Activated microglia surrounding amyloid -containing senile plaques synthesize interleukin-1, an inflammatory cytokine that has been postulated to contribute to Alzheimer's disease pathology. Studies have demonstrated that amyloid  treatment causes increased cytokine release in microglia and related cell cultures. The present work evaluates the specificity of this cellular response by comparing the effects of amyloid  to that of amylin, another amyloidotic peptide. Both lipopolysaccharide-treated THP-1 monocytes and mouse microglia showed significant increases in mature interleukin-1 release 48 h following amyloid  or human amylin treatment, whereas nonfibrillar rat amylin had no effect on interleukin-1 production by THP-1 cells. Lipopolysaccharide-stimulated THP-1 cells treated with amyloid  or amylin also showed increased release of the proinflammatory cytokines tumor necrosis factor-␣ and interleukin-6, as well as the chemokines interleukin-8 and macrophage inflammatory protein-1␣ and -1. THP-1 cells incubated with fibrillar amyloid  or amylin in the absence of lipopolysaccharide also showed significant increases of both interleukin-1 and tumor necrosis factor-␣ mRNA. Furthermore, treatment of THP-1 cells with amyloid fibrils resulted in an elevated expression of the immediate-early genes c-fos and junB. These studies provide further evidence that fibrillar amyloid peptides can induce signal transduction pathways that initiate an inflammatory response that is likely to contribute to Alzheimer's disease pathology.
We evaluated nonpsychotic behavioral adverse events (BAEs) in patients receiving levetiracetam (LEV) who switched to brivaracetam (BRV). Patients ≥16 years of age, receiving 2-3 antiepileptic drugs (AEDs), including LEV 1-3g/day, and experiencing BAEs within 16 weeks of LEV treatment initiation, enrolled in an open-label Phase 3b study (NCT01653262) comprising a ≤1-week screening period, an immediate switch from LEV to BRV 200mg/day (without titration), and a 12-week treatment period. The percentages of patients with investigator-assessed clinically meaningful reduction in BAEs, shift in maximum BAE intensity, and change in health-related quality of life (HRQoL) (Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P]) were assessed. Of 29 patients enrolled, 26 (89.7%) completed the study. At the end of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs. Physicians reported a reduction in the maximum intensity of primary BAEs in 27/29 (93.1%) patients. Mean change from baseline to Week 12 in QOLIE-31-P total score was 12.1, indicating improved HRQoL. During the treatment period, 23/29 (79.3%) patients reported treatment-emergent adverse events (TEAEs). One patient reported a serious TEAE (suicidal ideation and suicide attempt). Two patients discontinued BRV because of TEAEs. Findings from this small study suggest that patients experiencing BAEs associated with LEV may benefit from switching to BRV.
The results of this study suggest that LEV is a frequently used AED in the setting of acute brain injury and that it may be a desirable alternative to phenytoin. Prospective studies evaluating the long-term safety, efficacy and outcomes of LEV in this setting are indicated.
BackgroundLittle is known about the relationship between types of healthcare providers and outcomes in patients with epilepsy. This study compares the relative effects of provider type (epileptologist vs. other neurologist) and pharmacologic treatment (newer vs. older antiepileptic drugs) on seizure control in patients with epilepsy.MethodsWe conducted a retrospective study of patients with medication-resistant epilepsy. Consecutive charts of 200 patients were abstracted using a standard case report form. For each patient, data included seizure frequency and medication use prior to, and while being treated by an epileptologist. Changes in seizure frequency were modeled using a generalized linear model.ResultsAfter transferring care from a general neurologist to specialized epilepsy center, patients experienced fewer seizures (p < 0.001) and were more frequently seizure-free (p < 0.001). The improved seizure control was not related to treatment with newer vs. older antiepileptic drugs (p = 0.305).ConclusionOur findings suggest an association between subspecialty epilepsy care and improved seizure control in patients with medication-resistant epilepsy. Further research should prospectively determine whether patients with medication-resistant epilepsy would benefit from being routinely referred to an epilepsy specialist.
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