Neuropathology of SUDEP: Role of inflammation, blood-brain barrier impairment, and hypoxia (original) (raw)
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Brain inflammation as a biomarker in epilepsy
Biomarkers in Medicine, 2011
Experimental and clinical evidence have demonstrated the increased synthesis of specific inflammatory mediators, and the upregulation of their cognate receptors in the chronic epileptic brain, indicating that some proinflammatory pathways are activated in seizure foci. Inhibition of experimental seizures by pharmacological interference with specific proinflammatory signaling, together with evidence of changes in intrinsic susceptibility to seizures in transgenic mice with perturbed inflammatory pathways, was instrumental to establish the concept that brain inflammation has a role in the etiopathogenesis of seizures. Increasing evidence also highlights the possible involvement of inflammatory processes arising in the injured brain in the development of epilepsy (i.e., in epileptogenesis). Since brain inflammation in epilepsy is not a mere epiphenomenon of the pathology but is likely involved in the mechanisms underlying neuronal hyperexcitability, the onset of seizures and their recu...
Epilepsia, 2013
Purpose: Brain inflammation occurs during epileptogenesis and may contribute to the development and progression of temporal lobe epilepsy. Recently, several studies have indicated that seizures may also increase specific blood plasma cytokine levels in animal models as well as in human patients with epilepsy, suggesting that peripheral inflammation may serve as a biomarker for epilepsy. Moreover, studies in epilepsy animal models have shown that peripheral inflammation may play either a pathogenic or neuroprotective role. Methods: We evaluated the inflammatory response in blood plasma after electrically induced status epilepticus (SE) in a rat model for temporal lobe epilepsy. We measured blood plasma levels of the inflammation markers interleukin 1b (IL-1b), interleukin 6 (IL-6), by enzyme-linked immunosorbent assays (ELISAs) and Creactive protein (CRP) by immunoturbidimetry, at 1 day after SE (acute period), at 1 week (during the latent period), and at 2 months after SE, which is the chronic epileptic phase when spontaneous seizures occur. Plasma levels were also measured during pilocarpine-induced SE. These were compared with plasma levels after lipopolysaccharide injection, which causes sepsis. Key Findings: Although sepsis induced a huge surge in IL-1b and IL-6 levels, we did not detect a change in IL-1b, IL-6, or CRP plasma levels at any time point after electrically induced SE compared to control animals. SE induced by pilocarpine produced a rise in IL-6 and CRP but not IL-1b levels. Significance: These findings suggest that plasma levels of these inflammatory proteins cannot be used as biomarkers for temporal lobe epileptogenesis.
Hemogram parameters in epilepsy may be indicators of chronic inflammation and hypoxemia
Neurology and Clinical Neuroscience, 2017
Objective: To evaluate the hemogram parameters of patients with epilepsy during and after periods of seizure, and to compare these parameters with those in healthy subjects. Materials and method: Hemogram parameters of patients with epilepsy were analyzed retrospectively. Hemogram parameters were observed to display inflammatory status during seizure and seizure-free periods. Fifty-two patients with epilepsy and 48 healthy volunteers were included in the study. Results: White blood cell (WBC), neutrophil, and lymphocyte levels were significantly higher during seizures compared with seizure-free periods in patients with epilepsy. In addition, WBC, neutrophil and lymphocyte values of patients with epilepsy during seizure-free periods were significantly lower than those of healthy subjects. Independent of seizure status, patients with epilepsy had significantly increased mean corpuscular volume, mean platelet volume (MPV), and red blood cell distribution width (RDW) values compared wit...
bioRxiv, 2021
There is still a lack of robust data, acquired identically and reliably from tissues either surgically resected from patients with mesial temporal lobe epilepsy (mTLE) or collected in animal models, to answer the question of whether the degree of inflammation of the hippocampus differs between mTLE patients, and between epilepsy and epileptogenesis. Here, using highly calibrated RTqPCR, we show that neuroinflammatory marker expression was highly variable in the hippocampus and the amygdala of mTLE patients. This variability was not associated with gender, age, duration of epilepsy, seizure frequency, and anti-seizure drug treatments. In addition, it did not correlate between the two structures and was reduced when the inflammatory status was averaged between the two structures. We also show that brain tissue not frozen within minutes after resection had significantly decreased housekeeping gene transcript levels, precluding the possibility of using post-mortem tissues to assess phys...
Epilepsy Research, 2000
Neurodegeneration and gliosis have been extensively described after long-lasting seizures; evidence for cytokine involvement in neuron-glia interactions does exist. We have therefore studied the hippocampal expression of molecules responsible for immune and inflammatory reactions, at different time-points following either experimental status epilepticus (SE) or direct excitotoxic damage. Experiments consisting of immunohistochemical labeling of glial markers, major histocompatibility complex (MHC) and nuclear factor kB (NFkB), were performed. NFkB nuclear translocation was controlled and measured using the electrophoretic mobility shift assay. One day after SE, neurodegeneration was obvious in CA3 pyramidal layers; NFkB staining in neurons and its translocation to the nucleus enhanced. From day 4 to at least day 8 post-SE, MHC-positive microglia, NFkB over-expression in thickened astrocytes, and increased levels of its activated form could be observed. The excitotoxic model caused more severe lesions, but NFkB and MHC expression were similar in both models. These results suggest that during long-lasting seizures: (i) neuronal firing activates NFkB expression and translocation; (ii) microglia expresses MHC; (iii) astrocytes, probably stimulated by microglial cytokines, over-express NFkB, the activation of which induces a cascade of reactions, particularly the transcription of cytokines and/or neuroprotective molecules. Further clarification of the toxic or protective consequences of delayed inflammatory responses may be interesting in therapy of epilepsy.
Epilepsy and brain inflammation
Experimental Neurology, 2013
During the last decade, experimental research has demonstrated a prominent role of glial cells, activated in brain by various injuries, in the mechanisms of seizure precipitation and recurrence. In particular, alterations in the phenotype and function of activated astrocytes and microglial cells have been described in experimental and human epileptic tissue, including modifications in potassium and water channels, alterations of glutamine/glutamate cycle, changes in glutamate receptor expression and transporters, release of neuromodulatory molecules (e.g. gliotransmitters, neurotrophic factors), and induction of molecules involved in inflammatory processes (e.g. cytokines, chemokines, prostaglandins, complement factors, cell adhesion molecules) (Seifert et al., 2006; Vezzani et al., 2011; Wetherington et al., 2008). In particular, brain injury or proconvulsant events can activate microglia and astrocytes to release a number of proinflammatory mediators, thus initiating a cascade of inflammatory processes in brain tissue. Proinflammatory molecules can alter neuronal excitability and affect the physiological functions of glia by paracrine or autocrine actions, thus perturbing the glioneuronal communications. In experimental models, these changes contribute to decreasing the threshold to seizures and may compromise neuronal survival (Riazi et al., 2010; Vezzani et al., 2008). In this context, understanding which are the soluble mediators and the molecular mechanisms crucially involved in glio-neuronal interactions is instrumental to shed light on how brain inflammation may contribute to neuronal hyperexcitability in epilepsy. This review will report the clinical observations in drug-resistant human epilepsies and the experimental findings in adult and immature rodents linking brain inflammation to the epileptic process in a causal and reciprocal manner. By confronting the clinical evidence with the experimental findings, we will discuss the role of specific soluble inflammatory mediators in the etiopathogenesis of seizures, reporting evidence for both their acute and long term effects on seizure threshold. The possible contribution of these mediators to co-morbidities often described in epilepsy patients will be also discussed. Finally, we will report on the anti-inflammatory treatments with anticonvulsant actions in experimental models highlighting possible therapeutic options for treating drug-resistant seizures and for prevention of epileptogenesis.
Journal of the Neurological Sciences, 2013
Medial temporal lobe epilepsy is commonly associated with hippocampal atrophy on MRI and hippocampal sclerosis on histopathological examination of surgically-resected specimens. Likewise, it is well-established that prolonged seizures and status epilepticus can lead to hippocampal edema as noted on MRI. In this paper, the authors present an unusual patient with prolonged refractory status epilepticus, due to limbic encephalitis associated with anti-GAD antibody, who underwent palliative epilepsy surgery. Bilateral hippocampal edema was noted on preoperative MRI. Histologic evaluation confirmed presence of acute necrosis and neuronal loss in the left hippocampal formation. Follow-up MRI several months after surgery demonstrated severe atrophy of the contralateral right hippocampus. This is the first clear histopathological evidence that hippocampal atrophy following status epilepticus is the result of acute neuronal necrosis and cell loss.
Clinical and Developmental Immunology, 2004
Purpose: Elucidating the potential contribution of specific autoantibodies (Ab's) to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy patients with Rasmussen's encephalitis (RE) and 71 patients with other epilepsies were tested for Ab's to the "B" peptide (amino acids 372-395) of the glutamate/AMPA subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and additional autoimmune disease-associated autoantigens, and for the ability of their serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B Ab's were found in serum and CSF of most RE patients, and in serum of 17/71 (24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab's decreased drastically in CSF following functional-hemispherotomy, in association with seizure cessation and neurological improvement. Serum and CSF of two RE patients, and serum of 12/71 (17%) patients with other epilepsies, contained elevated anti-dsDNA Ab's, the hallmark of systemic-lupus-erythematosus. The sera (but not the CSF) of some RE patients contained also clinically elevated levels of "classical" autoimmune Ab's to glutamic-acid-decarboxylase, cardiolipin, b2-glycoprotein-I and nuclear-antigens SS-A and RNP-70. Sera and CSF of some RE patients caused substantial death of hippocampal neurons. Conclusions: Some epilepsy patients harbor Ab's to GluR3 and dsDNA on both sides of the bloodbrain barrier, and additional autoimmune Ab's only in serum. Since all these Ab's may be detrimental to the nervous system and/or peripheral organs, we recommend testing for their presence in epilepsy, and silencing their activity in Ab-positive patients.
Biochemical findings in sudden unexpected death in epilepsy: Hospital based case-control study
Journal of Forensic and Legal Medicine, 2019
A review study on the biochemistry of epilepsy showed that in epileptic patients, serum glucose and cholesterol concentrations are low, sodium is unaffected, potassium increases, glucose is high and mild hypocalcemia. We have conducted a biochemical study on sudden unexpected death in epilepsy (SUDEP) cases in an attempt to establish the characteristic biochemical values to diagnose these deaths. Methods: This was a hospital based case-control study done at All India Institute of Medical Sciences, New Delhi for one year. Twenty SUDEP cases and 20 age-and sex-matched controls were included in the study. Femoral blood, cerebrospinal fluid, vitreous humor, and pericardial fluid were biochemically analyzed for sodium, potassium, calcium, glucose, N-acetyl-cysteine activated creatine kinase (CK-NAC) and isoenzyme CK-MB. Result: Serum sodium, CK-MB and CK-NAC level was found significantly increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. Likewise, in CSF, sodium and CK-NAC was found increased and potassium level was found decreased in SUDEP cases. In vitreous humor, sodium and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to nonepileptic deaths. In pericardial fluid, sodium, CK-NAC and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. Conclusion: It concludes that high sodium level and low potassium level could be associated with SUDEP. However, this is a small size study, a larger study is needed to verify the findings. Furthermore, it is difficult to conclude whether these findings are exclusive to SUDEP.
Identification of Brain Cell Death Associated Proteins in Human Post-mortem Cerebrospinal Fluid
Journal of Proteome Research, 2006
Following any form of brain insult, proteins are released from damaged tissues into the cerebrospinal fluid (CSF). This body fluid is therefore an ideal sample to use in the search for biomarkers of neurodegenerative disorders and brain damage. In this study, we used human post-mortem CSF as a model of massive brain injury and cell death for the identification of such protein markers. Pooled post-mortem CSF samples were analyzed using a protocol that combined immunoaffinity depletion of abundant CSF proteins, off-gel electrophoresis, SDS-PAGE and protein identification by LC-MS/MS. A total of 299 proteins were identified, of which 172 proteins were not previously described to be present in CSF. Of these 172 proteins, more than 75% have been described as intracellular proteins suggesting that they were released from damaged cells. Immunoblots of a number of proteins were performed on individual post-mortem CSF samples and confirmed elevated concentrations in post-mortem CSF compared to ante-mortem CSF. Interestingly, among the proteins specifically identified in the postmortem CSF, several have been previously described as biochemical markers of brain damage.