Refractory Epilepsy Associated With Microglial Activation
ABSTRACT Experimental and clinical studies support a pathogenic role of microglial activation and proliferation (MAP) in epileptogenesis.
From a consecutive series of 319 surgically treated epilepsy cases, we retrospectively reviewed the histopathological sections of 92 cases to define the prevalence and severity of MAP after excluding the other 227 because of coexisting disorders that might contribute to MAP. Severity of MAP was compared with underlying abnormalities. We assessed the response to intravenous immunoglobulin and plasmapheresis in one patient with severe MAP who had failed multiple antiepileptic drugs and epilepsy surgery.
MAP was detected with routine (hematoxylin and eosin) stain in 46 of 92 cases (50%). MAP was mild in 32 cases (69.6%), moderate in 12 (26.1%), and severe in 2 (4.3%). The prevalence and severity of MAP were independent of underlying abnormalities. Immunomodulatory therapy was followed by a greater than 90% reduction in seizure activity in the treated patient.
MAP is prevalent in resected human epilepsy tissue. Failure to down-regulate MAP contributes to chronic neuronal hyperexcitability. We hypothesize that MAP initiates a cycle of inflammation-induced seizures and seizure-induced inflammation. Microglia-driven epilepsy may be a primary pathogenic process in a small number of cases, as suggested by the pathology and therapeutic response in our patient, but may contribute to epileptogenesis in many more.
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ABSTRACT: It is estimated that one in 26 people will develop epilepsy in their lifetime, amounting to almost 12 million people in the United States alone (Hesdorffer et al., 2011). Epilepsy is a group of conditions characterized by sporadic occurrence of seizures and unconsciousness. This severely limits the ability to perform everyday tasks and leads to increased difficulty with learning and memory, maintenance of steady employment, driving, and overall socioeconomic integration. A greater understanding of the cellular and molecular mechanisms underlying seizures and epilepsy is necessary, as it may lead to novel antiepileptic treatments. In this chapter, we will review the current literature surrounding the involvement of glial cells in epilepsy with particular emphasis on review of human tissue studies and some possible underlying mechanisms. Based on the current evidence and hypotheses of glial mechanisms in epilepsy, novel therapeutic opportunities for the treatment of epilepsy will also be presented.Neurochemistry International 01/2013; DOI:10.1016/j.neuint.2013.01.017 · 2.65 Impact Factor
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ABSTRACT: Objective To characterize the changes in microglial proinflammatory M1 and antiinflammatory M2 marker expression during epileptogenesis in the chronic pilocarpine and intrahippocampal kainate models.MethodsM1-activated microglia express proinflammatory cytokines driving infiltration of cells, whereas M2-activated microglia are more reparative, promoting phagocytosis of debris and expression of proteins associated with cellular stability and repair. Microglial markers were characterized as acute (3 days after status epilepticus [SE]), early chronic (21 days post-SE), and late chronic epileptic (5–12 months post-SE) time points. Following pilocarpine-SE, microglial markers were assessed by flow cytometry. Quantitative real-time polymerase chain reaction (RT-PCR) was used to measure messenger RNA (mRNA) levels of selected M1 (interleukin [IL] 1β, tumor necrosis factor α [TNFα] cluster of differentiation [CD],CD16, and CD86), interleukin-6 [IL-6], interleukin-12 [IL-12], Fc receptors 16, and CD86) and M2 (arginase 1 [Arg1], chitinase-3-like protein [Ym1], found in inflammatory zone [FIZZ-1] [FIZZ-1], mannose receptor C type-1 [CD206], interleukin-4 [IL-4], and interleukin-10 (IL-10)) markers in both models. Video–electroencephalography (EEG) recordings were used to quantify late chronic seizure frequency.ResultsThree days post-SE microglia in the pilocarpine model expressed M1 and M2 markers, but only M1 markers were upregulated after kainate-induced SE. After 3 weeks, M1/M2 marker expression was largely ablated in the hippocampal formation of both models. Small mRNA level increases of CD11b, glial fibrillary acidic protein (GFAP), and IL-1β were found in the pilocarpine model, consistent with IL-1β contributing to spontaneous seizures, whereas mRNA levels of TNFα and Ym1 were decreased. In the late chronic phase, some M1/M2 markers, IL-1β, TNFα, Arg1, Ym1, and CD206, resurged in the kainate, but not pilocarpine model, which may reflect and/or contribute to highly frequent seizures in kainate-SE mice.SignificanceThe common M1 upregulation acutely post-SE may signal a role early in epileptogenesis, with a more pure “inflamed” central nervous system state after kainate-SE, potentially contributing to the development of more frequent seizures. The difference may also be due to the contribution of peripheral inflammation after pilocarpine injection. In summary, the microglial inflammatory response during epileptogenesis is complex, varies between models, and appears to correlate with chronic seizure frequency.Epilepsia 04/2015; DOI:10.1111/epi.12960 · 4.58 Impact Factor
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ABSTRACT: The factors underlying epilepsy are multifaceted, but recent research suggests that the brain's neural circuits, which play a key role in controlling the balance between epileptic and antiepileptic factors, may lie at the heart of epilepsy. This article provides a comprehensive review of the neural mechanisms and potential treatment of intractable epilepsy from neural inflammatory responses, melanocortin circuits in brain and pedunculopontine tegmental nucleus. Further studies should be undertaken to elucidate the nature of neural circuits so that we may more effectively apply these new preventive and symptomatic therapies to the patient suffering from medically refractory seizures and its complications.American Journal of Translational Research 01/2014; 6(6):625-30. · 3.23 Impact Factor