Hippocampus and Insula Are Targets in Epileptic Patients With Glutamic Acid Decarboxylase Antibodies.
Falip Mercè,Rodriguez-Bel Laura,Castañer Sara,Sala-Padró Jacint,Miro Júlia,Jaraba Sónia,Casasnovas Carlos,Morandeira Francisco,Berdejo Javier,Carreño Mar
Frontiers in neurology
Antibodies to glutamic acid decarboxylase (GAD ab) have been found in patients with limbic encephalitis (LE) and chronic pharmacoresistant focal epilepsy (FE). The objectives of the study were to: (1) analyze the clinical and neuroimaging course of patients with FE+GAD ab, (2) compare these characteristics with a control group, and (3) describe the most affected cerebral areas with structural and functional imaging. Patients with FE + high titers of GAD ab and a follow-up of at least 5 years were selected. Titers of serum GAD ab exceeding 2,000 UI/ml were considered high. Evolutive clinical and radiological characteristics were studied in comparison to two different control groups: patients with bilateral or with unilateral mesial temporal sclerosis (BMTS or UMTS) of a non-autoimmune origin. A group of 13 patients and 17 controls were included (8 BMTS, 9 UMTS). The most frequent focal aware seizures (FAS) reported by patients were psychic (5/13: 33%). Somatosensorial, motor, and visual FAS (4/13:32%) (: 0.045), musicogenic reflex seizures (MRS), and a previous history of cardiac syncope were reported only patients (2/13:16% each) (: NS). Comparing EEG characteristics between patients and controls, a more widespread distribution of interictal epileptiform discharges (IED) was observed in FE+ GAD ab patients than in controls (:0.01). Rhythmic delta activity was observed in all controls in anterior temporal lobes while in patients this was less frequent (: 0.001). No IED, even in 24 h cVEEG, was seen in 6 patients (46%).First MRI was normal in 4/5 (75%) patients. During the follow-up mesial temporal lobe (MTsL) sclerosis was observed in 5/8 (62%) of patients. All patients had abnormal FDG-PET study. MTL hypometabolism was observed in 10/11 (91%) patients, being bilateral in 7/11 (63%). In controls, this was observed in 16/17 (94%), and it was bilateral in 8/17 (47%) (: NS). Insular hypometabolism was observed in 5/11 (45%) patients (:0.002). Clinical, EEG, and FDG-PET findings in FE+GAD ab suggest a widespread disease not restricted to the temporal lobe. Progressive MTL sclerosis may be observed during follow-up. In comparison to what is found in patients with non-autoimmune MTL epilepsy, insular hypometabolism is observed only in patients with GAD ab, so it may be an important diagnostic clue.
10.3389/fneur.2018.01143
Epilepsy Overview and Revised Classification of Seizures and Epilepsies.
Pack Alison M
Continuum (Minneapolis, Minn.)
PURPOSE OF REVIEW:The classification of seizures, epilepsies, and epilepsy syndromes creates a framework for clinicians, researchers, and patients and their families. This classification has evolved over the years, and in 2017 the International League Against Epilepsy (ILAE) published an operational classification of seizures and epilepsies. Understanding this classification is important in the diagnosis, treatment, and understanding of seizures and epilepsies, including epilepsy incidence. RECENT FINDINGS:The 2017 ILAE classification system builds on newly formulated definitions of seizures and epilepsy. Seizure classification begins by determining whether the initial manifestations of the seizure are focal or generalized. If the onset of the seizure is missed or unclear, the seizure is of unknown onset. Focal seizures are classified according to the individual's level of awareness, the most prominent motor or nonmotor features of the seizure, and whether the focal seizure evolves to a bilateral tonic-clonic seizure. Similarly, generalized seizures are classified according to motor or nonmotor manifestations. Motor seizures are either tonic-clonic or other motor seizures. Nonmotor generalized seizures primarily refer to absence seizures. Similar to seizure classification, the epilepsies can be classified as focal or generalized. In addition, the new classification system recognizes two new categories: combined generalized and focal epilepsy and unknown epilepsy. The concept of an epilepsy syndrome has been introduced under the new classification system and refers to a cluster of features incorporating seizure types, EEG, imaging, and other features including genetics. The new classification system emphasizes the etiology of seizures and epilepsies. SUMMARY:The recent ILAE seizure and epilepsy classification system aims to create a framework to better classify seizures and the epilepsies. Universal adoption and implementation of this system will enable patients, their families, clinicians, and researchers to better define and treat the epilepsies. Incidence studies have not generally classified seizures and the epilepsies, and use of this classification system, which emphasizes etiology, will lead to a better understanding of epilepsy incidence.
10.1212/CON.0000000000000707
Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
Fisher Robert S,Cross J Helen,French Jacqueline A,Higurashi Norimichi,Hirsch Edouard,Jansen Floor E,Lagae Lieven,Moshé Solomon L,Peltola Jukka,Roulet Perez Eliane,Scheffer Ingrid E,Zuberi Sameer M
Epilepsia
The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.
10.1111/epi.13670
Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy.
Brain : a journal of neurology
Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies.
10.1093/brain/awac150
Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy.
Pitkänen Asla,Sutula Thomas P
The Lancet. Neurology
During the past decade, it has become apparent that neural circuits undergo activity-dependent reorganisation. In pathological disorders with recurring episodes of excessive neural activity, such as temporal-lobe epilepsy, brain circuits can undergo continual remodelling. For clinical practice, seizure-induced remodelling implies that after a diagnosis of epilepsy, recurring seizures can cause continuing neural reorganisation and potentially contribute to progressive severity of the epilepsy and to cognitive and behavioural consequences. The alterations induced by seizures include neuronal death and birth, axonal and dendritic sprouting, gliosis, molecular reorganisation of membrane and extracellular-matrix proteins, and intermediates involved in cellular homoeostasis. These changes are influenced by genetic background and seizure type, thus identification of genetic risk factors should be a priority. Therapeutic modification of seizure-induced molecular and cellular responses offers new opportunities for intervention beyond seizure suppression.
10.1016/s1474-4422(02)00073-x
The cerebellum on the epilepsy frontline.
Trends in neurosciences
In a recent study, Streng and colleagues revealed that targeted activation of a specific fastigial output of the cerebellum can powerfully inhibit hippocampal seizures in mice. This study provides insights into how the cerebellum impacts hippocampal activity and opens the way to possible applications for treating temporal lobe epilepsy.
10.1016/j.tins.2022.02.003
The neurobiology of cognitive disorders in temporal lobe epilepsy.
Bell Brian,Lin Jack J,Seidenberg Michael,Hermann Bruce
Nature reviews. Neurology
Cognitive impairment, particularly memory disruption, is a major complicating feature of epilepsy. This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy (TLE). We present a brief overview of anatomical substrates of memory disorders in TLE, followed by a discussion of how our understanding of these disorders has been improved by studying the outcomes of anterior temporal lobectomy. The clinical efforts made to predict which patients are at greatest risk of experiencing adverse cognitive outcomes following epilepsy surgery are also considered. Finally, we examine the vastly changing view of TLE, including findings demonstrating that anatomical abnormalities extend far outside the temporal lobe, and that cognitive impairments extend beyond memory function. Linkage between these distributed cognitive and anatomical abnormalities point to a new understanding of the anatomical architecture of cognitive impairment in epilepsy. Clarifying the origin of these cognitive and anatomical abnormalities, their progression over time and, most importantly, methods for protecting cognitive and brain health in epilepsy, present a challenge to neurologists.
10.1038/nrneurol.2011.3
Breakdown of spatial coding and interneuron synchronization in epileptic mice.
Nature neuroscience
Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.
10.1038/s41593-019-0559-0
'Hippocampal innate inflammatory gliosis only' in pharmacoresistant temporal lobe epilepsy.
Brain : a journal of neurology
Drug-resistant mesial-temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as 'gliosis only' with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that 'gliosis only' represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. On the basis of their neuropathological exam, patients with hippocampus sclerosis and 'gliosis only' were characterized and compared within the whole cohort and within a subset of matched pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. 'Gliosis only' revealed demographics, clinical and neuropsychological outcome fundamentally different from hippocampus sclerosis. 'Gliosis only' patients had a significantly later seizure onset (16.3 versus 12.2 years, P = 0.005) and worse neuropsychological outcome after surgery compared to patients with hippocampus sclerosis. Epilepsy was less amendable by surgery in 'gliosis only' patients, resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% versus 68%, P = 0.0001, odds ratio = 2.8, confidence interval 1.7-4.7). This finding remained significant after multivariate and matched-pairs analysis. The 'gliosis only' group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in hippocampus sclerosis. RNA-sequencing of gliosis only patients deciphered a distinct transcriptional programme that resembles an innate inflammatory response of reactive astrocytes. Our data indicate a new temporal lobe epilepsy syndrome for which we suggest the term 'Innate inflammatory gliosis only'. 'Innate inflammatory gliosis only' is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, 'innate inflammatory gliosis only' patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients; surgical treatment of this subgroup should be considered with great precaution. 'Innate inflammatory gliosis only' requires innovative pharmacotreatment strategies.
10.1093/brain/awac293