Multimodal MRI Response to Fingolimod in Multiple Sclerosis: A Nonrandomized, Single Arm, Observational Study.

BACKGROUND AND PURPOSE: Fingolimod has a favorable effect on conventional MRI measures; however, its neuroprotective effect is not clear. We aim to investigate changes of conventional and advanced MRI measures in lesions and normal-appearing white matter (NAWM) over 2 years in fingolimod-treated patients. METHODS: Fifty relapsing-remitting multiple sclerosis patients and 27 healthy controls were enrolled in the study and underwent baseline, 1-year, and 2-year 3T MRI scans. T2 lesion volume, whole brain volume, cortical gray matter volume, white matter volume, corpus callosum area, percentage brain volume change (PBVC), Expanded Disability Status Scale, gadolinium-enhancing lesions, PBVC, magnetization transfer ratio (MTR), and diffusion tensor imaging metrics (fractional anisotropy [FA] and median diffusivity [MD]) in lesions and NAWM were calculated. Longitudinal changes were examined using one-way repeated measures ANOVA. Bonferroni correction for multiple testing was used when appropriate. RESULTS: Conventional MRI measures were unchanged in both groups. Lesion MTR increased significantly (P < .001), but NAWM-MTR remained unchanged. Lesion FA improved significantly in year 1 (P = .003) and over the study duration (P = .05). Lesion MD changed significantly from baseline to year 1 (P < .001) and remained stable over 2 years. NAWM-FA was significant from baseline to year 1 (P = .002) and from baseline to year 2 (P < .001). NAWM-MD was significant only from baseline to year 1 (P = .001). CONCLUSIONS: These findings suggest a possible neuroreparative effect of fingolimod on the MS lesions and NAWM. Larger and longer randomized studies are required to confirm these results.

Racial variations in lacosamide serum concentrations in adult patients with epilepsy.

Lacosamide (LCM) is a third-generation anti-epileptic drug (AED) for partial-onset epilepsy with minimal hepatic metabolism and drug-drug interactions. The impact of individual patient variables such as race on drug metabolism have been under-reported in AEDs and LCM has not been specifically investigated. Our aim was to assess the role race plays on serum LCM levels in the management of epilepsy. Thus, we retrospectively reviewed patients with focal seizures who received LCM and had LCM levels as part of their routine clinical care in our Level IV Epilepsy Center. Variables including age, race, gender, LCM serum levels, LCM daily dose, and concomitant AEDs were collected and analyzed. A total of 93 patients with 1-3 clinic visits yielded 122 LCM serum levels. African Americans (AA) comprised 62.3% of our serum samples. Daily LCM doses averaged 350 mg/day (range 50-1000 mg/day). Eighty-nine percent of patients took 1-2 other AEDs. Overall, AA patients had lower LCM levels (mean 6.8 µg/mL) compared to White patients (mean of 7.1 µg/mL) (p = .017) even when considering for the daily dose effect (p = .007). Analysis of co-variables did not have significant effect on LCM levels. Overall, AA patients had a weaker relationship between LCM daily dose (adjusted for weight) and serum levels as compared to White patients and require a higher LCM dose per weight to achieve similar levels. Differences in pharmacogenetics may play an important role in these findings and focus on how these variations impact seizure burden.

Anti-glutamic acid decarboxylase antibody (GAD) syndromes may have more aggressive disease course in African Americans and early onset of presentation compare to Caucasians group.

Anti-Glutamic acid decarboxylase antibodies (GAD) are increasingly diagnosed in the clinic and this antibody related syndromes can manifest commonly as autoimmune encephalitis, Stiff person syndrome and cerebellar ataxia. However, it is unclear if the race has role in age of incidence, presentation and severity of symptoms of anti-GAD associated conditions. In our cohort of 40 patients who were anti-GAD positive, we observed that the age at which the anti-GAD titers turned out to be positive was significantly lower in African Americans (AA) compared to Caucasians (Cau) irrespective of the type of conditions. However, the age at symptoms onset didn't differ significantly different between these groups. Furthermore, AA anti-GAD positive patients had seizures as their initial presentation that was significantly higher in incidence compared to Cau indicating that AA have more aggressive form of autoimmune phenomenon for reasons unknown. Future studies to explore the variations in autoimmune process and their phenotypes may aid in understanding anti-GAD syndromes differently between these racial groups.

Varicella zoster encephalitis in an immunocompromised patient presented with migraine type headache: A case report.

Varicella zoster virus (VZV) has been increasingly linked with encephalitis and atypical presentations in immunosuppressed patients. We present a patient with history of immunosuppressant intake for polymyositis who initially presented with throbbing frontal headache that raised the suspicion of migraine. She did not respond to anti-migraine medication and later developed stimulus induced myoclonus. She then had significant neurological decline and eventually became encephalopathic. Her initial imaging of brain was unremarkable which warranted further investigations. She was then diagnosed to be VZV positive in the cerebrospinal fluid (CSF) sample that confirmed VZV encephalitis. She responded well to IV Acyclovir treatment and her neurological function improved significantly. In this case, there was delay in diagnosis of VZV in the setting of immunosuppression and non-specific clinical presentation. Therefore, we encourage to strongly consider early VZV diagnostic work up and treatment in immunocompromised patients who can present with non-specific symptoms without a typical cutaneous rash.

Characterizing Fatigue-Related White Matter Changes in MS: A Proton Magnetic Resonance Spectroscopy Study.

Few cross-sectional studies have investigated the correlation between neurochemical changes and multiple sclerosis (MS) fatigue, but little is known on the fatigue-related white matter differences between time points. We aim to investigate the longitudinal neurometabolite profile of white matter in MS fatigue. Forty-eight relapsing remitting multiple sclerosis (RRMS) patients with an expanded disability status scale (EDSS) ≤ 4 underwent high field 1H-multivoxel magnetic resonance spectroscopy (MRS) at baseline and year 1. Fatigue severity was evaluated by the fatigue severity scale (FSS). Patients were divided into low (LF, FSS ≤ 3), moderate (MF, FSS = 3.1-5), and high fatigue (HF, FSS ≥ 5.1) groups. In a two-way analysis of variance (ANOVA), we observed a decline in the ratio of the sum of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) to the sum of creatine (Cr) and phosphocreatine (PCr) in the right anterior quadrant (RAQ) and left anterior quadrant (LAQ) of the MRS grid in the HF group at baseline and year 1. This decline was significant when compared with the LF group (p = 0.018 and 0.020). In a one-way ANOVA, the fatigue group effect was significant and the ratio difference in the right posterior quadrant (RPQ) and left posterior quadrant (LPQ) of the HF group was also significant (p = 0.012 and 0.04). Neurochemical changes in the bilateral frontal white matter and possibly parietooccipital areas were noted in the HF group at two different time points. Our findings may shed some light on the pathology of MS fatigue.

Racial differences in retinal neurodegeneration as a surrogate marker for cortical atrophy in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has both an inflammatory and a neurodegenerative component, with gray matter (GM) atrophy being an important contributor to disability. Optical coherence tomography (OCT) may serve as a prognostic tool for neuroaxonal health by measuring ganglion cell inner plexiform layer (GCIPL) thickness. There is a paucity of literature regarding the effects of race on pathobiology of MS, as racial minorities are underrepresented in research studies. OBJECTIVE: The aim of this paper is to compare the correlation between GM fraction (GMF) and GCIPL thickness in Caucasian Americans with MS (CAMS) and African Americans with MS (AAMS). METHODS: Fifty-nine patients with relapsing-remitting multiple sclerosis (RRMS) were included. Using a cross-sectional design, we compared the OCT (GCIPL thickness) and MRI (GMF) data of 32 CAMS and 27 AAMS patients. RESULTS: No significant correlation was observed between GMF and GCIPL in our study group (p = 0.127, r = 0.148). CAMS exhibited a significant correlation between these measures (p = 0.0004, r = 0.434), while in AAMS these measures did not correlate significantly (p = 0.187, r = -0.201). CONCLUSION: GCIPL might be a sensitive biomarker predicting GM atrophy and disability in CAMS, but not in AAMS. Larger studies are needed to investigate reliable biomarkers across races. Inclusion of AAMS in research studies is necessary to shed more light on the pathobiology of MS.

Structural and Neuronal Integrity Measures of Fatigue Severity in Multiple Sclerosis.

Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty-three Relapsing Remitting MS (RRMS) patients with MS-related fatigue (Fatigue Severity Scale (FSS) range: 1-7) and Expanded Disability Status Scale (EDSS) ≤ 4, were divided into high fatigue (HF, FSS ≥ 5.1) and low fatigue groups (LF, FSS ≤ 3). We measured T2 lesion load using a semi-automated technique. Cortical thickness, volume of sub-cortical nuclei, and brainstem structures were measured using Freesurfer. Cortical Diffusion Tensor Imaging (DTI) parameters were extracted using a cross modality technique. A correlation analysis was performed between FSS, volumetric, and DTI indices across all patients. HF patients showed significantly lower volume of thalamus, (p = 0.02), pallidum (p = 0.01), and superior cerebellar peduncle ((SCP), p = 0.002). The inverse correlation between the FSS score and the above volumes was significant in the total study population. In the right temporal cortex (RTC), the Radial Diffusivity ((RD), p = 0.01) and Fractional Anisotropy ((FA), p = 0.01) was significantly higher and lower, respectively, in the HF group. After Bonferroni correction, thalamic volume, FA-RTC, and RD-RTC remained statistically significant. Multivariate regression analysis identified FA-RTC as the best predictor of fatigue severity. Our data suggest an association between fatigue severity and volumetric changes of thalamus, pallidum, and SCP. Early neuronal injury in the RTC is implicated in the pathogenesis of MS-related fatigue.

Environmental Enrichment Mitigates Detrimental Cognitive Effects of Ketogenic Diet in Weanling Rats.

For decades, the ketogenic diet has been an effective treatment of intractable epilepsy in children. Childhood epilepsy is pharmacoresistant in 25-40 % of patients taking the current prescribed medications. Chronic seizure activity has been linked to deficits in cognitive function and behavioral problems which negatively affect the learning abilities of the child. Recent studies suggest the ketogenic diet (KD), a high fat with low carbohydrate and protein diet, has adverse effects on cognition in weanling rats. The diet reduces circulating glucose levels to where energy metabolism is converted from glycolysis to burning fat and generating ketone bodies which has been suggested as a highly efficient source of energy for the brain. In contrast, when weanling rats are placed in an enriched environment, they exhibit increased spatial learning, memory, and neurogenesis. Thus, this study was done to determine if weanling rats being administered a KD in an environmental enrichment (EE) would still exhibit the negative cognitive effects of the diet previously observed. The present study suggests that an altered environment is capable of reducing the cognitive deficits in weanling rats administered a KD. Learning was improved with an EE. The effect of diet and environment on anxiety and depression suggests a significant reduction in anxiety with enrichment rearing. Interestingly, circulating energy substrate levels were increased in the EE groups along with brain-derived neurotrophic factor despite the least changes in weight gain. In light of numerous studies using KDs that seemingly have adverse effects on cognition, KD-induced reductions in excitotoxic events would not necessarily eliminate that negative aspect of seizures.