In This Article
- Historically, accurate prediction of functional outcomes in patients with aneurysmal subarachnoid hemorrhage has been difficult
- Massachusetts General Hospital researchers conducting extensive metabolite profiling and analysis, or metabolomics, identified an association between early elevated taurine levels and positive 90-day functional outcomes
- Taurine, potentially working as an anti-inflammatory, may serve as a biomarker to drive development of protocols and interventions
- Researchers are planning further work including validation of the initial study and collaboration opportunities
Using advanced metabolite profiling and analysis, Massachusetts General Hospital researchers have identified a potential predictor of long-term functional outcomes in patients experiencing aneurysmal subarachnoid hemorrhage. A recent retrospective study suggests that evaluation of patient taurine levels at admission may allow physicians to accurately anticipate individual progression and recovery, bringing clarity to diagnostics that have been hampered by vaguely defined and poorly predictive assessment tools.
"Our ultimate vision is a clinical and pathological model that provides accurate prediction and the ability to improve outcomes," says Christopher Stapleton, MD, a Mass General neurosurgeon whose work around subarachnoid hemorrhage ranges from predictive growth and rupture models based on computational fluid dynamics to the design of endovascular treatment devices. "We're currently limited in our ability to treat and counsel patients and families dealing with this devastating diagnosis."
Aneurysmal Subarachnoid Hemorrhage
Some 30,000 Americans suffer an aneurysmal subarachnoid hemorrhage each year. In these patients, the rupture of an aneurysm releases blood into the space between the brain and the surrounding membrane.
For several weeks after such an event, the brain undergoes a tremendous inflammatory reaction. The neurologically devastating and sometimes fatal complications a patient might experience are:
- Vasospasm, a tightening of blood vessels in the brain that reduces blood flow
- Hydrocephalus, or swelling in the brain
- Ischemic stroke, often occurring as a result of vasospasm
Patients presenting with aneurysmal subarachnoid hemorrhage experience significant variance in outcomes. Although these patients are frequently healthy and young, with an average age of 55, the mortality rate is near 35%. An additional one-third face severe disability. Previous attempts at predictive models that gauge an individual's risk of complications have not provided accurate, generalizable results.
"Predicting an individual's progression of complications and outcomes currently relies on a crude rank and score methodology," says Dr. Stapleton.
In an attempt to find a better method of predicting outcomes, Dr. Stapleton, Aman Patel, MD, director of Cerebrovascular and Endovascular Neurosurgery, and Taylor Kimberly, MD, PhD, associate director of the Neurosciences Intensive Care Unit at Mass General, and colleagues responded with the development of a metabolomic study to identify a biomarker of functional outcome for this devastating diagnosis.
A metabolite is an amino acid, nitrate, sugar or lipid molecule created as a product of the body's metabolism. In the context of aneurysmal subarachnoid hemorrhage, these substances may arise as byproducts of the body's metabolic reaction to injury. Metabolomics allows researchers to conduct an extensive analysis of plasma, spinal fluid or urine for the presence of, or an alteration in, a single molecule or classes of molecules.
In developing the study of aneurysmal subarachnoid hemorrhage patients, Dr. Stapleton drew from a previous body of metabolite profiling work that successfully identified biomarkers for ischemic stroke patients. Such biomarkers are in the early phases of application in cerebrovascular disease clinical protocols.
Identifying Candidate Biomarkers of Functional Outcomes
Dr. Stapleton's high-throughput, retrospective metabolomic study, reported in the Journal of Neurosurgery, initially enrolled 191 patients presenting with a diagnosis of aneurismal subarachnoid hemorrhage based on non-contrast CT scan results. Catheter-based angiography and CT angiography narrowed the cohort to 137 patients with a confirmed aneurysmal source of subarachnoid hemorrhage.
Researchers assessed 90-day functional outcomes using the modified Rankin Scale (mRS). An mRS score of 0-2 indicated patients were fully independent with no neurological issues and limited disability. Patients with scores of 3-5 and 6 (death) were considered poor outcomes.
Where possible, clinicians collected blood, cerebrospinal fluid and urine on the following days post-hemorrhage:
- 0-5 days
- 6-10 days
- 11-14 days
Dr. Stapleton and Dr. Kimberly conducted extensive profiling of 163 plasma metabolites, comparing the relative levels of these candidate biomarkers during each collection date range.
Early Elevated Taurine as Predictor of Functional Outcome
Plasma analysis, followed by EN (elastic net) and LASSO (least absolute shrinkage and selection operator) machine learning analysis, initially identified six metabolites as potential biomarkers. Further multivariate and univariate analyses of these metabolites showed an association between elevated taurine levels and good 90-day functional outcomes. Researchers narrowed their focus to taurine and began evaluating its levels for each date range. They found that patients with good outcomes had plasma taurine concentrations that were 21.9% higher than patients with poor outcomes between days 0 and 5 after hemorrhage.
The investigators further validated results through logistic regression, adjusting for general and diagnosis-specific factors including:
- Hunt and Hess grade, a scale that defines the severity of a subarachnoid hemorrhage
- Modified Fisher grade, which assesses risk based on amount and type of blood on CT scan
- Delayed cerebral ischemia, which is delayed stroke after aneurysm
After regression, the taurine findings remained a significant independent differentiator between patients with good and poor outcomes.
In patients with good 90-day outcomes, taurine levels were 21.9% higher in days 0-5 and a statistically significant predictor of a good outcome. During in-hospital stays, high taurine at admission was associated with low Hunt and Hess grade and lack of delayed cerebral ischemia.
In patients with poor 90-day outcomes (including death), low taurine levels were associated with death. During in-hospital stays, low taurine was associated with the onset of delayed cerebral ischemia.
"Taurine has risen as a candidate biomarker that may drive innovations such as rapid metabolic testing, early intervention and improved counseling for patients and families," notes Dr. Stapleton.
Exploring the Influence of Taurine on Outcomes
Dr. Stapleton's research into the effects of trauma-induced taurine production and individual outcomes continues, focusing on the metabolic mechanism that drives taurine development and the causal relationship between early elevated taurine levels and good outcomes.
"One high-priority avenue of exploration is the linkage between taurine and the inhibition of pro-inflammatory cytokines, which may reduce the incidence of vasospasm complications and improve outcomes" he says.
His next efforts will include a prospective study with a new cohort of patients. Mass General may consider a partnership with an external institution to provide additional supporting data.
"We view our taurine findings as an important beginning. Further research may include the development of early interventions such as metabolite alteration or medication therapy and ultimately to reduction in specific complications of aneurysmal subarachnoid hemorrhage," says Dr. Stapleton. "Metabolite profiling has the potential to significantly alter the devastating impacts of this diagnosis."
Learn more about the Neuroendovascular Program at Mass General
Refer a patient to the Department of Neurosurgery