Developmental mechanisms underlying pediatric epilepsy

Abstract

Pediatric epilepsy affects a large proportion of children, with a huge variability in seizure onset. Due to complicated etiology, wide range of associated comorbidities, and difficulty in obtaining clear physiological data from children, epilepsy management in pediatric patients often poses a critical challenge. Importantly, around 30% of these patients remain non-responsive to current anti-seizure drugs and develop a higher risk of developmental and cognitive delay and, in worse situations, premature death. One of the key treatment methods currently used for drug-resistant epilepsies is surgical resection of the epileptic foci. However, such patients often develop new epileptic foci post-surgery. This, in turn, enhances the need for recurrent invasive brain surgeries, impairing the overall quality of life in these children. Thus, mechanistic understanding of different types of pediatric epilepsy is critical to discovering more targeted molecular approach(es). For a long time, the occurrence of epilepsy was considered solely due to the abnormal functioning of single ion channels. However, in recent years, a huge number of genetic and non-genetic (environmental) factors have been associated with different types of pediatric epilepsy. Clinical diagnoses, coupled with a basic understanding of molecular and cellular mechanisms using different model systems, have been instrumental in unraveling new avenues for modern non-invasive targeted pharmacological therapies. Yet, the field has just started to evolve, and many challenges and contradictory hypotheses still exist. This comprehensive review discusses underlying developmental mechanisms associated with pediatric epilepsy. Specifically, we highlight how the PI3K-AKT-MTOR pathway acts as a critical node interconnecting the diverse mechanistic strategies, that may eventually help overcome the seizure burden in the future.

Keywords: Cilia; PI3K-AKT–MTOR pathway; SUDEP; drug resistance; epilepsy – abnormalities; neurodevelopment; pediatric epilepsy; sleep and circadian rhythm.

Figure 1

Seizure onset for different pediatric epilepsies. Green blocks represent the age range in which different types of pediatric epilepsy show seizure onset. The first year of age (0–1 year) has been subdivided into 0 m, 3 m, 6 m, and 9 m of age (m, months). SeLNE, self-limited neonatal epilepsy; SeLIE, self-limited infantile epilepsy; SeLFNIE, self-limited familial neonatal-infantile epilepsy; SeLECTS, self-limited epilepsy with a centrotemporal spike; SeLEAS, self-limited epilepsy with autonomic seizures; COVE, childhood occipital visual epilepsy; POLE, photosensitive occipital lobe epilepsy; EIDDE, early infantile developmental and epileptic encephalopathy; EIMFS, epilepsy of infancy with migrating focal seizures; LGS, Lennox–Gastaut syndrome; DEE SWAS, developmental and/or epileptic encephalopathy with spike–wave activation in sleep; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; GTCA, epilepsy with generalized tonic–clonic seizures alone; FS, febrile seizures; MTLE, mesial temporal lobe epilepsy.

Figure 2

Types of pediatric epilepsies and connection to childhood death. (A) Schematic demonstrating overlapping features of different types of early-onset epilepsy. The overlapping sets mark the complexity of the scenario. (B) Genetic generalized epilepsies (GGE) and febrile seizures often make children predisposed to various premature death. The size of the circles/ovals is arbitrary and does not indicate the frequency of occurrence or other parameters. IGE, idiopathic generalized epilepsy; JME, juvenile myoclonic epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy; GTCA, epilepsy with generalized tonic–clonic seizures alone; MTLE, mesial temporal lobe epilepsy; DEE, developmental and/or epileptic encephalopathy.

Figure 3

Network excitation in healthy and epileptic brain. (A) In a healthy brain, excitatory neurons (ENs) generate a balanced output due to feedback/feedforward inhibition from interneurons (INs). (B) In epileptic patients with channel mutations, this inhibition is reduced due to hypoexcitability or impaired action potential propagation in interneurons, or (C) ENs become inherently hyperexcitable or have a lower threshold for action potentials. These events can occur independently or together, leading to network hyperexcitation. ENs, excitatory neurons; INs, interneurons; IPSP, inhibitory postsynaptic potential; GOF, a gain of function; LOF, loss of function; Na_V, voltage-gated sodium channel; K_V, voltage-gated potassium channel.

Figure 4

Cascade of neurogenesis and gliogenesis in developing mouse brain. The schematic of a coronal hemi-section of a developing mouse cortex shows that the initial phase of brain development involves the expansion of the progenitor pool (neuroepithelial cells and RGCs). This is followed by the formation of neurons (neurogenesis) and glia (gliogenesis) either directly (from RGCs) or indirectly (from IPCs). Newly formed neurons migrate toward the pial surface with the help of radial glial projections and occupy in an inside-out fashion (late-born neurons occupy upper layers, and early-born neurons occupy deep layers). CR cells regulate this radial migration process. Neurogenesis and gliogenesis are followed by synaptogenesis and functional network formation. RGCs, radial glial cells; IPCs, intermediate progenitor cells; CR cells, Cajal–Retzius cells; CP, cortical plate; IZ, intermediate zone; SVZ, subventricular zone; VZ, ventricular zone; E, embryonic; P, postnatal.

Figure 5

Potential role of primary cilia in epilepsy. Primary cilia sense the presence of extracellular cues via signaling receptors. This leads to a cellular cascade that may lead to activation/inactivation of a set of genes. These transcriptional changes can alter the docking or recycling of surface proteins which include signaling receptors and ion channels. In epilepsy, the absence of primary cilia is observed in a proportion of cells. This makes cells insensitive to “cilia-mediated signal sensing.” Making aberrant regulation of ion channels which may tweak the excitation/inhibition balance. Dotted arrows indicate the proposed pathways.

Figure 6

Interconnection of epilepsy with body rhythms and sleep. (A) Summary diagram representing the close association between sleep deprivation and epilepsy. Schematic demonstrates a patient suffering from either sleep deprivation or epilepsy triggers a higher risk of SUDEP. (B) Sleep deprivation in rodents is induced by changing the environment or application of stress. (C) Some of the common molecular and physiological mechanisms underlying sleep deprivation and epilepsy are shown. (D) Close association of sleep deprivation and epilepsy introduces a novel therapeutic angle.

Figure 7

Converging influence of PI3K-AKT–MTOR pathway on epilepsy. The figure summarizes the varied roles of the PI3K-AKT–MTOR pathway in regulating channel protein synthesis, cell migration, formation of primary cilia, and molecular circuit of the circadian clock, besides its function in cell proliferation and differentiation. Mutations in the pathway components can alter these above-mentioned processes, which, in turn, may lead to epilepsy.