Abstract
Ung H, Cazares C, Nanivadekar A, Kini L, Wagenaar J, Becker D, Krieger A, Lucas T, Litt B, Davis KA. Brain 2017;140:2157–2168.
Cognitive deficits are common among epilepsy patients. In these patients, interictal epileptiform discharges, also termed spikes, are seen routinely on electroencephalography and believed to be associated with transient cognitive impairments. In this study, we investigated the effect of spikes on memory encoding and retrieval, taking into account the spatial distribution of spikes in relation to the seizure onset zone as well as anatomical regions of the brain. Sixty-seven patients with medication refractory epilepsy undergoing continuous intracranial electroencephalography monitoring engaged in a delayed free recall task to test short-term memory. In this task, subjects were asked to memorize and recall lists of common nouns. We quantified the effect of each spike on the probability of successful recall using a generalized logistic mixed model. We found that in patients with left lateralized seizure onset zones, spikes outside the seizure onset zone impacted memory encoding, whereas those within the seizure onset zone did not. In addition, spikes in the left inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, and fusiform gyrus during memory encoding reduced odds of recall by as much as 15% per spike. Spikes also reduced the odds of word retrieval, an effect that was stronger with spikes outside of the seizure onset zone. These results suggest that seizure onset regions are dysfunctional at baseline, and support the idea that interictal spikes disrupt cognitive processes related to the underlying tissue.
Commentary
Memory and cognitive complaints are frequent among patients with epilepsy, and these indicators negatively impact quality of life. Multiple factors contribute to these cognitive deficits: time lapse since seizure onset, type, etiology and frequency of seizures, comorbid mood disorders, social isolation, and side effects of medications. The anatomical region affected by focal epilepsy is also a good predictor for specific cognitive deficits; in fact, the study of temporal lobe epilepsy has been one of the main sources of knowledge into the anatomy of memory function (1).
For a long time, our main strategy to prevent cognitive decline has been to control seizures and reduce medications, hoping to prevent cognitive side effects. However, a new factor has come into play as a possible contributor to cognitive decline and a target for therapy: By definition, interictal epileptiform discharges (IEDs) are not associated with any noticeable clinical changes and are frequently overlooked when we interpret the EEG (1). We often use these discharges to confirm the diagnosis of epilepsy and aid in the localization of the epileptogenic zone—rarely as a surrogate for disease severity but almost never as a target for treatment. In fact, we often teach our trainees to “treat the patient, not the EEG” and to avoid overinterpreting findings; that said, the relatively benign clinical significance we attribute to IEDs may not be the case with specific cognitive deficits in patients with epilepsy.
Transient cognitive effects of IEDs in cognition have been highlighted by task- and time-specific cognitive testing that co-localize to a specific cortical area. This phenomenon is known as “transitory cognitive impairment” (TCI) and has been described for decades (2), but testing it requires a high level of spike localization and reliable time locked neuropsychological testing.
Ung et al. set themselves to evaluate the impact of IEDs in memory performance and understand what spatial and temporal characteristics of these IEDs affect specific memory processes. For this purpose, they tested 67 patients undergoing intracranial EEG recordings, using a controlled memory task that included a distractor for attention between encoding and recall. They independently evaluated the effect of IEDs arising from different anatomical localizations in relation to memory encoding and retrieval.
The authors found cortical structures in the left temporal lobe (left inferior, middle, and superior temporal gyri and the fusiform gyrus) particularly sensitive to the presence of IED during encoding of memory, and they were able to quantify the detrimental effect of a single spike within these areas for this specific memory process. They also discovered that spikes outside of the seizure onset zone have a greater effect on memory than do spikes within the seizure onset zone, which supports the understanding that pathological cortex is less likely to be functional.
IEDs arising from the hippocampus have also been described as deleterious to memory maintenance and retrieval—but not to encoding (3). Others have also described IEDs arising from left temporal and parietal cortices as affecting memory function and highlighted the effect of timing and location of IEDs to be greater than the spike rate (4). Another interesting study by Matsumoto et al. (5) proposed a different mechanism for the relation between spikes and cognitive tasks: They observed a decrease in spike rate during successful memory tasks and suggested that successful mental processing can modulate IEDs.
The clinical effect of IEDs by themselves is difficult to quantify; just as with IEDs, cognitive deficits and mood disorders may precede the presentation of seizures in more than half of patients newly diagnosed with epilepsy (6); however, healthy individuals can have IEDs of unknown (or unmeasured) clinical significance.
If IEDs arising from cognitive eloquent areas are indeed not benign, then TCI may lead to clinically relevant cognitive problems in patients with epilepsy (7) and potentially to chronic cognitive decline. Realizing how frequently we see IEDs in routine and prolonged EEGs, we cannot help wondering about the clinical significance this new knowledge brings to our clinic. Specific situations come to mind that include the ability to perform in cognitively demanding activities such as reading, learning, and driving. In children, this concept can take on a whole new dimension as we consider the effect of frequent TCI in a developing brain (8), which may result in long-term cognitive deficits, behavioral problems, or psychiatric comorbidities.
The question arises: Should we treat IEDs? Can we treat them? The answer is not clear at this point, but a growing amount of information is starting to point that way. We may already have data to support the need to perform neuro-cognitive testing earlier in our patients with epilepsy, with or without cognitive complaints. We should also become more diligent in quantifying, localizing, and reporting IEDs in clinical EEGs. When indicated, we should consider some anti-seizure medications such as levetiracteam and lamotrigine, which have shown to be more effective than others at decreasing IEDs (7, 9). At the same time, we should keep in mind that cognitive deficits are often seen as side effects of anti-seizure medications, and trying to eliminate IEDs may be a cognitive price too high to pay.