Differences in visual information processing style between Idiopathic Generalized Epilepsy with and without photosensitivity.

PURPOSE: Recently, altered visual cortical processes i.e., lack of habituation to visual evoked potentials (VEP), has been highlighted in both photosensitive epilepsy and in a specific i.e., analytic mode of processing visual inputs. In this study we aimed at evaluating the relationship between photosensitivity (PS) and analytic style of processing visual information, in a sample of 30 patients with Idiopathic Generalized Epilepsy (IGE) and matched healthy controls. METHODS: At our Epilepsy unit of the Sapienza University of Rome, we consecutively enrolled 15 patients with IGE with PSand matched them with 15 patients with IGE without PS and 15 Healthy Volunteers. All patients underwent EEG recording in basal conditions during hyperventilation (3 Min), and intermittent light stimulation. The most effective frequencies comprised from 12 to 16 Hz. The instruments used to gather psychological cognitive behavioral data, consisted of participation in two tests: the Sternberg-Wagner Self-Assessment Inventory and the Mariani Learning Style Questionnaire. RESULTS: Compared to controls, both IGE groups show significantly higher scores for the analytic style (One-way ANOVA, F(2,44) = 110.3, p < 0.0001). Epilepsy groups thereby showed very distinctive cognitive styles as measured with the Sternberg test. In the visual style, scores of the photosensitive Individuals with IGE were significantly higher than the non-photosensitive individuals with IGE (p < 0.0001, Tukey's post hoc test). CONCLUSIONS: An association between analytic style of processing visual information and PS in IGE has been shown. The common neurophysiological features between these two factors, suggest the possibility to evaluate this cognitive behavior as a potential target for nonpharmacological therapeutic strategies in photosensitive epilepsy.

Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review.

BACKGROUND: Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients. MATERIAL AND METHODS: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included. RESULTS: Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies. CONCLUSIONS: Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.

Management of epilepsy in brain tumors.

Epilepsy in brain tumors (BTE) may require medical attention for a variety of unique concerns: epileptic seizures, possible serious adverse effects of antineoplastic and antiepileptic drugs (AEDs), physical disability, and/or neurocognitive disturbances correlated to tumor site. Guidelines for the management of tumor-related epilepsies are lacking. Treatment is not standardized, and overall management might differ according to different specialists. The aim of this document was to provide directives on the procedures to be adopted for a correct diagnostic-therapeutic path of the patient with BTE, evaluating indications, risks, and benefits. A board comprising neurologists, epileptologists, neurophysiologists, neuroradiologists, neurosurgeons, neuro-oncologists, neuropsychologists, and patients' representatives was formed. The board converted diagnostic and therapeutic problems into seventeen questions. A literature search was performed in September-October 2017, and a total of 7827 unique records were retrieved, of which 148 constituted the core literature. There is no evidence that histological type or localization of the brain tumor affects the response to an AED. The board recommended to avoid enzyme-inducing antiepileptic drugs because of their interference with antitumoral drugs and consider as first-choice newer generation drugs (among them, levetiracetam, lamotrigine, and topiramate). Valproic acid should also be considered. Both short-term and long-term prophylaxes are not recommended in primary and metastatic brain tumors. Management of seizures in patients with BTE should be multidisciplinary. The panel evidenced conflicting or lacking data regarding the role of EEG, the choice of therapeutic strategy, and timing to withdraw AEDs and recommended high-quality long-term studies to standardize BTE care.

Network characteristics in benign epilepsy with centro-temporal spikes patients indicating defective connectivity during spindle sleep: A partial directed coherence study of EEG signals.

OBJECTIVE: To investigate the changes in EEG connectivity in children with the typical presentation of benign epilepsy with centro-temporal spikes (BECTS). METHODS: We compared awake and spindle-sleep EEG recordings obtained by a standard electrode array in patients with lateralised (10 Right, 9 Left-BECTS) or bilateral spikes (10 MF-BECTS) and in 17 age-matched controls. We analysed EEG activity using partial directed coherence, an estimator of connectivity based on the multivariate autoregressive models and calculated in- and out-degrees, strength, clustering coefficient and betweenness centrality. RESULTS: In comparison with the controls, the awake EEG recordings of the patients with lateralised BECTS showed a minimal increase in out-degrees on F4 and F3. The greater differences, found during sleep, included significant reductions in both in- and out-degrees and strength in all of the patient groups, but in T4 or T3 showing increased out-degrees and strength in Right and Left-BECTS. Betweenness centrality was significantly reduced on C3 and C4 in the patients with MF-BECTS. CONCLUSIONS: Our observations suggest that the main finding in BECTS patients is widely reduced local connectivity. SIGNIFICANCE: The network changes in BECTS can be interpreted as a permissive condition occurring in a developmental window that predisposes to seizure generation during spindle-sleep.

The impact of genetic and experimental studies on classification and therapy of the epilepsies.

Different types of epilepsy are associated with gene mutations, in which seizures can be the only symptom (genetic epilepsies) or be one of the elements of complex clinical pictures that are often progressive over time (epileptic or epileptogenic encephalopathies). In epileptogenic encephalopathies, epileptic seizures and other neurological and cognitive signs are symptoms of genetically determined neuropathological or neurochemical disorders. In epileptic encephalopathies, epileptic activity itself is thought to contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. The distinction is conceptually clear and clinically relevant, as the different categories have a different prognosis in terms of both epilepsy and associated neurological and cognitive picture, but the boundaries are sometimes difficult to define in the clinical practice. Here we review the genetic epilepsies from the clinician perspective. A monogenic inheritance has been defined only in a minority of idiopathic epilepsies making improper to rename genetic the category of idiopathic epilepsies, until the presumptive multigenic mechanism will be demonstrated. A search for gene mutations must be done in any patient with candidate genetic types of epilepsy or epileptic/epileptogenic encephalopathy (e.g. familial forms) to complete the diagnostic process, define the prognosis and optimize the therapy. Advanced methods are available to express the gene variant in experimental model systems and test its effect on the properties of the affected protein, on neuronal excitability and on phenotypes in model organisms, and may help in identifying treatments with compatible action mechanisms. The influence of genetic studies on epilepsy taxonomy is now a matter of discussion: their impact on the international classification of the epilepsies will hopefully be defined soon.

Epileptic headache: A rare form of painful seizure.

PURPOSE: To describe the concept, features and mechanisms of epileptic headache (EH). METHODS: Analysis of all published articles concerning EH and related subjects. RESULTS: There are more than 30 published case studies of patients with headache as the only manifestation of a seizure, a condition that has been variously called "EH", "ictal epileptic headache", "hemicrania epileptica", "cephalic pain seizure". It is necessary to differentiate EH from "migralepsy" and "ictal non-epileptic headache". EH may be an isolated event or the initial phase of a seizure followed by other manifestations. An isolated EH is clinically relevant because it is often symptomatic of structural brain disease; this underlines the importance of a differential diagnosis as the head pain of EH has no specific diagnostic characteristics. The described cases indicate that the location of the foci may vary, thus suggesting the involvement of different parts of the pain network. EH is a "focal aware" seizure, but there are a few reports of cases in which it was associated with generalised epileptiform activity. A correct diagnosis of EH requires an ictal EEG recording showing epilepsy-compatible discharges that coincide with the onset and cessation of the headache. A rapid response to the acute administration of an antiepileptic drug may support the diagnosis. CONCLUSIONS: EH is a particular type of pain seizure that has a complex pathophysiology and, when isolated, requires differential diagnostic consideration. We believe that, although it is not frequent, pain as an ictal symptom should be highlighted in the operational classification of seizure types.

Patterns of care of brain tumor-related epilepsy. A cohort study done in Italian Epilepsy Center.

Epilepsy is the most common comorbidity in patients with brain tumors. STUDY AIMS: To define characteristics of brain tumor-related epilepsy (BTRE) patients and identify patterns of care. Nationwide, multicenter retrospective cohort study. Medical records of BTRE patients seen from 1/1/2010 to 12/31/2011, followed for at least one month were examined. Information included age, sex, tumor type/treatments, epilepsy characteristics, antiepileptic drugs (AEDs). Time to modify first AED due to inefficacy and/or toxicity was assessed with the Kaplan-Meier method and Cox proportional hazard models were used to identify predictors of treatment outcome. Enrolled were 808 patients (447 men, 361 women) from 26 epilepsy centers. Follow-up ranged 1 to 423 months (median 18 months). 732 patients underwent surgery, 483 chemotherapy (CT), 508 radiotherapy. All patients were treated with AEDs. Levetiracetam was the most common drug. 377 patients (46.7%) were still on first drug at end of follow-up, 338 (41.8%) needed treatment modifications (uncontrolled seizures, 229; side effects, 101; poor compliance, 22). Treatment discontinuation for lack of efficacy was associated with younger age, chemotherapy, and center with <20 cases. Treatment discontinuation for side effects was associated with female sex, enzyme-inducing drugs and center with > 20 cases. About one-half of patients with BTRE were on first AED at end of follow-up. Levetiracetam was the most common drug. A non enzyme-inducing AED was followed by a lower risk of drug discontinuation for SE.

Analytic information processing style in epilepsy patients.

Relevant to the study of epileptogenesis is learning processing, given the pivotal role that neuroplasticity assumes in both mechanisms. Recently, evoked potential analyses showed a link between analytic cognitive style and altered neural excitability in both migraine and healthy subjects, regardless of cognitive impairment or psychological disorders. In this study we evaluated analytic/global and visual/auditory perceptual dimensions of cognitive style in patients with epilepsy. Twenty-five cryptogenic temporal lobe epilepsy (TLE) patients matched with 25 idiopathic generalized epilepsy (IGE) sufferers and 25 healthy volunteers were recruited and participated in three cognitive style tests: "Sternberg-Wagner Self-Assessment Inventory", the C. Cornoldi test series called AMOS, and the Mariani Learning style Questionnaire. Our results demonstrate a significant association between analytic cognitive style and both IGE and TLE and respectively a predominant auditory and visual analytic style (ANOVA: p values <0,0001). These findings should encourage further research to investigate information processing style and its neurophysiological correlates in epilepsy.

The complex interrelations between two paroxysmal disorders: headache and epilepsy.

The interrelations between headache/migraine and epileptic seizures are an interesting topic, still lacking a systematization, which is the objective of the present revision. We organize the general setting on: (a) a distinction between pre-ictal, ictal, post-ictal and inter-ictal headaches, assuming "ictal" as epileptic seizure, and (b) the kind of headache, if it is of migraine type or not. Concerning pre-ictal migraine/headache, the necessity of its differentiation from an epileptic headache presenting as an aura of a seizure is stressed; this is connected with the indefiniteness of the term "migralepsy". The term "migraine aura-triggered seizure" should be used only in front of a proven triggering effect of migraine. Epileptic headache (called also "ictal epileptic headache") is a well-characterized entity, in which different types of head pain may occur and an ictal EEG is necessary for the diagnosis. It may present as an isolated event ("isolated epileptic headache"), requiring a differential diagnosis from other kinds of headache, or it may be uninterruptedly followed by other epileptic manifestations being in this case easily identifiable as an epileptic aura. Hemicrania epileptica is a very rare variant of epileptic headache, characterized by the ipsilaterality of head pain and EEG paroxysms. Ictal non-epileptic headache needs to be differentiated from epileptic headache. Post-ictal headaches are a frequent association of headache with seizures, particularly in patients suffering also from inter-ictal headache-migraine. The reported systematization of the topic led us to suggest a classification which is shown in Appendix.

Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations.

OBJECTIVE: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations. METHODS: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients. RESULTS: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%). CONCLUSIONS: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.

Movement-activated cortical myoclonus in Dravet syndrome.

PURPOSE: we characterized multifocal myoclonus in Dravet syndrome (DS) that was never systematically typified before. METHODS: we studied EEG-EMG recordings of 19 consecutive patients, aged 2-29 years, with DS associated with SCN1A gene mutations to detect and evaluate myoclonus based on the spectrum of EMG activity on antagonist muscle pairs and cortico-muscular coherence (CMC). RESULTS: multifocal action myoclonus was detected in all patients corresponding to brief EMG bursts, which occurred synchronously on antagonist muscles at a frequency peaking in beta band. There was significant CMC in beta band, and a cortico-muscular transfer time consistent with a cortical origin of the jerks. The somatosensory evoked potentials (SSEPs) were giant in only one patient who also showed exaggerated long-loop reflexes (LLRs). The nine patients who had experienced myoclonic seizures showed greater CMC. CONCLUSIONS: The cortical myoclonus consistently observed in patients with DS shows features that are similar to those characterizing progressive myoclonus epilepsy, but differs because it does not have a severely worsening course and is not commonly associated with increased SSEPs or enhanced LLRs. This kind of myoclonus is an intrinsic feature of DS associated with SCN1A mutations, and may be a cause of disability. SIGNIFICANCE: We hypothesize that myoclonus is generated in cortical motor areas by hyper-synchronous oscillations, which are possibly due to sodium channel dysfunction.

Neurophysiology of myoclonus and progressive myoclonus epilepsies.

The high temporal resolution of neurophysiological recordings makes them particularly suited to faithfully describing the time course of rapid events such as myoclonus and to precisely measure its time relationship with other related activities. In progressive myoclonus epilepsies (PMEs) polygraphy with simultaneous EMG-EEG recordings is a crucial tool for defining the characteristic of myoclonic jerks their topography over different muscles (namely antagonists), their time course and relationship with vigilance muscle activation and stimulations. Moreover on polygraphic recordings it is possible to detect EEG activities associated to myoclonic jerks and define their time relationship with myoclonus thus differentiating cortical types of myoclonus from subcorticallly generated ones. Tanks to the back averaging technique non obvious time-locked EEG potentials can be detected on polygraphy , furthermore in stimulus sensitive myoclonus the analysis can include the potential evoked by the somatosensory stimulus (SEP). The polygraphic recording also gives information on muscle activity suppression occurring after jerk or as pure negative myoclonus. Besides the time domain analysis, techniques based on frequency analysis have been developed to evaluate EEG-EMG coherence. The neurophysiological techniques provide investigators and clinicians with an invaluable information to define the type of myoclonus and its generating circuitry thus substantially contributing in the diagnosis and management of PMEs.

Altered EEG resting-state effective connectivity in drug-naïve childhood absence epilepsy.

OBJECTIVE: We investigated interictal EEG activity in patients with childhood absence seizures with the aim of detecting markers of network defects generating "idiopathic" hyperexcitability in this form of epilepsy. METHODS: We included 11 drug-naïve patients with childhood absence epilepsy (CAE), and 11 age matched controls (CTRL). We analyzed interictal EEG using partial directed coherence (PDC), a connectivity estimator in frequency domain based on autoregressive multivariate (MVAR) modeling giving the advantage of indicating the direction and strength of the interactions between multiple variables. RESULTS: Our results revealed the presence of an abnormal cortico-cortical network occurring in the interictal condition in CAE and involving a large span of frequencies, with prominence in the alpha band; the most evident finding was a highly significant increase of out-going connectivity involving frontal and central cortical areas in CAE patients compared to CTRL subjects. CONCLUSIONS: Our observation indicates that, in interictal conditions, a distorted network characterizes CAE, and a hyperconnected network is already detectable under resting conditions in the delta, theta and alpha bands. SIGNIFICANCE: The increased interictal EEG connectivity demonstrated here provides support for a persistent abnormal relationship between the thalamus and a hyperexcitable cortex outside the ictal phase.

Juvenile myoclonic epilepsy: A system disorder of the brain.

The prevailing understanding of generalized epilepsy is shaped by the traditional definition that "the responsible neuronal discharge takes place, if not throughout the entire grey matter, then at least in the greater part of it and simultaneously on both sides". This view is no longer tenable since concurrent findings using multiple methods have accumulated to reveal the role of bilateral networks of distributed and selective cortical and subcortical structures in so-called generalized ictogenesis. Most of this research has been focused on juvenile myoclonic epilepsy (JME), which today is commonly considered the archetypical syndrome of the idiopathic generalized epilepsies. Based upon recent research in the fields of clinical epileptology, neuropsychology and psychiatry, clinical neurophysiology, neuroimaging and epilepsy genetics this article, for the first time, unites these new findings into a comprehensive nosological view. Genetically determined dysfunctions of important cognitive systems like visuomotor coordination and linguistic communication appear now as key mechanisms of seizure generation in JME. This review suggests a new paradigm to consider JME as a system disorder of the brain analogous to other neurological system disorders.

Self-rated and assessed cognitive functions in epilepsy: impact on quality of life.

AIM OF THE STUDY: To compare the effects of perceived and assessed cognitive functions on quality of life (QoL) in patients with epilepsy (PWE). METHODS: The study analyzed the data from a series of PWE who compiled the Quality of Life in Epilepsy-89 Inventory (QOLIE-89) and the Multiple Ability Self-Report Questionnaire (MASQ) for QoL and perceived cognitive abilities, respectively. The State-Trait Anxiety and Beck Depression inventories were used to assess mood. Neuropsychological tests evaluated abstract reasoning, attention, conceptual-motor tracking, constructional praxis, language, verbal and non-verbal memory, abstraction, category shifting, verbal fluency, and visual-spatial abilities. RESULTS: The QOLIE-89 overall score was predicted by the Mood and Attention and Executive Functions factors and MASQ scores, explaining 38, 6, and 4% of its variance, while disease duration, seizure frequency, and schooling determined 16%. The QOLIE-89 Psychosocial, Cognitive, and Physical Performance sub-domains related to mood. The Cognitive and Physical Performance factors also related to the MASQ and Attention and Executive Functions factor scores, respectively. CONCLUSIONS: In PWE, self-rated and assessed cognitive deficits may influence QoL, explaining 10% of its variance irrespective from mood and clinical variables. Treating cognitive deficits and their perception may help improve QoL.

Are there really "epileptogenic" mechanisms or only corruptions of "normal" plasticity?

Plasticity in the nervous system, whether for establishing connections and networks during development, repairing networks after injury, or modifying connections based on experience, relies primarily on highly coordinated patterns of neural activity. Rhythmic, synchronized bursting of neuronal ensembles is a fundamental component of the activity-dependent plasticity responsible for the wiring and rewiring of neural circuits in the CNS. It is therefore not surprising that the architecture of the CNS supports the generation of highly synchronized bursts of neuronal activity in non-pathological conditions, even though the activity resembles the ictal and interictal events that are the hallmark symptoms of epilepsy. To prevent such natural epileptiform events from becoming pathological, multiple layers of homeostatic control operate on cellular and network levels. Many data on plastic changes that occur in different brain structures during the processes by which the epileptogenic aggregate is constituted have been accumulated but their role in counteracting or promoting such processes is still controversial. In this chapter we will review experimental and clinical evidence on the role of neural plasticity in the development of epilepsy. We will address questions such as: is epilepsy a progressive disorder? What do we know about mechanism(s) accounting for progression? Have we reliable biomarkers of epilepsy-related plastic processes? Do seizure-associated plastic changes protect against injury and aid in recovery? As a necessary premise we will consider the value of seizure-like activity in the context of normal neural development.