Characterization of antiseizure medications effects on the EEG neurodynamic by fractal dimension.

Objectives: An important challenge in epilepsy is to define biomarkers of response to treatment. Many electroencephalography (EEG) methods and indices have been developed mainly using linear methods, e.g., spectral power and individual alpha frequency peak (IAF). However, brain activity is complex and non-linear, hence there is a need to explore EEG neurodynamics using nonlinear approaches. Here, we use the Fractal Dimension (FD), a measure of whole brain signal complexity, to measure the response to anti-seizure therapy in patients with Focal Epilepsy (FE) and compare it with linear methods. Materials: Twenty-five drug-responder (DR) patients with focal epilepsy were studied before (t1, named DR-t1) and after (t2, named DR-t2) the introduction of the anti-seizure medications (ASMs). DR-t1 and DR-t2 EEG results were compared against 40 age-matched healthy controls (HC). Methods: EEG data were investigated from two different angles: frequency domain-spectral properties in δ, θ, α, ß, and γ bands and the IAF peak, and time-domain-FD as a signature of the nonlinear complexity of the EEG signals. Those features were compared among the three groups. Results: The δ power differed between DR patients pre and post-ASM and HC (DR-t1 vs. HC, p < 0.01 and DR-t2 vs. HC, p < 0.01). The θ power differed between DR-t1 and DR-t2 (p = 0.015) and between DR-t1 and HC (p = 0.01). The α power, similar to the δ, differed between DR patients pre and post-ASM and HC (DR-t1 vs. HC, p < 0.01 and DR-t2 vs. HC, p < 0.01). The IAF value was lower for DR-t1 than DR-t2 (p = 0.048) and HC (p = 0.042). The FD value was lower in DR-t1 than in DR-t2 (p = 0.015) and HC (p = 0.011). Finally, Bayes Factor analysis showed that FD was 195 times more likely to separate DR-t1 from DR-t2 than IAF and 231 times than θ. Discussion: FD measured in baseline EEG signals is a non-linear brain measure of complexity more sensitive than EEG power or IAF in detecting a response to ASMs. This likely reflects the non-oscillatory nature of neural activity, which FD better describes. Conclusion: Our work suggests that FD is a promising measure to monitor the response to ASMs in FE.

Enlarged Virchow Robin spaces associate with cognitive decline in multiple sclerosis.

The clinical significance of Virchow Robin spaces (VRS) in inflammatory brain disorders, especially in multiple sclerosis (MS), is still undefined. We analysed enlarged VRS (eVRS) by means of phase sensitive inversion recovery (PSIR) MRI sequence and investigated their association with inflammation or brain atrophy, and to clinical or physical disability. Forty-three MS patients (21 clinically isolated syndrome suggestive of MS [CIS], 15 RRMS, 7 progressive [PMS]) and 10 healthy controls (HC) were studied. 3DT1, 3DFLAIR and 2DPSIR images were obtained with a 3T MRI scanner. eVRS number and volume were calculated by manual segmentation (ITK-SNAP). Freesurfer was used to assess brain parenchymal fraction (BPF). All patients underwent clinical (EDSS) and cognitive (Rao's BRB and DKEFS) evaluation. eVRS number and volume resulted significantly higher on 2D-PSIR compared to both 3D-T1 (p<0.001) and 3D-FLAIR (p<0.001) and were significantly increased in CIS compared to HC (p<0.05), in PMS and RRMS compared to CIS (p<0.001) and in male versus female patients (p<0.05). eVRS volume increased significantly with disease duration (r = 0.6) but did not correlate with EDSS. eVRS significantly correlated with SPARTd (r = -0.47) and DKEFSfs (r = -0.46), especially when RRMS and PMS were merged in a single group (r = 0.89, p = 0.002 and r = 0.66, p = 0.009 respectively), while no correlation was found with BPF (r = 0.3), gadolinium-enhancing lesions (r = 0.2) and WMT2 lesion volume (r = 0.2). 2DPSIR allowed the detection of an impressive higher number of eVRS compared to 3DT1 and 3DFLAIR. eVRS associate with SPARTd and DKEFSfs failure in relapse-onset MS, suggesting they may contribute to cognitive decline in MS.

Disease-modifying drugs reduce cortical lesion accumulation and atrophy progression in relapsing-remitting multiple sclerosis: results from a 48-month extension study.

Cortical lesions (CLs) and atrophy are pivotal in multiple sclerosis (MS) pathology. This study determined the effect of disease modifying drugs (DMDs) on CL development and cortical atrophy progression in patients with relapsing-remitting MS (RRMS) over 48 months. Patients (n = 165) were randomized to sc IFN ß-1a 44 µg, im IFN ß-1a 30 µg, or glatiramer acetate 20 mg. The reference population comprised 50 DMD-untreated patients with RRMS. After 24 months, 43 of the untreated patients switched to DMDs. The four groups of patients were followed up for an additional 24 months. At 48 months the mean standard deviation number of new CLs was significantly lower in patients treated with sc IFN ß-1a (1.4 ± 1.0, range 0-5) compared with im IFN ß-1a (2.3 ± 1.3, range 0-6, P = 0.004) and glatiramer acetate (2.2 ± 1.5, range 0-7, P = 0.03). Significant reductions in CL accumulation and new white matter and gadolinium-enhancing lesions were also observed in the 43 patients who switched to DMDs after 24 months, compared with the 24 months of no treatment. Concluding, this study confirms that DMDs significantly reduce CL development and cortical atrophy progression compared with no treatment.

Cerebrospinal fluid IL-1ß correlates with cortical pathology load in multiple sclerosis at clinical onset.

The cerebrospinal fluid levels of interleukin-1 beta and structural magnetic resonance parameters of cortical damage, i.e., cortical lesion number and volume, and global cortical thickness, were analysed in multiple sclerosis patients at clinical onset. Cerebrospinal fluid interleukin-1 beta levels strongly correlated with cortical lesion load and cortical thickness, while correlation with white matter lesion load was modest. Interleukin-1 beta, intrathecally produced by infiltrating lymphocytes and activated microglia, may constitute a possible link between inflammation and neurodegeneration in multiple sclerosis.

Cortical Pathology in RRMS: Taking a Cue from Four Sisters.

Background. Although grey matter pathology is a relevant aspect of multiple sclerosis (MS) both with physical and cognitive rebounds, its pathogenesis is still under investigation. To what extent the familial and sporadic cases of MS differ in cortical pathology has not been elucidated yet. Here we present a multiple case report of four sisters affected by MS, all of them having a very high burden of cortical pathology. Methods. The clinical and grey matter MRI parameters of the patients were compared with those of twenty-five-aged matched healthy women and 25 women affected by sporadic MS (matched for age, disease duration, EDSS, and white matter lesion load). Results. Despite their short disease duration (<5 years), the four sisters showed a significant cortical thinning compared to healthy controls (P = 0.003) and sporadic MS (P = 0.041) and higher CLs number (P < 0.001) and volume (P < 0.001) compared to sporadic MS. Discussion. Although limited to a single family, our observation is worth of interest since it suggests that familial factors may account for a peculiar involvement of the cortex in MS pathology. This hypothesis should be further evaluated in a large number of multiplex MS families.

Cortical diffusion-tensor imaging abnormalities in multiple sclerosis: a 3-year longitudinal study.

PURPOSE: To evaluate whether diffusion-tensor imaging can be combined with double inversion recovery to improve the detection of structural changes occurring in the cortex of patients with multiple sclerosis (MS). MATERIALS AND METHODS: Once local ethics committee approval and informed consent were obtained, 168 patients with relapsing-remitting MS and 45 sex- and age-matched control subjects were included in a 3-year longitudinal study. Expanded Disability Status Scale (EDSS) and magnetic resonance (MR) imaging examinations were performed at study entry and after 3 years. Number and volume of cortical lesions, T2 white matter lesion volume (WMLV), and fractional anisotropy (FA) and mean diffusivity (MD) of normal-appearing gray matter (NAGM) and cortical lesions were analyzed. Between-group differences in terms of NAGM-FA and NAGM-MD were assessed with analysis of variance followed by Tukey test correction. RESULTS: At baseline, NAGM-FA was higher in patients (mean ± standard deviation, 0.149 ± 0.011) than in control subjects (0.125 ± 0.008; P < .001) and higher in patients with cortical lesions (0.154 ± 0.011) than in those without (0.138 ± 0.010; P < .001). Moreover, FA was higher in cortical lesions than in NAGM (P < .001). After 3 years, NAGM-FA was unchanged in control subjects and increased in patients (0.154 ± 0.012; P < .001), especially in patients with worsened EDSS score (0.170 ± 0.011; P < .001). The same behavior was observed for NAGM-MD. At baseline, NAGM-FA significantly correlated with EDSS score (r = 0.75; P < .001) and cortical lesion volume (r = 0.850; P < .001). Multivariate analysis identified NAGM-FA (B = 0.654; P < .001) and T2 WMLV (B = 0.310; P < .001) as independent predictors of EDSS score, while NAGM-FA change (B = 0.523; P < .001) and disease duration (B = 0.342; P < .001) were independent predictors of EDSS change. CONCLUSION: Compared with control subjects, patients with RRMS had an increase in FA of NAGM that strongly correlated with cortical lesion volume and clinical disability.

No evidence of JC virus reactivation in natalizumab treated multiple sclerosis patients: an 18 month follow-up study.

BACKGROUND AND AIM: Natalizumab, used as therapy for multiple sclerosis (MS), has been associated with progressive multifocal leucoencephalopathy (PML), a potentially fatal disease caused by JC virus (JCV), which is not predictable by specific markers. This study evaluated whether JCV reactivation occurred in the urine and/or plasma in 42 MS patients treated with natalizumab over 18 months, and followed by a thorough monitoring programme. METHODS: 42 patients (F/M: 24/18, mean age 34.4±8.9 years) were followed-up by: urine and plasma JCV-DNA PCR assay, immune cell subsets analysis, clinical and MRI evaluation, quality of life, fatigue and mood assessment. RESULTS: JCV data. At baseline, 11/42 (26%) patients had JCV viruria, persistent at serial controls. One patient acquired viruria at month 1 and one patient at month 12. No patient had JCV viraemia at baseline; three patients acquired viraemic (one at month 6, one at month 13 (both transiently) and one at month 12 (persistently viraemic)). The prevalence of JCV in both urine and plasma did not change significantly from baseline to months 12 and 18. No patient had clinical or MRI evidence of PML. Immunological data. Circulating B cells showed greater expansion (300% increase in absolute number) since the first infusion. NK cell count doubled with no change in percentage while T cell count increased with a reduced percentage, reflecting a clear redistribution in the lymphocyte compartment. CD4+ and CD8+ T cells increased proportionally, with no change in their percentage. Clinical data. 27 patients (64%) were disease free after 1 year. A marked improvement in quality of life was reported by 72% of patients. CONCLUSIONS: No evidence of subclinical JCV reactivation was found in our natalizumab treated MS patients up to 18 months of therapy, notwithstanding the marked increase in circulating B cells observed. Moreover, the efficacy of natalizumab, its tolerability and the positive impact on quality of life were confirmed in this study.