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When I was reviewing the current clinical trials for Alzheimer’s disease (AD) a few months ago, I noted that the phase II trial of levetiracetam was particularly exciting — because if it works, it would require a massive reconceptualization in AD pathogenesis.

That’s mainly because levetiracetam is an anti-seizure medication, and focal seizures haven’t been traditionally associated with AD.

But our available tools for measuring focal seizures are quite poor — for example, they only cover a very small portion of the brain, mostly at the surface. So it is quite possible that AD pathogenesis could involve localized seizures early in the disease process, especially in a “buried” brain region like the hippocampus.

Now, Lam et al have provided some more evidence for the microseizure/focal memory-associated seizure hypothesis in AD, with a case report on two patients, both of whom were experiencing early stages of memory loss.

For both of these patients, the team used a minimally invasive surgical technique to place medial temporal electrodes for monitoring, which has been described in several previous studies including a 2005 study from Zumsteg et al that has a nice diagram:

Screen Shot 2017-09-11 at 6.59.24 PM

Localization of medial temporal lobe/foramen ovale (FO) electrode; https://doi.org/10.1016/j.clinph.2005.08.009

(Note that the hippocampus, that old memory-associated stalwart, is in the medial temporal lobe.)

One of the patients that Lam et al were treating had evidence of recurrent subclinical seizures in the medial temporal lobe (MTL), which were more prevalent during sleep.

Remarkably, treating her with 1500 mg/d of levetiracetam led to abrogation of the seizures, and she had only “mild progression” of her cognitive deficits.

Intriguingly, when she missed several doses of levetiracetam, she noticed a confusion spell. But like anything, this could just be correlation — maybe she missed doses because of worsening AD pathophysiology in that time period, and the confusion spell was an exaggerated symptom of this. Missing doses is certainly not a formal crossover or washout study. Still, intriguing.

The other patient that Lam et al were treating also had frequent MTL seizure activity that was exacerbated during sleep, as well as classic symptoms of early onset AD (eg, CSF pTau levels of 73.2 pg/ml).

Unfortunately, levetiracetam was not tolerated in this second patient, which the authors state was “owing to worsening mood.”

It would be great news if early AD pathophysiology were related to seizures, even in a subset of patients, because we already have drugs to treat seizures. So I agree with the authors that more research is certainly needed in this area.

That said, the evidence so far is certainly interesting, but far from definitive. Something like this study, but with a sample size of 10-20 and good correlations of MTL seizure activity with cognitive decline and/or confusion episodes, would be a great next step.

It would also be nice to know how common MTL seizure activity is during sleep in asymptomatic elderly people.

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