A comparative study of fatigue and processing speed in patients with multiple sclerosis treated with natalizumab or rituximab.

Background: Fatigue is the most debilitating symptom in patients with multiple sclerosis (MS). Natalizumab and rituximab are the most used MS disease modifying therapies in Sweden, but comparative data on the effect on fatigue is sparse. Objective: Primary objective was to compare fatigue levels between patients on natalizumab and rituximab. As secondary objective, we assessed processing speed, an attention domain quality, between treatment groups. Method: In this Swedish multicentre cross-sectional study, patients with relapsing-remitting MS and >24 months treatment duration were identified in the Swedish MS-registry. Fatigue was assessed using the Fatigue Scale for Motor and Cognitive functions (FSMC) and processing speed using Symbol Digit Modalities Test (SDMT). Results: 128 patients were enrolled (natalizumab: 56, rituximab: 72). No significant differences in FSMC were found when adjusting for potential confounders (p = 0.936), with age having the biggest impact, correlating with increased fatigue. Individuals on natalizumab performed significantly better on SDMT at cross-section (natalizumab 64.7, rituximab 56.2; p = 0.003), with an improvement from treatment initiation, compared to rituximab (change: natalizumab 8.9, rituximab -1.0; p = 0.002). Conclusion: We found no difference in fatigue levels between natalizumab and rituximab cohorts. Patients treated with natalizumab showed significantly better results on SDMT than patients on rituximab.

Reduced long-term mortality after successful resective epilepsy surgery: a population-based study.

BACKGROUND: We investigated all-cause and epilepsy-related mortality in patients operated with resective epilepsy surgery and in non-operated patients with drug-resistant epilepsy. Our hypothesis was that patients who proceed to surgery have lower mortality over time compared with non-operated patients. METHOD: Data from 1329 adults and children from the Swedish National Epilepsy Surgery Register and 666 patients with drug-resistant epilepsy who had undergone presurgical work-up but not been operated were analysed. The operated patients had follow-ups between 2 and 20 years. We used the Swedish Cause of Death Register to identify deaths. Autopsy reports were collected for patients with suspected sudden unexpected death in epilepsy (SUDEP). Kaplan-Meier and Cox regression analyses were performed to identify predictors for mortality and SUDEP. RESULTS: SUDEP accounted for 30% of all deaths. Surgery was associated with lower all-cause mortality (HR 0.7, 95% CI 0.5 to 0.9), also when adjusted for age, sex and tonic-clonic seizures at inclusion. The benefit of surgery seemed to persist and possibly even increase after 15 years of follow-up. Risk factors of mortality for operated patients were persisting seizures and living alone. Of the operated patients, 37% had seizures, and these had a higher risk of mortality (HR 2.1, 95% CI 1.4 to 3.0) and SUDEP (HR 3.5, 95% CI 1.7 to 7.3) compared with patients with seizure freedom at last follow-up. CONCLUSIONS: In this large population-based epilepsy surgery cohort, operated patients had a lower all-cause mortality compared with non-operated patients with drug-resistant epilepsy. Seizure freedom was the most important beneficial factor for both all-cause mortality and SUDEP among operated patients.

Structural association between heterotopia and cortical lesions visualised with 7 T MRI in patients with focal epilepsy.

PURPOSE: To analyze structural characteristics of malformations of cortical development (MCD) at 7T and 3T MRI. METHODS: Twenty-five patients were examined with a 7T MRI-scanner in addition to 3T examinations performed for epilepsy evaluation. 7T sequences included a 3D-T1-weighted (T1w) MPRAGE, 3D-T2w FLAIR, and heavily T2w axial and coronal high-resolution (0.5 × 0.5 × 0.75-1.0 mm3) 2D-TSE sequences. Images were reviewed for 7T MRI imaging characteristics of MCD, visibility and frequency of identified lesions on 7T and on 3T (original reports and second reading). RESULTS: In 25 patients 112 lesions were identified (57 gray matter (GM) heterotopia, 37 focal cortical dysplasia (FCD), and 18 other MCD). Imaging characteristics of the 37 FCD were cortical thickening (n = 11); GM-WM border blurring (n = 30); GM signal intensity changes (n = 18); juxtacortical WM signal intensity changes (n = 18); and transmantle WM signal intensity changes (n = 11). None of the 7T MRI sequences was sufficient to detect all types of lesions. Heterotopia were in general isointense to normal GM. Structural associations between 36 heterotopia and overlaying cortex were observed, composed either of a direct connection, vessel-like structures, or GM-like bridges. FCD were mentioned in 30% (11 of 37) of the original reports at 3T, and in 57% (21 of 37) after second reading. FCD connections to subcortical heterotopia were clinically not reported at all. CONCLUSION: 7T MRI revealed subtle connections between heterotopia and previous unidentified pathology in overlaying cortex. These findings may be significant for the understanding of the anatomical seizure origin and propagation pathways.

Inflammatory reaction in the retina after focal non-convulsive status epilepticus in mice investigated with high resolution magnetic resonance and diffusion tensor imaging.

Pathophysiological consequences of focal non-convulsive status epilepticus (fNCSE) have been difficult to demonstrate in humans. In rats fNCSE pathology has been identified in the eyes. Here we evaluated the use of high-resolution 7 T structural T1-weighted magnetic resonance imaging (MRI) and 9.4 T diffusion tensor imaging (DTI) for detecting hippocampal fNCSE-induced retinal pathology ex vivo in mice. Seven weeks post-fNCSE, increased number of Iba1+ microglia were evident in the retina ipsilateral to the hemisphere with fNCSE, and morphologically more activated microglia were found in both ipsi- and contralateral retina compared to non-stimulated control mice. T1-weighted intensity measurements of the contralateral retina showed a minor increase within the outer nuclear and plexiform layers of the lateral retina. T1-weighted measurements were not performed in the ipsilateral retina due to technical difficulties. DTI fractional anisotropy(FA) values were discretely altered in the lateral part of the ipsilateral retina and unaltered in the contralateral retina. No changes were observed in the distal part of the optic nerve. The sensitivity of both imaging techniques for identifying larger retinal alteration was confirmed ex vivo in retinitis pigmentosa mice where a substantial neurodegeneration of the outer retinal layers is evident. With MR imaging a 50 % decrease in DTI FA values and significantly thinner retina in T1-weighted images were detected. We conclude that retinal pathology after fNCSE in mice is subtle and present bilaterally. High-resolution T1-weighted MRI and DTI independently did not detect the entire pathological retinal changes after fNCSE, but the combination of the two techniques indicated minor patchy structural changes.

Physical Activity Reduces Epilepsy Incidence: a Retrospective Cohort Study in Swedish Cross-Country Skiers and an Experimental Study in Seizure-Prone Synapsin II Knockout Mice.

BACKGROUND: Epilepsy patients commonly exercise less than the general population. Animal studies indicate beneficial effects of physical activity in established epilepsy, while its effect on the development is currently less known. METHODS: Here, we investigated the incidence of epilepsy during 20 years in a cohort of participants from the long-distance Swedish cross-country ski race Vasaloppet (n = 197,685) and compared it to the incidence of non-participating-matched controls included in the Swedish population register (n = 197,684). Individuals diagnosed with diseases such as stroke and epilepsy before entering the race were excluded from both groups. Experimentally, we also determined how physical activity could affect the development of epilepsy in epilepsy-prone synapsin II knockout mice (SynIIKO), with and without free access to a running wheel. RESULTS: We identified up to 40-50% lower incidence of epilepsy in the Vasaloppet participants of all ages before retirement. A lower incidence of epilepsy in Vasaloppet participants was seen regardless of gender, education and occupation level compared to controls. The participants included both elite and recreational skiers, and in a previous survey, they have reported a higher exercise rate than the general Swedish population. Sub-analyses revealed a significantly lower incidence of epilepsy in participants with a faster compared to slower finishing time. Dividing participants according to specified epilepsy diagnoses revealed 40-50% decrease in focal and unspecified epilepsy, respectively, but no differences in generalized epilepsy. Voluntary exercise in seizure-prone SynIIKO mice for 1 month before predicted epilepsy development decreased seizure manifestation from > 70 to 40%. Brain tissue analyses following 1 month of exercise showed increased hippocampal neurogenesis (DCX-positive cells), while microglial (Iba1) and astrocytic activation (GFAP), neuronal Map2, brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B intensity were unaltered. Continued exercise for additionally 2 months after predicted seizure onset in SynIIKO mice resulted in a 5-fold reduction in seizure manifestation (from 90 to 20%), while 2 months of exercise initiated at the time of predicted seizure development gave no seizure relief, suggesting exercise-induced anti-epileptogenic rather than anti-convulsive effect. CONCLUSION: The clinical study and the experimental findings in mice indicate that physical activity may prevent or delay the development of epilepsy.

Test-specific differences in verbal memory assessments used prior to surgery in temporal lobe epilepsy.

OBJECTIVE: To study the relationship between two commonly used verbal memory tests in presurgical evaluation for temporal lobe epilepsy (TLE) in Sweden, the Claeson-Dahl Test for verbal learning and retention (CDT) and the Swedish version of the Rey Auditory Verbal Learning Test (RAVLT). METHODS: Fifty-nine patients with TLE (male: 41%, mean: age 41.7 ±â€¯12.3 years; epilepsy onset at mean age: 18.3 ±â€¯13.1 years) previously tested with the CDT, the RAVLT, and three nonverbal memory tests on the same occasion were included. We performed (1) a principal component analysis (PCA) on test performances in the CDT and the RAVLT as well as in nonverbal memory tests; (2) a Pearson's correlation analysis for memory components, biological age, education, age at epilepsy onset, and self-rating scores for depression and anxiety; and (3) an estimation of clinically significant verbal memory impairment in patients with left TLE and left-sided hippocampal sclerosis. RESULTS: The PCAs showed coherence between the learning variables of the CDT and the RAVLT and divergence between the recall variables of the two tests. The RAVLT delayed recall variable was correlated to four out of five nonverbal memory measures. Both tests showed 70-80% clinically significant impairment of verbal memory in patients with left TLE, with or without hippocampal sclerosis, similar to other cohorts with resistant TLE. CONCLUSIONS: The construct structure of the two verbal memory differs. It was shown that the RAVLT correlated with visuospatial memory, whereas the CDT did not. The study highlights that there are important nonoverlapping features regarding verbal recall of the two tests, indicating that these tests cannot fully replace one another.