Abstracts

Rationale: Long-term intracranial EEG has demonstrated circadian and multiday modulation of seizure risk in humans. Sleep and behavioral state are important determinants of seizure risk, however circadian and multiday seizure rhythms, as determined by intracranial EEG, have not been evaluated in the context of sleep and behavioral state. Periodic patterns of seizure risk suggest chronotherapy, whereby electrical stimulation and medications are delivered based on seizure risk, may be useful. Dogs can accommodate neurostimulation devices designed for humans and may be a model platform for chronotherapy development.  Methods: Six dogs with naturally occurring epilepsy were monitored with long-term intracranial EEG devices (NeuroVista or Medtronic Summit RC+S). Seizures were identified by a detection algorithm with epileptologist confirmation. Automated sleep staging was performed with a previously validated algorithm (Kremen V., et al., J Neural Eng, 2019, 16(2)). The MATLAB circular statistics toolbox was used to evaluate periodicity of seizures over multiple periods (1 day, 7 days, and median inter-seizure interval). Seizure timing data were visualized with angular histograms.  The R-value, a measurement of non-uniformity of seizure timing, was calculated by summating vectors directed from the origin to each seizure location plotted around a circle representing one cycle period. Statistical significance was determined by the Rayleigh test (P<0.05). To remove bias from seizure clusters, only lead seizures were analyzed for multiday periods. Mayo Clinic, UC-Davis, and U. Minnesota IACUCs approved the study.  Results: Mean recording duration was 10.7 months (range 4.6 to 15.8 months). 4 dogs had statistically significant periodicity of seizure timing - 3 dogs had circadian seizure rhythms, and one had a 7-day rhythm. Rhythms and phase preference of seizure timing was subject specific. Figure 1 shows the circadian rhythm evaluation for dog #2, demonstrating circadian phase preference (P < 0.00001). Conclusions: Circadian and multiday seizure cycles are common in dogs with naturally occurring epilepsy, as in humans. Sleep and behavioral state may play a role in circadian seizure rhythms. Periodic fluctuations in seizure risk may guide intentional timing of medication and brain stimulation therapy. These findings suggest dogs could provide a model system for chronotherapy development for epilepsy.  Funding: NeuroVista Inc. and Medtronic Inc. supplied devices. Supported by NIH grants UH2 NS095495 and R01 NS092882.