Neurocognitive profile in patients with idiopathic generalized epilepsies: Differences between patients, their biological siblings, and healthy controls.

BACKGROUND: Idiopathic generalized epilepsy (IGE) is one of the most common epilepsies and is believed to have a strong genetic origin. Patients with IGE present largely heterogeneous neurocognitive profiles and might show some neurocognitive impairments. Furthermore, IGE siblings may demonstrate worse results in neuropsychological tests as well. In our study, we aimed to map the neurocognitive profile both in patients with IGE and the siblings. We also sought to establish a neurocognitive profile for each IGE syndrome. METHODS: The research sample included 110 subjects (IGE n = 46, biological siblings BS n = 16, and healthy controls n = 48) examined. Subjects were neuropsychologically examined in domains of intelligence, attention, memory, executive, and motor functions. The data obtained from the examination were statistically processed to determine whether and how IGE patients (including distinct syndromes) and the siblings differed neurocognitively from healthy controls (adjusted z-scores by age, education, and gender, and composite z-scores of cognitive domains). Data on anti-seizure medication, including defined daily doses, were obtained and included in the analysis. RESULTS: IGE patients and their biological siblings performed significantly worse in most of the neuropsychological tests than healthy controls. The neurocognitive profile of composite z-scores showed that IGE and biological siblings had equally significantly impaired performance in executive functions. IGE group also demonstrated impaired composite attention and motor function scores. The profile of individual IGE syndromes showed that JAE, JME, and EGTCS had significantly worse performance in composite execution score and motor function score. JAE presented significantly worse performance in intelligence and attention. JME exhibited significantly worse composite score in the attention domain. Anti-seizure medication, depression, and quality of life were unrelated to cognitive performance in IGE group. The level of depression significantly predicted the overall value of quality of life in patients with IGE, while cognitive domains, sociodemographic, and clinical factors were unrelated. CONCLUSION: Our study highlights the importance to consider the neurocognitive profile of IGE patients that can lead to difficulties in their education, acceptance, and management of coping strategies. Cognitive difficulties of IGE siblings could support a hypothesis that these impairments emerge from heritable traits.

Interpretable functional specialization emerges in deep convolutional networks trained on brain signals.

Objective.Functional specialization is fundamental to neural information processing. Here, we study whether and how functional specialization emerges in artificial deep convolutional neural networks (CNNs) during a brain-computer interfacing (BCI) task.Approach.We trained CNNs to predict hand movement speed from intracranial electroencephalography (iEEG) and delineated how units across the different CNN hidden layers learned to represent the iEEG signal.Main results.We show that distinct, functionally interpretable neural populations emerged as a result of the training process. While some units became sensitive to either iEEG amplitude or phase, others showed bimodal behavior with significant sensitivity to both features. Pruning of highly sensitive units resulted in a steep drop of decoding accuracy not observed for pruning of less sensitive units, highlighting the functional relevance of the amplitude- and phase-specialized populations.Significance.We anticipate that emergent functional specialization as uncovered here will become a key concept in research towards interpretable deep learning for neuroscience and BCI applications.

Soluble vascular endothelial growth factor receptor-1 is reduced in patients with resistant hypertension after renal denervation.

Renal denervation (RDN) has been shown in several studies to reduce blood pressure (BP) in patients with resistant hypertension (RH). Data on potential biomarkers associated with BP changes remain scarce. We evaluated whether soluble vascular endothelial growth factor receptor (sVEGFR-1) is affected by the procedure. A total of 57 patients with RH participated in this study. BP and heart rate were recorded at baseline and at 3 months follow-up, at which time blood samples were collected to determine the levels of sVEGFR-1, VEGF-A, VEGF-C, nitric oxide (NO), soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1. None of the biomarkers had a predictive value that could identify responders vs non-responders to RDN. However, sVEGFR-1 concentration was dramatically reduced after RDN (5913±385 vs 280±57 pg ml-1, P<0.001). At the same time VEGF-A levels were significantly increased (10.0±3.0 vs 55.5±7.9 pg ml-1, P<0.001), without significant changes in VEGF-C. NO levels were significantly increased after RDN in the whole group (82.6±6.2 vs 106.9±7.8 µM, P=0.021). Interestingly, the elevation in NO levels at 3 months was only seen in patients who demonstrated a reduction in systolic BP of ⩾10 mm Hg (78.9±8.3 vs 111.6±11.7 µM, P=0.018). We report a significant reduction in sVEGFR-1 levels after RDN procedure, which was accompanied by a significant increase in VEGF-A concentration as well as NO. Changes in plasma cytokines were not quantitatively linked to magnitude of BP reduction. An RDN-induced reduction in sVEGFR-1 plasma levels and increase in VEGF-A would raise the VEGF-A/sVEGFR-1 ratio, thereby increasing VEGF-A bioavailability to act on its full-length receptor and may contribute to the BP-lowering effect potentially via NO-mediated pathways.

The relationships between quantitative MR parameters in hippocampus in healthy subjects and patients with temporal lobe epilepsy.

We introduce a new magnetic resonance (MR) method based on a pixel-by-pixel image processing to examine relationships between metabolic and structural processes in the pathologic hippocampus. The method was tested for lateralization of the epileptogenic zone in patients with temporal lobe epilepsy (TLE). Twenty patients with drug-resistant TLE and fifteen healthy controls were examined at 3T. The measurement protocol contained T2-weighted MR images, spectroscopic imaging, diffusion tensor imaging and T2 relaxometry. Correlations between quantitative MR parameters were calculated on a pixel-by-pixel basis using the CORIMA program which enables automated pixel identification in the normal tissue according to control data. All MR parameters changed in the anteroposterior direction in the hippocampus and correlation patterns and their slopes differed between patients and controls. Combinations of T2 relaxation times with metabolite values represent the best biomarkers of the epileptogenic zone. Correlations with mean diffusivity did not provide sufficiently accurate results due to diffusion image distortions. Quantitative MR analysis non-invasively provides a detailed description of hippocampal pathology and may represent complementary tool to the standard clinical protocol. However, the automated processing should be carefully monitored in order to avoid possible errors caused by MR artifacts.

Genetic detection of Dobrava-Belgrade hantavirus in the edible dormouse (Glis glis) in central Serbia.

Hantaviruses are endemic in the Balkans, particularly in Serbia, where sporadic cases and/or outbreaks of hantaviral human disease have been reported repeatedly, and evidenced serologically. Here, we present genetic detection of Dobrava-Belgrade virus (DOBV) hantaviral sequences in wild rodents trapped in central Serbia. All the animals were pre-screened serologically by indirect immunofluorescence (IF) test and only those with a positive finding of hantaviral antigens were further tested by polymerase chain reaction. Of the total of 104 trapped animals, 20 were found to be IF positive and of those three were positive for hantaviral RNA: one Microtus arvalis for Tula virus, and one each of Apodemus agrarius and Glis glis for DOBV. Phylogenetic analysis of the obtained sequences implies putative DOBV spillover infection of A. agrarius and G. glis from Apodemus flavicollis. However, future investigations should help to identify the most common natural host and geographical distribution of DOBV in its reservoir hosts in Serbia.

The diffusion parameters of the extracellular space are altered in focal cortical dysplasias.

Most hypotheses concerning the mechanisms underlying seizure activity in focal cortical dysplasia (FCD) are based on alterations in synaptic transmission and glial dysfunction. However, neurons may also communicate by extrasynaptic transmission, which was recently found to affect epileptiform activity under experimental conditions and which is mediated by the diffusion of neuroactive substances in the extracellular space (ECS). The ECS diffusion parameters were therefore determined using the real-time iontophoretic method in human neocortical tissue samples obtained from surgically treated epileptic patients. The obtained values of the extracellular space volume fraction and tortuosity were then correlated with the histologicaly assessed type of cortical malformation (FCD type I or II). While the extracellular volume remained unchanged (FCD I) or larger (FCD II) than in normal/control tissue, tortuosity was significantly increased in both types of dysplasia, indicating the presence of additional diffusion barriers and compromised diffusion, which might be another factor contributing to the epileptogenicity of FCD.

Densities of parvalbumin-immunoreactive neurons in non-malformed hippocampal sclerosis-temporal neocortex and in cortical dysplasias.

The changes in density of inhibitory parvalbumin-immunoreactive interneurons were quantitatively studied by immunohistochemistry in a series of human neocortical samples comprising the spectrum of malformations of cortical development (MCD) encountered in epilepsy surgery and the non-malformed hippocampal sclerosis-temporal neocortex in patients with refractory temporal lobe epilepsy. The highest relative density of parvalbumin-immunoreactive cells was obtained in the control samples (n = 21). The number of parvalbumin-immunoreactive neurons was significantly decreased in non-malformed hippocampal sclerosis-temporal neocortex (n = 73, 80.5% of control values). In a proportion of the latter samples as well as in two controls we observed patchy regions of absence of parvalbumin staining. The total counts of parvalbumin-immunoreactive cells in all the categories of MCD - "mild MCD" (n = 25), focal cortical dysplasia type I (n = 19) and type II (n = 15) - were decreased representing 72.4%, 55.0% and 12.2% of control values, respectively. Significantly different parvalbumin-immunoreactive cell densities were demonstrated between the focal cortical dysplasia types IIA and IIB. In "mild MCD", we observed a more pronounced decrease of parvalbumin-immunoreactive cells in the infragranular layers. No significant differences were revealed between the temporal and extratemporal examples of analogous MCD types. This study provides evidence for reduction of inhibitory parvalbumin-immunoreactive interneurons in the epileptic neocortex affected by MCD as well as in morphologically unaffected epileptic temporal neocortex, thus representing a possible mechanism for their epileptogenicity.

Comparison of different methods of time shift measurement in EEG.

Digital signal processing techniques are often used for measurement of small time shifts between EEG signals. In our work we tested properties of linear cross-correlation and phase/coherence method. The last mentioned method was used in two versions. The first version used fast Fourier transform (FFT) algorithm and the second was based on autoregressive modeling with fixed or adaptive model order. Methods were compared on several testing signals mimicking real EEG signals. The accuracy index for each method was computed. Results showed that for long signal segments all methods bring comparably good results. Accuracy of FFT phase/coherence method significantly decreased when very short segments were used and also decreased with an increasing level of the additive noise. The best results were obtained with autoregressive version of phase/coherence. This method is more reliable and may be used with high accuracy even in very short signals segments and it is also resistant to additive noise.

Cyclosporine-related neurotoxicity in a patient after bilateral lung transplantation for cystic fibrosis.

Cyclosporine (CsA) is a widely used immunosuppressant following solid organ transplantation. CsA administration is associated with a number of systemic complications, including neurotoxicity. A 33-year-old man with cystic fibrosis, who underwent bilateral lung transplantation, presented with severe neurotoxic symptoms leading to coma in association with CsA administration combined with high doses of methylprednisolone for treatment of an acute rejection episode. After discontinuation of CsA, a quick resolution of his clinical status was observed, as well as of the pathological findings on magnetic resonance imaging (MRI). CsA was replaced with tacrolimus leading to an uneventful course.

[Microscopic disorders of cortical development of the brain and its etiopathogenic importance for detection in patients with temporal epilepsy associated with hippocampal sclerosis]. / Mikroskopické poruchy kortikálního vývoje mozku a etiopatogenetický význam jejich detekce u pacientu s temporální epilepsií pri skleróze hipokampu.

Hippocampal sclerosis represents a common structural basis of temporal lobe epilepsy. However, the etiological factors and mechanisms leading to its development still remain unexplained. In our study, we present neuropathological findings in the resected hippocampus and the pole of the temporal lobe in 15 patients with hippocampal sclerosis. "Initial precipitating injuries" that are thought to cause the development of hippocampal sclerosis (febrile seizures in early childhood, head injury or meningoencephalitis) were present in the history of 12 patients. In the remaining 3 cases, no predisposing factors were found. Attention was paid to the histopathological identification of disturbed neuronal migration and differentiation in the temporal lobe. These defects were observed in 7 cases; in three of these, no predisposing factors were stated in the patients' histories. We suggest that in these cases, hippocampal sclerosis arises due to previously undetected disorders of cortical development. A latent neocortical malformation may also contribute to the development of hippocampal sclerosis in patients with an initial precipitating injury in anamnensis. Histopathological examination of resected epileptic brain tissue can provide insights into the individual pathogenesis of epileptic disorders, especially by the detection of microscopic disorders of cortical development.

Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries.

A recent United Kingdom cost minimization analysis (CMA) of four antiepileptic drugs (AEDs) used to treat newly diagnosed adult epilepsy demonstrated that a new drug, lamotrigine (LTG), incurred higher costs than carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), whose costs were similar. This analysis took account of each drug's side-effect and tolerability profile. The present analysis investigated the costs of treatment with LTG, CBZ, PHT, and VPA in 12 European countries. Data were derived from published sources and from a panel of locally based experts. When no published data were available, estimates were obtained using expert opinion by a consensus method. These data were incorporated into a treatment pathway model, which considered the treatment of patients during the first 12 months after diagnosis. The primary outcome considered was seizure freedom. Randomized controlled trials demonstrate that the drugs considered are equally effective in terms of their ability to achieve seizure freedom, and thus the most appropriate form of economic evaluation is a CMA. These trials provided data on the incidence of side effects, dosages, and retention rates. The economic perspective taken was that of society as a whole and the analysis was calculated on an "intent-to-treat" basis. Only direct medical costs were considered. In each country considered, LTG was twofold to threefold more expensive than the other drugs considered. A sensitivity analysis demonstrated that varying each of the assumptions (range defined by expert panels) did not significantly alter the results obtained.

[The nocturnal eating syndrome (2 case reports and polysomnography)]. / Syndrom nocního ujídání (dve kazuistiky a polysomnografie).

The nocturnal eating syndrome (NES) is a nocturnal sleep disorder caused by repeated awakening and the inability to fall a sleep again unless the patient ingests some food or drinks something. In children the NES is frequent, in adults rather rare and may be associated with various pathological conditions. The latter include in particular somnabulism, periodic movements of the lower extremities, narcolepsy, chronic triazolam intoxication, probably anorexia nervosa, and other eating disorders. The authors submit two case-histories of middle aged women (30 and 37 years old) without disturbances of the day-time eating behaviour, without obvious psychopathology where the symptomatology of NES developed slowly from the age of 14 and 25 years resp. Both patients ate at night small amounts of easily consumed foods which they went to fetch in the kitchen as often as five times per night. Their behaviour was calm and aimed. Usually they did not remember the nocturnal eating. Polysomnographic examination in both patients revealed poor sleep with frequent changes of the sleep stages, with frequent awakenings, in both patients incl. even awakening from deep NREM sleep. The authors conclude that in these two patients NES with somnabulism is involved.