In search of epilepsy biomarkers in the immature brain: goals, challenges and strategies

Abstract

Epilepsy and seizures are very common in the early years of life and are often associated with significant morbidity and mortality. Identification of biomarkers for the early detection of epileptogenicity, epileptogenesis, comorbidities, disease progression and treatment implementation will be very important in implementing more effective therapies. This article summarizes the current needs in the search for new early life epilepsy-related biomarkers and discusses the candidate biomarkers that are under investigation, as well as the challenges associated with the identification and validation of these biomarkers.

Figure 1. Asynchronous brain development across species and developmental processes

(A) The temporal evolution of different developmental processes in the human and rat brain. The age units represent periods equivalent to the gestation: 23 days in rats, 9 months in humans [48,49,51]. (B) Developmental milestones in humans, dogs, mice and cats. Developmental milestones are expressed as the approximate age when adult-like response appears or the neonatal response disappears (data are from [50]). The currently accepted developmental periods equivalent to the infantile stage are presented in the boxes adjacent to the Y-axis for humans, mice, dogs and cats. Please note that many reflexes and behaviors that are maturing during the human infantile stage (righting reflex, tonic neck reflex, crossed extensors) have already matured before the equivalent infantile stage in rats.

Figure 2. Age-specific changes in the expression and function of neurotransmitter systems

(A–D) Age-specific changes in the expression of GABA_A receptor subunits (A), chloride cotransporters KCC2, NKCC1 and GABA_A receptor responses ((B) hippocampus), and NMDA receptors in the hippocampus (C) and cortex (D) of rats. The expression of these receptors and cotransporters changes with age and brain region. In certain cases, these developmental changes alter the function of the relevant receptors, as shown in (B). The developmental increase in KCC2 and decrease in NKCC1 results in the shift of GABA_A receptor responses from depolarizing to hyperpolarizing (reviewed in [47,79]). NMDA: N-methyl-D-aspartate; PN: Postnatal day. (A & B) Reproduced with permission from [47]. (C & D) Reproduced with permission from [86].

Figure 3. Changes in GABA_A receptor expression in the hippocampus after status epilepticus

SE changes the expression of GABA_A receptor subunits in the hippocampus, in a manner that depends upon age at SE induction, subunit type, model of SE induction, and time of observation of changes after the induced SE. All studies are from pilocarpine or lithium–pilocarpine SE, except for the study indicated by †, which utilized kainic acid SE. The data are from representative references on this topic [–85]. PN: Postnatal day; SE: Status epilepticus. Reproduced with permission from [47].

Figure 4. Age-specific changes in seizure-induced pathology and epileptogenic changes

(A) Induction of SE produces neuronal loss, glial activation, inflammation, neurogenesis and synaptic reorganization in a manner that depends upon age at induction of SE. The scale is arbitrary, with positive values if an increase in the stated outcomes is observed and negative values if reduction in the outcomes is seen (i.e., neurogenesis). (B & C) The likelihood of developing epilepsy (B) or increasing susceptibility to induced seizures (assessed by flurothyl or kindling) (C) after SE induced by chemoconvulsants (kainic acid, lithium–pilocarpine) is dependent on the age at induction of the SE. The data are reviewed in [50,87,88]. PN: Postnatal day; SE: Status epilepticus.