Role of the glymphatic system and perivascular spaces as a potential biomarker for post-stroke epilepsy.

Stroke is one of the most common causes of acquired epilepsy, which can also result in disability and increased mortality rates particularly in elderly patients. No preventive treatment for post-stroke epilepsy is currently available. Development of such treatments has been greatly limited by the lack of biomarkers to reliably identify high-risk patients. The glymphatic system, including perivascular spaces (PVS), is the brain's waste clearance system, and enlargement or asymmetry of PVS (ePVS) is hypothesized to play a significant role in the pathogenesis of several neurological conditions. In this article, we discuss potential mechanisms for the role of perivascular spaces in the development of post-stroke epilepsy. Using advanced MR-imaging techniques, it has been shown that there is asymmetry and impairment of glymphatic function in the setting of ischemic stroke. Furthermore, studies have described a dysfunction of PVS in patients with different focal and generalized epilepsy syndromes. It is thought that inflammatory processes involving PVS and the blood-brain barrier, impairment of waste clearance, and sustained hypertension affecting the glymphatic system during a seizure may play a crucial role in epileptogenesis post-stroke. We hypothesize that impairment of the glymphatic system and asymmetry and dynamics of ePVS in the course of a stroke contribute to the development of PSE. Automated ePVS detection in stroke patients might thus assist in the identification of high-risk patients for post-stroke epilepsy trials. PLAIN LANGUAGE SUMMARY: Stroke often leads to epilepsy and is one of the main causes of epilepsy in elderly patients, with no preventative treatment available. The brain's waste removal system, called the glymphatic system which consists of perivascular spaces, may be involved. Enlargement or asymmetry of perivascular spaces could play a role in this and can be visualised with advanced brain imaging after a stroke. Detecting enlarged perivascular spaces in stroke patients could help identify those at risk for post-stroke epilepsy.

Reduced total number of enlarged perivascular spaces in post-traumatic epilepsy patients with unilateral lesions - a feasibility study.

BACKGROUND: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE+) from chronic TBI patients without PTE (PTE-) in a feasibility study. METHODS: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived. RESULTS: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE+ cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE- cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE+ (M=1.21e-4, IQR [8.89e-5]) and PTE- cases (M=2.79e-4, IQR [6.25e-5]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups. CONCLUSION: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker.

Asymmetric distribution of enlarged perivascular spaces in centrum semiovale may be associated with epilepsy after acute ischemic stroke.

OBJECTIVE: To investigate the factors influencing enlarged perivascular space (EPVS) characteristics at the onset of acute ischemic stroke (AIS), and whether the PVS characteristics can predict later post-stroke epilepsy (PSE). METHODS: A total of 312 patients with AIS were identified, of whom 58/312 (18.6%) developed PSE. Twenty healthy participants were included as the control group. The number of PVS in the basal ganglia (BG), centrum semiovale (CS), and midbrain (MB) was manually calculated on T2 -weighted MRI. The scores and asymmetry index (AI) of EPVS in each region were compared among the enrolled participants. Other potential risk factors for PSE were also analyzed, including NIHSS at admission and stroke etiologies. RESULTS: The EPVS scores were significantly higher in the bilateral BG and CS of AIS patients compared to those of the control group (both p < 0.01). No statistical differences in EPVS scores in BG, CS, and MB were obtained between the PSE group and the nonepilepsy AIS group (all p > 0.01). However, markedly different AI scores in CS were found between the PSE group and the nonepilepsy AIS group (p = 0.004). Multivariable analysis showed that high asymmetry index of EPVS (AI≥0.2) in CS was an independent predictor for PSE (OR = 3.7, 95% confidence interval 1.5-9.1, p = 0.004). CONCLUSIONS: Asymmetric distribution of EPVS in CS may be an independent risk factor and a novel imaging biomarker for the development of PSE. Further studies to understand the mechanisms of this association and confirmation with larger patient populations are warranted.

The effect of injection time on rates of epileptogenic zone localization using SISCOM and STATISCOM.

BACKGROUND: The identification of hyperperfusion on ictal single-photon emission computed tomography (SPECT) scan is a technique for the localization of the epileptogenic zone (EZ) in patients with focal epilepsy undergoing presurgical evaluation. The accuracy of this technique has been improved by subtraction from an interictal image and coregistration with magnetic resonance imaging (MRI) (subtraction ictal SPECT coregistered to MRI (SISCOM)), and subsequently by the development of Statistical Ictal SPECT Co-registered to MRI (STATISCOM) which is reported to further improve localization accuracy by statistically accounting for random variation between images. However, the use of ictal SPECT is limited by the necessity for rapid injection of the radiotracer. The purpose of this study was to investigate the effect of tracer injection time on EZ localization rates using both STATISCOM and SISCOM. METHODS: Consecutive patients with drug-resistant focal epilepsy who had an ictal SPECT scan while admitted to the video-electroencephalography (EEG) monitoring unit at the Royal Melbourne Hospital, Victoria, Australia, and a subsequent interictal scan, between 2009 and 2017 were included. The information collected included age, sex, seizure type, epilepsy diagnosis, and injection time. Statistical Ictal SPECT Co-registered to MRI and SISCOM images were generated and reviewed by two blinded reviewers. The rates of potential localization of the EZ, and the agreement with the EEG, were determined for each scan. Localization rates were compared between ictal scans with different radiotracer injection time windows (<30 s, 30-45 s, 45-60 s, 60-90 s, 90-120 s, >120 s). RESULTS: Seventy patients (male = 32, 16-67 years) were included in the study. Overall agreement between the primary raters was moderate for STATISCOM (k = 0.44) and SISCOM (k = 0.57). The ability of SPECT to localize the potential EZ was 69% (48/70) for STATISCOM and 59% (41/70) for SISCOM. Injection time was not associated with the rate of localizing the potential EZ for STATISCOM (p = 0.64), whereas for SISCOM there was a trend that shorter injection times were associated with better ability to localize the potential EZ (p = 0.06). Agreement between SPECT and video-EEG data was 54% (38/70) for STATISCOM and 39% (27/70) for SISCOM. Statistical Ictal SPECT Co-registered to MRI did not show any difference of agreement across injection time groups (p = 0.42) whereas SISCOM showed better agreement with video-EEG data in the earlier injection time groups (p = 0.02). No differences in agreement between SPECT and video-EEG data were seen between patients with and without MRI lesions for either STATISCOM or SISCOM. Statistical Ictal SPECT Co-registered to MRI showed significantly better agreement for temporal than extratemporal seizures, with no difference of agreement between early (<45 s) and late (>45 s) injections. CONCLUSION: Statistical Ictal SPECT Co-registered to MRI showed overall higher agreement rates with EZ localization by video-EEG than SISCOM, which was not affected by the injection times. Statistical Ictal SPECT Co-registered to MRI may provide localizing information for "late" injections where visual reads and SISCOM are inconclusive.