Neuron-specific enolase as a prognostic biomarker in acute ischemic stroke patients treated with reperfusion therapies

 Prognostication is fucking useless, NOTHING HERE GET YOU RECOVERED! I'd have you all fired!

Neuron-specific enolase as a prognostic biomarker in acute ischemic stroke patients treated with reperfusion therapies

Tiago Esteves Freitas^1*†Ana Isabel Costa²Leonor Neves³Carolina Barros¹Mariana Martins¹Pedro Freitas¹Duarte Noronha⁴Patrício Freitas¹Teresa Faria²Sofia Borges⁵Sónia Freitas⁵Eva Henriques⁵Ana Célia Sousa⁵

• ¹Stroke Centre, Hospital Dr. Nélio Mendonça, Funchal, Portugal
• ²Internal Medicine Department, Hospital Dr. Nélio Mendonça, Funchal, Portugal
• ³Internal Medicine Department II, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal
• ⁴Neurology Department, Hospital Dr. Nélio Mendonça, Funchal, Portugal
• ⁵Centro de Investigação Clínica Dra. Maria Isabel Mendonça, Funchal, Portugal

Introduction: Ischemic stroke is a significant global health concern, with reperfusion therapies playing a vital role in patient management. Neuron-specific enolase (NSE) has been suggested as a potential biomarker for assessing stroke severity and prognosis, however, the role of NSE in predicting long-term outcomes in patients undergoing reperfusion therapies is still scarce.

Aim: To investigate the association between serum NSE levels at admission and 48 h after reperfusion therapies, and functional outcomes at 90 days in ischemic stroke patients.

Methods: This study conducted a prospective cross-sectional analysis on consecutive acute ischemic stroke patients undergoing intravenous fibrinolysis and/or endovascular thrombectomy. Functional outcomes were assessed using the modified Rankin Scale (mRS) at 90 days post-stroke and two groups were defined according to having unfavorable (mRS3-6) or favorable (mRS0-2) outcome. Demographic, clinical, radiological, and laboratory data were collected, including NSE levels at admission and 48 h. Spearman’s coefficient evaluated the correlation between analyzed variables. Logistic regression analysis was performed to verify which variables were independently associated with unfavorable outcome. Two ROC curves determined the cut-off points for NSE at admission and 48 h, being compared by Delong test.

Results: Analysis of 79 patients undergoing reperfusion treatment following acute stroke revealed that patients with mRS 3–6 had higher NIHSS at admission (p < 0.0001), higher NIHSS at 24 h (p < 0.0001), and higher NSE levels at 48 h (p = 0.008) when compared to those with mRS 0–2. Optimal cut-off values for NSE₀ (>14.2 ng/mL) and NSE_48h (>26.3 ng/mL) were identified, showing associations with worse clinical outcomes. Adjusted analyses demonstrated that patients with NSE_48h > 26.3 ng/mL had a 13.5 times higher risk of unfavorable outcome, while each unit increase in NIHSS_24h score was associated with a 22% increase in unfavorable outcome. Receiver operating characteristic analysis indicated similar predictive abilities of NSE levels at admission and 48 h (p = 0.298). Additionally, a strong positive correlation was observed between NSE_48h levels and mRS at 90 days (r = 0.400 and p < 0.0001), suggesting that higher NSE levels indicate worse neurological disability post-stroke.

Conclusion: Serum NSE levels at 48 h post-reperfusion therapies are associated with functional outcomes in ischemic stroke patients, serving as potential tool for patient long-term prognosis.

1 Introduction

Prognostication plays an essential role(NO it doesn't, because currently this will predict failure to recover. Prognostication is totally fucking useless in getting survivors recovered! Since you don't know that, you are all fired! Change that to; 'Do these protocols and you will 100% recover! Anything less is medical malpractice!') in decision making by offering patients and their families the necessary information to set realistic and achievable care goals. It helps determine eligibility for specific benefits and targets interventions to those who are most likely to benefit. Prognostication includes three main components: clinicians estimate the likelihood of a particular outcome over a certain period using their clinical judgment or other tools; this estimate is shared with the patient according to their preferred way of receiving information; and the patient or their surrogate uses this information to make informed clinical decisions (1).

Age, stroke severity, stoke mechanism, infarct location, comorbid conditions, clinical findings, and related complications influence stroke prognosis. Whether reperfusion therapies (fibrinolysis and/or thrombectomy) are conducted and the quality of stroke unit care given, including early start of physical rehabilitation and prompt introduction of secondary prevention measures, also influence the outcome of ischemic stroke (2).

Patient history, clinical examination and imaging technology have been the cornerstone in assessing stroke patients, guiding therapeutic decisions, and monitoring disease progression. Akin to the established gold standard in Cardiology, where biomarkers such as high sensitivity troponins have revolutionized the assessment of myocardial infarction (3), incorporating biomarkers into stroke management holds immense potential. These biomarkers offer a promising avenue to identify patients at heightened risk of severe disease, tailor treatment strategies, predict the response to reperfusion therapies and reasonably predict the overall prognosis and outcomes. While numerous proteins serve as markers of brain tissue damage, inflammation and coagulation/thrombosis, their utility is hindered by a lack of specificity to ischemic stroke, given that various other diseases processes can also damage the brain tissue (4).

For a biomarker to prove useful in stroke management, it should meet some basic criteria: be specific to the brain tissue, rise immediately within hours of a tissue insult, proportionally reflect the extent of brain damage, and ultimately serve as a reliable prognostic indicator for the event (5). Numerous biomarkers have been associated with short-and long-term clinical outcomes after stroke, but most of them have failed to improve the prediction capacities of conventional clinical variables. Biomarkers of ischemic brain injury include S100 calcium binding protein B (S-100B), neuron-specific enolase (NSE), myelin basic protein and glial fibrillary acid protein, among others (6).

The NSE is a dimeric intracellular neuronal glycolytic enzyme, primarily located in the cytoplasm of neurons, cells of the diffuse neuroendocrine system and erythrocytes. Elevated levels of NSE have been observed in response to sudden central nervous system events, such as cerebral infarction, subarachnoid hemorrhage, head injury, hypoxia, seizures, and cardiac arrest. These conditions are characterized by the disruption of the blood–brain barrier and subsequent damage of neuronal cells, leading to a leakage of NSE, which can be detected in cerebral spinal fluid but also in saliva or blood samples (7). Several studies propose NSE as a marker of brain damage following an ischemic event. There is also a correlation between NSE levels and acute ischemic stroke severity, infarction volume, extent of brain tissue damage [as clinically measured by the National Institutes of Health Stroke Scale (NIHSS) score], and poor functional outcomes (5, 8, 9).

NSE levels change dynamically following symptom onset, reflecting the necrosis of neuronal cells within the ischemic penumbra. Lower NSE levels are associated with clinical diffusion mismatch (7), serving as an alternative indicator for salvageable ischemic tissue that may be more responsive to interventions such as intravenous fibrinolysis and/or mechanical thrombectomy. However, high NSE levels are not exclusive to ischemic stroke and can also be found in other diseases such as neuroendocrine cell cancers like small cell lung cancers, neuroblastomas, melanomas and carcinoid tumors (10).

Since its approval by the European Stroke Organization in 2008, intravenous thrombolysis with alteplase has been a recognized systemic reperfusion treatment for patients with acute ischemic stroke (11). The pivotal MR CLEAN study published in 2015 further solidified the landscape by demonstrating the safety, efficacy and favorable impact on functional outcomes associated with intraarterial thrombectomy (12).

Building upon these advancements, our study aimed to evaluate the relationship between NSE levels at patient admission and 48 h post-reperfusion therapies, and functional outcome in ischemic stroke patients.