The Link Between Sepsis, Brain Dysfunction, and Long-Term Cognitive Defects: Neurological Consequences and Pathophysiology of Sepsis-Associated Encephalopathy

Written By Michelle Chan

Introduction

Sepsis is caused by the body’s dysregulated response to an infection. Sepsis-associated encephalopathy (SAE) is brain dysfunction that occurs due to the activation of the immune response within the central nervous system (CNS), triggered by sepsis-related inflammation. SAE is distinct from other types of encephalopathy and does not involve direct infection of the CNS (not the result of a primary CNS infection), nor structural abnormality (except for certain postmortem neuropathology studies of patients with septic shock that have reported cerebral abscesses). SAE is thought to be the most common cause of encephalopathy in the intensive care unit and is reported in up to 70% of patients with sepsis.

Presentation of SAE

In the early stages of SAE, acute encephalopathy and disturbed cerebral function arise, with symptoms ranging in severity, from delirium to coma. Delirium is often the first manifestation of sepsis, making it useful in providing information to potentially help diagnose patients. 

Diagnosis of SAE

SAE is a diagnosis of exclusion. Specific markers for SAE do not exist, so diagnosis relies on the ruling-out of primary CNS infection, other causes of encephalopathy, and other diseases, such as meningitis. 

Laboratory evidence of SAE may manifest as abnormalities in somatosensory evoked potentials, electroencephalography (EEG) measurements, levels of biomarkers of CNS injury and neuroradiological tests. 

Clinical evaluations are used to check the motor response, brainstem reflexes, and mental status of the patient. Biochemical and electrophysiological tests are also conducted, which can involve using neuron-specific enolase and S100 beta as serum biomarkers to help diagnose SAE.

EEG can rule out non-convulsive seizures, aid in diagnosing the neurological complications of sepsis (especially in non-cooperative patients) and help detect the severity of the disease. EEG abnormalities include generalised slowing in background activity, epileptiform discharges, triphasic waves, and theta and delta waves. Dysfunction of deeper structures of the brain is shown through triphasic waves and a burst-suppression pattern. Theta and delta waves indicate diffuse cortical dysfunction. This means that in patients with mild to moderate encephalopathy, theta waves are often present. It also means that in comatose patients, delta activity arises because the impairment in consciousness level is during deep sedation and more severe.

Neuroimaging techniques, such as MRI, are used in patients with SAE who have seizures, persistent encephalopathy and focal neurological signs. In over 50% of cases, MRIs detect brain injury and abnormalities, such as changes in white matter, cerebrovascular complications and other non-specific patterns (such as vasogenic oedema). CT scans should also be performed in patients with SAE to exclude other aetiologies, such as brain lesions (although, these can sometimes be detected in the most severe cases) or other intracranial abnormalities.

Pathophysiology of SAE

The following mechanisms can contribute to the brain dysfunction and injury caused by SAE and lead to white matter changes and cognitive impairment:

1. Cytokine storm and neuroinflammation

Pro-inflammatory cytokines— such as TNF-α, IL-1β and IL-6 - are released and pass through the blood-brain barrier (BBB) via transport proteins, causing it to leak, leading to an influx of immune cells and inflammatory mediators across the BBB. The cytokines activate microglial cells (immune cells of the brain) and cause neuroinflammation, leading to the release of more cytokines, inflammatory mediators, and reactive oxygen species, causing more oxidative stress and neuronal damage. This inflammatory cascade modifies the cytoskeletal structure and damages the cell monolayer, causing abnormal neuronal function and damages vascular endothelium cells, leading to the breakdown of intracellular junctions which causes microvascular leaking and damage to the BBB. Reactive oxygen species and nitric oxide are involved in mechanisms which damage nerve cells and increase apoptosis.

2. Metabolic disturbances

Sepsis can cause mitochondrial dysfunction. This is likely to be mediated by nitric oxide, reactive oxygen species and cytokines, which can have damaging effects on the neurons. Neural cell mitochondrial dysfunction causes a reduction in ATP production, resulting in insufficient energy supply to neurons, as well as leading to neural cell apoptosis.

3. Microvascular and blood-brain barrier alterations

Cerebral microvasculature endothelial cells form the blood-brain barrier (BBB) which protects the brain from changes in the composition of plasma and from compounds in the blood which can disrupt neuronal function.The dysregulated immune response caused by sepsis can cause vascular endothelial cell damage, interrupting tight junction proteins between blood vessels, causing the BBB to leak. This allows monocytes to infiltrate, leading to vasogenic oedema and a heightened neural inflammatory response. This increased brain volume caused by the oedema can also lead to impaired cerebral perfusion (attributed to the Monroe-Kellie doctrine). Furthermore, the BBB is a component of the neurovascular unit, which is formed from cells such as astrocytes and pericytes, both of which are essential to maintain the integrity of the BBB. Thus, dysfunction of these cells causes BBB compromise. 

4. Neurotransmitter disturbances

Some studies have shown that neurotransmitter systems - such as cholinergic, dopaminergic, noradrenergic, GABAergic and serotonergic pathways - could be affected by SAE and lead to delirium in critically ill septic patients. Changes in the cholinergic pathway could lead to changes in the expression of receptors for gamma-aminobutyric acid (GABA), noradrenaline, serotonin and dopamine. Decline in cholinergic function can cause cognitive decline and delirium, both symptoms that are commonly seen in SAE. Insufficient acetylcholine activity can be caused by reduced acetylcholine synthesis and cholinergic synaptic dysfunction due to lack of acetylcholine being produced. Changes in the concentrations of the relevant neurotransmitters can lead to a reduced utilisation of glucose in the brain regions of the serotonergic and noradrenergic system. A study shows that the metabolic changes of these brain regions can be associated with SAE.

Consequences of SAE

SAE can lead to structural brain injury and complications involving damage to the CNS in the long term. This can lead to motor, sensory, or cognitive deficits, seizures, and emotional instability. Neuropsychiatric symptoms, such as depression, anxiety, or cognitive disturbances, may persist in patients with SAE.

SAE is associated with long-term cognitive decline and neurodegenerative diseases, including dementia and Alzheimer’s disease. After being discharged, some patients develop long-term cognitive and functional impairments, potentially leading to higher mortality rates. In one study, it was found that septic patients with organ dysfunction were three times more likely to develop moderate to severe cognitive impairment. There are several possible mechanisms behind this cognitive impairment. A long-term effect of inflammation caused by sepsis is the accumulation of amyloid-beta and tau, which are both associated with cognitive dysfunction and the development of Alzheimer’s disease. Amyloid-beta accumulation and tauopathy can lead to atrophy and changes in white matter, resulting in cognitive impairment. Problems with microglial cell activation due to SAE also contribute to the associated long-term cognitive decline. The chemokine signalling pathway in cytotoxic microglial cells can cause neuronal apoptosis in brain regions linked to cognition, which could bring about deterioration of cognitive function and increase the risk of dementia. Excessive microglia activation can trigger neurotoxic and pro-inflammatory molecules being created, causing the development of age-related diseases, such as dementia. Finally, a study showed that a neuroinflammatory phenotype switch could occur due to acute systemic inflammation (which can be caused by sepsis), involving IL-1β triggering amplified responses in astrocytes and microglia and increasing neuronal network dysfunction, worsening neuroinflammation in Alzheimer’s disease.

Sepsis can also cause damage or dysfunction to peripheral nerves, referred to as ‘critical illness polyneuropathy’, an acute sensory–motor axonal polyneuropathy involving reduced nerve action potential amplitude. It causes mobility issues, weakness and muscle atrophy which can last for years after discharge.

Management of SAE

Early detection of SAE is important for early investigation and treatment. Broad spectrum antibiotics are necessary if the cause is not known. Once the cause is known, the spectrum of antibiotics is narrowed. Managing symptoms is essential, such as treating delirium with antipsychotic therapy or sedative drugs. Ensuring levels of oxygenation, blood pressure, and metabolic balance are maintained is essential. However, the potential neurotoxic effects of some medications used to treat SAE must be closely monitored (for example, antifungals and beta-lactam antibiotics).

By studying the aforementioned mechanisms of SAE, researchers have identified key therapeutic targets when treating SAE. These include the  prevention of BBB damage, regulation of microglial activation and the use of antioxidants, such as glutathione which is used to counteract oxidative stress during sepsis. Future treatments will hopefully effectively target these areas and exploit the inflammatory mechanisms of SAE to improve neurologic outcomes of SAE.

Conclusion

Neurological complications of sepsis significantly impact both short-term and long-term outcomes. This article has shown the neurological consequences of sepsis-associated encephalopathy  (long-term cognitive decline, critical illness polyneuropathy and other deficits) and the pathophysiology of SAE (cytokine storm and inflammation, metabolic disturbances, microvascular and BBB alterations and neurotransmitter imbalances). More studies should investigate the effects of sepsis-associated encephalopathy due to its effects on the brain, leading to brain dysfunction and possible long-term consequences. The main consequence of sepsis-associated encephalopathy that this article has focused on is the potential long-term cognitive decline which can be attributed to the accumulation of amyloid-beta and tau and microglial cell activation. Cytokines activating microglial cells seem to be the underlying factor behind a few problems associated with sepsis-associated encephalopathy.

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