Modeling seizures in the Human Phenotype Ontology according to contemporary ILAE concepts makes big phenotypic data tractable.

OBJECTIVE: The clinical features of epilepsy determine how it is defined, which in turn guides management. Therefore, consideration of the fundamental clinical entities that comprise an epilepsy is essential in the study of causes, trajectories, and treatment responses. The Human Phenotype Ontology (HPO) is used widely in clinical and research genetics for concise communication and modeling of clinical features, allowing extracted data to be harmonized using logical inference. We sought to redesign the HPO seizure subontology to improve its consistency with current epileptological concepts, supporting the use of large clinical data sets in high-throughput clinical and research genomics. METHODS: We created a new HPO seizure subontology based on the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types, and integrated concepts of status epilepticus, febrile, reflex, and neonatal seizures at different levels of detail. We compared the HPO seizure subontology prior to, and following, our revision, according to the information that could be inferred about the seizures of 791 individuals from three independent cohorts: 2 previously published and 150 newly recruited individuals. Each cohort's data were provided in a different format and harmonized using the two versions of the HPO. RESULTS: The new seizure subontology increased the number of descriptive concepts for seizures 5-fold. The number of seizure descriptors that could be annotated to the cohort increased by 40% and the total amount of information about individuals' seizures increased by 38%. The most important qualitative difference was the relationship of focal to bilateral tonic-clonic seizure to generalized-onset and focal-onset seizures. SIGNIFICANCE: We have generated a detailed contemporary conceptual map for harmonization of clinical seizure data, implemented in the official 2020-12-07 HPO release and freely available at hpo.jax.org. This will help to overcome the phenotypic bottleneck in genomics, facilitate reuse of valuable data, and ultimately improve diagnostics and precision treatment of the epilepsies.

Clasificación de las epilepsias generalizadas idiopáticas en mayores de 16 años / Classification of idiopathic generalised epilepsies in patients over 16 years of age

Introducción. Las epilepsias generalizadas idiopáticas (EGI) son un conjunto de síndromes electroclínicos con distintos fenotipos. Nuestro objetivo es analizar dichos fenotipos en pacientes mayores de 16 años. Pacientes y métodos. Analizamos retrospectivamente una serie de pacientes con EGI. Los clasificamos en epilepsia de ausencias infantil (EAI), epilepsia de ausencias juvenil (EAJ), epilepsia mioclónica juvenil (EMJ), epilepsia con crisis tonicoclónicas sólo (ECTC), epilepsia con ausencias y mioclonías palpebrales (EAM) y epilepsia fotogénica pura (EF). Resultados. Incluimos 308 pacientes, mayoritariamente mujeres (56,8%). La EMJ fue más prevalente (40,9%), seguida de la ECTC (30%), la EAJ (10%), la EAM (8,7%), la EAI (7,7%) y la EF (1,6%). Los tipos de crisis que presentaron más pacientes fueron las tonicoclónicas (89,6%), las mioclónicas (45,4%), las ausencias (31,4%), las crisis reflejas (13,3%), las mioclonías palpebrales (12,6%), las crisis psicógenas no epilépticas (3,6%) y el estado epiléptico (1,9%). Todos tenían descargas punta-onda generalizada en el electroencefalograma (EEG). El 19,2% presentó descargas asimétricas y el 28,2%, respuesta fotoparoxística. Observamos diferencias entre síndromes en politerapia (p < 0,0001), retirada de tratamiento (p = 0,01) y estar libres de crisis por encima de los 50 años (p = 0,004). Conclusiones. La EMJ fue la EGI más frecuente. Las crisis tonicoclónicas generalizadas fueron el tipo de crisis que presentaron más pacientes, seguidas de las mioclónicas, las ausencias y las crisis reflejas. El EEG mostró en más de una cuarta parte de los pacientes una respuesta fotoparoxística, y en uno de cada cinco, anomalías asimétricas. Se observaron diferencias según el síndrome en politerapia, persistencia de crisis y retirada de tratamiento (AU)

Introduction. Idiopathic generalised epilepsies (IGE) are a set of electroclinical syndromes with different phenotypes. Our aim is to analyse those phenotypes in patients over 16 years of age. Patients and methods. We conducted a retrospective analysis of a series of patients with IGE. They were classified as childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), epilepsy with tonicclonic seizures only (TCSE), epilepsy with eyelid myoclonias and absences (EMA) and pure photogenic epilepsy (PE). Results. We included 308 patients, the majority females (56.8%), in our study. JME was the most prevalent (40.9%), followed by TCSE (30%), JAE (10%), EMA (8.7%), CAE (7.7%) and PE (1.6%). The types of seizures presented by the most patients were tonic-clonic (89.6%), myoclonic (45.4%), absence (31.4%), reflex seizures (13.3%), eyelid myoclonias (12.6%), non-epileptic psychogenic seizures (3.6%) and status epilepticus (1.9%). They all had generalised spike-and-wave discharges in the electroencephalogram (EEG). 19.2% presented asymmetrical discharges and 28.2% showed a photoparoxysmal response. We observed differences between syndromes in polytherapy (p < 0.0001), withdrawal of therapy (p = 0.01) and being seizure-free beyond the age of 50 (p = 0.004). Conclusions. JME was the most frequent. Generalised tonic-clonic seizures were the type of seizures presented by the most patients, followed by myoclonic, absent and reflex seizures. The EEG showed a photoparoxysmal response in over a quarter of the patients, and one in five displayed asymmetrical anomalies. Differences were observed according to the syndrome in polytherapy, persistence of seizures and withdrawal of treatment (AU)

AERRPS, DESC, NORSE, FIRES: multi-labeling or distinct epileptic entities?

In this review, we report a case of an adolescent girl presenting with epileptic encephalopathy preceded by febrile illness, demarcate the clinical phenotypic homogeneity among previously reported cases, and hypothesize on potential mechanisms based on current experimental evidence. Our literature review revealed >249 cases that share several main features: febrile illness with no preceding condition, negative laboratory studies including cerebrospinal fluid (CSF) analysis, status epilepticus refractory to conventional pharmacotherapy, and long-term developmental delays. This condition appears to have many names, the most recent of which is "FIRES" (fever-induced refractory epileptic encephalopathy). It seems likely that the described cases are representing the same entity. The possibility of a genetic or acquired channelopathy can be raised in light of negative infectious, autoimmune, microscopic, and gross pathology findings.

Improved patient specific seizure detection during pre-surgical evaluation.

OBJECTIVE: There is considerable interest in improved off-line automated seizure detection methods that will decrease the workload of EEG monitoring units. Subject-specific approaches have been demonstrated to perform better than subject-independent ones. However, for pre-surgical diagnostics, the traditional method of obtaining a priori data to train subject-specific classifiers is not practical. We present an alternative method that works by adapting the threshold of a subject-independent to a specific subject based on feedback from the user. METHODS: A subject-independent quadratic discriminant classifier incorporating modified features based partially on the Gotman algorithm was first built. It was then used to derive subject-specific classifiers by determining subject-specific posterior probability thresholds via user interaction. The two schemes were tested on 529 h of intracranial EEG containing 63 seizures from 15 subjects undergoing pre-surgical evaluation. To provide comparison, the standard Gotman algorithm was implemented and optimised for this dataset by tuning the detection thresholds. RESULTS: Compared to the tuned Gotman algorithm, the subject-independent scheme reduced the false positive rate by 51% (0.23 to 0.11 h(-1)) while increasing sensitivity from 53% to 62%. The subject-specific scheme further improved sensitivity to 78%, but with a small increase in false positive rate to 0.18 h(-1). CONCLUSIONS: The results suggest that a subject-independent classifier scheme with modified features is useful for reducing false positive rate, while subject adaptation further enhances performance by improving sensitivity. The results also suggest that the proposed subject-adapted classifier scheme approximates the performance of the subject-specific Gotman algorithm. SIGNIFICANCE: The proposed method could potentially increase the productivity of offline EEG analysis. The approach could also be generalised to enhance the performance of other subject independent algorithms.

Vigabatrin but not valproate prevents development of age-specific flexion seizures induced by N-methyl-D-aspartate (NMDA) in immature rats.

In immature rats, N-methyl-D-aspartate (NMDA) induces several seizure types: flexion seizures (FS; in rats younger than 3 weeks), clonic seizures (in animals older than 3 weeks), and clonic-tonic seizures (CTS; in rats of all ages). FS represent a model of human infantile spasms. Effects of vigabatrin and valproate against all types of NMDA-induced seizures were studied in rats at postnatal days 12 (P12) and 25 (P25). NMDA (60 or 300 mg/kg) was injected to animals pretreated with vigabatrin (300-1,200 mg/kg; 24 h before NMDA) or valproate (100-400 mg/kg; 15 min before NMDA). Vigabatrin suppressed FS in P12 rats, but was ineffective against CTS in both age groups. Valproate suppressed CTS in P12, but not in P25 rats. Clonic seizures were rare in NMDA-treated P25 rats, but valproate pretreatment increased their incidence significantly. Neither drug decreased NMDA-induced mortality, which occurred within approximately 15 min after NMDA administration and reached almost 100% in all groups.

[Contemporary opinions on classification, pathogenesis and treatment of drug-resistant epilepsy]. / Wspólczesne poglady na klasyfikacje, patogeneze i postepowanie w padaczce lekoopornej.

Epilepsy is one of the most frequent neurological disorders, both in children and adult persons. About 0.5-1% of general population suffer from epilepsy, which means that about 50 million people in the world are affected. First years of life and very late adulthood are periods in human's life particularly predisposing to epilepsy. Repetitive epileptic seizures may cause many life-threatening situations and significantly lower patient's quality of life. To the most serious complications belong status epilepticus and sudden unexpected deaths due to epilepsy (SUDEP). Absences from work or school caused by seizures, difficulties in social life, frequent injuries and necessity of polytherapy are also important for patients. All these factors result in low self-esteem and poor quality of life. The main aim of the treatment was control of epileptic seizures. However, despite of new antiepileptic drugs developed almost every year, in one third of all patients with epilepsy seizures remain out of control. Those patients are regarded to have "drug-resistant epilepsy". Despite of significant scale of the problem, there is no one definition of the phenomenon. In the presented review the authors outline current definitions, recent opinions on pathogenesis and risk factors, and provide practical rules of pharmacotherapy of epilepsy, which should help to restrict drug-resistancy.

Idiopathic generalized epilepsies of adolescence.

The prevalence of idiopathic generalized epilepsies (IGEs) has been assessed as being 15-20% of all epilepsies. The seizure types in IGEs are typical absences, myoclonic jerks, and generalized tonic-clonic seizures (TCS), alone or in varying combinations and with variable severity. The seizures tend to be more frequent on awakening and with sleep deprivation. This group of clinical conditions includes among others, age-related epilepsy syndromes of adolescence such as juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized TCS or epilepsy with grand mal on awakening (EGMA). The classification of IGEs follows two schools of thought; one maintains that IGEs are a group of different and separate syndromes while the other suggests that IGEs are one biological continuum. Patients with IGEs may have mild impairment of cognitive functions, especially verbal memory and other frontal lobe functions, despite a normal IQ, and some seem to have characteristic personality traits, although further studies are needed to support this theory. They appear to lack a degree of self-control, to neglect their physical needs, and are poorly compliant with therapy. Some patients become obstinate and are impressionable. The cognitive and behavioral aspects of these patients suggest an involvement of frontal lobes.

Development of a validated clinical case definition of generalized tonic-clonic seizures for use by community-based health care providers.

PURPOSE: To develop and test a clinical case definition for identification of generalized tonic-clonic seizures (GTCSs) by community-based health care providers. METHODS: To identify symptoms that can help identify GTCSs, patients with history of a jerky movements or rigidity in any part of the body ever in life were recruited from three sites: the community, secondary care hospital, and tertiary care hospital. These patients were administered a 14-item structured interview schedule focusing on the circumstances surrounding the seizure. Subsequently, a neurologist examined each patient and, based on available investigations, classified them as GTCS or non-GTCS cases. A logistic regression analysis was performed to select symptoms that were to be used for case definition of GTCSs. Validity parameters for the case definition at different cutoff points were calculated in another set of subjects. RESULTS: In total, 339 patients were enrolled in the first phase of the study. The tertiary care hospital contributed the maximal number of GTCS cases, whereas cases of non-GTCS were mainly from the community. At the end of phase I, the questionnaire was shortened from 14 to eight questions based on statistical association and clinical judgment. After phase II, which was conducted among 170 subjects, three variables were found to be significantly related to the presence of GTCSs by logistic regression: absence of stress (13.1; 4.1-41.3), presence of frothing (13.7; 4.0-47.3), and occurrence in sleep (8.3; 2.0-34.9). As a case definition using only three variables did not provide sufficient specificity, three more variables were added based on univariate analysis of the data (incontinence during the episode and unconsciousness) and review of literature (injury during episode). A case definition consisting of giving one point to an affirmative answer for each of the six questions was tested. At a cutoff point of four, sensitivity was 56.9 (47.4-66.0) and specificity, 96.3 (86.2-99.4). Among the 197 GTCS and 26 new non-GTCS patients recruited from hospitals from select SEAR Member Countries, in phase III, the sensitivity of this clinical case definition was 72% and specificity, 100%. A stratified analysis by gender in all the three phases did not show any differences between the sexes. CONCLUSIONS: Based on these criteria, we recommend that all patients with a history of two or more episodes of jerking or rigidity of limbs, having a score of > or =4 in the case definition, be identified as having GTCSs and started on antiepileptic medications. This clinical case definition can be very useful for community-based health care providers to identify and manage cases of GTCSs in the community. This should play a major role in the reduction of treatment gap for epilepsy in developing countries.

Overview: idiopathic generalized epilepsies.

The idiopathic generalized epilepsies (IGEs) are an underemphasized topic. Two reasons for this relative lack of attention are that these epilepsies tend to be more easily controlled than the symptomatic partial and generalized epilepsies, and they are not as common. Because IGE usually arises in childhood or adolescence, these epilepsies may be thought of as a pediatric problem. However, a large number of patients continue to have seizures in adult life. Many exciting developments in understanding the pathophysiology, genetic etiology, and expanded treatment options warrant a reexamination of this important group of the epilepsies. This article reviews the more common IGE syndromes and associated seizure types as the first step in identifying the recent advances in our knowledge of these syndromes.

Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.

A group of infant onset epilepsies manifest very frequent generalized tonic-clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever-sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.

Psychoses and epilepsy: are interictal and postictal psychoses distinct clinical entities?

PURPOSE: To evaluate further the relevance of designating psychotic episodes as either postictal or interictal, we compared several biologic variables between epilepsy patients with and without psychosis. METHODS: The study subjects comprised 282 patients with psychosis (36 with postictal psychosis, 224 with interictal psychosis, and 22 with both postictal and interictal psychoses, i.e., bimodal psychosis), and 658 epilepsy patients without psychosis. The clinical characteristics of these patients were reviewed retrospectively by experienced neuropsychiatrists. Factors predicting the development of each type of psychosis were determined by serial multivariate logistic regression analyses. RESULTS: Factors that were comparable between postictal and interictal psychoses were intellectual function, family history of psychosis, epilepsy type, and the presence of complex partial seizures. In contrast, age at the onset of epilepsy and at the onset of psychosis and the presence of generalized tonic-clonic seizures differed for the three types of psychosis. Patients with bimodal psychosis showed characteristics associated with both postictal and interictal psychoses. CONCLUSIONS: This study documented conditions, including both general factors and epilepsy-related factors, common to epilepsy patients with psychosis, regardless of chronologic distinctions. Certain epileptic processes appear to have equal influence on postictal and interictal psychoses. However, some differences between postictal and interictal psychoses suggest that these chronologic descriptors are valid. Our findings confirmed that psychosis associated with epilepsy should not be defined as a single, simple condition but rather as a complex condition with several possible subcategories.

Idiopathic generalized epilepsies with pure grand mal: clinical data and genetics.

OBJECTIVE: To analyze the clinical features and family history of patients with idiopathic generalized epilepsy (IGE), with pure grand mal (GM), divided into epilepsies with GM occurring exclusively on awakening (GMA) and random GM (RGM). METHODS: We studied retrospectively 98 patients from a large epilepsy outpatient clinic. All patients had a full clinical examination and computed cerebral tomography scans (CCT) or magnetic resonance imaging (MRI) when feasible. We analyzed seizure type, seizure frequency, provocative factors, prognosis, electroencephalography (EEG) findings and family history. RESULTS: Sixty-eight patients had GMA and 30 had RGM. The mean age at seizure onset was 16.6 years (+/-6.3 S.D., range: 5-41) and 16.7 years in those with RGM (+/-7.5 S.D., range: 4-42, NSD). Patients with GMA had a longer course of active epilepsy (median 8.5 years) compared to RGM (median 2 years). Seizure-provoking factors, especially sleep deprivation, were significantly (P=0.001) more common in patients with GMA (52/68, 77%) than in the group with RGM (13/30, 43%). Of all patients, 23% (23/98) reported first degree relatives with seizures or epilepsy. Pure GM was found in 41% (12/29) of affected first degree relatives, other idiopathic generalized epilepsy syndromes were less frequently observed (4/29, 14%). The concordance rate was high within the syndrome - none of the patients with RGM had an affected relative with GMA and vice versa only two of affected relatives of GMA patients had RGM. CONCLUSION: GMA seems to be associated with a longer duration of active epilepsy, a higher relapse rate and a stronger tendency to be precipitated by seizure provoking factors. The different concordance rates between the syndromes suggest a genetically different background.

Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis.

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.

Phenomenology of simple partial seizures.

Based on a sample of 325 inpatients we present the subjective experiences during simple partial seizures. In a majority of cases, auras comprised composed forms of different symptomatic qualities. We describe rules which seem to govern sequences of aura phenomena. Autonomous and vestibular sensations were shown to have preceding positions related to others, olfactory and gustatory sensations preferred a following position. The tentative explanation of the findings favours the idea of heterogeneity rather than the concept of a focal discharge in a simple partial seizures.

Basic mechanisms of seizure expression.

While there are many types of seizures, our understanding of their pathophysiology is limited to a few types. On the basis of the behavior of neurons during a seizure, two fundamental types of paroxysms are recognized--spike-wave electrographic seizures and tonic-clonic electrographic seizures. When the former type of paroxysm takes place throughout the forebrain, an absence seizure ensues. When the latter type of paroxysm takes place within a limited set of neurons, a simple partial or complex partial seizure takes place, depending on the functional anatomy. When the latter type of paroxysm takes place throughout the forebrain, a generalized convulsion takes place. The basic cellular and synaptic processes that underlie electrographic spike-wave and tonic-clonic paroxysms are complex and dissimilar between the two types of discharges. This paper reviews these multiple processes. The diverse pathophysiological mechanisms presented provide a theoretical substrate for rational polypharmacy directed to seizure suppression.

Classifications and epidemiologic considerations of epileptic seizures and epilepsy.

The manifestations of epileptic disorders are widely known to be extremely protean. Classifying the disorders is a way of achieving a common understanding of the terminology used in identifying seizure disorders in the clinical or research settings. Two International Classifications have been developed, namely the International Classification of Epileptic Seizures and the International Classification of Epilepsy and Epileptic Syndromes. The first divides epileptic seizures into two major categories: partial and generalized. Partial epileptic seizures are further classified according to the impairment or the preservation of consciousness into simple partial and complex partial seizures. Either condition may secondarily generalize into tonic-clonic seizures. Under the International Classification, epilepsy and epileptic syndromes are initially classified according to their corresponding types of seizures into localization-related and generalized disorders. Each disorder is further classified according to the relationship to etiologic or predisposing factors into symptomatic, cryptogenic, or idiopathic types. The classifications undoubtedly will be further revised as more is learned about epileptic disorders with advances in electrophysiology, neuroimaging techniques, and molecular genetics. An overview of the epidemiology of epileptic disorders shows that, contrary to the popular belief, they are primarily disorders of childhood; age-specific incidence rates of first unprovoked seizure and of epilepsy are highest in the elderly. An appreciation of the epidemiology of seizure disorders is essential in their clinical and laboratory evaluation.

Idiopathic generalized epilepsy of adolescence: are the syndromes clinically distinct?

Juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures (GTCS) on awakening are the three syndromes of idiopathic generalized epilepsy of adolescent onset currently included in the classification of epilepsy syndromes of the International League Against Epilepsy (ILAE). Although they differ in their predominant seizure types, the syndromes share several clinical features, thus giving rise to questions of phenotypic overlap and purity. We studied the clinical features of 101 patients with idiopathic generalized epilepsy beginning in adolescence. A standardized interview was used to elucidate seizure phenomenology, precipitants, frequency, and response to treatment. Groups defined by seizure type were compared and their similarities examined. The group with myoclonic but not absence seizures (21 patients) corresponded to the ILAE syndrome of juvenile myoclonic epilepsy, whereas those with absences but not myoclonus (37 patients) resembled juvenile absence epilepsy. Twenty-six patients shared the features of juvenile myoclonic epilepsy and juvenile absence epilepsy. Epilepsy with GTCS on awakening was not a specific syndromic entity; 10 patients had this seizure type alone. Seven patients were without a syndromic diagnosis. In these patients only GTCS occurred, but neither on awakening nor in the evening period of relaxation. We conclude that whilst syndromes of idiopathic generalized epilepsy of adolescence can be recognized, the current classification does not include all patients. In addition, the boundaries between the syndromes are indistinct, suggesting underlying neurobiological, possibly genetic, relationships.