Refractory Epilepsy Associated With Microglial Activation

Department of Neurology, NYU Comprehensive Epilepsy Center, USA.
The Neurologist (Impact Factor: 1.16). 09/2011; 17(5):249-54. DOI: 10.1097/NRL.0b013e31822aad04
Source: PubMed


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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    • "The inclusion of those tumour pixels with high [11C]-(R)PK11195 signals in the reference cluster will lead to underestimation of BPND. Regarding the second problem, nonneoplastic cerebral regions might be affected by intrahemispheric and transhemispheric diaschisis [54, 55], oedema or abnormal electroactivity induced by seizures, any of which could trigger local or diffuse neuroinflammatory responses and thus increased [11C]-(R)PK11195 uptake by activated microglia [56–58]. It is possible that the supervised clustering could be biased by such background changes and extract abnormal pixels as reference. "
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    ABSTRACT: Purpose Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [11C]-(R)PK11195. We sought to characterize the [11C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two reference tissue input functions (supervised cluster analysis versus cerebellar grey matter) for the estimation of [11C]-(R)PK11195 binding in gliomas and surrounding brain structures. Methods Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [11C]-(R)PK11195 PET scans. Tissue time–activity curves (TACs) were extracted from tumour regions as well as grey matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BPND) were generated with the simplified reference tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumour tissue sections by immunohistochemistry. Results Three types of regional kinetics were observed in individual tumour TACs: GM-like kinetics (n = 6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n = 8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n = 9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumour grade. There was good agreement between parametric maps of BPND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BPND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochemistry confirmed that TSPO expression increased with tumour grade. Conclusion The three types of [11C]-(R)PK11195 kinetics in gliomas are determined in part by tracer delivery, and indicated that kinetic analysis is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BPND estimates in approximately half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theoretical and practical considerations.
    Full-text · Article · May 2013 · European Journal of Nuclear Medicine
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    • "The infiltration of leukocytes into sclerotic tissue was detected in both human specimens and animal models using immunohistochemistry (Zattoni et al., 2011). Microglia activation and proliferation is prevalent in resected human epileptic tissue (Najjar et al., 2011). Histological characteristics of FCD include cortical laminar disorganization and abnormal neuronal and astroglial cell types. "
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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.
    Full-text · Article · Jan 2013 · Neurochemistry International
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    ABSTRACT: Neuroinflammation (NI) is an important factor of many CNS diseases, and alleviating NI is believed to reduce disease severity and improve patient outcome in a majority of cases. There are a variety of traditionally druggable targets for NI such as enzymes, receptors, and ion channels. In this review, targets are highlighted where advances in medicinal chemistry have been achieved in the recent past and include purinergic receptors P2X 4 and P2X 7, kynurenine pathway metabolizing enzymes indole 2,3-dioxygenase and kynurenine aminotransferase, toll-like receptors TLR4 and TLR9, and the fractalkine receptor CX3CR1. These targets are also linked to biological mechanisms underlying NI and disease. Even though increased risk of infection is a potential issue for NI targets owing to immunomodulatory effects, there is significant opportunity to discover new molecules for the alleviation of NI in CNS diseases.
    No preview · Chapter · Jan 2012
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