Blood-brain barrier disruption in post-traumatic epilepsy. J Neurol Neurosurg Psychiatr

Department of Physiology, Zlotowski Center for Neuroscience, Ben-Gurion University, 84105 Beer-Sheva, Israel.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 08/2008; 79(7):774-7. DOI: 10.1136/jnnp.2007.126425
Source: PubMed


Traumatic brain injury (TBI) is an important cause of focal epilepsy. Animal experiments indicate that disruption of the blood-brain barrier (BBB) plays a critical role in the pathogenesis of post-traumatic epilepsy (PTE).
To investigate the frequency, extent and functional correlates of increased BBB permeability in patient with PTE.
32 head trauma patients were included in the study, with 17 suffering from PTE. Patients underwent brain MRI (bMRI) and were evaluated for BBB disruption, using a novel semi-quantitative technique. Cortical dysfunction was measured using electroencephalography (EEG), and localised using standardised low-resolution brain electromagnetic tomography (sLORETA).
Spectral EEG analyses revealed significant slowing in patients with TBI, with no significant differences between patients with epilepsy and those without. Although bMRI revealed that patients with PTE were more likely to present with intracortical lesions (p = 0.02), no differences in the size of the lesion were found between the groups (p = 0.19). Increased BBB permeability was found in 76.9% of patients with PTE compared with 33.3% of patients without epilepsy (p = 0.047), and could be observed years following the trauma. Cerebral cortex volume with BBB disruption was larger in patients with PTE (p = 0.001). In 70% of patients, slow (delta band) activity was co-localised, by sLORETA, with regions showing BBB disruption.
Lasting BBB pathology is common in patients with mild TBI, with increased frequency and extent being observed in patients with PTE. A correlation between disrupted BBB and abnormal neuronal activity is suggested.

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Available from: Iilan Shelef, Nov 18, 2015
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    • "The cytoskeleton is crucial in forming, anchoring, and maintaining the BBB (Zlokovic, 2008). Disruption of the BBB leads to increased permeability of large molecules, such as albumin, into the CNS, causing neuronal dysfunction, edema, and a lower seizure threshold (Abbott et al., 2006; Hawkins and Davis, 2005; Tomkins et al., 2008; van Vliet et al., 2007). Dystrophin, a major actin-binding component of the dystrophin glycoprotein complex (DGC), links cytoskeletal and membrane elements in the muscle (Tinsley et al., 1994) and brain (Lidov et al., 1990, 1993). "
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    ABSTRACT: Dystrophin, the main component of the dystrophin–glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the blood–brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38 ± 0.30 × 10- 4 mm2/s) and 10-month-old (6.93 ± 0.53 × 10- 4 mm2/s) mdx mice as compared to WT (8.49 ± 0.24 × 10- 4, 8.24 ± 0.25 × 10- 4 mm2/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.
    Full-text · Article · Nov 2014 · NeuroImage
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    • "evidence from experimental animal studies that BBB dysfunction can be caused by seizure activity (reviewed in [3] [4] [5] [6] [7]). However, research in the last decade shows that BBB disruption can also lead to epilepsy or aggravate the epileptic condition [8] [9] [10] [11] [12] [13] [14] [15] [16]. Since BBB dysfunction can also occur in brain diseases without the comorbidity of seizures or epilepsy it is not clear how BBB disruption can cause epilepsy by itself. "
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    ABSTRACT: The blood–brain barrier (BBB) is a dynamic and complex system which separates the brain from the blood. It helps to maintain the homeostasis of the brain, which is essential for normal neuronal functioning. BBB function is impaired in several neurological diseases, including epilepsy in which it may lead to abnormal and excessive neuronal firing. In this review we will discuss how BBB dysfunction can affect neuronal function and how this can lead to seizures and epilepsy. We will also summarize new therapies that aim to preserve or restore BBB function in order to prevent or reduce epileptogenesis.
    Full-text · Article · Nov 2014 · Seminars in Cell and Developmental Biology
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    • "Experimental blockade of TGF-β signaling following BBB disruption decreased those transcriptional responses and prevented epileptogenesis. BBB disruption has been demonstrated in patients with posttraumatic epilepsy (Tomkins et al., 2008) and in patients with brain tumors who developed epilepsy (Marchi et al., 2007). Thus, pathogenetic neurovascular interactions which involve astroglial dysfunction, changes in the immune response, and gene expression changes that promote neuronal hyperexcitability may play a critical role in epileptogenesis. "
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    ABSTRACT: Neuronal excitability of the brain and ongoing homeostasis depend not only on intrinsic neuronal properties, but also on external environmental factors; together these determine the functionality of neuronal networks. Homeostatic factors become critically important during epileptogenesis, a process that involves complex disruption of self-regulatory mechanisms. Here we focus on the bioenergetic homeostatic network regulator adenosine, a purine nucleoside whose availability is largely regulated by astrocytes. Endogenous adenosine modulates complex network function through multiple mechanisms including adenosine receptor-mediated pathways, mitochondrial bioenergetics, and adenosine receptor-independent changes to the epigenome. Accumulating evidence from our laboratories shows that disruption of adenosine homeostasis plays a major role in epileptogenesis. Conversely, we have found that reconstruction of adenosine's homeostatic functions provides new hope for the prevention of epileptogenesis. We will discuss how adenosine-based therapeutic approaches may interfere with epileptogenesis on an epigenetic level, and how dietary interventions can be used to restore network homeostasis in the brain. We conclude that reconstruction of homeostatic functions in the brain offers a new conceptual advance for the treatment of neurological conditions which goes far beyond current target-centric treatment approaches.
    Full-text · Article · Jul 2013 · Frontiers in Cellular Neuroscience
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