Nuno Canas

Brain-derived neurotrophic factor facilitates glutamate and inhibits GABA release from hippocampal synaptosomes through different mechanisms

Brain-derived neurotrophic factor (BDNF) has an acute excitatory effect on rat hippocampal synaptic transmission. To compare the action of BDNF upon the release of excitatory and inhibitory neurotransmitters in the hippocampus, we studied the effect of acutely applied BDNF on the K+-evoked glutamate and on the K+-evoked gamma-aminobutyric acid (GABA) release from rat hippocampal nerve terminals (synaptosomes). The acute application of BDNF (30-100 ng/ml) enhanced the K+-evoked [3H]glutamate release. This effect involved tyrosine-kinase B (TrkB) receptor phosphorylation and Ca2+ entry into synaptosomes through voltage-sensitive calcium channels, since it was abolished by K252a (200 nM), which prevents TrkB-mediated phosphorylation, and by CdCl2 (0.2 mM), a blocker of voltage-sensitive calcium channels. In contrast, BDNF (3-100 ng/ml) inhibited K+-evoked [3H]GABA release from hippocampal synaptosomes. This action was also mediated by phosphorylation of the TrkB receptor, but was independent of Ca2+ entry into synaptosomes through voltage-sensitive calcium channels. Blockade of transport of GABA with SKF 89976a (20 microM) prevented the inhibitory action of BDNF upon GABA release, indicating that BDNF influences the activity of GABA transporters. It is concluded that BDNF influences in an opposite way, through distinct mechanisms, the release of glutamate and the release of GABA from hippocampal synaptosomes.

The electroclinical-imagiological spectrum and long-term outcome of transient periictal MRI abnormalities

The electroclinical-imagiological spectrum and long-term outcome of transient periictal MRI abnormalities (TPMA) remains largely unclear. This prompted us to perform a prospective observational cohort study, including electroencephalography (EEG) and multi-sequence MRI, in 19 consecutive patients (8 female, mean age 51.7 years) with TPMA induced by convulsive and non-convulsive status epilepticus (n=14) or isolated seizures. TPMA were associated with focal, lateralized or diffuse EEG abnormalities, and were mostly focal unilateral and cortico-subcortical (n=11), less frequently cortically restricted, bilateral, hemispheric and with remote lesions (pulvinar, cerebellum); 66.7% had cortico-pial contrast enhancement and 93.7% restriction on diffusion-weighted imaging, with cortical cytotoxic edema on apparent-diffusion coefficient, only tumor-like TPMA (n=5) presenting noticeable subcortical vasogenic edema. The heterogeneity of clinical, EEG and MRI findings contributed to a 38.6% strict focal topographic concordance between them, with the more widespread findings also attributable to the time lag between studies, seizure dynamics/etiologies and cerebral reserve. At follow-up (mean duration 29.6 months, 3-120), the brain damage induced by TPMA was responsible for a high incidence of clinical and MRI sequelae (63.2%), only tumor-like/small TPMA induced by acute symptomatic seizures presenting good clinical outcomes. Our findings may contribute to a better definition and comprehension of the TPMA electroclinical-imagiological spectrum, pathophysiology and long-term outcome.

Pathophysiology and Long-Term Outcome of Reversible Tumor-Like Lesions Induced by Presenting Status Epilepticus

Within the spectrum of reversible neuroimaging abnormalities induced by status epilepticus (SE) tumor‐like lesions (TLL) have been rarely described. Their etiology, pathophysiology, and long‐term outcome remain uncertain. These issues could be clarified by long‐term magnetic resonance imaging (MRI) studies in TLL induced by presenting SE.

The electroclinical spectrum, etiologies, treatment and outcome of nonconvulsive status epilepticus in the elderly

BACKGROUND Nonconvulsive status epilepticus (NCSE) in the elderly is particularly difficult to diagnose, mainly due to subtle clinical manifestations and associated comorbidities. The recently validated electroencephalography (EEG) diagnostic criteria for NCSE and the proposed operational classification of status epilepticus provide tools that can allow an earlier diagnosis and better management of NCSE in this age group, possibly contributing to reduce its high mortality. MATERIAL AND METHODS we used these tools to identify and characterize a cohort of elderly (>60year-old) patients admitted at our institution in a 3-year period; the video-EEG and clinical files of the patients fulfilling EEG diagnostic criteria for NCSE were reviewed, being in this study described their electroclinical spectrum, etiologies, treatment, inhospital mortality, and status epilepticus severity score (STESS). RESULTS Fourty patients (23 women; mean age 76.6years) were identified. Although dyscognitive NCSE associated with >2.5Hz of epileptiform discharges (ED) was the most frequent electroclinical phenotype, this was quite heterogeneous, ranging from patients with aura continua to patients in coma, associated with frequent ED or rhythmic slow activities. Acute symptomatic (45%) and multifactorial (27.5%) etiologies were the most common, and associated with the worst prognosis. There was a trend to use newer antiepileptic drugs in the early steps of NCSE treatment. The inhospital mortality was high (22.5%) and predicted by STESS scores ≥3. CONCLUSION In the elderly, NCSE has heterogeneous electroclinical phenotypes and etiologies. In spite of the treatment limitations conditioned by the comorbidities, more aggressive treatments could be justified to reduce mortality in patients with high STESS scores.

N170 asymmetry as an index of inferior occipital dysfunction in patients with symptomatic occipital lobe epilepsy

OBJECTIVE Localizing epileptic foci in posterior brain epilepsy remains a difficult exercise in surgery for epilepsy evaluation. Neither clinical manifestations, neurological, EEG nor neuropsychological evaluations provide strong information about the area of onset, and fast spread of paroxysms often produces mixed features of occipital, temporal and parietal symptoms. We investigated the usefulness of the N170 event-related potential to map epileptic activity in these patients. METHODS A group of seven patients with symptomatic posterior cortex epilepsy were submitted to a high-resolution EEG (78 electrodes), with recordings of interictal spikes and face-evoked N170. Generators of spikes and N170 were localized by source analysis. Range of normal N170 asymmetry was determined in 30 healthy volunteers. RESULTS In 3 out of 7 patients the N170 inter-hemispheric asymmetry was outside control values. Those were the patients whose spike sources were nearest (within 3cm) to the fusiform gyrus, while foci further away did not affect the N170 ratio. CONCLUSIONS N170 event-related potential provides useful information about focal cortical dysfunction produced by epileptic foci located in the close neighborhood of the fusiform gyrus, but are unaffected by foci further away. SIGNIFICANCE The N170 evoked by faces can improve the epileptic foci localization in posterior brain epilepsy.

MRI Abnormalities Induced by Seizures

When computed tomography started to be used routinely in the evaluation of patients presenting with seizures it became evident that some periictal abnormalities disappeared in follow-up studies with no specific treatment except antiepileptics. These findings suggested that those reversible abnormalities were not structural but functional, possibly resulting from the cerebral edema induced by seizure activity (Goulatia et al. 1987; Sammaritano et al., 1985; Sethi et al., 1985). With the advent of MRI and it’s increasingly use in the acute phase of seizures, these seizureinduced abnormalities were also demonstrated, being described as periictal or reversible MRI abnormalities (Cole 2004; Briellmann et al., 2005); since follow-up MRI studies disclosed that irreversible brain damage can occur in the regions previously affected by them, they are now better defined as transient periictal MRI abnormalities (TPMA). In this way, TPMA should only be considered if two conditions are fulfilled: first, the brain MRI signal abnormalities demonstrated periictally must be attributable to seizures and not other causes; and second, that these abnormalities totally or partially reverse on subsequent MRI studies. Besides the detection of TPMA, MRI can provide us with a unique non-invasive diagnostic tool to better understand the physiopathological mechanisms underlying TPMA formation, and to identify and predict the brain damage induced by seizures. In this chapter, we review the neuroimaging features, differential diagnosis, pathophysiology, electroclinical-imagiological spectrum and outcome of TPMA, highlighting the fundamental role of multi-sequence MRI studies in their investigation.