Seizure prediction and control in epilepsy

The first part of my thesis presents an overview of the different approaches used in the past two decades in the attempt to forecast epileptic seizure on the basis of intracranial and scalp EEG. Past research could reveal some value of linear and nonlinear algorithms to detect EEG features changing over different phases of the epileptic cycle. However, their exact value for seizure prediction, in terms of sensitivity and specificity, is still discussed and has to be evaluated. In particular, the monitored EEG features may fluctuate with the vigilance state and lead to false alarms. Recently, such a dependency on vigilance states has been reported for some seizure prediction methods, suggesting a reduced reliability. An additional factor limiting application and validation of most seizure-prediction techniques is their computational load. For the first time, the reliability of permutation entropy [PE] was verified in seizure prediction on scalp EEG data, contemporarily controlling for its dependency on different vigilance states. PE was recently introduced as an extremely fast and robust complexity measure for chaotic time series and thus suitable for online application even in portable systems. The capability of PE to distinguish between preictal and interictal state has been demonstrated using Receiver Operating Characteristics (ROC) analysis. Correlation analysis was used to assess dependency of PE on vigilance states. Scalp EEG-Data from two right temporal epileptic lobe (RTLE) patients and from one patient with right frontal lobe epilepsy were analysed. The last patient was included only in the correlation analysis, since no datasets including seizures have been available for him. The ROC analysis showed a good separability of interictal and preictal phases for both RTLE patients, suggesting that PE could be sensitive to EEG modifications, not visible on visual inspection, that might occur well in advance respect to the EEG and clinical onset of seizures. However, the simultaneous assessment of the changes in vigilance showed that: a) all seizures occurred in association with the transition of vigilance states; b) PE was sensitive in detecting different vigilance states, independently of seizure occurrences. Due to the limitations of the datasets, these results cannot rule out the capability of PE to detect preictal states. However, the good separability between pre- and interictal phases might depend exclusively on the coincidence of epileptic seizure onset with a transition from a state of low vigilance to a state of increased vigilance. The finding of a dependency of PE on vigilance state is an original finding, not reported in literature, and suggesting the possibility to classify vigilance states by means of PE in an authomatic and objectic way. The second part of my thesis provides the description of a novel behavioral task based on motor imagery skills, firstly introduced (Bruzzo et al. 2007), in order to study mental simulation of biological and non-biological movement in paranoid schizophrenics (PS). Immediately after the presentation of a real movement, participants had to imagine or re-enact the very same movement. By key release and key press respectively, participants had to indicate when they started and ended the mental simulation or the re-enactment, making it feasible to measure the duration of the simulated or re-enacted movements. The proportional error between duration of the re-enacted/simulated movement and the template movement were compared between different conditions, as well as between PS and healthy subjects. Results revealed a double dissociation between the mechanisms of mental simulation involved in biological and non-biologial movement simulation. While for PS were found large errors for simulation of biological movements, while being more acurate than healthy subjects during simulation of non-biological movements. Healthy subjects showed the opposite relationship, making errors during simulation of non-biological movements, but being most accurate during simulation of non-biological movements. However, the good timing precision during re-enactment of the movements in all conditions and in both groups of participants suggests that perception, memory and attention, as well as motor control processes were not affected. Based upon a long history of literature reporting the existence of psychotic episodes in epileptic patients, a longitudinal study, using a slightly modified behavioral paradigm, was carried out with two RTLE patients, one patient with idiopathic generalized epilepsy and one patient with extratemporal lobe epilepsy. Results provide strong evidence for a possibility to predict upcoming seizures in RTLE patients behaviorally. In the last part of the thesis it has been validated a behavioural strategy based on neurobiofeedback training, to voluntarily control seizures and to reduce there frequency. Three epileptic patients were included in this study. The biofeedback was based on monitoring of slow cortical potentials (SCPs) extracted online from scalp EEG. Patients were trained to produce positive shifts of SCPs. After a training phase patients were monitored for 6 months in order to validate the ability of the learned strategy to reduce seizure frequency. Two of the three refractory epileptic patients recruited for this study showed improvements in self-management and reduction of ictal episodes, even six months after the last training session.

Applicazione della neurodiagnostica avanzata allo studio dei disturbi psicologici nelle malattie infiammatorie croniche intestinali

Background and aim Ulcerative Colitis (UC) and Crohn’s Disease (CD), collectively labelled as inflammatory bowel disease (IBD), are idiopathic, chronic inflammatory disorder of the bowel with a remitting and relapsing course. IBD are associated to poor emotional functioning and psychological distress. We have investigated the brain involvement in patients with IBD using functional magnetic resonance imaging (fMRI). Materials and methods We developed an emotional visual task to investigate the emotional functioning in 10 UC patients and 10 healthy controls (HC). Furthermore, we have compared the brain stress response between a group of 20 CD patients and a group of 18 HC. Finally, we evaluated potential morphological differences between 18 CD patients and 18 HC in a voxel based morphometry (VBM) study. Results We found brain functional changes in UC patients characterized by decreased activity in the amygdala in response to positive emotional stimuli. Moreover, in CD patients, the brain stress response and habituation to stressful stimuli were significantly different in the medial temporal lobe (including the amygdala and hippocampus), the insula and cerebellum. Finally, in CD patients there were morphological abnormalities in the anterior mid cingulated cortex (aMCC). Conclusion IBD are associated to functional and morphological brain abnormalities. The previous intestinal inflammatory activity in IBD patients might have contributed to determine the functional and morphological changes we found. On the other hand, the dysfunctions of the brain structures we found may influence the course of the disease. Our findings might have clinical implications. The differences in the emotional processing may play a role in the development of psychological disorders in UC patients. Furthermore, in CD patients, the different habituation to stress might contribute to stress related inflammatory exacerbations. Finally, the structural changes in the aMCC might be involved in the pain symptoms associated to the bowel disorder.

Distacco di retina e lavoro manuale: utilizzo delle schede di dimissione ospedaliera per uno studio di incidenza

Introduzione. La movimentazione manuale di carichi è stata recentemente proposta come un possibile determinante del distacco di retina. Al fine di confortare quest’ipotesi, sono stati analizzati i tassi di incidenza di distacco di retina regmatogeno (DRR) idiopatico, trattato chirurgicamente, tra i residenti in Toscana addetti ad attività lavorative manuali, non manuali e casalinghe. Metodi. Le schede di dimissione ospedaliera (SDO) della Toscana contengono anche informazioni codificate sulla categoria generica di impiego. Sono stati utilizzati i dati di tutti i pazienti residenti in Toscana con una SDO emessa da un qualsiasi ospedale italiano nel periodo 1997-2009, con diagnosi principale di DRR (ICD-9: 361,0-361,07 e 361,9) e con DRG 36 (“interventi sulla retina”). Dopo l’eliminazione dei soggetti che non soddisfacevano i criteri di eligibilità, è stato deciso di restringere la popolazione in studio ai soggetti di età 25-59 anni, successivamente classificati in addetti ad attività lavorative manuali, non manuali o casalinghe. Risultati. Sono stati identificati 1.946 casi. Tra gli uomini, gli addetti ad attività lavorative manuali hanno riportato un tasso di incidenza standardizzato per età 1,8 volte più alto rispetto agli addetti ad attività lavorative non manuali (17,4 [IC95%, 16,1–18,7] vs. 9,8 [IC95%, 8,8–10,8]). Tra le donne, i tassi di incidenza standardizzati per età erano 1,9 volte più alti negli addetti ad attività lavorative manuali (11,1 [IC95%, 9,8–12,3]) e 1,7 volte più alti nelle casalinghe (9,5 [IC95%, 8,3–10,8]) rispetto agli addetti ad attività lavorative non manuali (5,7 [IC95%, 4,8–6,6]). Conclusioni. Lo studio mette in evidenza come gli addetti ad attività lavorative manuali siano maggiormente affetti da DRR idiopatico rispetto agli addetti ad attività lavorative non manuali. Questi risultati supportano l’ipotesi che la movimentazione manuale di carichi, che difficilmente può ritrovarsi come compito di attività lavorative non manuali, possa avere un ruolo causale nella genesi della patologia.

Caratterizzazione clinica, eziopatogenetica e ricerca di marker diagnostici nella poliradicoloneurite acuta idiopatica del cane

La poliradicoloneurite acuta idiopatica (ACIP) è una patologia infiammatoria che interessa le radici di più nervi spinali, descritta soprattutto nel cane, più raramente nel gatto, caratterizzata da insorgenza acuta di paresi/paralisi flaccida. L’ACIP mostra notevoli similitudini con la sindrome di Guillan-Barrè dell’uomo (GBS), in cui la patogenesi è su base autoimmunitaria ed è stata correlata con la presenza di alcuni fattori scatenanti (trigger). Lo scopo di questo lavoro è stato quello di caratterizzare l’ACIP in 26 cani, descrivendone la sintomatologia, l’evoluzione clinica, i risultati degli esami diagnostici. La diagnosi si è basata sui riscontri dell’anamnesi, della visita neurologica e del decorso confermata, quando possibile, dai rilievi elettrodiagnostici. Su tutti i cani è stata valutata l’esposizione a specifici agenti infettivi (Toxoplasma gondii, Neospora canunim, Ehrlichia canis, Leishmania infantum), o altri fattori (come vaccinazioni) che potrebbero aver agito da “trigger” per l’instaurarsi della patologia; sull’intera popolazione e su 19 cani non neurologici (gruppo di controllo), si è proceduto alla ricerca degli anticorpi anti-gangliosidi. La sintomatologia di più frequente riscontro (25/26) ha coinvolto la funzione motoria (paresi/plegia) con prevalente interessamento dei 4 arti (24/25) . Sei cani hanno ricevuto una terapia farmacologica, che non ne ha influenzato il decorso, favorevole in 24/26 casi. In 9 pazienti è stata rilevata una precedente esposizione a potenziali trigger; in 10 casi si è riscontrato un titolo anticorpale positivo ad almeno un agente infettivo testato. In 17/26 cani si è ottenuto un titolo anticorpale anti-GM2 e anti-GA1; nella popolazione di controllo solo un caso è risultato positivo. Questi risultati hanno contribuito a consolidare le conoscenze di questa patologia, validando l’utilità della ricerca anticorpale anti-gangliosidica per la diagnosi di ACIP e facendo intravedere la possibilità che l’ACIP possa essere assimilate alla GBS anche dal punto di vista patogenetico, per la quale potrebbe essere considerata come modello animale spontaneo.

Hypertension, hypercholesterolemia, hyperaldosteronism: a genetic perspective for personalized therapy.

Essential, primary, or idiopathic hypertension is defined as high BP in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, hyperaldosteronism, or other causes of secondary hypertension are not present. Essential hypertension accounts for 80-90% of all cases of hypertension; it is a heterogeneous disorder, with different patients having different causal factors that may lead to high BP. Life-style, diet, race, physical activity, smoke, cultural level, environmental factors, age, sex and genetic characteristics play a key role in the increasing risk. Conversely to the essential hypertension, secondary hypertension is often associated with the presence of other pathological conditions such as dyslipidaemia, hypercholesterolemia, diabetes mellitus, obesity and primary aldosteronism. Amongst them, primary aldosteronism represents one of the most common cause of secondary hypertension, with a prevalence of 5-15% depending on the severity of blood pressure. Besides high blood pressure values, a principal feature of primary aldosteronism is the hypersecretion of mineralcorticoid hormone, aldosterone, in a manner that is fairly autonomous of the renin-angiotensin system. Primary aldosteronism is a heterogeneous pathology that may be divided essentially in two groups, idiopathic and familial form. Despite all this knowledge, there are so many hypertensive cases that cannot be explained. These individuals apparently seem to be healthy, but they have a great risk to develop CVD. The lack of known risk factors makes difficult their classification in a scale of risk. Over the last three decades a good help has been given by the pharmacogenetics/pharmacogenomics, a new area of the traditional pharmacology that try to explain and find correlations between genetic variation, (rare variations, SNPs, mutations), and the risk to develop a particular disease.