In the context of focal and drug-resistant epilepsy, surgical resection of the epileptogenic zone may be the only therapeutic option for reducing or suppressing seizures. In many such patients, ...intracranial stereo-EEG recordings remain the gold standard for the epilepsy surgery work-up. Assessing the extent of the epileptogenic zone and its organisation is a crucial objective, and requires advanced methods of signal processing. Over the last ten years, considerable efforts have been made to develop signal analysis techniques for characterising the connectivity between spatially distributed regions.
The aim of this study was to evaluate the changes in dynamic connectivity pattern under inter-ictal, pre-ictal and ictal conditions using signals derived from stereo-EEG recordings of 10 patients with Taylor-type focal cortical dysplasia. A causal linear multivariate method – partial directed coherence – and indices derived from graph theory were used to characterise the synchronisation property of the lesional zone (corresponding to the epileptogenic zone in our patients) and to distinguish it from other regions involved in ictal activity or not.
The results show that a significantly different connectivity pattern (mainly in the gamma band) distinguishes the epileptogenic zone from other cortical regions not only during the ictal event, but also during the inter- and pre-ictal periods. This indicates that the lesional nodes play a leading role in generating and propagating ictal EEG activity by acting as the hubs of the epileptic network originating and sustaining seizures. Our findings also indicate that the cortical regions beyond the dysplasia involved in the ictal activity essentially act as “secondary” generators of synchronous activity. The leading role of the lesional zone may account for the good post-surgical outcome of patients with type II focal cortical dysplasia as resecting the dysplasia removes the epileptogenic zone responsible for seizure organisation. Furthermore, our findings strongly suggest that advanced signal processing techniques aimed at studying synchronisation and characterising brain networks could substantially improve the pre-surgical evaluation of patients with focal epilepsy, even in cases without an associated anatomically detectable lesion.
►Type-II focal cortical dysplasia is a model of drug-resistant epilepsy. ►PDC and graph indexes are appropriate tools to localise the epileptogenic zone. ►The lesional nodes play a leading role in the epileptogenic network. ►An abnormal connectivity characterises the inter-ictal activity of the lesional leads. ►Cortical regions outside dysplasia act as secondary sources of synchronous activity.
Sialidoses Franceschetti, Silvana; Canafoglia, Laura
Epileptic disorders,
September 2016, Letnik:
18, Številka:
s2
Journal Article
Recenzirano
Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with infantile onset, has a more ...severe phenotype characterized by coarse facial features, hepatomegaly, dysostosis multiplex, and developmental delay while patients with the late and milder type, known as “cherry red spot‐myoclonus syndrome” develop myoclonic epilepsy, visual impairment and ataxia in the second or third decade of life. The diagnosis is usually suggested by increased urinary bound sialic acid excretion. We recently described genetically diagnosed patients with a specially mild phenotype, no retinal abnormalities and normal urinary sialic acid. This observation suggests that genetic analysis or the demonstration of the neuraminidase enzyme deficiency in cultured fibroblasts are needed to detect and diagnose mildest phenotypes.
Highlights • Effective EEG connectivity was evaluated, using partial directed coherence (PDC), in childhood absence epilepsy (CAE) patients and controls. • Compared to controls, CAE patients showed ...increased interictal connectivity in the delta, theta and alpha bands. • In CAE, frontal and central EEG electrodes acted as sources of an abnormal information flow, mostly directed to posterior areas.
Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Mutations causing FHM type 3 have been identified in SCN1A , the gene encoding the Na ᵥ1.1 Na ⁺ channel, which is also a ...major target of epileptogenic mutations and is particularly important for the excitability of GABAergic neurons. However, functional studies of Na V1.1 FHM mutations have generated controversial results. In particular, it has been shown that the Na V1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to Na V1.1 mutants that cause severe epilepsy, but we have observed gain-of-function effects for other Na V1.1 FHM mutants. Here we show that Na V1.1-L1649Q is nonfunctional because of folding defects that are rescuable by incubation at lower temperatures or coexpression of interacting proteins, and that a partial rescue is sufficient for inducing an overall gain of function because of the modifications in gating properties. Strikingly, when expressed in neurons, the mutant was partially rescued and was a constitutive gain of function. A computational model showed that 35% rescue can be sufficient for inducing gain of function. Interestingly, previously described folding-defective epileptogenic Na V1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of Na V1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.
Anatomical complexity and data dimensionality present major issues when analysing brain connectivity data. The functional and anatomical aspects of the connections taking place in the brain are in ...fact equally relevant and strongly intertwined. However, due to theoretical challenges and computational issues, their relationship is often overlooked in neuroscience and clinical research. In this work, we propose to tackle this problem through Smooth Functional Principal Component Analysis, which enables to perform dimensional reduction and exploration of the variability in functional connectivity maps, complying with the formidably complicated anatomy of the grey matter volume. In particular, we analyse a population that includes controls and subjects affected by schizophrenia, starting from fMRI data acquired at rest and during a task-switching paradigm. For both sessions, we first identify the common modes of variation in the entire population. We hence explore whether the subjects' expressions along these common modes of variation differ between controls and pathological subjects. In each session, we find principal components that are significantly differently expressed in the healthy vs pathological subjects (with p-values < 0.001), highlighting clearly interpretable differences in the connectivity in the two subpopulations. For instance, the second and third principal components for the rest session capture the imbalance between the Default Mode and Executive Networks characterizing schizophrenia patients.
We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and ...2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.
Summary
Purpose
Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' ...phenotype and show reduced γ‐aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS.
Methods
We have studied heterozygous NaV1.1 knock‐out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia‐induced seizures.
Key Findings
In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre‐epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4‐aminopyridine in the epileptic period. During in vivo hyperthermia‐induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase.
Significance
We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches.
Mutations of the voltage gated Na+ channel NaV1.1 (SCN1A) are important causes of different genetic epilepsies and can also cause familial hemiplegic migraine (FHM-III). In previous studies, some ...rescuable epileptogenic folding defective mutants located in domain IV of NaV1.1 have been identified, showing partial loss of function also with maximal rescue. Variable rescue may be one of the causes of phenotypic variability, and rescue might be exploited for therapeutic approaches. Recently, we have identified a folding defective FHM-III NaV1.1 mutant that showed overall gain of function when rescued, consistent with a differential pathomechanism.
Here, we have evaluated functional properties and cell surface expression of six NaV1.1 epileptogenic missense mutations in different rescuing conditions, including a novel one that we have developed expressing a selective sodium channel toxin (CsEI) targeted to the endoplasmic reticulum (ER). All the mutants showed loss of function and reduced cell surface expression, consistently with possibility of rescue. Four of them were rescuable by incubation at low temperature and interactions with different co-expressed proteins or a pharmacological chaperone (phenytoin). Notably, CsEI was able to rescue four mutants. Thus, NaV1.1 folding defective mutants can be relatively common and mutations inducing rescuable folding defects are spread in all NaV1.1 domains. Importantly, epileptogenic mutants showed overall loss of function even upon rescue, differently than FHM-III ones. The effectiveness of CsEI demonstrates that interactions in the ER are sufficient for inducing rescue, and provides a proof of concept for developing possible therapeutic approaches that may overcome some limitations of pharmacological chaperones.
•We studied functional effects of six NaV1.1 epileptogenic missense mutations.•They showed loss of function and reduced surface expression, possibly because of rescuable folding defects.•Four of them were rescuable by low temperature or interactions with proteins or drugs.•We developed a new rescue method which may overcome some limitations of existing ones.•All mutants showed loss of function even upon rescue, differently than migraine ones.
Aims The coronavirus SARS‐CoV‐2 disease (COVID‐19) pandemic affects availability and performance of neurophysiological diagnostic methods, including EEG. Our objective was to outline the current ...situation regarding EEG‐based investigations across Europe.
Methods A web‐based survey was distributed to centres within the European Reference Network on rare and complex epilepsies (ERN EpiCARE). Responses were collected between April 9 and May 15, 2020. Results were analysed with Microsoft Excel, Python Pandas and SciPy.
Results Representants from 47 EpiCARE centres from 22 countries completed the survey. At the time of completing the survey, inpatient video‐EEGs had been stopped or restricted in most centres (61.7% vs. 36.2% for adults, and 38.3% vs. 53.2% for children). Invasive investigations and epilepsy surgery were similarly affected. Acute EEGs continued to be performed, while indications for outpatient EEGs were limited and COVID‐19 triage put in place. The strictness of measures varied according to extent of the outbreak in a given country.
Conclusions The results indicate a profound impact of COVID‐19 on neurophysiological diagnostics, especially inpatient video‐EEGs, invasive investigations, and epilepsy surgery. The COVID‐19 pandemic may hamper care for patients in need of EEG‐based investigations, particularly patients with seizure disorders. ERN EpiCARE will work on recommendations on how to rapidly adapt to such situations in order to alleviate consequences for our patients.
This study presents a brief review of literature exploring simple EEG-polygraphic examinations and procedures that can be carried out at a patient's bedside. These include EEG with a common electrode ...array and sleep evaluation. The review briefly discusses more complex analytical techniques, such as the application of advanced EEG signal processing methods developed by our research group, to define what type of consistent markers are suitable for clinical use or to better understand complex patient conditions. These advanced analytical techniques aim to detect relevant EEG-based markers that could be useful in evaluating patients and predicting outcomes. These data could contribute to future developments in research.
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