brain that couldnt keep up with cognitive demands. Now many believe the reverse is true that hyperactivity is pathological and interferes with memory and that this imbalance is a core feature of Alzheimers disease.

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Who Might Be Affected By Seizures

For a long time, researchers believed epileptic seizures occurred only in people who had long been diagnosed with dementia. It was thought they were a reflection of how much the brain had changed and shrunk because of it.

However, more recent research has suggested that seizures can occur early-on in Alzheimers disease. In some people, seizures may happen even before memory problems become apparent.

As part of my research, I recruited people from the local memory clinic here in Exeter. We asked them questions about epilepsy.

Seizures And Dementia In The Elderly

Seizures can be described as uncontrolled and sudden electrical disturbances that happen in the brain.

This can cause levels of unconsciousness, feeling, or movements as well as changes in behavior.

While seizures are usually an indication that a person has epilepsy, not everyone who experiences seizures has epilepsy.

Naturally, persons who have dementia are at risk of seizures.

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Preclinical Models Of Aging And Epilepsy Should Address Clinical Needs

Despite the greater incidence of epilepsy in elderly individuals and increased risk of comorbid seizures in AD patients, few aged animal seizure and epilepsy models have been sufficiently characterized to support drug discovery for aging-related seizures . Comparative pharmacology with prototypical ASDs has not been extensively collected in the available animal models of AD to inform on the potential pharmacokinetic, toxicity, or drug interactions in aged or geriatric populations. This is in stark contrast to the rigorous evaluation of comparative pharmacology in rodent drug-resistant epilepsy models . Information concerning the risk of seizure in rodents with AD-associated mutations would support their utility for moderate- to high-throughput preclinical approaches for drug development for aged and geriatric patients with seizures. Mouse strain alone can significantly impact seizure threshold , as can age , but whether there are additive effects of aging and AD-associated mutations on seizure susceptibility or ASD efficacy should be more comprehensively assessed.

Table 2 Preclinical studies of ASD efficacy and tolerability on acute or chronic seizures in animal models of Alzheimers disease-associated genetic variants

Understanding Early Onset Dementia

Some chapters of the Alzheimer’s Association are beginning to use the name younger-onset dementia instead of early-onset dementia. Members of the association state there can be confusion for families hearing the diagnosis of early-onset dementia. âEarly onset” does not refer to the stage of the disease it refers to the age at which a person is diagnosed with dementia.

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Characteristics Of The Study Population

After selecting patients and patient matching, the epilepsy and comparison cohorts comprised 675 and 2,025 individuals, respectively. Table 1 lists the demographic data and comorbid conditions of both cohorts. In the epilepsy cohort, the mean age was 62.5 ± 9.5 years, which was similar to the mean age of 62.4 ± 9.5 years in the comparison cohort. The individuals between 50 and 59 years of age comprised ~46% of the cohorts of patients with epilepsy and control subjects. For the parameters of many of the comorbidities, the analysis of matched patients revealed significant differences between the epilepsy and control cohorts. Expectedly, patients in the epilepsy cohort generally had more comorbidities than those in the comparison cohort.

Table 1. Characteristics of the epilepsy and comparison cohorts.

Network Remodeling In Ad And Tle Mouse Models

Based on a growing appreciation of network level dysfunction in AD, Palop examined the hippocampus in J20 mice and discovered striking evidence for hippocampal network axon remodeling that is similar, but not identical to, the changes identified in both patients with temporal lobe epilepsy and experimental models of hippocampal seizures . The cellular changes included ectopic sprouting of dentate granule cell mossy fibres and sprouting of fibers containing the inhibitory neurotransmitter NPY, two structural alterations long known to be present in human and experimental models of temporal lobe epilepsy and believed to be the direct result of excess glutamate toxicity and seizure-induced cell death . An additional feature noted in the AD models was loss of calbindin, a calcium binding protein, staining in granule cell bodies. Convulsive seizures with associated hippocampal network plasticity have been confirmed in other AD mouse models .

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Study Design And Population

This retrospective cohort study encompassing the period between January 1, 2000, and December 31, 2013, included the inpatient and outpatient claim data from the LHID. Among the one million beneficiaries in the LHID, we excluded those with lost/unidentified records for sex and birth month/year. After excluding individuals aged < 50 years, those aged 50 years at the start of the study duration were enrolled . Additionally, we excluded individuals diagnosed with epilepsy before the start of the study duration those with dementia occurrence before the beginning of the follow-up period and those with pre-existing diagnoses of diabetes mellitus , cerebrovascular disease , head injury , and Parkinsons disease before the start of the follow-up period. Moreover, individuals with no medical claim records during the follow-up period were excluded. Ultimately, we included 182,147 individuals for the present study. Figure 2 shows the selection flow of the study population.

Figure 2.The flow of the study population.