Elsevier

The Lancet Neurology

Volume 16, Issue 4, April 2017, Pages 311-322
The Lancet Neurology

Review
Epileptic activity in Alzheimer's disease: causes and clinical relevance

https://doi.org/10.1016/S1474-4422(17)30044-3Get rights and content

Summary

Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised 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.

Introduction

The transient worsening of cognitive symptoms is frequent in patients with Alzheimer's disease, sometimes raising the possibility of underlying epilepsy. Caregivers might report that the patient seems to “check out” for periods of time or appears more confused than usual on some days than on others. These changes warrant attention, since new evidence indicates that seizures and network hyperexcitability can occur in the early stages of Alzheimer's disease and contribute to cognitive decline.1, 2, 3, 4, 5 Treatment options with antiepileptic drugs (AEDs) are available, but the decisions on whether to treat seizures and the choice of AED for an individual with Alzheimer's disease can be difficult. Even more challenging is the decision on whether to treat subclinical epileptiform activity (ie, the occurrence of epileptiform activity in the absence of clinical seizures). This Review provides an update on the mechanisms and therapeutic implications of epilepsy associated with Alzheimer's disease. We will also provide guidance on assessing and treating patients with Alzheimer's disease and suspected seizures.

Section snippets

Risk of seizures in Alzheimer's disease

The increased prevalence of seizures in patients with Alzheimer's disease, in relation to older populations without dementia, has been noted since Alois Alzheimer's earliest patient descriptions. Initial studies focused on seizures in patients with advanced Alzheimer's disease, many of whom were living in institutions. However, in transgenic mouse models of Alzheimer's disease,6 seizures and epileptiform activity can occur before amyloid β plaque deposition. This new evidence has made

Seizure semiology in Alzheimer's disease

The predominant seizure subtype in patients with Alzheimer's disease is non-motor complex partial seizures (table 1).2, 3, 4, 21 Some symptoms of these seizures can overlap with cognitive features of Alzheimer's disease, but they can often be distinguished as epileptic events by their recurrent and stereotyped nature, and supported by epileptiform activity on EEG. These episodes can include amnestic spells, déjà vu or jamais vu, speech arrest, staring spells, and unexplained emotions (eg, fear

Subclinical and interictal epileptiform activity

Epileptiform activity is defined as paroxysmal sharp waveforms (spikes and sharp waves) on EEG, lasting 20 to 200 ms, that disrupt background activity and are associated with a subsequent slow wave. Such activity is named interictal epileptiform activity when it is detected in patients with seizures, and subclinical epileptiform activity when detected in patients without known seizures. The sensitivity of scalp EEG recordings to detect epileptiform activity depends on the type of EEG protocol

Treatment approaches

Several factors must be considered when deciding to treat seizures in patients with Alzheimer's disease, including age, comorbidities, drug interactions, cognitive and non-cognitive side-effects, and optimal dose. In patients with epileptiform activity but no witnessed seizures, the decision of whether to treat with AEDs is controversial, and should be based on the clinician's judgment on whether so-called silent seizures might be contributing to cognitive symptoms (eg, cognitive fluctuations

Cognition and epileptiform activity

In patients with Alzheimer's disease in whom epileptiform activity is detected, potential acute and chronic effects of such activity on cognitive functions should be considered. In rodent models and in patients with interictal epileptiform discharges in the hippocampus, epileptiform events disrupt short-term memory retrieval.74 These findings have been observed in human beings by use of depth electrodes in patients with refractory seizures. However, such invasive testing is rarely done in

Conclusions and future directions

Patients with mild cognitive impairment or Alzheimer's disease are prone to seizures and clinically silent forms of aberrant network activity, which can be associated with cognitive decline. Evidence for detrimental network hyperexcitability in the early stages of Alzheimer's disease raises new therapeutic opportunities for antiepileptic strategies that might complement or enhance existing approaches, and potentially modify disease progression. No guidelines are available for treating

Search strategy and selection criteria

We selected references by reviewing the authors' personal files and by searching PubMed for manuscripts published in English before Dec 1, 2016, with the term “Alzheimer's disease” and assorted combinations of the following terms: “epilepsy”, “seizures”, “epileptiform activity”, “network hyperexcitability”, “antiepileptic drugs”, “antiseizure drugs”, “anticonvulsants”, “Down syndrome”, “trisomy 21”, “dementia”, “neurodegenerative disease”, “early-onset”, “presenilin 1', “presenilin 2”, and

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