Evaluation of Patients Affected by Traumatic and Hypoxic-ischemic Brain Injury

According to the World Health Organization, perinatal asphyxia is the leading cause of severe neurological disabilities and the second leading cause of neonatal death among term infants, with an incidence of 3.94-5.12 per 1,000 live births. Perinatal asphyxia leads to neonatal hypoxic-ischemic encephalopathy, which remains a common cause of neonatal death and long-term disability, affecting 1.5-3 per 1,000 live births in developed countries and up to 26 per 1,000 live births in developing countries. Neonatal hypoxic-ischemic encephalopathy represents a clinical syndrome characterized by neurological function disturbances in the early days of life for infants born after the 35th week of gestation. This condition is marked by altered consciousness levels or seizures, often associated with difficulties in initiating and maintaining breathing, as well as depression of tone and reflexes. There are many potential causes of neonatal encephalopathy, the most common being a hypoxic-ischemic insult. Other causes include infections, perinatal stroke, intracranial hemorrhage, congenital brain malformations, and metabolic and genetic syndromes. Neonatal hypoxia-ischemia is the most common cause of death and disability in newborns and is often associated with persistent motor, sensory, and cognitive deficits. The pathophysiology following neonatal hypoxic-ischemic brain injury is complex and unfolds in several stages. Hypoxic-ischemic encephalopathy evolves through distinct phases: after the initial hypoxic-ischemic event, there is an acute damage phase characterized by anaerobic metabolism, oxidative stress, excitotoxicity, and necrosis of neuronal cells. This phase is followed by a latency period lasting 1-6 hours, marked by neuroinflammation and activation of apoptotic cascades. Within 6-15 hours, a secondary phase develops characterized by cytotoxic edema, excitotoxicity, and cerebral hyperperfusion. Finally, the last phase occurs in the weeks or months following the injury and involves delayed cell death and remodeling of the damaged brain. Currently, therapeutic hypothermia is the standard care for neonates with moderate to severe hypoxic-ischemic encephalopathy. Hypothermia involves cooling the entire body to an internal temperature of 33.5 °C for 72 hours within 6 hours of birth. Scientific evidence indicates that therapeutic hypothermia inhibits key steps in the excitotoxic-oxidative cascade. This therapy improves neurological outcomes at 18 months and at 6 years of age, reducing mortality from 25% to 9% and disability from 20% to 16%, and is now recommended as standard care. However, it does not provide complete neuroprotection and is only partially effective. Even after treatment, there remains a high prevalence of neurological morbidity and mortality affecting 40-50% of surviving neonates undergoing therapeutic hypothermia. After hypothermia treatment, a significant percentage of neonates still develop long-term neurodisabilities. Therefore, it is essential to further optimize and enhance neonatal care. Additional neuroprotective interventions are currently being evaluated in randomized controlled trials, focusing on erythropoietin, allopurinol, topiramate, caffeine, melatonin, or stem cells. However, even experimental therapies have not yet proven effective in improving outcomes for these patients. Following hypoxic-ischemic injury, multiple pathophysiological events trigger secondary injuries. Therefore, the early blockade of these damage mechanisms could lead to a substantial long-term therapeutic effect. New treatments with good therapeutic windows are urgently needed to ensure the best possible preservation of neurological tissue for patients exposed to hypoxic-ischemic insult. Traumatic brain injury (TBI) is a common cause of morbidity and mortality among children and young adults in developed countries. The incidence of TBI has increased in recent years, but the prognosis for these patients has not changed substantially. Approximately 10% of patients with TBI present injuries that require hospitalization, and about 2% have fatal injuries. TBI occurs most frequently in very young children (ages 0 to 4) and in adolescents or young adults (ages 15 to 24), with a subsequent peak incidence in older adults. Post-traumatic brain injuries exhibit a complex pathophysiology, ranging from neuroinflammation and neurodegeneration to increased cerebral blood flow and blood-brain barrier permeability, leading to microvascular brain damage. Primary damage initiates a cascade of biochemical, metabolic, and inflammatory alterations that result in secondary damage associated with glutamatergic excitotoxicity, vascular dysfunction, calcium overload, and neuroinflammation. This primary injury rapidly triggers secondary injury that evolves over weeks or months. Recent studies have proposed the key role of immune system intermediaries and neuroinflammation to explain the pathophysiology of TBI, both acutely and long-term. Indeed, neuroinflammatory processes can persist for several months, thereby contributing to chronic alterations and an acceleration of brain aging in post-TBI patients. Currently, therapies that have shown promising results in patients with post-traumatic brain injuries are unfortunately still limited, especially in the management of severe TBI. Immediately after TBI, multiple pathophysiological events trigger the spread of secondary damage. Therefore, early blockade of one of the damage mechanisms could result in a substantial long-term therapeutic effect. New treatments with a broader therapeutic window are urgently needed to counteract early and chronic pathophysiological events.