Striking New-Onset Seizure Risk in Dementia Patients

Megan Brooks

July 16, 2019

LOS ANGELES — Patients with dementia are at significantly higher risk for generalized or partial seizures disorders, new research suggests.

In a national database study, patients with Alzheimer disease (AD) experienced epileptic seizures up to 6.5 times more often than their cognitively normal peers — often without the knowledge of their physician.

"Clinicians should be alert to the possibility of seizures coexisting with dementia," Ruby Castilla-Puentes, MD, director of neuroscience clinical research at Janssen Pharmaceuticals, told Medscape Medical News.

"It is probably advisable to investigate seizures in...AD patients in the early stages of cognitive decline to exclude alternative symptomatic causes," she added.

The study was presented here at the Alzheimer's Association International Conference (AAIC) 2019.

Potential Mechanism

Castilla-Puentes and Miguel Habeych, MD, MPH, University of Cincinnati in Ohio, analyzed a large US national managed care database that included more than 2.8 million individuals aged 60 years or older. Of these individuals, 79,561 (2.8%) had been diagnosed with dementia.

Compared with individuals without dementia, those with dementia had a significantly higher risk for new-onset seizure disorders of different types. They had a 6.5 times' greater risk for seizure disorders overall (hazard ratio [HR], 6.5; 95% confidence interval [CI], 4.4 – 9.5).

Table. Risk for Other Types of Seizure Disorders in Patients With Dementia

Condition HR (95% CI)
Grand mal status 6.5 (5.7 – 7.3)
Partial seizures 6.0 (5.5 – 6.6)
Motor simple partial status 5.6 (3.5 – 9.0)
Epilepsy 5.0 (4.8 – 5.2)
Complex partial epileptic seizures 4.9 (4.6 – 5.2)
Generalized convulsive epilepsy 4.8 (4.5 – 5.0)
Localization-related epilepsy 4.5 (4.1 – 4.9)
Petit mal status 4.2 (2.9 – 6.1)
Complex febrile seizures 2.5 (1.6 – 3.9)

 

Castilla-Puentes said a number of factors may contribute to the pathogenesis of seizures in patients with dementia.

"Studies show that risk of seizures is increased in patients with early-onset AD. This may be related to the higher prevalence of genetic mutations in early-onset AD," she explained.

Excessive levels of amyloid in the brain may also play a role. A study in mice showed that brain amyloid may cause spontaneous seizure activity even in the absence of neurodegeneration, she said.

"Structural alterations in neurons related to tau pathology, including loss of synaptic contacts and aberrant neuronal sprouting, may facilitate development of recurrent seizure activity," Castilla-Puentes said.

She noted that some medications commonly used to treat dementia patients, such as antipsychotics and acetylcholinesterase inhibitors, or the combination of antimuscarinic and acetyl-cholinesterase inhibitors, can also contribute to seizure disorders in the elderly.

Clear Association

A related study featured here at AAIC 2019 also suggests higher rates of seizures and recurring seizures in patients with dementia.

Jonathan Vöglein, MD, Ludwig-Maximilians-Universität München and the German Center for Neurodegenerative Diseases, Munich, and colleagues analyzed data from the National Alzheimer's Coordinating Center on 20,745 older adults, including 9127 with AD dementia.

The prevalence of active seizures was higher in individuals with AD dementia than in those without the condition (1.51% vs 0.35%; P < .0001; odds ratio [OR], 4.34; 95% CI, 3.01 – 6.27).

Patients with AD were also twice as likely to have a history of seizures (3.14% vs 1.57%; P < .0001; OR, 2.03; 95% CI, 1.67 – 2.46).

The prevalence of active seizures rose with duration of AD dementia, from 1.51% at 4.8 years of disease duration to 5.43% at 11 years (OR, 1.55; 95% CI, 1.39 – 1.73; P < .0001).

More than two thirds (70.4%) of those with AD dementia who experienced a seizure had a second seizure within the next 7.5 months.

A history of seizure was associated with both younger age at onset of cognitive symptoms (64.7 years, vs 70.4 years with no seizure history; P < .0001) and worse cognitive and functional performance after adjusting for age and disease duration (mean Mini–Mental State Examination score, 16.6 vs 19.6; mean Clinical Dementia Rating–Sum of Boxes score, 9.3 vs 6.8; P < .0001).

"It's pretty clear that there is an association between seizures and Alzheimer's disease. Whether the seizures are causing Alzheimer's disease or the Alzheimer's disease is causing the seizures, or both, is not fully clear," Vöglein told Medscape Medical News.

"The exceptionally high recurrence risk of seizures in AD dementia patients, the association of seizures with worse cognitive and functional performance and with a younger age of disease onset may implicate the consideration of an antiepileptic treatment after a first epileptic seizure in patients with AD dementia," he added.

He noted that the frequency of seizures in patients with AD dementia could be underestimated.

"One reason for that could be that patients with AD dementia are more likely to spontaneously report memory problems or other cognitive symptoms than events that are suspicious regarding seizures, because those problems are subjectively more important to them. Second, patients with AD dementia may forget events that are suspicious regarding seizures. A detailed probing of the patient and a proxy regarding a history of seizures may address those issues," Vöglein said.

Brain Storms

Commenting on the studies for Medscape Medical News, Maria Carrillo, PhD, chief science officer of the Alzheimer's Association, said that clinicians may not think about checking for seizures in people with dementia.

"However, what these studies tell us is that people with a diagnosis of Alzheimer's dementia or any dementia have an increased risk of a first-time seizure, and a second or third seizure is not uncommon," Carillo said.

"In epilepsy, neural circuits go awry and generate electrical storms, and you can certainly imagine that the cellular damage caused by dementia in the brain might be a trigger for epileptic seizures. Early epileptic seizures have also been shown to increase risk for dementia," she added.

"The important message for clinicians is to be on the lookout for seizures, because they're certainly not good for your brain, and there are good medications to address seizures," said Carrillo.

The first study was funded by Janssen Neuroscience. The second study was funded by the German Center for Neurodegenerative Diseases. Castilla-Puentes is an employee of Johnson & Johnson. Vöglein and Carrillo have reported no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2019: Abstracts P2-311 and P2-297. Presented July 15, 2019.

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