Mechanisms of blood-retinal barrier disruption related to intraocular inflammation and malignancy.

Blood-retinal barrier (BRB) disruption is a common accompaniment of intermediate, posterior and panuveitis causing leakage into the retina and macular oedema resulting in vision loss. It is much less common in anterior uveitis or in patients with intraocular lymphoma who may have marked signs of intraocular inflammation. New drugs used for chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, EGFR inhibitors, bispecific anti-EGFR inhibitors, MET receptor inhibitors and Bruton tyrosine kinase inhibitors) can also cause different types of uveitis and BRB disruption. As malignant disease itself can cause uveitis, particularly from breast, lung and gastrointestinal tract cancers, it can be clinically difficult to sort out the cause of BRB disruption. Immunosuppression due to malignant disease and/or chemotherapy can lead to infection which can also cause BRB disruption and intraocular infection. In this paper we address the pathophysiology of BRB disruption related to intraocular inflammation and malignancy, methods for estimating the extent and effect of the disruption and examine why some types of intraocular inflammation and malignancy cause BRB disruption and others do not. Understanding this may help sort and manage these patients, as well as devise future therapeutic approaches.

Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain.

BACKGROUND: Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase. METHODS: Using ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico. RESULTS: Isoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo. CONCLUSIONS: The results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia.

Quantitative analysis of magnetic resonance images for characterization of blood-brain barrier dysfunction in dogs with brain tumors.

BACKGROUND: Blood-brain barrier (BBB) permeability can be assessed quantitatively using advanced imaging analysis. HYPOTHESIS/OBJECTIVES: Quantification and characterization of blood-brain barrier dysfunction (BBBD) patterns in dogs with brain tumors can provide useful information about tumor biology and assist in distinguishing between gliomas and meningiomas. ANIMALS: Seventy-eight hospitalized dogs with brain tumors and 12 control dogs without brain tumors. METHODS: In a 2-arm study, images from a prospective dynamic contrast-enhanced (DCE; n = 15) and a retrospective archived magnetic resonance imaging study (n = 63) were analyzed by DCE and subtraction enhancement analysis (SEA) to quantify BBB permeability in affected dogs relative to control dogs (n = 6 in each arm). For the SEA method, 2 ranges of postcontrast intensity differences, that is, high (HR) and low (LR), were evaluated as possible representations of 2 classes of BBB leakage. BBB score was calculated for each dog and was associated with clinical characteristics and tumor location and class. Permeability maps were generated, using the slope values (DCE) or intensity difference (SEA) of each voxel, and analyzed. RESULTS: Distinctive patterns and distributions of BBBD were identified for intra- and extra-axial tumors. At a cutoff of 0.1, LR/HR BBB score ratio yielded a sensitivity of 80% and specificity of 100% in differentiating gliomas from meningiomas. CONCLUSIONS AND CLINICAL IMPORTANCE: Blood-brain barrier dysfunction quantification using advanced imaging analyses has the potential to be used for assessment of brain tumor characteristics and behavior and, particularly, to help differentiating gliomas from meningiomas.

Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD.

Spreading depolarization (SD) occurs in a plethora of clinical conditions including migraine aura, delayed ischemia after subarachnoid hemorrhage and malignant hemispheric stroke. It describes waves of near-breakdown of ion homeostasis, particularly Na+ homeostasis in brain gray matter. SD induces tone alterations in resistance vessels, causing either hyperperfusion in healthy tissue; or hypoperfusion (inverse hemodynamic response = spreading ischemia) in tissue at risk. Observations from mice with genetic dysfunction of the ATP1A2-encoded α2-isoform of Na+/K+-ATPase (α2NaKA) suggest a mechanistic link between (1) SD, (2) vascular dysfunction, and (3) salt-sensitive hypertension via α2NaKA. Thus, α2NaKA-dysfunctional mice are more susceptible to SD and show a shift toward more inverse hemodynamic responses. α2NaKA-dysfunctional patients suffer from familial hemiplegic migraine type 2, a Mendelian model disease of SD. α2NaKA-dysfunctional mice are also a genetic model of salt-sensitive hypertension. To determine whether SD thresholds and hemodynamic responses are also altered in other genetic models of salt-sensitive hypertension, we examined these variables in stroke-prone spontaneously hypertensive rats (SHRsp). Compared with Wistar Kyoto control rats, we found in SHRsp that electrical SD threshold was significantly reduced, propagation speed was increased, and inverse hemodynamic responses were prolonged. These results may have relevance to both migraine with aura and stroke.

The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS).

BACKGROUND: The effect of diet on age-related brain atrophy is largely unproven. OBJECTIVES: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy. METHODS: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols). RESULTS: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P < 0.001; LVV change: 3.2% ± 4.5% compared with 1.3% ± 4.1%; 95% CI: -3.1%, -0.8%; P = 0.001). In subjects ≥ 50 y old, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared with HDG (HOC: -0.8% ± 1.6% compared with -1.3% ± 1.4%; 95% CI: -1.5%, -0.02%; P = 0.042; LVV: 2.3% ± 4.7% compared with 4.3% ± 4.5%; 95% CI: 0.3%, 5.2%; P = 0.021). Similar patterns were observed among younger subjects. Improved insulin sensitivity over the trial was the parameter most strongly associated with brain atrophy attenuation (P < 0.05). Greater Mankai, green tea, and walnut intake and less red and processed meat were significantly and independently associated with reduced HOC decline (P < 0.05). Elevated urinary concentrations of the polyphenols urolithin-A (r = 0.24; P = 0.013) and tyrosol (r = 0.26; P = 0.007) were significantly associated with lower HOC decline. CONCLUSIONS: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186.

TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer.

Proper neuronal function requires strict maintenance of the brain's extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood-brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain.

Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

Blood-brain barrier dysfunction in canine epileptic seizures detected by dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVE: Dogs with spontaneous or acquired epilepsy exhibit resemblance in etiology and disease course to humans, potentially offering a translational model of the human disease. Blood-brain barrier dysfunction (BBBD) has been shown to partake in epileptogenesis in experimental models of epilepsy. To test the hypothesis that BBBD can be detected in dogs with naturally occurring seizures, we developed a linear dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis algorithm that was validated in clinical cases of seizing dogs and experimental epileptic rats. METHODS: Forty-six dogs with naturally occurring seizures of different etiologies and 12 induced epilepsy rats were imaged using DCE-MRI. Six healthy dogs and 12 naive rats served as control. DCE-MRI was analyzed by linear-dynamic method. BBBD scores were calculated in whole brain and in specific brain regions. Immunofluorescence analysis for transforming growth factor beta (TGF-ß) pathway proteins was performed on the piriform cortex of epileptic dogs. RESULTS: We found BBBD in 37% of dogs with seizures. A significantly higher cerebrospinal fluid to serum albumin ratio was found in dogs with BBBD relative to dogs with intact blood-brain barrier (BBB). A significant difference was found between epileptic and control rats when BBBD scores were calculated for the piriform cortex at 48 hours and 1 month after status epilepticus. Mean BBBD score of the piriform lobe in idiopathic epilepsy (IE) dogs was significantly higher compared to control. Immunohistochemistry results suggested active TGF-ß signaling and neuroinflammation in the piriform cortex of dogs with IE, showing increased levels of serum albumin colocalized with glial acidic fibrillary protein and pSMAD2 in an area where BBBD had been detected by linear DCE-MRI. SIGNIFICANCE: Detection of BBBD in dogs with naturally occurring epilepsy provides the ground for future studies for evaluation of novel treatment targeting the disrupted BBB. The involvement of the piriform lobe seen using our linear DCE-MRI protocol and algorithm emphasizes the possibility of using dogs as a translational model for the human disease.

Bioenergetic Mechanisms of Seizure Control.

Epilepsy is characterized by the regular occurrence of seizures, which follow a stereotypical sequence of alterations in the electroencephalogram. Seizures are typically a self limiting phenomenon, concluding finally in the cessation of hypersynchronous activity and followed by a state of decreased neuronal excitability which might underlie the cognitive and psychological symptoms the patients experience in the wake of seizures. Many efforts have been devoted to understand how seizures spontaneously stop in hope to exploit this knowledge in anticonvulsant or neuroprotective therapies. Besides the alterations in ion-channels, transmitters and neuromodulators, the successive build up of disturbances in energy metabolism have been suggested as a mechanism for seizure termination. Energy metabolism and substrate supply of the brain are tightly regulated by different mechanisms called neurometabolic and neurovascular coupling. Here we summarize the current knowledge whether these mechanisms are sufficient to cover the energy demand of hypersynchronous activity and whether a mismatch between energy need and supply could contribute to seizure control.

Simulation of spreading depolarization trajectories in cerebral cortex: Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage.

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival-differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury.

Event-Associated Oxygen Consumption Rate Increases ca. Five-Fold When Interictal Activity Transforms into Seizure-Like Events In Vitro.

Neuronal injury due to seizures may result from a mismatch of energy demand and adenosine triphosphate (ATP) synthesis. However, ATP demand and oxygen consumption rates have not been accurately determined, yet, for different patterns of epileptic activity, such as interictal and ictal events. We studied interictal-like and seizure-like epileptiform activity induced by the GABAA antagonist bicuculline alone, and with co-application of the M-current blocker XE-991, in rat hippocampal slices. Metabolic changes were investigated based on recording partial oxygen pressure, extracellular potassium concentration, and intracellular flavine adenine dinucleotide (FAD) redox potential. Recorded data were used to calculate oxygen consumption and relative ATP consumption rates, cellular ATP depletion, and changes in FAD/FADH2 ratio by applying a reactive-diffusion and a two compartment metabolic model. Oxygen-consumption rates were ca. five times higher during seizure activity than interictal activity. Additionally, ATP consumption was higher during seizure activity (~94% above control) than interictal activity (~15% above control). Modeling of FAD transients based on partial pressure of oxygen recordings confirmed increased energy demand during both seizure and interictal activity and predicted actual FAD autofluorescence recordings, thereby validating the model. Quantifying metabolic alterations during epileptiform activity has translational relevance as it may help to understand the contribution of energy supply and demand mismatches to seizure-induced injury.

Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.

UNLABELLED: The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT: In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.

Autosomal dominant epilepsy with auditory features: a new LGI1 family including a phenocopy with cortical dysplasia.

We report a new family with autosomal dominant epilepsy with auditory features (ADEAF) including focal cortical dysplasia (FCD) in the proband. We aim to identify the molecular cause in this family and clarify the relationship between FCD and ADEAF. A large Iranian Jewish family including 14 individuals with epileptic seizures was phenotyped including high-resolution 3-T MRI. We performed linkage analysis and exome sequencing. LGI1, KANK1 and RELN were Sanger sequenced. Seizure semiology of 11 individuals was consistent with ADEAF. The proband underwent surgery for right mesiotemporal FCD. 3-T MRIs in four individuals were unremarkable. Linkage analysis revealed peaks on chromosome 9p24 (LOD 2.43) and 10q22-25 (LOD 2.04). A novel heterozygous LGI1 mutation was identified in all affected individuals except for the proband indicating a phenocopy. Exome sequencing did not reveal variants within the chromosome 9p24 region. Closely located variants in KANK1 and a RELN variant did not segregate with the phenotype. We provide detailed description of the phenotypic spectrum within a large ADEAF family with a novel LGI1 mutation that was conspicuously absent in the proband with FCD, demonstrating that despite identical clinical symptoms, phenocopies in ADEAF families may exist. This family illustrates that rare epilepsy syndromes within a single family can have both genetic and structural etiologies.

Differential TGF-ß Signaling in Glial Subsets Underlies IL-6-Mediated Epileptogenesis in Mice.

TGF-ß1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-ß1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-ß signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6 -: treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-ß1 -: induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-ß signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte -: neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-ß1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.

Neurocysticercosis: A natural human model of epileptogenesis.

OBJECTIVE: To develop a better understanding of mechanisms of seizures and long-term epileptogenesis using neurocysticercosis. METHODS: A workshop was held bringing together experts in epilepsy and epileptogenesis and neurocysticercosis. RESULTS: Human neurocysticercosis and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures. Inflammatory responses to degenerating forms and later-stage calcified parasite granulomas are associated with seizures and epilepsy. Other mechanisms may also be involved in epileptogenesis. SIGNIFICANCE: Naturally occurring brain infections with neurocysticercosis offer a unique opportunity to develop treatments for one of the world's most common causes of epilepsy and for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state.

Detection of cerebral hyperperfusion syndrome after carotid endarterectomy with CT perfusion.

We present the case of a 60-year-old female patient, who developed symptomatic internal carotid artery stenosis and subsequently underwent carotid endarterectomy. Four days after an uneventful surgery the patient developed confusion, seizures, and was admitted to the ICU. CT perfusion revealed reduced ispilateral time-to-peak and mean-transient-time and increased cerebral blood volume and cerebral blood flow, confirming the diagnosis of cerebral hyperperfusion syndrome. We thus propose CT perfusion as a diagnostic means for cerebral hyperperfusion syndrome, a syndrome that remains underdiagnosed.

Quantitative imaging assessment of blood-brain barrier permeability in humans.

The blood-brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the "post-pre" and the "linear dynamic" methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such "easy to use" and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.

Albumin storage in neoplastic astroglial elements of gangliogliomas.

PURPOSE: Low-grade neuroepithelial tumors are frequent neuropathological findings in patients with pharmacoresistant epilepsies. Little is known regarding epileptogenic mechanisms in this group of neoplasms with gangliogliomas (GG) as the most common entity. Presence of hemosiderin deposits in GG points to impairment of the blood-brain barrier (BBB). Therefore, we hypothesized a potential role of BBB dysfunction and astrocytic albumin uptake as potential epileptogenic factor in GG. METHODS: Prussian blue staining and fluorescent double-immunohistochemistry with antibodies against albumin, GFAP, CD34 and GLUT-1 were used to analyze hemosiderin deposits and astroglial albumin accumulation in tumor and adjacent pre-existing brain tissue of GG (n=10) and several control groups, i.e. dysembryoplastic neuroepithelial tumors (DNT; n=5), focal cortical dysplasia with balloon cells (FCD IIb; n=10), astrocytomas WHO grade II (n=5) and clear renal cell carcinoma brain metastases (RCCM, n=6). RESULTS: Our results revealed strong hemosiderin deposits in GG. Intriguingly, we noted substantial albumin uptake exclusively in neoplastic glial cell components of GG and DNT, whereas no significant albumin was present in perilesional reactive astrocytes. Strikingly, we did not observe substantial albumin uptake in further controls. CONCLUSION: Glial albumin uptake was restricted to long-term epilepsy associated, vasculature-containing tumors. Intratumoural BBB dysfunction in concert with subsequent accumulation of albumin by neoplastic glial cell elements represent a new putatively epileptogenic mechanism for long-term epilepsy-associated tumors.