Multiple Seizures Research Articles

Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity.

Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment. Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared. Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03). Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

CHD2-Related CNS Pathologies.

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.

Expanding the Spectrum of EEG Periodic Discharges in Subacute Sclerosing Panencephalitis: A Case Report

Abstract Background Atypical electroencephalogram (EEG) abnormalities emerge in patients with subacute sclerosing panencephalitis (SSPE), especially in cases with an atypical clinical presentation that can lead to diagnostic difficulties. Case Report In this article, we presented a case of SSPE with an atypical onset with epileptic seizures and Parkinson's features. The neurological examination during the initial evaluation of the patient showed extrapyramidal syndrome, hyperreflexia, intention tremor, and dysmetria. Cranial magnetic resonance imaging was normal. Video EEGs were performed in wakefulness and sleep. In wakefulness, multiple brief seizures (1–1.5 seconds were recorded, consisting of gradual bending of the body forward and to the right that lacked the sudden characteristic of myoclonia. During those episodes, we recorded generalized epileptiform activity of 4 or 5 sharp waves, with higher amplitude in the anterior regions, in some of the paroxysms superimposed on a slow wave or followed by a high amplitude slow wave. The paroxysms appeared periodically every 15 to 30 seconds. However, 2 months later, the EEG showed typical periodic generalized activity of biphasic/triphasic slow waves (Radermecker complexes), accompanied by myoclonias. Conclusion We reported a peculiar EEG pattern in a patient with SSPE that consists of periodic generalized activity of sharp waves. Atypical EEG patterns can appear when the disease progresses, but initially too, before typical periodic complexes and can complicate the diagnostic process.

A Mixed Filtering Approach for Real-Time Seizure State Tracking Using Multi-Channel Electroencephalography Data.

Real-time continuous tracking of seizure state is necessary to develop feedback neuromodulation therapy that can prevent or terminate a seizure early. Due to its high temporal resolution, high scalp coverage, and non-invasive applicability, electroencephalography (EEG) is a good candidate for seizure tracking. In this research, we make multiple seizure state estimations using a mixed-filter and multiple channels found over the entire sensor space; then by applying a Kalman filter, we produce a single seizure state estimation made up of these individual estimations. Using a modified wrapper feature selection, we determine two optimal features of mixed data type, one continuous and one binary analyzing all available channels. These features are used in a state-space framework to model the continuous hidden seizure state. Expectation maximization is performed offline on the training and validation data sets to estimate unknown parameters. The seizure state estimation process is performed for multiple channels, and the seizure state estimation is derived using a square-root Kalman filter. A second expectation maximization step is utilized to estimate the unknown square-root Kalman filter parameters. This method is tested in a real-time applicable way for seizure state estimation. Applying this approach, we obtain a single seizure state estimation with quantitative information about the likelihood of a seizure occurring, which we call seizure probability. Our results on the experimental data (CHB-MIT EEG database) validate the proposed estimation method and we achieve an average accuracy, sensitivity, and specificity of 92.7%, 92.8%, and 93.4%, respectively. The potential applications of this seizure estimation model are for closed-loop neuromodulation and long-term quantitative analysis of seizure treatment efficacy.

Improved Performance of Carbamazepine and Benzodiazepine by Oxygen Enrichment through Perfluorodecalin for Lennox-Gastaut Type of Seizures

Lennox-Gastaut syndrome is commonly characterized by a triad of features including multiple seizure types, intellectual disability or regression. The long-term prognosis for Lennox-Gastaut syndrome is generally poor due to uncontrolled seizures. Lennox-Gastaut syndrome type of seizures is epilepsy which is due to abnormal vibrations occurring in seizures. During the time of such abnormal vibrations, both the seizures and the lungs suffer a lack in oxygen content to a considerable extent. This results in prolonged vibrations and loses of nervous control. As a neuro-lung protective strategy, a novel attempt has been made to enrich both seizures and lungs with oxygen content through the support of perfluorodecalin (an excellent oxygen carrier) C10F18 along with an enhancement in the antiepileptic activity by the two chosen antiepileptic drugs carbamazepine and benzodiazepine. The ultraviolet-visible spectrophotometer, fluorescence spectrograph, ultrasonic laser diffraction and scanning electron microscope studies reveals the co-existence of fluorine and drug in the emulsion produced by the sonication of both perfluorodecalin and the drug together. The presence of adequate fluorine and carbon play a catalytic role in ensuring the oxygen content and the antiepileptic activity of drug components.

Different Prognostic Patterns in Epilepsies and Considerations About the Denotations of Atypical Patterns.

Epilepsy is a dynamic and heterogeneous neurological disease, and in long-term studies on prognosis, classically 5 basic patterns (early remission, late remission, relapsing-remitting, worsening, and non-remitting) have been identified. The most frequent pattern was relapsing-remitting course, and factors such as the presence of genetic etiology, rare seizures at the beginning of epilepsy and the absence of psychiatric comorbid diseases were found to be related with this pattern as well as reaching 5 years of remission in the follow-ups. Anti-seizure drug resistance (ASD-R) and factors affecting the presence of this resistance (such as symptomatic etiology, abnormal electroencephalographic findings, having multiple seizure types together, status epilepticus and febrile seizure history) decrease the chance of remission, while idiopathic/genetic etiology, generalized epilepsy, and absence of comorbid diseases seem to be associated with achieving long-term remission. Apart from these basic course patterns, there are some patients with an "atypical prognosis" such as drug-resistant juvenile myoclonic epilepsy (JME), benign hippocampal sclerosis-related mesial temporal lobe epilepsy (HS-MTLE), and severe childhood epilepsy with centro-temporal spikes (CESTS), in which the pathophysiological mechanisms underlying these patterns have not been clarified despite the suggestions of various hypotheses. The presence of comorbid diseases such as hormonal factors (as in catamenial epilepsy), autoimmune processes, thyroid disorders and metabolic and psychiatric diseases may also cause an atypical prognostic pattern by affecting the course of the disease. In this review, our aim is to provide the clinician with an up-to-date and questioning perspective on the prognostic markers of epilepsy, by examining in detail some specific epilepsy syndromes that may show atypical prognosis as well as the general prognostic features of epilepsy.

Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies.

Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient’s lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%–68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%–78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat–OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a ‘one size fits all’ approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.

Chapter 10 - Gelastic seizures and the hypothalamic hamartoma syndrome: Epileptogenesis beyond the lesion?

The clinicoradiologic syndrome of hypothalamic hamartoma (HH) manifests with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, precocious puberty, behavioral disturbances, and cognitive impairment. Gelastic seizures are an early marker of epilepsy with HH in most of the cases. Despite a high variability, two major epilepsy phenotypes can be distinguished, based on electroclinical features: (i) focal seizures with epigastric or déjà-vu aura, loss of consciousness, and oroalimentary or gestural automatisms suggestive of temporal lobe involvement; and (ii) motor seizures with tonic, atonic, myoclonic, or versive phenomena, suggesting frontoparietal network involvement, with possible evolution toward an epileptic encephalopathy. The underlying physiopathologic mechanisms are not completely elucidated. The well-known intrinsic epileptogenicity of the HH represents the rationale for direct HH-aiming surgical procedures, with variable success in achieving seizure freedom. The concept of kindling-like secondary epileptogenesis has been suggested as a possible putative mechanism since the very beginnings of the hamartocentric era. Accordingly, a cortical area with enhanced epileptogenic properties due to an independent stage of secondary epileptogenesis would be responsible for seizures persisting after hamartoma ablation. However, recent intracerebral stereotactic EEG (SEEG) explorations demonstrated more complex, both reciprocal and hierarchical, relationships within the hypothalamo-cortical epileptogenic networks. Network formation may be due to either secondary epileptogenesis or widespread epileptogenicity present at the outset. A short time window from epilepsy onset to surgery seems to be crucial to cure epilepsy by direct surgery addressing a hamartoma. SEEG exploration may be reasonably proposed in cases where clinical data suggest an extension of the epileptogenic zone outside the limits of the HH, especially in focal seizures with impaired awareness and absence of gelastic seizures, or after a failure of the direct HH-aiming procedure.

CHILD WITH MILLER-DIEKER SYNDROME SURVIVING MORE THAN A DECADE: RARE INSTANCE IN LITERATURE

Miller Dieker Syndrome (MDS) is characterized by abnormal brain development and lissencephaly. As a result, babies have severe intellectual disability, developmental delay, multiple seizures and hypotonia. Characteristic facial features and mental retardation is indicative of a karyotypic evaluation. Microdeletion of chromosome 17p13.3 confirms the diagnosis. Management includes genetic counselling, frequent medical check-up, palliative treatment with physiotherapy and seizure control.

The unmet need for rapid epileptic seizure termination (REST).

Approximately 40% of epilepsy patients will continue to experience breakthrough seizures despite stable antiepileptic drug regimens. Rescue treatments have demonstrated efficacy and safety for select seizure emergencies. Outpatient administered intranasal and rectally delivered medications are regulatory approved for acute repetitive seizures (ARS), and injectable benzodiazepines are indicated for parenteral treatment of established status epilepticus. Despite these advances, no studies have been shown to abort an ongoing seizure following patient or caregiver home administration of therapy at the first clinical sign of seizure onset. Such treatment would require rapid systemic absorption without intravenous access, and evidence of seizure cessation within minutes of administration that is superior to placebo (eg, seizure self-regulation). Rapid epileptic seizure termination (REST) treatment may apply to multiple seizure emergencies beyond ARS, including focal or generalized seizures preceded by an aura, flurries of absence or myoclonic seizures, or prolonged focal and generalized seizures at high risk of progression to status epilepticus. Novel investigational drug delivery systems have demonstrated feasibility of intraictal delivery and seizure cessation by two minutes. Ongoing randomized trials of REST treatment for diverse seizure emergencies hold the potential to decrease bouts of mental and physical incapacitation in patients with drug-resistant epilepsy.

Neuronal Firing and Waveform Alterations through Ictal Recruitment in Humans.

Analyzing neuronal activity during human seizures is pivotal to understanding mechanisms of seizure onset and propagation. These analyses, however, invariably using extracellular recordings, are greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons. To address these analytical difficulties, we developed a novel template-matching-based spike sorting method, which enabled identification of 1239 single neurons in 27 patients (13 female) with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing with widespread intense activation and stereotyped action potential alterations in tissue that was invaded by the seizure: neurons displayed increased waveform duration (p < 0.001) and reduced amplitude (p < 0.001), consistent with prior animal studies. By contrast, neurons in "penumbral" regions (those receiving intense local synaptic drive from the seizure but without neuronal evidence of local seizure invasion) showed stable waveforms. All neurons returned to their preictal waveforms after seizure termination. We conclude that the distinction between "core" territories invaded by the seizure versus "penumbral" territories is evident at the level of single neurons. Furthermore, the increased waveform duration and decreased waveform amplitude are neuron-intrinsic hallmarks of seizure invasion that impede traditional spike sorting and could be used as defining characteristics of local recruitment.SIGNIFICANCE STATEMENT Animal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proven difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude as the neurons are recruited to the seizure, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

Proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis

Hippocampal sclerosis (HS) is the most common neuropathological condition in adults with drug-resistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy (MTLE) syndrome. Although epileptogenic brain tissue is associated with glutamate excitotoxicity leading to oxidative stress, the proteins that are targets of oxidative damage remain to be determined. In the present study we designed comprehensive analyses of changes in protein expression level and protein oxidation status in the hippocampus or neocortex to highlight proteins associated with excitotoxicity by comparing MTLE patients with relatively mild excitotoxicity (MTLE patients without HS, MTLE-non-HS) and those with severe excitotoxicity (MTLE patients with HS, MTLE-HS). We performed 2-dimensional fluorescence difference gel electrophoresis, 2D-oxyblot analysis, and mass spectrometric amino acid sequencing. We identified 16 proteins at 18 spots in which the protein expression levels differed between sclerotic and non-sclerotic hippocampi. In the sclerotic hippocampus, the expression levels of several synaptic proteins were decreased, and those of some glia-associated proteins increased. We confirmed histologically that all MTLE-HS cases examined exhibited severe neuronal cell loss and remarkable astrocytic gliosis in the hippocampi. In all MTLE-non-HS cases examined, neurons were spared and gliosis was unremarkable. Therefore, we consider that decreased synaptic proteins are a manifestation of loss of neuronal cell bodies and dendrites, whereas increased glia-associated proteins are a manifestation of proliferation and hypertrophy of astrocytes. These are considered to be the result of hippocampal sclerosis. In contrast, the expression level of d-3-phosphoglycerate dehydrogenase (PHGDH), an l-serine synthetic enzyme expressed exclusively by astrocytes, was decreased, and that of stathmin 1, a neurite extension-related protein expressed by neurons, was increased in the sclerotic hippocampus. These findings cannot be explained solely as the result of hippocampal sclerosis. Rather, these changes can be involved in the continuation of seizure disorders in MTLE-HS. In addition, the protein carbonylation detection, an indicator of protein oxidation caused by excitotoxicity of multiple seizures and/or status epilepticus, revealed that the carbonyl level of collapsin response mediator protein 2 (CRMP2) increased significantly in the sclerotic hippocampus. In conclusion, protein identification following profiling of protein expression levels and detection of oxidative proteins indicated potential pathognomonic protein changes. The decreased expression of PHGDH, increased expression of stathmin 1, and carbonylation of CRMP2 differentiate between MTLE with and without HS. Therefore, further investigations of PHGDH, stathmin 1 and CRMP2 are promising to study more detailed effects of excitotoxicity on epileptogenic hippocampal tissue.

The role of inflammatory markers and calculated osmotic pressure in the classification of febrile seizures.

Systemic inflammatory response may contribute to the onset of febrile seizures (FSs). The neutrophil-to-lymphocyte ratio (NLR) has been reported to be useful for differentiating simple and complex FSs in children with a first FS. This study aimed to determine whether easily measurable inflammatory markers were useful for distinguishing between the types of FSs in children with FSs not limited to the first FS. We conducted a retrospective study of children aged 6-60 months who were presented to the Atsugi City Hospital in Japan for the treatment of FSs between December 2018 and February 2020. A complex FS was defined as a seizure with multiple seizures during the same febrile illness, prolonged seizures and/or focal seizures. A simple FS was defined as a seizure without the characteristics of complex FS. We assessed complete blood count, C-reactive protein, and calculated osmotic pressure. A total of 205 children with FSs (simple, 139; complex, 66) fulfilled the inclusion criteria. None of the inflammatory markers, including NLR, could predict the FS type. The median osmotic pressure was 279.0, 278.8, 283.3, and 278.3 mOsm/kg H2O for children with simple, multiple, prolonged, and focal seizures, respectively. Children with prolonged seizures had a significantly higher calculated osmotic pressure than those with simple FSs (p<0.001) and multiple seizures during the same febrile illness (p=0.004). Easily measurable inflammatory markers, including NLR, were not useful for distinguishing between types of FSs in children. Large multicenter studies are needed to evaluate the association between osmotic pressure and FS.

Clinical profile of children with epilepsy: a cross-sectional study

Introduction: One of the most common chronic neurological disorders is epilepsy, affecting as many as 45 million individuals worldwide. The occurrence is higher in children below the age of three. Around 60 percent to 70 percent of epilepsy patients have an effective response to treatment with antiepileptic medications. This cross-sectional study aimed to explore the clinical profile of children with epilepsy.Methods: Total of 100 children with different types of epilepsy was included in this study. After getting informed consent from the parents, all the demographic data, family history, clinical and laboratory investigations were recorded, and the results were statistically analyzed and discussed.Results: 69 patients had tonic-clonic seizures, 15 patients had a complete partial seizure, 7 patients had absence seizures, 4 patients had unclassified seizures, 3 patients had simple partial seizures, 1 patient had myoclonic seizures, atonic seizures and multiple seizures. Aetiology, 72 patients had an idiopathic cause, 10 patients had hypoxic ischemia, 8 patients had Central nervous system (CNS) infection, 4 patients had cerebral palsy and space-occupying lesion, 2 patients had trauma. Comorbidity, 84 patients had none, 4 patients had mental retardation, 3 patients had eye diseases, cerebral palsy, protein-energy malnutrition, mental retardation with cerebral palsy, 1 patient had a hearing impairment. Drug therapy, 63 patients had sodium valproate, 11 patients had carbamazepine, 2 patients had multidrug treatment, and 1 patient had sodium phenytoin.Conclusion: A significant amount of the aetiology of the condition is expressed among preventable causes of epilepsy. For generalized tonic clonic seizure, sodium valproate was observed to have more positive effects in paediatric patients.

Development and validation of a predictive model for the diagnosis of neural antibody-mediated epilepsy/ seizure in patients with new-onset seizure or established epilepsy

PurposeCurrently, the diagnosis of neural antibody-mediated epilepsy/seizure (NAME/S)relies heavily on neural antibody testing, which is time-consuming, costly and introduces diagnostic delays. A statistical tool to predict the probability of a patient with NAME/S is lacking. We aimed to construct a predictive model to help clinicians expedite the diagnostic process. MethodsWe retrospectively recruited subjects (206 in the development group and 62 in the validation group) with new-onset seizures or established epilepsy suspected to have presented with antibody-mediated seizures between January 2014 and December 2019. We collected data about demographics, medical history, clinical manifestations and follow up. Binary logistic regression was used to select potential predictors for the construction of a predictive model. Five-fold cross and bootstrap validation were applied to avoid overfitting. Concordance index, calibration plots and decision curve analysis were used to assess its performance. ResultsThe model, incorporating presence/absence of tumour, psychiatric/cognitive/emotional changes, language disturbances, sensory auras, tonic-clonic seizures, multiple seizure events, hyponatremia and MRI inflammation, was visualized as a nomogram. The crude and adjusted concordance indices were both 0.88 with a cut-off value of 0.62, sensitivity of 83.2 % and specificity of 77.4 %. The slope and intercept of the calibration curve were 0 and 1, respectively. The model also showed good performance in the validation group with a concordance index of 0.82, cut-off value of 0.33, sensitivity of 75.5 % and specificity of 73.1 %. The slope was 0.86 and the intercept was 0.039. Decision curve analysis showed that the model was useful with an optimal threshold probability of ＞4 % in both groups. ConclusionsDespite limitations such as sample volume and selection bias in subject enrolment, this model may be used to estimate the individualized probability of having NAME/S, deserving further exploration and validation.

Outcome analysis of children with rolandic discharges on EEG: A real-world study

ObjectiveTo evaluate the efficacy of drugs for patients with central mid-temporal (rolandic) discharges detected by electroencephalogram (EEG). MethodsThis retrospective study enrolled 430 patients with rolandic discharges, who were treated at the Neuroelectrophysiology Center of the Children’s Hospital of Nanjing Medical University from February 2015 to February 2018. Patients were divided into three groups according to medication: levetiracetam (LEV), oxcarbazepine (OXC) and sodium valproate (VPA). All patients were followed up for at least 2 years, and the seizure frequency, EEG results and side effects of drugs were recorded. ResultsRolandic epilepsy (RE) occurred in 398/430 patients. Rolandic discharges were also found in those with febrile seizures, tic disorders, and attention deficit hyperactivity disorder. Thirty-one patients experienced only one seizure and no relapse, while 367 patients experienced more than two seizures (including 364 receiving drug treatment). The failure rate of LEV as initial therapy was significantly higher than those of OXC and VPA. The overall efficacy of OXC was higher than that of LEV. However, none of the three medications could control rolandic discharges. Moreover, the side effects of the three drugs were mild. ConclusionsRolandic discharges are common in children with RE and other diseases, such as febrile seizures, tic disorders, and attention deficit hyperactivity disorder. Patients with only one seizure need no treatment. Those with multiple seizures can be treated with OXC, LEV, and VPA. OXC serves as the initial antiepileptic drug with a lower failure rate and significant efficacy.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2mg/kg/d up to 0.7mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6months. Fifty-two patients were enrolled, with a median age of 8.6years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n=7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

The Impact of Clinical Seizure Characteristics on Recognition and Treatment of New-onset Focal Epilepsy in Emergency Departments.

Many people with new-onset focal epilepsy initially seek evaluation in emergency departments (EDs), and treatment decisions in EDs can influence likelihood of seizure recurrence. Using data collected for the Human Epilepsy Project (HEP), we assessed the effect of clinical seizure characteristics on ED clinical management. There were 447 participants with new-onset focal epilepsy seen within 4months of treatment initiation who were eligible and enrolled in HEP. Seizure calendars and medical records were collected. Based on clinical descriptions, seizures were categorized by semiology according to International League Against Epilepsy (ILAE) classifications as either focal nonmotor or focal motor seizures. Overall, 279 of 447(62%) of participants had presented to an ED prior to or at time of epilepsy diagnosis. A total of 132 of 246 (53%) with initial nonmotor seizures presented to an ED. Of these, eight (6%) presented with a first-lifetime nonmotor seizure. The other 124 (94%) presented after multiple seizures: seven (5%) with multiple nonmotor seizures and 117 (89%) with a first-lifetime motor seizure after having prior nonmotor seizures. A total of 147 of 201 (73%) participants with initial motor seizures presented to an ED. Of these, 134 (92%) presented with a first-lifetime motor seizure and 13 (9%) with multiple motor seizures. There was no difference in the likelihood of antiseizure medication initiation between participants who had multiple prior nonmotor seizures followed by a motor seizure (thereby fulfilling the criterion for an epilepsy diagnosis) versus those presenting with a single lifetime motor seizure (39% vs. 43%). There was no difference in recognition of seizures as the presenting complaint (85% vs. 87%) or whether the participant was admitted or referred to a neurologist (87% vs. 79%). This study contributes to evidence of underrecognition of nonmotor focal seizure semiologies in ED settings, which can support large-scale interventions aimed at improving recognition, specialist consultation, and treatment in ED settings.

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox–Gastaut syndrome: A prospective observational clinical study

IntroductionLennox–Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy. MethodsThis was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ± 16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300–2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. ResultsAfter 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. ConclusionAdjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.

Seizure outcome during bilateral, continuous, thalamic centromedian nuclei deep brain stimulation in patients with generalized epilepsy: a prospective, open-label study

ObjectiveWe report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE). MethodsTwenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300μsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline. ResultsMedian age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p < 0.001), atypical absence seizures (p < 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (>50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033). DiscussionThis prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy.