Subhabrata Mitra, Gemma Bale, Sean Mathieson, Cristina Uria-Avellana, Judith Meek, Ilias Tachtsidis, Nicola J. Robertson. Changes in cerebral oxidative metabolism during neonatal seizures following hypoxic–ischemic brain injury. Front. Pediatr., 10 August 2016.
Seizures are common following hypoxic–ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic–ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism.
From the article
This is the first report of Δ[oxCCO] fluxes during recurrent seizures in the neonatal brain following perinatal hypoxic–ischemic injury. These fluxes are described relative to changes in cerebral oxygenation, hemodynamics, and electrophysiology. Neuronal energy demand rapidly increased at the onset of seizures reflected by a rapid increase in the mean aEEG activity coinciding with a rise in Δ[oxCCO]. These changes in [oxCCO] occurred even when cerebral tissue oxygenation and hemodynamics were compromised (both Δ[HbD] and Δ[HbT] started to fall before the onset of seizures). After the peak of the seizure activity, energy consumption decreased and Δ[oxCCO] returned toward and below baseline.
Preclinical studies show that broadband NIRS measured CCO signal follows the same trajectory and correlates with high-energy phosphates during primary and secondary energy failure following hypoxic–ischemic brain injury, indicating its ability to represent the changes in mitochondrial energy state. High-energy phosphate stores have also been shown to decline during seizures in both clinical and preclinical studies. Our observed increase in mitochondrial oxidative metabolism during neonatal seizures concurs with these findings and the progressive decrease in [oxCCO] baseline with recurrent seizures in our study indicated a decrease in mitochondrial oxidative metabolism. As cerebral glycogen stores and NADH decline during seizures , this fall in substrate supply further leads to the increase in the oxidation of cytochrome-c-oxidase .
Cerebral oxygenation fell rapidly before the onset of electrographic seizures but soon recovered in parallel with cerebral blood volume. Both parameters continued to increase during the ictal period. Although the cerebral blood volume and oxygenation stabilized, the Δ[oxCCO] continued to drop in the postictal period. A similar mismatch between cerebral hemodynamics and metabolism during post-asphyxial seizures has been described in near-term fetal sheep. Frontal preictal hemodynamics (fall in Δ[HbD] and Δ[HbT] during seizures 2, 4, and 5) and metabolic changes (fall in Δ[oxCCO] during seizures 4 and 5) were noted prior to the onset of seizures. Preictal frontal hemodynamic changes have been previously described in a neonate and in adults. These preictal changes indicate an imminent electrographic seizure. The early preictal drop in Δ[oxCCO] coinciding with a drop in cerebral oxygenation during seizures 4 and 5 indicates a more linear oxygen dependency of Δ[oxCCO] [compared with an initial metabolic buffering period noted during transient anoxia in newborn piglet brain]. This becomes more evident with decreasing mitochondrial energy production following repeated seizures. Oxygenation along with changes in substrate supply and the energy demand are the most important physiological stimuli to influence the redox state of CCO within the ETC. Availability of oxygen relates to oxidation state of CCO in an asymptotic fashion.
Our clinical data complement and extend the previous preclinical studies, which have shown intraneuronal depletion of ATP and increase of ADP, decrease in cortical tissue pH, increased glycolytic flux , increased cerebral oxygen consumption, and oxidation of intramitochondrial NADH during seizures.
We are not able to comment whether [oxCCO] baseline would have returned toward baseline after seizure cessation as our recording stopped at 90 min. However, our observed Δ[oxCCO] baseline drift during the study could be related to increased adenosine concentrations, resulting in suppression of mitochondrial metabolism. Excessive neuronal activation, as occurs during a seizure, leads to neuronal release of adenosine that acts on synapses and terminates seizures. Interestingly, the EEG background remained suppressed for another 30 min after we stopped NIRS monitoring. A clinical decision was taken after the second seizure to stop rewarming, lower the body temperature by 1°C, and commence a bolus dose of phenobarbitone. Ictal changes in cerebral metabolism and hemodynamics followed similar pattern before and after these changes. Ventilatory oxygen delivery and transcutaneous CO2 readings remained stable during the study…
We present a set of novel bedside observations related to brain metabolism during seizures in the newborn brain after perinatal hypoxic–ischemic injury. A rapid increase in Δ[oxCCO], a non-invasive real-time measurement of mitochondrial oxidative metabolism, at the onset of seizures correlated with changes in mean EEG voltage indicating an increase in neuronal activation and energy demand. The progressive fall in the Δ[oxCCO] baseline during repeated seizures indicated a decrease in mitochondrial oxidative metabolism, which could explain the exacerbation of brain injury after repeated or prolonged seizures. However, the interpretation of these measurements is complex, and it is unclear to what extent such changes contribute to long-term neurodevelopmental outcome.
Post a Comment