Rationale:
Cerebral small vessel disease (cSVD), a very common aging-related pathology, has been identified as a risk factor for late-onset epilepsy and is linked with cognitive impairment. Sleep and cognition are also closely intertwined, with sleep microarchitecture playing a critical role in optimal cognitive functioning, including memory consolidation. Given the established links between cSVD and cognition, we investigated how cSVD correlates with sleep integrity in individuals with late-onset unexplained epilepsy (LOUE).Methods:
This was prospective study. Inclusion criteria: new-onset seizures within 5 years, age ≥55 y, absence of cortical lesions on MRI and provoking factors. Participants underwent an MRI including multidirectional diffusion-weighted imaging (MD-DWI). The DWI data were analyzed to extract 2 measures which have been closely linked to vascular cognitive impairment: peak width of skeletonized mean diffusivity (PSMD) and free water (FW), a measure of the signal fraction of water molecules not constrained by their local environment. Using linear regression models, we first evaluated which vascular risk factors were associated with higher FW and PSMD.
A 24-hour EEG was obtained within 1 year of the MRI. Sleep was manually scored across the 4 sleep stages, and features related to microarchitecture: sleep spindles and slow oscillations (SO) were extracted at 19 electrodes. Measures of interest for the SO included: amplitude, duration, and rate, for spindles: frequency, density and duration, and for spindle-SO coupling : magnitude, overlap, and coupled density. A generalized permutation approach was then performed to investigate the association between PSMD, and FW with sleep stages and microarchitecture while controlling for age, sex, and education.
Results:
74 participants were recruited mean age 70.7 ± 7.0 years, 50% female. Prevalence of vascular risk factors included: 53% with history of hypertension, 4% history of diabetes, and 3% active smokers. Mean FW was 0.19 ± 0.03, and Mean PSMD was 2.31 ± 0.63. When controlling for age and sex, hypertension was associated with higher free water (β=+0.013, p=0.02), but not PSMD.
There was no correlation between PSMD and duration of sleep stages, or sleep microarchitecture features (spindles, SO, and spindle-SO coupling). In contrast higher FW, indicative of increased signal fraction of interstitial water, was associated with higher SO amplitude (electrodes: Fz, Fp2, F3, F4, C4, F8, T4), and longer duration (Fp2, F7, F8, T4), but was not associated with sleep stage duration, spindle features or Spindle-SO coupling measures.
Conclusions:
In LOUE, a history of hypertension is a risk factor for worse cSVD, with evidence of increased free water fraction on DWI. This measure appears to specifically impact sleep slow oscillation features—such as amplitude and duration—while sparing spindles and spindle-SO coupling, suggesting preserved thalamo-cortical integrity despite white matter disruption. These findings highlight the complex interplay between vascular risk factors, disrupted white matter integrity, and sleep microarchitecture in LOUE.Funding:
Funding Source: American Epilepsy Society Junior Investigator Award, NIH K23NS119798 (RAS)