SANTA CLARA, CA—The mechanisms that allow the neonatal brain to develop quickly also make it highly susceptible to age-specific seizure syndromes that can lead to lifelong neurologic and cognitive disability, according to Frances Jensen, MD, of Children’s Hospital Boston. At the 37th Annual Meeting of the Child Neurology Society, Dr. Jensen emphasized that while new understanding of infant brain neurochemistry, such as the unique properties of synaptic glutamate receptors, including the N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, may offer new avenues for treatment of infant epilepsy, researchers and clinicians must exercise caution and ensure that normal brain development is not impeded.
Age-specific seizure syndromes occur exclusively or in distinctive ways in children younger than 2 years. “For example, neonatal and febrile seizures occur exclusively at specific developmental stages, where the developing brain is more vulnerable to seizure triggers such as hypoxia and hyperthermia,” explained Dr. Jensen, who is also Professor of Neurology at Harvard Medical School in Boston. “Another example of a stage-specific form of epilepsy is the disorder infantile spasms, which occurs between 1 and 18 months of life and is very different, phenotypically, from other seizure syndromes, with a unique hypsarrhythmia pattern on the EEG. Somewhat later in early childhood, there is a high incidence of absence epilepsy, likely related to the unique thalamocortical circuitry of this age-group. If we can understand what’s going on with these unique developmental stages, we might come up with age-specific therapeutic targets, perhaps age-specific biomarkers of disease.”
Dr. Jensen reviewed treatment studies from the past 10 years, noting that most treatments for adult epilepsy are ineffective in infants. “The immature brain, especially the prenatal brain, is very far from being a small adult brain,” she said. “It’s basically a different species.”
Citing a study by Painter et al showing that phenobarbital and phenytoin were effective in about half of infants being treated for neonatal seizures, as well as Sankar and Painter’s overview of numerous other failed attempts to treat infant seizures with barbiturates and benzodiazepines, Dr. Jensen explained that GABA receptor agonists are less effective in the infant brain due to its inherently excitatory state. “Epilepsy in the mature nervous system, essentially, is when excitation outweighs inhibition,” she said. “We think of GABA as the inhibitory neurotransmitter and glutamate as the excitatory neurotransmitter. Normally in the adult brain, inhibition is sufficient to prevent seizures. However, in the baby, at baseline, excitation outweighs inhibition, because the immature brain is designed by nature to be more excitable. Excitation has been shown to be very important for synaptic development, brain development, and activity-mediated development. This makes infants more prone to seizures and gives us clues as to age-specific therapies.”
Several excitatory neurotransmitters, including NMDA and AMPA receptors, are very active in the neonatal brain. Furthermore, AMPA receptors lack the GluR2 subunit and are calcium-permeable during development, which can cause excitotoxicity when combined with calcium-permeable NMDA receptors.
In addition to excitation outweighing classical GABAergic inhibition, some of the cortical neuronal GABA receptors in the immature brain are actually excitatory. These paradoxically excitatory GABA receptors are also present at high levels in fetal brain, gradually decreasing after the first year of life.
In one study, Dr. Jensen’s group induced seizures in newborn rats through acute hypoxia and then treated them with topiramate, which they have shown acts as an AMPA receptor antagonist in this setting. They found a strongly dose-dependent reduction in the number of seizures. Dr. Jensen reported similar results with talampanel, a specific GYKI compound that acts only on AMPA receptors. Levetiracetam is another potential treatment targeting this pathway. Thought to work by blocking vesicle protein 2A, it also behaves as an AMPA receptor antagonist. MR2B, which is similarly elevated during the first year of life, also provides wide-open calcium channels and may be a good therapeutic target.
Another target is chloride, and a difference in neuronal chloride levels is critical for the paradoxical excitatory effects of GABA in the immature brain. In the neonatal brain, the NKCC1 ion cotransporter, which transports chloride into cells, is at peak levels and acts unopposed, because KCC2, which pumps chloride out of cells, is not yet being produced at sufficient levels. Chloride accumulates within the cell, and when GABA opens this channel, the cell depolarizes, producing paradoxical excitation. NKCC1 could therefore be another age-specific target. One way to block NKCC1 is through bumetanide, a potent FDA-approved diuretic. “Phenobarbital and bumetanide combine for a particularly nice effect at suppressing seizures,” Dr. Jensen said. “In our hypoxic rat model, we looked at numbers of seizures and frequency of ictal events. Phenobarbital alone only gets rid of about 50% of the seizures, like in the human studies, but the combination of bumetanide and phenobarbital shows a marked improvement and apparent synergy.”