When the body experiences high levels of inflammation – such as during bacterial or viral infections – it changes the way our brain works, which in turn affects our mood and motivation. In older patients, this acute inflammation can produce a profound disturbance of brain function known as delirium. Everyone will have experienced as a child or adolescent that sometimes when one contracted a severe fever, one felt exhausted and sometimes without any desire to eat. Systemic infection, indeed, triggers a spectrum of metabolic and behavioral changes, termed sickness behavior, which includes fever, lethargy, loss of appetite and anhedonia (loss of interest). Disease behavior is an evolutionarily conserved response and represents a reprogramming by the organism to conserve energy and maximize the likelihood of recovery. Disease behavior sometimes includes cognitive impairment.
Delirium is an acute and fluctuating onset syndrome characterized by the inability to sustain attention, decreased awareness and severe cognitive impairment. Basically is a complex cognitive disorder characterized by acute deterioration in awareness, attention and cognition, which affects memory, language, orientation and perception. It occurs in people who are medically unwell, due to the underlying disease (e.g. sepsis, dementia, cancer, chronic kidney failure) or temporary issues and the subsequent medical treatment (e.g. surgery, medication). Delirium is associated with prolonged hospitalization: indeed, it affects approximately 1 in 5 hospitalized patients or 1/3 for those over 80 and may lead to subsequent cognitive decline and increased risk of dementia, but the neurobiological understanding of delirium is limited. In the last two decades, several hypotheses have been proposed to unravel the pathobiogenesis of this condition.
Current hypotheses include: neuronal ageing, neuroinflammation, oxidative stress, neuroendocrine dysregulation, neurotransmitter unbalance and disruption to the circadian rhythm. A reduction in glucose metabolism seen in people with delirium is a model with developing evidence. Indeed, scientists at Trinity College in Dublin have found that artificially inducing peripheral inflammation in mice triggered sudden-onset cognitive dysfunction and that this is mediated by an energy metabolism disorder. In these experiments, the inflammation left the mice with lower levels of blood sugar. When the animals were supplemented with glucose, their cognitive performance returned to normal, despite continued inflammation. Simply providing glucose to patients is unable to treat delirium in most cases, but the data collectively underscores that adequate oxygen and glucose supply to the brain becomes important, especially in older patients.
In humans, cytokines in the brain cause norepinephrine to be released, while at the peripheral level they lower blood sugar; the combination of effects would lead to delirium.Beside bacterial or viral diseases, inflammation is coexisting with a tumoral disease. There are already evidence that the guilty actors in this framework are immune cytokines. A recent meta-analytic review on the issue reported that there are at least 40 common biomarkers between the regular delirium and the form induced by late-stage cancer. Among them, five are C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor alpha (TNF-α). But there are also biomarkers not shared: for example, in sepsis-induced delirium there is CRP, cortisol and S100B protein; none of them, instead apperas in the cerebrospinal fluid of patients with cancer and delirium.
The reason for the probable appearance of delirium in cancer patients is certainly given by the cytokines produced by the tumor, as well as by its greed for glucose as a source of energy. It is not impossible that, alongside the inflammatory action of cytokines in the brain, there are hypoglycemic peaks in these patients that trigger the appearance of the phenomenon. And what aboutnthe delirium in a much more frequent contest: the neurologic wards filled with patients having brain stroke? The pathogenesis in this case is due to the reworking of the brain lesion, especially if its nature is hemorrhagic rather than ischemic. The haemorrhagic infarction activates the proliferation of astrocytes which, like fibroblasts, pushed by oxidative stress, the release of cytokines from the microglia and by alterations of their neurochemistry, proliferate and circumscribe the damage.
This undergoes remodeling in weeks and what remains is only a necrotic area, that will be replaced by a scar deposit rich in astrocytes (glial scar). And indeed these cells are the responsible for the onset of phenomena like seizures, hallucinations, cognitive impairment and delirium. They are “electrically” active, strongly greedy for glucose and reshuffling the neurotrasmitter network of the damaged area. Glutamate is perhaps the main neurotransmitter that astrocyte use for their dialogue with neural cells. It is derived from glutamine and its metabolism is strongly dependent on cellular degradation of glucose (glycolysis). It has several types of receptors, the most common of which are metabotropic (mGlu) and ionotropic ones, the most famous of which is NMDAR o N-methyl-D-aspartate receptor. This ion channel activated by glutamate allows sodium and calcium to enter neurons, triggering nervous electrical excitability.
Repeated stimulation, such as that which occurs in cerebral infarct lesions, however, can ultimately kill neurons due to the phenomenon of excitotoxicity. Once a patient with brain stroke has shown seizure-like phenomena ora dissociation or delirium-like symptoms, is has indeed become glood clinical practice to administer antagonists like levetiracetam for the post-discharge rehab period, especially if the patients have been diagnosed with subarachnoid hemorrage. Finally, it is increasingly evident how elderlies that had undergone surgical procedures like femur fracture re-synthesis due to a pathological fall, knee arthroplasty and the like, have the tendency to develop delirium and overt dementia. It is speculated that therse subjects were already “borderline” for developing a form of dementia, since tehy already suffered with cerebrovascular disease and initial cognitive impairment.
These patients are most of the times cardiopatic, they use diuretics to control their high blood pressure and, in a good portion of the whole, they may have a nutritional deficiency. To solve the bone fracture by surgical intervention, anesthesia is required. Here it comes that, sometimes, in an average timelapse of 48-72 hours post-surgery, these patients start to have memory problems, judgement lapses, even aggression or oppositive behavior to medical treatments. Sometimes these patients have also type 2 diabetes, with or without complications, which may enhance the blood glucose unbalance and thin the gap between the traumatic injury and the onset of the delirium. This is why current strategies deemed opportune to treat the problem cover the proper i.v. hydration, narrowing the blood loss during the surgery, eventually supplying that with a transfusion, blood glucose monitoring, opportune nutrional load, improvement of kidney or liver function and avoiding a deep anesthesia.
Indeed, a very recent report found that anesthesia in a rat model of senile dementia (tauopathy), led to the enhanced expression of genes like beta-amyloid and other related to the Alzheimer disease. There are, finally, increasing evidence that general anesthesia may cowork with gut dysbiosis in allowing a thin thread between intestine and brain to undergo rupture. This would corroborate the clinical experience of people undergoing delirium and a sudden (then at least) permanent cognitive decline after a post-traumatic surgery requiring general anesthesia.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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