Pathways Case Report: The Neurobiology of Delirium in a Septic Elderly Hospitalized Patient
In This Case Study
- A 78-year-old woman with a history of poorly controlled type 2 diabetes mellitus and diabetic kidney disease presented to Massachusetts General Hospital for acute physical and mental decline
- The patient was found at home by a family member in unsafe living conditions (moldy foods, trash pile up), with open leg wounds, and was too weak to walk independently
- The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on elucidating the pathophysiology of this patient's delirium
A 78-year-old woman with a history of poorly controlled type 2 diabetes mellitus and diabetic kidney disease presented to Massachusetts General Hospital for acute physical and mental decline. The patient was found at home by a family member in unsafe living conditions (moldy foods, trash pile up), with open leg wounds, and was too weak to walk independently. Upon review of the chart, the patient had been living independently and was generally oriented to person, place, and time. However, there were provider concerns for recent medication non-adherence and behaviors suggestive of cognitive impairment. On arrival, the patient was found to be hypotensive, hypothermic, lethargic, and oriented only to self. She was started on fluids and antibiotics and admitted for septic shock secondary to infection by Serratia bacteria. Over the next few days, the patient became increasingly drowsy to the point where she was in a coma-like state, despite not receiving any sedating medications. The neurology team was consulted and, after an extensive workup to rule out other causes, it was determined that she likely had dense, hypoactive delirium. While she had several possible risk and precipitating factors for developing delirium, her current episode was thought to be primarily driven by her sepsis.
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The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on elucidating the pathophysiology of this patient's delirium, driven by two questions:
- How might systemic inflammation precipitate delirium in a vulnerable individual?
- Are there any potential pharmacological interventions for delirium?
Background and Diagnosis
Given that delirium is a complex, multifactorial phenomenon, it is thought that there are multiple different neurobiological mechanisms (or endotypes) that can lead to the clinical phenotype of delirium. In other words, delirium may be a spectrum of diseases with unique mechanisms. There are four different potential mechanisms proposed for delirium: bioenergetic insufficiency, neuroinflammation, neurotransmitter imbalance, and impaired network connectivity1. The first proposed mechanism, bioenergetic insufficiency, posits that a lack of adequate glucose or oxygen or metabolic derangements (i.e., hyponatremia, uremia) diffusely in the central nervous system (CNS) can precipitate delirium, particularly in patients with premorbid factors such as advanced age and Alzheimer's disease. Neurons are essentially starved for key nutrients beyond their capacity to function, leading to diffuse dysfunction.
Next, the neuroinflammation hypothesis argues that systemic inflammation triggered by insults (e.g., trauma and sepsis) can activate the immune cells of the CNS (i.e., microglia, astrocytes) to release reactive oxygen species and other inflammatory mediators that can precipitate to neuronal injury. In situations where microglia and astrocytes have been "primed" by prior aging and neurodegeneration, they are likely to be even more reactive to peripheral cytokines leading to greater neuronal insult. The greater the insult, and the fewer the functional reserves at baseline, the more likely someone is to develop delirium.
The third proposed etiology of delirium is related to disturbances in neurotransmitter balance. This imbalance may be induced by anticholinergic or GABAergic medications, impaired renal or hepatic clearance of such drugs, polypharmacy, or drug withdrawal. Finally, the fourth proposed mechanism, impaired network connectivity, suggests that our brain functions best with strong integration between different neural networks. Aging or other neurodegenerative pathologies break down those connections, making us more vulnerable to confusion when an outside insult, such as an anticholinergic medication, disrupts the balance.
While one of the neurobiological pathways outlined above may be enough to trigger delirium, in many instances, such as that of a 78-year-old woman with septic shock, there may have been hits along multiple delirium-causing pathways potentiating the severity of her hypoactive delirium. For example, her age and her history suggest an underlying cognitive impairment, which would limit her cognitive reserve. When presented with insults from a flood of peripheral inflammation due to a bloodstream infection, a temporary lack of adequate nutrients to the brain from shock, a toxic insult from inadequate renal function and certain antibiotics, her higher-level neural networks and ability to process information may temporarily shut down. Thankfully, with the resolution of her infection, cessation of antibiotic therapy, and transfer from the ICU to the general medicine floor, the patient gradually returned to her mental baseline.
Given that our patient's case was likely initially triggered by sepsis, we wanted to further explore the neuroinflammatory mechanism of delirium. We hypothesized that the release of proinflammatory molecules via systemic processes activates primed glial cells, thereby propagating neuronal and network dysfunction in delirium.
Summary and Future Steps
The heterogeneity of delirium in both its triggers and manifestations has created challenges in studying its pathophysiology. Yet, a more complete understanding of delirium is necessary to inform the development of new preventative and therapeutic strategies2. Future investigations will require a coordinated effort involving cellular and animal models alongside human studies to address how disruption of underlying molecular pathways and neural networks leads to delirium.
Possible cellular studies include a combination of unbiased approaches, such as single-cell RNA-sequencing to identify changes in neuronal and glial states in response to systemic inflammation in animal models. Additionally, we need more targeted studies on isolated glial and neuronal cells to assess cytokine production, metabolism, and neurotransmitter release. Cellular mechanisms of delirium identified in animal studies should further be validated in induced pluripotent stem cell models from patients and age-matched controls to study the contribution of these pathways to human disease. The identification of neural networks involved in delirium can be facilitated by recent advances in functional neuroimaging including new PET ligands to image specific neurotransmitter systems3 and diffusion-weighted MRI-based methods to visualize glial activation in vivo4.
From a translational perspective, biomarkers and targeted treatments have remained elusive in the field of delirium. Approaches to discovering delirium biomarkers include quantitative proteomic analyses in cerebrospinal fluid (CSF) to identify putative CSF biomarkers, followed by validation in blood using targeted assays. CSF and blood should be collected at multiple time points throughout delirium to correlate biomarker levels to delirium severity and duration. Modulation of the glymphatic system, a recently described pathway of waste clearance in the CNS, has been suggested to play a role in diverse neurologic pathologies5. As delirium may involve impaired CNS clearance of factors such as proinflammatory molecules and toxins, future studies aimed at increasing glymphatic flow through sleep or medications such as dexmedetomidine may lay the foundation for new delirium treatments6. Importantly, a large, longitudinal cohort study implementing several of the aforementioned methods, including serial CSF collection for biomarker detection and functional neuroimaging, would likely be required to better understand the intricate pathophysiology of delirium as well as its potential relationship to other neurologic disorders such as dementia7.
In summary, the Pathways team hypothesized that in this elderly, hospitalized patient with concomitant sepsis and probable underlying cognitive impairment, systemic inflammation likely promoted activation of primed glial cells in the CNS, thus disrupting neuronal homeostasis, impairing neural network interconnectivity, and ultimately precipitating delirium. Given the high prevalence and morbidity of delirium, future studies applying diverse approaches will be necessary to discover key targetable pathways to not only prevent and treat delirium but mitigate its long-term sequelae.
References
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