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Clinical and experimental insight in pathophysiology, comorbidity and therapy of absence seizures

Crunelli, Vincenzo ORCID:, Lorincz, Magor L., McCafferty, Cian, Regis, Lambert C., Leresche, Nathalie, Di Giovanni, Giuseppe and David, Francois 2020. Clinical and experimental insight in pathophysiology, comorbidity and therapy of absence seizures. Brain 143 (8) , pp. 2341-2368. 10.1093/brain/awaa072

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Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New fMRI-MEG and fMRI-EEG studies provide conclusive evidence that changes in BOLD signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave-discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anesthetized models show that in contrast to the predominant opinion cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual corticothalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Oxford University Press
ISSN: 0006-8950
Funders: Wellcome Trust
Date of First Compliant Deposit: 10 March 2020
Date of Acceptance: 31 January 2020
Last Modified: 05 May 2023 21:13

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