. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013 Sep 1;70(9):1158-66. PubMed.

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  1. These authors represent the major, if not the only, group of researchers devoted to analysis of Aβ’s effects on inhibitory/excitatory balance, neuronal sprouting, characteristics of epileptiform activity in the temporal lobe subregions, neuronal network alteration, and how these correlate with cognitive decline both in animal models and in humans. This article is, to my knowledge, the only one to compare epileptic and non-epileptic MCI subjects with respect to their cognitive decline and treatment outcome. A potentially intriguing finding is that amnestic MCI subjects lack subclinical epileptiform EEG activity compared to controls.

    The authors are developing an innovative and interesting approach to researching Alzheimer's disease causes. There are, however, a few aspects of the study design that complicate interpretation. First, there is no reliable measure of cognitive outcome to fully demonstrate any impact of antiepileptic treatment on the progression of cognitive decline. This would be most informative. Second, the lack of genetic data on the ApoE polymorphisms (only 11 of the 60 patients enrolled) is a pity since Apoe E4/E4 is a risk factor for both epilepsy and cognitive decline and might be responsible for the fact that aMCI and AD patients with epilepsy have an earlier onset and a faster progression. Finally, the authors present no clear clinical evidence for diagnostic certainty (PIB imaging only for 9 patients, spinal fluid markers only for 3, and no post-mortem analysis).

  2. The evidence is clear that seizures plus dementia are worse than dementia alone. Poorly controlled seizures are well known to induce neuronal loss and inflammation in the hippocampus, affecting memory circuits (medial temporal lobe sclerosis or hippocampal sclerosis). The present study moves these findings forward into earlier stages of disease, such as mild cognitive impairment (MCI). Raising suspicion of subclinical or partial seizure rather than focusing on pure convulsive seizures is important clinically. Since only 7 percent of MCI (17/233) and 6 percent of AD patients (63/1024) were found to have seizure activity in this study, routine EEG for the purpose of detecting seizures without clinical suspicion is not warranted given the low pre-test probability. In subjects reporting paroxysmal events (transient cognitive/language/behavior deficits) that resolve, consideration of EEG is important clinically, with the caveat that neither the present paper nor others in the literature have ever shown improvement in cognitive/behavioral/psychiatric symptoms of dementia with improved seizure control or the use of anti-epileptic drugs.

    EEG may be more globally useful to detect degenerative disease by focusing on slowing and other non-epileptiform characteristics, although this remains to be proven. Our work suggests that algorithms can be created using EEG patterns that can detect early cognitive impairment. These effectively act as biomarkers of disrupted neuronal connectivity and function, before overt structural biomarkers such as MRI can detect such changes.

    I would be cautious about making recommendations for anti-epileptic drugs based on retrospective analysis of their use in such a small cohort. While the authors discuss this caveat, they still make a strong recommendation for levitiracetam or lamotrigine. Only prospective clinical trials will tell if these drugs may be beneficial . Trials of drugs in subjects with dementia/MCI and seizures is warranted given the prevalence of such cases in the U.S. population. Given more than five million people have AD, and an estimated seven million have MCI, about 720,000 people would potentially benefit from a successful therapy in the US alone.

    The earlier onset of dementia in cases with seizures is expected from what we know of mixed dementia states. Data shows that pathologies are additive. We recently examined brain bank data on subjects with MCI or dementia who had had seizures, and, after controlling for the degree of cognitive impairment, we found that those with seizures had significantly lower pathology than those without seizures, suggesting that the seizure disorder added to the degenerative AD pathology to exacerbate the cognitive decline. (We have presented this, but it is not yet published.) Thus, the earlier age of onset for cognitive symptoms if patients have concomitant seizure disorder. It makes sense to aggressively identify and treat concomitant seizures in dementia, but again proven benefit of such an approach is lacking despite strong supportive data and medical rationale.

    Overall this is a much-needed exploration into the association of degenerative disease, even in a prodromal phase, with seizures. If identifying such patients and treating them could delay MCI by seven years and AD by five years, in just 6 percent of patient, this would be a major victory for hundreds of thousands in the U.S. and millions worldwide.

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