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 functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent 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-anaesthetized 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 cortico-thalamic 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.

中文翻译：

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对失神发作的病理生理学、合并症和治疗的临床和实验见解。

儿童和青少年的失神发作通常被认为是相对良性的，因为它们的非惊厥性质和成年早期的大量汇款发生率。然而，最近的研究表明，30% 的失神发作儿童具有抗药性，60% 的儿童受到严重的神经精神合并症的影响，包括注意力、认知、记忆力和情绪障碍。特别是，在癫痫诊断之前可以检测到注意力缺陷，即使在药物控制癫痫发作并且丙戊酸单一疗法加重癫痫发作时也可能持续存在。新的功能性 MRI-脑磁图和功能性 MRI-EEG 研究提供了确凿的证据表明，在癫痫发作开始前至少 1 分钟，可以在特定的皮质网络中检测到失神发作儿童的血氧水平依赖性信号幅度和频率的变化，尖峰- 波放电在癫痫发作开始时不会泛化，并且在发作间期仍然存在异常的皮质网络状态。从神经生物学的角度来看，最近在非麻醉模型中对具有单细胞分辨率的大型神经元集合进行的电记录和成像表明，与主流观点相反，皮质机制，而不是专门的丘脑节律发生，是驱动癫痫发作的关键。并确定尖峰波频率。虽然同步发作期放电表征了群体水平的皮质和丘脑活动，但个体皮质丘脑和丘脑皮质神经元很少被招募到连续癫痫发作和癫痫发作内的连续阵发性周期。新的证据加强了先前关于基底神经节网络在失神发作中的重要作用的发现，特别是黑质 GABA 能神经元放电的发作期增加。因此，丘脑 ictogenesis 的一个关键特征是丘脑皮质神经元抑制的强大增加，这种神经元至少来自两个来源，即黑质和丘脑网状核。这无疑为总放电的发作期减少和 T 型钙通道介导的丘脑皮质神经元爆发性放电的发作期增加提供了主要贡献，尽管后者对于癫痫发作不是必需的。此外，在一些失神发作的儿童和动物模型中，星形胶质细胞 GABA 转运蛋白 GAT-1 的功能丧失增强了丘脑抑制的发作性增加，而 GAT-1 不一定源自其基因的突变。总之，这些新的临床和实验发现为我们对失神发作的理解带来了范式转变的观点，并要求仔细选择初始单一疗法和对受影响儿童的持续神经精神病学评估。本文讨论这些问题，以集中未来的临床和实验研究，并帮助确定治疗失神发作及其合并症的新治疗靶点。星形胶质细胞 GABA 转运蛋白 GAT-1 的功能丧失增强了丘脑抑制的发作性增加，这不一定源自其基因的突变。总之，这些新的临床和实验发现为我们对失神发作的理解带来了范式转变的观点，并要求仔细选择初始单一疗法和对受影响儿童的持续神经精神病学评估。本文讨论这些问题，以集中未来的临床和实验研究，并帮助确定治疗失神发作及其合并症的新治疗靶点。星形胶质细胞 GABA 转运蛋白 GAT-1 的功能丧失增强了丘脑抑制的发作性增加，这不一定源自其基因的突变。总之，这些新的临床和实验发现为我们对失神发作的理解带来了范式转变的观点，并要求仔细选择初始单一疗法和对受影响儿童的持续神经精神病学评估。本文讨论这些问题，以集中未来的临床和实验研究，并帮助确定治疗失神发作及其合并症的新治疗靶点。这些新的临床和实验发现为我们对失神发作的理解带来了范式转变的观点，并要求仔细选择初始单一疗法和对受影响儿童的持续神经精神病学评估。本文讨论这些问题，以集中未来的临床和实验研究，并帮助确定治疗失神发作及其合并症的新治疗靶点。这些新的临床和实验发现为我们对失神发作的理解带来了范式转变的观点，并要求仔细选择初始单一疗法和对受影响儿童的持续神经精神病学评估。本文讨论这些问题，以集中未来的临床和实验研究，并帮助确定治疗失神发作及其合并症的新治疗靶点。