Focal Epilepsy Of Unknown Cause Research Articles

Peripheral blood regulatory B and T cells are decreased in patients with focal epilepsy

Patients with focal epilepsy of unknown cause (FEoUC) may display T cell infiltration in post-surgery brain specimens and increased serum levels of pro-inflammatory cytokines produced by B and T cells, indicating potential involvement of adaptive immunity. Our study aimed to investigate the peripheral blood distribution of B and T cell subgroups to find clues supporting the distinct organization of adaptive immunity in FEoUC. Twenty-two patients with FEoUC and 25 age and sex matched healthy individuals were included. Peripheral blood mononuclear cells were immunophenotyped by flow cytometry. Expression levels of anti-inflammatory cytokines and FOXP3 were measured by real-time PCR. Carboxyfluorescein succinimidyl ester (CFSE) proliferation assay was conducted using CD4+ T cells. Patients with FEoUC showed significantly decreased regulatory B (Breg), B1a, plasmablast and regulatory T (Treg) cell percentages, and increased switched memory B and Th17 cell ratios. Moreover, CD4+CD25+CD49d− Tregs of FEoUC patients displayed significantly reduced TGFB1 and FOXP3, but increased IL10 gene expression levels. CD4+ helper T cells of patients with FEoUC gave more exaggerated proliferation responses to phytohemagglutinin, anti-CD3 and anti-CD28 stimulation. Patients with FEoUC display increased effector lymphocyte, decreased regulatory lymphocyte ratios, and impaired Treg function and enhanced lymphocyte proliferation capacity. Overall, this pro-inflammatory phenotype lends support to the involvement of adaptive immunity in FEoUC.

35 MoCA performance as an indicator of NSAb positivity in focal epilepsy: A preliminary analysis

Objective:Researchers are increasingly finding that the presence of neuronal surface antibodies (NSAb) may account for a larger percentage of outpatient epilepsy cases than previously thought (Elisak et al., 2018; Brenner et al., 2013). However, systematic NSAb screening is not included in standard epilepsy care (Kambadja et al., 2022). The Montreal Cognitive Assessment (MoCA; Nasreddine, 2005) is one of the most commonly used screening tools among physicians (Judge et al., 2019) across various neurological conditions, and has previously been validated in populations with autoimmune encephalitis (Hebert et al., 2018). Because patients with NSAb associated epilepsy often present with cognitive dysfunction (Greco et al., 2006), a MoCA is often administered as part of standard clinical care. The present analysis compared MoCA performance profiles in epilepsy patients with and without the presence of serum NSAbs. We explored what specific cognitive profile, as defined by the MoCA, may predict NSAb positivity.Participants and Methods:Forty-eight epilepsy patients were enrolled through an outpatient epilepsy clinic or during non-intensive or elective hospital stays. Participants were eligible if they met one of three diagnostic categories: focal epilepsy of unknown cause (n = 33), lesional focal epilepsy (n = 5), or generalized epilepsy (n = 4). All participants signed consent, underwent a comprehensive interview, which included MoCA testing, and serum NSAb testing paralleling standard clinical practice. Mann-U Whitney tests were run to compare overall MoCA and subgroup domain performance between groups.Results:Six patients (13%), all with focal epilepsy of unknown cause, had positive NSAb panels (LGI1: n = 3; GAD65: n = 2; CASPR2: n = 1). There was no significant difference in overall MoCA scores between participants with focal epilepsy of unknown cause who were antibody positive versus negative, and antibody positive versus antibody negative lesional or generalized epilepsy. However, when analyzing by MoCA subgroup, we found that antibody positive patients performed significantly worse on delayed recall than antibody negative patients with focal epilepsy of unknown cause (Mdn = 1.5 vs 3), U(Nantibodynegative=27, Nantibodypositive=6) = 69.00, p = .02. There was no significant difference in other MoCA cognitive domain tests, and delayed recall scores did not significantly differ between antibody positive patients and those with lesional focal and generalized epilepsy.Conclusions:These preliminary findings suggest that episodic memory impairment, as measured by delayed recall on the MoCA, may predict NSAb antibody positivity among patients with focal epilepsy of unknown cause. This may relate to specific predilection of the hippocampal regions in antibody-mediated epileptogenesis and pathology.

Psychiatric comorbidity in relation to clinical characteristics of epilepsy: A retrospective observational study

PurposePrevalence of psychiatric disorders in people with epilepsy is high. However, diagnostic validity and information about the nature of the seizure disorders are often poor in population-based studies. In a well validated and classified patient sample, we investigated psychiatric comorbidity according to clinical characteristics. MethodParticipants in The Trøndelag Health Study (HUNT) with ≥ 2 diagnostic epilepsy codes during 1987–2019 were identified. Medical records were reviewed, and epilepsy was validated and classified according to ILAE. Psychiatric comorbidity was defined by ICD-codes. ResultsIn 448 individuals with epilepsy, 35% had at least one psychiatric disorder (anxiety and related disorders 23%, mood disorders 15%, substance abuse and personality disorders 7%, and psychosis 3%). Comorbidity was significantly higher in women than in men (p = 0.007). The prevalence of psychiatric disorders was 37% in both focal and generalized epilepsy. In focal epilepsy, it was significantly lower when etiology was structural (p = 0.011), whereas it was higher when the cause was unknown (p = 0.024). Comorbidity prevalence was 35% both in patients achieving seizure freedom and in those with active epilepsy but 38% among 73 patients with epilepsy resolved. ConclusionJust over one third of people with epilepsy had psychiatric comorbidities. The prevalence was equal in focal and generalized epilepsy but was significantly higher in focal epilepsy of unknown cause compared to lesional epilepsy. Comorbidity was independent of seizure control at last follow-up but was slightly more common in those with resolved epilepsy, often having non-acquired genetic etiologies possibly linked to neuropsychiatric susceptibility.

Focal epilepsies: update on diagnosis and classification.

Correctly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self-limited focal epilepsy syndromes (e.g., self-limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self-limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions - developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug-resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo-resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high-quality educational resources concerning epilepsy.

Autoimmune Mechanisms in Focal Epilepsy of Unknown Cause

ABSTRACT The manifestation of immunological findings in diverse disorders presenting with seizures points to autoimmunity and inflammation in the etiology of epilepsy. Typical examples of autoimmunity-associated epilepsy are autoimmune encephalitis, Rasmussen encephalitis, and glutamic acid decarboxylase (GAD) antibody-positive temporal lobe epilepsy (TLE). The last entity is a typical example of antibody-positive focal epilepsy of unknown cause (FEUC). One of the most prominent findings emphasizing the coexistence of epilepsy and autoimmunity is the detection of anti-neuronal antibodies in patients manifesting with seizures. Emergence of antibody-producing plasma cells in the early course of GAD-antibody-positive TLE and induction of seizures in rodents upon intracerebral administration of N-methyl-D-aspartate receptor antibodies indicate that anti-neuronal antibodies may play a causal (rather than bystander) role in the induction of seizures. By contrast, innate immunity of the central nervous system (CNS) and infiltrating cytotoxic T-cells appear to participate in Rasmussen encephalitis and autoimmune encephalitis with antibodies to intracellular antigens. In addition, repetitive seizures may activate glial cells through the release of damage-associate molecular pattern mediators and activation of toll-like receptors, which in turn leads to disrupted blood–brain barrier and increased cerebral infiltration of peripheral blood immune cells. In conclusion, complex interactions of humoral and cellular immunity in the CNS appear to cause or at least contribute to seizure induction in FEUC. The nature of these interactions has recently started to be understood. Investigation of these mechanisms is substantial for the discovery of new treatment strategies and biomarkers in epilepsy.

Kv5.1 antibody in epilepsy patients with unknown etiology

BackgroundNeuronal autoantibodies and favorable response to immunosuppressive treatment have been described in patients with chronic epilepsy of unknown cause, suggesting autoimmune etiology. Our aim was to identify novel epilepsy-specific autoantibodies reactive with neuronal surface antigens. MethodsSera of 172 epilepsy patients with unknown cause and 30 healthy controls were screened with indirect immunofluorescence to identify IgG reacting with primary rat neuronal cultures. Putative target autoantigens were investigated with immunoprecipitation (IP) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies using SH-SY5Y cells. Validation of LC-MS/MS results was carried out by IP and immunocytochemistry assays. ResultsAntibodies to neuronal cell surface antigens were detected in 18 epilepsy patients. LC-MS/MS analysis identified voltage-gated potassium channel modifier subfamily F member 1 (KCNF1, Kv5.1) as the single common cell surface antigen in 4 patients with Lennox-Gastaut syndrome (n = 2), focal epilepsy of unknown cause (n = 1) and mesial temporal lobe epilepsy with hippocampal sclerosis (n = 1). These patients had the common features of early seizure onset and treatment-resistance. IP assays and co-localization (serum IgG and commercial Kv5.1-antibody) studies done with non-fixed Kv5.1-transfected HEK293 cells and primary neuronal cultures confirmed the presence of Kv5.1-antibody in 4 epilepsy patients identified by LC-MS/MS. Similar findings were not obtained by sera of other patients with epilepsy, patients with autoimmune encephalitis and healthy controls. ConclusionThe herein described novel neuronal surface antibody to Kv5.1 appears to be associated with treatment-resistant epilepsy of unknown cause. Exact clinical and pathogenic significance of this antibody remains to be elucidated.

Late-Onset Focal Epilepsy: Electroclinical Features and Prognostic Role of Leukoaraiosis.

The aim of this study was to describe the electroclinical and prognostic characteristics, and to investigate the role of leukoaraiosis in outpatients with new-onset elderly focal epilepsy aged ≥60 years, referred to a tertiary epilepsy center between 2005 and December 31, 2020. Among the 720 patients who were referred to the center, we retrospectively selected 162 consecutive outpatients, with a first referral for recent-onset focal epilepsy of unknown cause (UC) or structural cause (SC), and collected a clinical and standard-Electroencephalogram (S-EEG), 24-h ambulatory EEG (A-EEG), and neuroimaging data. We also analyzed the seizure prognosis after titration of the first antiseizure medication (ASM). One hundred and four UC and 58 SC patients, followed up for 5.8 ± 5.3 years (mean ± SD), were included. Compared with the SC group, the patients with UC showed a predominance of focal seizures with impaired awareness (51.9% of cases) and focal to bilateral tonic-clonic seizures during sleep (25%); conversely, the SC group, more frequently, had focal to bilateral tonic-clonic seizures during wakefulness (39.6%) and focal aware seizures (25.8%) (p < 0.0001). Oral or gestural automatisms were prevalent in UC epilepsy (20.2 vs. 6.9% in the SC group, p = 0.04). In UC compared to patients with SC, interictal epileptiform discharges showed a preferential temporal lobe localization (p = 0.0007), low expression on S-EEG, and marked activation during deep Non-Rapid Eye Movement (NREM) sleep (p = 0.003). An overall good treatment response was found in the whole sample, with a probability of seizure freedom of 68.9% for 1 year. The cumulative probability of seizure freedom was significantly higher in the UC compared with the SC group (p < 0.0001). The prognosis was worsened by leukoaraiosis (p = 0.012). In the late-onset focal epilepsy of unknown cause, electroclinical findings suggest a temporal lobe origin of the seizures. This group showed a better prognosis compared with the patients with structural epilepsy. Leukoaraiosis, per se, negatively impacted on seizure prognosis.

Adaptive immunity cells are differentially distributed in the peripheral blood of glycine receptor antibody-positive patients with focal epilepsy of unknown cause

AimGlycine receptor (GlyR) autoantibodies (Ab) have been recently detected in epilepsy patients. Our study aimed to investigate the peripheral blood distribution of B and T cell subgroups responsible for antibody production to find clues supporting the distinct organization of adaptive immunity in focal epilepsy of unknown cause (FEUC). MethodSeven GlyR-Ab positive and 15 GlyR-Ab negative FEUC patients and 25 age-sex matched healthy individuals were included. Peripheral blood mononuclear cells were isolated and immunophenotyped by flow cytometry. ResultsThere were no significant differences between CD19+ B, CD3+ T, CD4+ helper T, CD8+ cytotoxic T, and CD19+CD24++CD38++ regulatory B cell ratios among the groups. GlyR-Ab negative epilepsy patients had significantly higher CD19+IgD+CD27− naive B cells and GlyR-Ab positive patients showed reduced percentages of CD19+CD38+CD138+ plasma cells than healthy controls. By contrast, GlyR-Ab positive patients exhibited significantly increased CD3+CD4+CD25highregulatory T (Treg) cells and CD3+CD4+CD25highCD127low/- Treg cells and relatively increased CD19+IgD-CD27+ memory B cells without attaining statistical significance. ConclusionThe increase of Tregs, which are capable of suppressing B cells, maybe a compensating countermeasure to prevent the conversion of effector B cell subgroups. Thus, our findings lend support to the involvement of adaptive immunity in focal epilepsy of unknown cause.

Thalamohippocampal atrophy in focal epilepsy of unknown cause at the time of diagnosis.

Patients with chronic focal epilepsy may have atrophy of brain structures important for the generation and maintenance of seizures. However, little research has been conducted in patients with newly diagnosed focal epilepsy (NDfE), despite it being a crucial point in time for understanding the underlying biology of the disorder. We aimed to determine whether patients with NDfE show evidence of volumetric abnormalities of subcortical structures. Eighty-two patients with NDfE and 40 healthy controls underwent magnetic resonance imaging scanning using a standard clinical protocol. Volume estimation of the left and right hippocampus, thalamus, caudate nucleus, putamen and cerebral hemisphere was performed for all participants and normalised to whole brain volume. Volumes lower than two standard deviations below the control mean were considered abnormal. Volumes were analysed with respect to patient clinical characteristics, including treatment outcome 12months after diagnosis. Volume of the left hippocampus (p(FDR-corr) =0.04) and left (p(FDR-corr) =0.002) and right (p(FDR-corr) =0.04) thalamus was significantly smaller in patients relative to controls. Relative to the normal volume limits in controls, 11% patients had left hippocampal atrophy, 17% had left thalamic atrophy and 9% had right thalamic atrophy. We did not find evidence of a relationship between volumes and future seizure control or with other clinical characteristics of epilepsy. Volumetric abnormalities of structures known to be important for the generation and maintenance of focal seizures are established at the time of epilepsy diagnosis and are not necessarily a result of the chronicity of the disorder.

Peripheral blood expression levels of inflammasome complex components in two different focal epilepsy syndromes

BackgroundAlthough the role of inflammation in epilepsy pathogenesis has been extensively investigated, the inflammasome complex, a key component of neuroinflammation, has been understudied in epilepsy patients. MethodsTo better understand the involvement of this system in epilepsy, levels of inflammasome complex components (NLRP1, NLRP3, CASP1, ASC), end-products of inflammasome complex activity [IL-1β, IL-18, nitric oxide synthase (NOS) isoforms] and other inflammatory factors (NFκB, IL-6, TNF-α) were measured in peripheral blood of patients with focal epilepsy of unknown cause (FEoUC) (n = 47), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (n = 35) and healthy controls using real time qPCR and/or ELISA. ResultsInflammasome complex associated factors were either downregulated or unchanged in epilepsy patients. Likewise, flow cytometry studies failed to show an increase in ratios of NLRP3-expressing CD3+ and CD14+ peripheral blood mononuclear cells (PBMC) in epileptic patients. Anti-neuronal antibody positive epilepsy patients showed increased NLRP1 and neuronal NOS mRNA expression levels, whereas patients under poly-therapy showed reduced serum inflammasome levels. FEoUC patients demonstrated increased PBMC NFκB mRNA expression levels and serum IL-1β and IL-6 levels. Both MTLE-HS and FEoUC patients displayed higher ratios of NFκB-expressing CD14+ PBMC than healthy controls. ConclusionsAlthough previous clinical studies have implicated increased inflammasome complex expression levels in epilepsy, our results indicate suppressed inflammasome complex activity in the peripheral blood of focal epilepsy patients. Alternatively, the IL-6-NFκB signaling pathway, appears to be activated in focal epilepsy, suggesting that factors of this pathway might be targeted for future theranostic applications.

Reflex epileptic features in patients with focal epilepsy of unknown cause

ObjectivesThere is a gap of knowledge regarding reflex seizures in patients with focal epilepsy of unknown cause (FEUC). We aimed to evaluate the prevalence, demographic and clinical characteristics of reflex seizures in patients with FEUC to provide an insight to the underlying ictogenic mechanisms and to draw attention to this important but under-investigated topic. Patients and methodsAfter carefully questioning for reflex triggers, 186 patients diagnosed according to ILAE criteria and followed-up for a minimum of 5 years were included. The demographic and clinical properties as well as electrophysiological and neuroimaging data of these patients were reevaluated and compared to the patients without reflex seizures. ResultsThe reflex seizure rate was 6.5 % in patients with FEUC. Patients with reflex features had lower monotherapy rates (p = 0.005) and higher major depression rates (p = 0.001) than patients without reflex features. The distribution of the patients according to their reflex triggers were as follows: hot-water induced (n = 3, 25 %), photosensitive (n = 2, 16.7 %), eating- induced (n = 2, 16.7 %), musicogenic (n = 2, 16.7 %), startle induced (n = 2, 16.7 %) and both musicogenic and startle type (n = 1, 8.3 %) respectively. The drug resistance rate of patients with reflex seizures was 25 % (n = 3). One patient with drug resistant reflex seizures showed benefit from epilepsy surgery and became seizure-free during last 3 years of follow-up. ConclusionA careful and thoroughly history taking specifically questioning and focusing on seizure inducing factors in patients with FEUC is needed to confirm the presence of reflex seizures in patients with FEUC, who had higher rates of polytherapy and major depression. Elaborative evaluation of reflex features in FEUC might contribute to effective seizure control, ensure new therapeutic approaches, enlighten the obscurity and the resulting anxiety of having a diagnosis of FEUC in epilepsy patients.

Long-term follow-up of a large cohort with focal epilepsy of unknown cause: deciphering their clinical and prognostic characteristics.

Focal epilepsy of unknown cause (FEUC) is an under-investigated topic despite its remarkable frequency. We aimed to report the long-term follow-up findings along with the drug-response, 5year remission rates and diagnostic changes to give an insight about the heterogeneous characteristics of FEUC. Demographic, clinical, neurophysiological and imaging data of 196 patients diagnosed as FEUC according to ILAE criteria, with a minimum 5-year follow-up were evaluated in a tertiary epilepsy center. The drug resistance, 5years of remission and relapse rates were investigated and the subgroups were compared statistically. The rate of drug resistance was 21.8% and status epilepticus (p < 0.001), abnormal neurological examination (p = 0.020), seizure onset before 10years (p = 0.004) and a high initial seizure frequency (p = 0.006) were significant predictors of drug resistance. The rates of terminal 5-year remission, 5-year remission ever and relapse were 39.9%, 44.26% and 24.04%, respectively. There were 13 patients (6.6%) with a changed final diagnosis. Drug resistance (p = 0.004), pathological EEG (p = 0.034) and status epilepticus (p = 0.021) were negative variables for achieving remission. The lobar localization of seizures was not a predictor of remission or relapse. Onset after 10years of age had a higher probability of achieving a 5-year remission according to Kaplan-Meier curves (p < 0.001). Focal epilepsy of unknown cause has a benign electroclinical subgroup with favorable long-term course, lower drug resistance and higher 5years of terminal remission and remission ever rates, when appropriately treated. Our findings might be valuable in terms of counseling and management of patients with FEUC at the first referral to epilepsy clinics.

Follow-up of patients with epilepsy harboring antiglycine receptor antibodies

ObjectiveThe long-term follow-up of patients with epilepsy harboring autoantibodies against the glycine receptor (also glycine receptor antibodies or GlyR-Ab) is not well-known. Our aim was to investigate the 5-year prognosis and treatment response of patients with epilepsy who were seropositive for GlyR-Ab. MethodsClinical features; electroencephalogram (EEG), neuroradiological, and neuropathological findings; and treatment responses of patients with epilepsy with GlyR-Ab seropositivity were investigated. ResultsThirteen (5.46%) of 238 patients with epilepsy were GlyR-Ab positive: focal epilepsy of unknown cause (FEoUC) was diagnosed in four (7.27%) out of 55 patients, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in five (4.5%) out of 111 patients, epileptic encephalopathy (EE) in two (4%) out of 50 patients, and status epilepticus (SE) in two (9.09%) out of 22 patients. None of the patients developed any other neurological symptoms or cancer during the 5-year follow-up. Seven of them had seizures that were resistant to antiepileptic drug (AED). Immunotherapy was used in two patients (with FEoUC and EE) improving seizure control. Three patients with MTLE-HS benefited from epilepsy surgery, and another patient with EE showed spontaneous remission. ConclusionGlycine receptor antibodies are detected in a wide spectrum of epileptic disorders with unclear pathogenic significance. Two GlyR-Ab seropositive patients with AED-resistant epilepsy treated with intravenous immunoglobulin (IVIg) showed clear benefit from immunotherapy. Future studies will be valuable in determining the role of screening patients with drug-resistant epilepsy for GlyR-Ab in order to identify patients who may benefit or respond to immunotherapy.

Reliability of the early syndromic diagnosis in adults with new-onset epileptic seizures: A retrospective study of 116 patients attended in the emergency room

PurposeNew-onset seizures (NOS) are a common reason for emergency department (ED) consultations. Decisions regarding treatment and further examinations are made based on the initial evaluation. We aimed to evaluate the reliability of the early syndromic diagnosis in NOS and find predictive factors to establish a consistent early diagnosis based on the semiology and prompt supplementary examinations. MethodsWe recruited patients attended in our ED for NOS over 2 years (2014–2015), excluding patients with a loss of consciousness of suspected non-epileptic origin. All patients were assessed by a neurologist. A baseline diagnosis was established according to clinical findings and neuroimaging/EEG data.Over 1 year of follow-up in our Epilepsy Unit, a definite diagnosis was made based on clinical progress and further examinations. Results116 patients were recruited (mean age 56.5 ± 22.1 years; 50% women). 47% were seizures of unknown cause. The concordance index between the baseline and definite diagnosis was κ = 0.662 (the diagnosis changed during follow-up in 25% of patients). Focal epilepsy of unknown cause was the baseline diagnosis that most often changed at follow-up (diagnostic change, 41.2%; p < 0.001). Lesions detected on CT-scanning and EEG abnormalities predicted the final diagnosis with the greatest accuracy (p = 0.009 and p = 0.026, respectively). Pathological findings in the MRI studies performed and seizure recurrence were not key factors for diagnostic changes. ConclusionDespite prompt examinations, the baseline epilepsy diagnosis changes within a short time period in 25% of patients. The presence of neuroimaging lesions and EEG abnormalities was associated with the greatest diagnostic accuracy in these cases.

Hyperventilation in Patients With Focal Epilepsy: Electromagnetic Tomography, Functional Connectivity and Graph Theory - A Possible Tool in Epilepsy Diagnosis?

Hyperventilation (HV) is a commonly used electroencephalogram activation method. We analyzed EEG recordings in 22 normal subjects and 22 patients with focal epilepsy of unknown cause. We selected segments before (PRE), during (HYPER), and 5 minutes after (POST) HV. To analyze the neural generators of EEG signal, we used standard low-resolution electromagnetic tomography (sLORETA software). We then computed EEG lagged coherence, an index of functional connectivity, between 19 regions of interest. A weighted graph was built for each band in every subject, and characteristic path length (L) and clustering coefficient (C) have been computed. Statistical comparisons were performed by means of analysis of variance (Group X Condition X Band) for mean lagged coherence, L and C. Hyperventilation significantly increases EEG neural generators (P < 0.001); the effect is particularly evident in cingulate cortex. Functional connectivity was increased by HV in delta, theta, alpha, and beta bands in the Epileptic group (P < 0.01) and only in theta band in Control group. Intergroup analysis of mean lagged coherence, C and L, showed significant differences for Group (P < 0.001), Condition (P < 0.001), and Band (P < 0.001). Analysis of variance for L also showed significant interactions: Group X Condition (P = 0.003) and Group X Band (P < 0.001). In our relatively small group of epileptic patients, HV is associated with activation of cingulate cortex; moreover, it modifies brain connectivity. The significant differences in mean lagged coherence, path length, and clustering coefficient permit to hypothesize that this activation method leads to different brain connectivity patterns in patients with epilepsy when compared with normal subjects. If confirmed by other studies involving larger populations, this analysis could become a diagnostic tool in epilepsy.

The recognition and treatment of autoimmune epilepsy in children.

There is emerging interest in autoimmune epilepsy, which represents a small but potentially treatable form of epilepsy. Most insights into autoimmune epilepsy derive from the recent descriptions of autoimmune encephalitis that takes two general forms: a focal encephalitis (such as limbic) or a diffuse encephalitis (such as anti-N-methyl-D-aspartate receptor [NMDAR] encephalitis). The features of autoimmune epilepsy include acute or subacute onset of seizures, usually in the context of encephalopathy, and inflammation of the central nervous system on testing cerebrospinal fluid or magnetic resonance imaging. Neuronal antibodies associated with autoimmune encephalitis and seizures in children include NMDAR, voltage-gated potassium channel complex, glycine receptor, γ-Aminobutyric acid type A receptor (GABA(A)R), γ-Aminobutyric acid type B receptor (GABA(B)R), and glutamic acid decarboxylase antibodies. These antibodies support the diagnosis of autoimmune epilepsy, but are not essential for diagnosis. When autoimmune epilepsy is suspected, first-line immune therapy with corticosteroids in addition to intravenous immunoglobulin or plasma exchange should be considered. Second-line therapy with rituximab or cyclophosphamide can be considered if the syndrome is severe. A response to immune therapy supports the diagnosis of autoimmune epilepsy. Neuronal antibodies are increasingly found in patients with focal epilepsy of unknown cause who do not have 'encephalitis'. Recent epidemiological studies support the link between epilepsy and autoimmune diseases. Future studies need to define the spectrum of autoimmune epilepsy and focus on early identification and treatment.

Interictal spiking in adult newly-diagnosed focal epilepsy of unknown cause: The effect of age

ObjectiveTo assess the yield of interictal EEG spiking in standard and whole-night sleep EEGs in elderly subjects with recent-onset focal seizures compared to younger patients. MethodsDetection of interictal epileptiform abnormalities (IEAs) and rating of mean spike index (number of interictal discharges/minute) values for different sleep stages (NREM stages 1–2 and 3–4 and REM sleep) in standard EEG (S-EEG) and 24-h ambulatory EEG (A-EEG) at first referral in three groups of thirty consecutive outpatients [aged 20–39 (young), 40–59 (adults) and ⩾60years (elderly)], retrospectively selected according to a subsequent diagnosis of focal epilepsy of unknown cause, no sleep disorders or drugs or comorbidities affecting sleep and EEG. ResultsElderly subjects showed a lower rate of IEAs on S-EEG (p<0.01) but a higher propensity for spiking during deep NREM sleep, 11/30 showing IEAs exclusively during stages 3–4. Mean spike index showed a significant increase in IEAs between sleep stages 1–2 and 3–4 in the elderly subjects (p<0.001). ConclusionsA significant association emerged between IEAs during deep sleep and age (p<0.001). SignificanceEEG recordings covering deep NREM sleep should be recommended when IEAs detection is needed to support a diagnosis of epilepsy in elderly subjects.

Assessment of everyday executive functioning in children with frontal or temporal epilepsies

Executive functions are particularly vulnerable in case of brain disruption during childhood, when the brain is not fully mature. Some studies showed impairments of executive functions in children with epilepsy, but only a few of them investigated the impact of executive dysfunctions on daily life. The aim of this study was to understand the everyday executive functioning of children with epilepsy both at home and in school. We administered the Behavior Rating Inventory of Executive Function to parents and teachers of 53 children (7–16years of age) with structural epilepsies or epilepsies of unknown cause of temporal lobe (n=25) or frontal lobe (n=28). The results indicated a global executive impairment in the whole group of patients, compared with normative data, with no difference between the group with temporal lobe epilepsy (TLE) and that with frontal lobe epilepsy (FLE), except for monitor domain, which seemed more frequently impaired in the group with FLE. Congruence between parent and teacher ratings was found. The frequency of seizures was not related to executive dysfunction, whereas the number of antiepileptic drugs tended to positively correlate with working memory impairment. Onset of epilepsy at a younger age was also related to more executive difficulties but only according to teacher ratings. Lastly, duration of epilepsy was strongly associated with executive deficits reported in the context of school. Our results support the executive dysfunction hypothesis in daily life of children with structural focal epilepsy or focal epilepsy of unknown cause and are consistent with the early brain vulnerability hypothesis currently prevalent in the context of child neuropsychology. The BRIEF appears to be a clinically useful tool for assessing executive function impairment in this clinical population.

Investigation of neuronal autoantibodies in two different focal epilepsy syndromes

Neuronal antibodies have been identified in patients with seizures as the main or sole symptom. Our aim was to investigate the prevalence of these autoantibodies in patients with focal epilepsy of unknown cause (FEoUC) and in the group having mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). We studied anti-neuronal antibodies of consecutive adult patients diagnosed with FEoUC and MTLE-HS in our epilepsy center. The clinical and laboratory features of antibody-positive patients were compared with those of seronegative patients. The responses to therapy have also been investigated. Sera from 81 patients with epilepsy were tested. We found antibodies against glycine receptor (GLY-R) in 5 (6.2%), contactin-associated protein 2 (CASPR-2) in 4 (4.9%), N-methyl-d-aspartate receptor (NMDA-R) in 2 (2.5%), and voltage-gated potassium channel (VGKC)-complex in 2 (2.5%) of our patients with epilepsy. Psychotic attacks and nonspecific magnetic resonance imaging (MRI) white matter changes (WMCs) showed significant associations in seropositive patients (p=0.003 and p=0.03, respectively). Poor drug-response rates and total seizure counts were also higher in the seropositive patients but without reaching statistical significance. Three seropositive patients with previous epilepsy surgery showed typical histopathologic results for MTLE-HS, but not inflammatory changes. Moreover, some patients harboring these antibodies partly benefited from immunotherapy. We detected neuronal antibodies in one sixth of patients with focal epilepsy, GLY-R antibodies being the leading one. Psychosis or nonspecific MRI WMCs were frequent in the seropositive group. Our results suggested that relevant antibodies should be screened for a treatment possibility in these groups.

Calcium channel antibodies in patients with absence epilepsy

Autoimmunity has aroused interest in the last years as a contributory mechanism of epilepsy, especially in epilepsies with unknown cause or therapy resistance. Since the relationship of absence epilepsy (AE) with calcium channels is well established, we aimed to investigate related antibodies in patients diagnosed with AE. Consecutive patients with typical absence seizures having either childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) with generalized spike and wave discharges on electroencephalography (EEG) were included after their consent. The patients were diagnosed according to the International League Against Epilepsy (ILAE) 2010 criteria. Antibodies against P-Q type voltage gated calcium channels (VGCC) and T-type VGCC subunit Cav3.2 (encoded by the CACNA1H gene) were investigated by RIA and ELISA, respectively. We searched for these antibodies in 32 patients with AE and 53 patients with focal epilepsy of unknown cause (FEOUC) as the disease control group; furthermore, 30 healthy persons served as the healthy controls. Eleven patients (34.3%) with AE had CAE and the remaining patients had JAE. Only a 47-year-old female FEOUC patient, who also had systemic lupus erythematosus with normal MRI scans showed antibodies against P-Q type VGCC, whereas no antibody positivity could be found in other FEOUC and AE patients and healthy controls. Our results might suggest that calcium channel antibodies do not play an important role in the pathophysiology of AE. Further studies with larger groups of other epileptic syndromes are needed to confirm our results.