Advances in biomarkers for predicting outcomes in pediatric neurosurgical hemorrhagic conditions: a narrative review to enhance quality of care

Abstract

Pediatric neurosurgical hemorrhagic conditions, such as subarachnoid hemorrhage, intracerebral hemorrhage, and arteriovenous malformations, present unique diagnostic and therapeutic challenges. Advances in biomarker research offer promising opportunities to enhance diagnostic precision, outcome prediction, and personalized therapeutic strategies.

This narrative review aims to synthesize current evidence on the role of biomarkers in pediatric neurosurgical hemorrhagic conditions and highlight their integration into clinical practice to improve outcomes.

This narrative review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to ensure transparency and reproducibility. A comprehensive literature search was performed across PubMed and EMBASE for studies published between January 2000 and February 2024, with earlier landmark studies included for context. English-language articles were screened based on relevance, with two reviewers independently selecting studies on biomarkers in pediatric hemorrhagic neurosurgical conditions. Studies with no relevant biomarker information, non-english articles, and case-reports were excluded. Data were extracted on biomarker types, functions, detection methods, and clinical outcomes. Thematic analysis was used to synthesize findings, and the quality of included systematic reviews was assessed using AMSTAR 2.

Biomarkers like S100B and neuron-specific enolase aid in prognostication and therapeutic guidance, especially when combined with imaging modalities. Challenges in lack of standardized protocols, high costs, and limited pediatric-specific research persist. Global collaboration and innovative approaches are critical to address these barriers and optimize biomarker utility in clinical settings. Biomarkers represent a transformative approach in pediatric neurosurgery, enhancing diagnostic accuracy and treatment personalization. Future efforts should focus on validating pediatric-specific biomarkers, addressing disparities in health care access (or overcoming barriers to implementation), and fostering global collaboration to standardize biomarker use.

Introduction

Pediatric neurosurgical hemorrhagic conditions, encompassing subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and arteriovenous malformations (AVMs), present unique challenges in clinical care due to their distinct etiology, pathophysiology, and management. These conditions contribute significantly to the global burden of pediatric stroke, with an estimated annual incidence of hemorrhagic strokes ranging from 1.2 to 13 cases per 100 000 children^[1]. Incidence rates vary based on demographics and geographical regions; for instance, low- and middle-income countries experience significant diagnostic and treatment challenges due to limited health care infrastructure^[2].

SAH refers to bleeding into the subarachnoid space, primarily caused by ruptured intracranial aneurysms, and accounts for 5–10% of strokes in the pediatric population. Early intervention is crucial to mitigate risks such as aneurysm re-rupture and long-term neuropsychological impairments^[3]. ICH, characterized by bleeding directly into the brain parenchyma, accounts for 23–70% of pediatric hemorrhagic strokes and often stems from vascular anomalies like AVMs or cavernomas. Despite the greater neuroplasticity in children, ICH remains associated with significant cognitive and adaptive deficits^[2,4]. AVMs are congenital tangles of abnormal blood vessels connecting arteries and veins, predisposing pediatric patients to ICH, with rupture risks heightened by features like small nidus size and deep venous drainage^[5,6].

Accurate outcome prediction is crucial for tailoring interventions and long-term care strategies, enabling clinicians to make decisions on therapeutic intensity, rehabilitation, and family counseling. This need is further emphasized by the complexity of pediatric neurosurgical hemorrhagic conditions, where timely and precise assessments can significantly impact patient outcomes. Molecular biomarkers, such as circulating microRNAs (miRNAs), neuron-specific enolase (NSE), and S100B, are vital in this context. S100B, a calcium-binding protein, demonstrates high sensitivity in identifying brain injuries and correlates strongly with poor outcomes when used alongside neuroimaging findings^[7,8].

Recent advances emphasize the integration of biomarker data with imaging modalities like computed tomography (CT) and digital subtraction angiography for precise diagnosis and risk stratification. For example, trajectory analyses of biomarkers such as myelin basic protein (MBP) and NSE provide insights into disease progression, offering improved outcome prediction models^[1,7]. In addition to biomarker innovations, advancements in pediatric neurosurgical management have included minimally invasive endovascular techniques, enhanced neurocritical care protocols, and improved perioperative monitoring strategies, which collectively contribute to better clinical outcomes and reduced long-term morbidity^[6]. These multimodal approaches enhance understanding of injury mechanisms, enabling early identification of high-risk patients and potentially guiding experimental therapeutic trials.

This review synthesizes advancements in biomarker research to improve the diagnosis, outcome prediction, and care of pediatric neurosurgical hemorrhagic conditions. By integrating findings across clinical and laboratory studies, the article underscores the transformative potential of biomarkers in addressing the multifaceted challenges of pediatric neurosurgery while highlighting the need for continued research in developing robust, evidence-based predictive models. For the purpose of this review, “pediatric” encompasses the full 0–18 year age range, including neonates, infants, children, and adolescents, in accordance with World Health Organization (WHO) and American Academy of Pediatrics (AAP) standards. This scope is consistently applied across all sections of the review.

HIGHLIGHTS

• Biomarkers enhance diagnostic accuracy: S100B and neuron-specific enolase aid in early detection of brain injury.

• Improved outcome prediction: Biomarkers predict complications like hydrocephalus and vasospasm.

• Personalized treatment: Biomarkers guide treatment intensity and rehabilitation.

• Overcoming barriers: Standardization and cost-effectiveness are crucial for wider use.

• Future directions: AI and precision medicine will revolutionize biomarker applications.

This manuscript was prepared in accordance with the TITAN Guidelines 2025 governing Al use in scholarly publications^[9].

Methodology

Review design and framework

This narrative review was conducted in accordance with the PRISMA framework to ensure methodological transparency and reproducibility. The PRISMA flowchart (Fig. 1) has been incorporated to illustrate the study identification, screening, eligibility, and inclusion processes.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework.

Data sources and search strategy

A comprehensive literature search was performed across three major databases – PubMed (60 articles) and EMBASE (70 articles). The search covered publications primarily from January 2000 to February 2024, though earlier seminal studies were also included to contextualize recent advancements in biomarker research.

The search strategy utilized a combination of controlled vocabulary and free-text terms, incorporating Boolean operators to enhance specificity and sensitivity.

The search string was structured as follows: “biomarker OR biological marker OR molecular marker AND pediatric OR child OR infant OR adolescent AND neurosurgery OR neurosurgical procedures OR brain surgery AND hemorrhage OR haemorrhage OR intracerebral hemorrhage OR subarachnoid hemorrhage OR brain bleed AND treatment outcome OR prognosis OR clinical outcomes OR mortality OR morbidity AND health care quality OR quality of care OR healthcare quality.” Only English-language articles were included.

Study selection

Following removal of duplicates, studies were screened based on title and abstract relevance, and eligible full-text articles were reviewed for inclusion. Two reviewers independently conducted the selection process, with disagreements resolved through consensus or third-party adjudication.

Inclusion and exclusion criteria

The inclusion criteria comprised studies focusing on pediatric populations from neonates to adolescents (0–18 years), in line with WHO and AAP definitions. Eligible studies addressed the role of biomarkers in pediatric hemorrhagic neurosurgical conditions – such as SAH, ICH, AVMs, and intraventricular hemorrhage (IVH) – and evaluated biomarkers for diagnostic, prognostic, or predictive purposes.

Exclusion criteria encompassed studies exclusively involving adult populations, lacking original data, or unrelated to hemorrhagic conditions.

Data extraction and management

Key information extracted from each study included population characteristics, type, and function of biomarkers studied (e.g., S100B, NSE, GFAP, NfL, and miRNAs), methodological details (such as sample source and detection techniques), and clinical outcomes (e.g., mortality, functional recovery, and complication rates).

Quality Assessment

To assess methodological quality, systematic reviews and meta-analyses identified within the dataset were assessed using the AMSTAR 2 checklist to evaluate methodological quality. Observational studies were qualitatively reviewed, emphasizing sample robustness, biomarker specificity, and clinical significance.

Data synthesis and analysis

Although the primary format of the review is narrative, thematic analysis was employed to synthesize findings across studies. Themes were inductively developed to capture recurring concepts such as biomarker classification (diagnostic, prognostic, and predictive), integration with imaging techniques, and application in personalized treatment strategies.

This methodology enabled a nuanced synthesis of emerging and established evidence, supporting the development of a comprehensive framework for understanding the clinical utility of biomarkers in pediatric neurosurgical hemorrhagic conditions.

Overview of pediatric hemorrhagic neurosurgical conditions

Pediatric hemorrhagic neurosurgical conditions encompass a wide range of pathologies, each with distinct etiologies, clinical manifestations, and challenges in management. Key conditions include SAH, ICH, AVMs, and other hemorrhagic entities such as epidural hematomas (EDH) and subdural hematomas (SDH). In recent years, biomarkers have emerged as valuable tools in enhancing the diagnosis, prognosis, and management of these conditions, offering insights into disease progression and guiding personalized treatment strategies.

Germinal matrix hemorrhage (GMH) and Choroid Plexus IVH are highly prevalent in neonates and preterm infants, due to the vascular fragility of the germinal matrix. GMH occurs in 67% of infants born at 28–32 weeks and 80% at 23–24 weeks, with 90% of hemorrhages detected within 4 days of birth and 40% within the first 5 hours^[10]. IVH often accompanies GMH, contributing to complications like post-hemorrhagic hydrocephalus and cognitive impairments^[11]. Biomarkers such as S100B and interleukin-6 (IL-6) show promise in early detection and prognosis. Elevated S100B levels correlate with brain injury severity, while IL-6 reflects inflammatory responses that exacerbate hydrocephalus risk^[12].

Pediatric SAH is a rare but life-threatening condition mainly caused by factors such as ruptured intracranial aneurysms, vascular malformations, or infections, which result in blood accumulation in the subarachnoid space. In children, it often arises from congenital issues, including connective tissue disorders like Marfan syndrome and vascular abnormalities such as Moyamoya disease. Mycotic aneurysms, linked to infections like bacterial endocarditis, are also more prevalent in children. Symptoms include seizures, lethargy, vomiting, and signs of raised intracranial pressure (ICP). Complications include hydrocephalus due to blood clot obstruction. Advancements in endovascular therapies and aneurysm coiling have improved survival rates, though long-term neuropsychological outcomes vary^[3,13].

Pediatric ICH accounts for 23–70% of pediatric hemorrhagic strokes and is often caused by vascular malformations (e.g., AVMs), coagulopathies (e.g., hemophilia), or systemic diseases such as sickle cell disease. The presentation and outcomes of pediatric ICH differ significantly from adults. Vascular malformations are the most common etiology, contributing to 40–90% of cases. Age-specific variations include a higher prevalence of coagulopathies in neonates and an increased frequency of AVMs in older children. ICH often results in neurological and cognitive deficits, including impaired verbal comprehension and working memory, with recovery trajectories influenced by early intervention and neuroplasticity. Novel biomarkers, such as S100B and NSE, combined with neuroimaging, have shown potential for predicting outcomes and guiding interventions^[1,2].

AVMs are the most common cause of spontaneous ICHs in children, contributing to 30–50% of cases. These congenital vascular lesions feature direct arteriovenous shunting without capillaries, resulting in increased pressure on venous structures and high rupture risks. Pediatric AVMs are more likely to present with hemorrhage compared to adults, with bleeding risks estimated at 2–10% annually. Key predictors of rupture include deep venous drainage, nidus size, and associated aneurysms. Advanced multimodal management, including microsurgical resection, embolization, and stereotactic radiosurgery, has improved survival rates. However, controversy remains regarding the optimal treatment sequence and timing, especially in younger patients with complex AVMs^[7,14].

EDH and SDH, though less common, are critical in pediatric neurosurgery. EDHs typically follow trauma and involve bleeding between the dura mater and the skull. They often present with subtle symptoms such as scalp hematoma and transient loss of consciousness, requiring high diagnostic vigilance. SDHs, frequently associated with abusive head trauma, result from bridging vein tears and can cause seizures, lethargy, and vomiting. Advances in imaging techniques, such as thin-section CT and magnetic resonance imaging (MRI), have enhanced diagnostic precision, aiding in timely surgical interventions or non-operative management in stable cases^[15,16]. In summary, pediatric hemorrhagic neurosurgical conditions present significant diagnostic and therapeutic challenges, but advancements in biomarkers, imaging techniques, and multimodal management strategies continue to improve diagnostic precision, treatment outcomes, and long-term care for this vulnerable population.

Clinical presentation

Pediatric hemorrhagic neurosurgical conditions vary in clinical presentation based on underlying pathology, severity, and age. Common symptoms include headaches from increased ICP, described as pulsatile or sharp and localized to the hemorrhage site. Vomiting often occurs due to ICP changes, typically without nausea. Seizures affect up to 60% of pediatric patients with ICH and AVMs, frequently presenting at diagnosis and potentially recurring if untreated. Neurological deficits-including hemiparesis, aphasia, or cranial nerve palsies-often indicate significant brain involvement or mass effect caused by hemorrhage^[17–19].

Compared to adults, pediatric patients often exhibit more subtle or nonspecific symptoms, which can lead to delays in diagnosis and treatment. For instance, infants may present with irritability, lethargy, or poor feeding, rather than the sudden, severe headache commonly reported by adults. These differences underscore the importance of heightened clinical vigilance in pediatric populations^[20].

The variation in clinical presentation between children and adults can significantly impact the diagnosis and treatment timeline. In children, the subtlety of symptoms may lead to delays in seeking medical attention and initiating appropriate interventions, increasing the risk of complications such as hydrocephalus or rebleeding. Early recognition and intervention are crucial to minimize long-term neurological deficits and improve overall outcomes^[21].

Conditions like chronic subdural hematoma (CSDH) in children often present with prolonged nonspecific symptoms, such as chronic headache and behavioral changes, complicating early diagnosis^[19]. In more acute cases like EDHs, the classic lucid interval – initial improvement in consciousness followed by rapid deterioration – occurs in only 7–14% of cases, emphasizing the need for vigilance in atypical presentations^[22]. The complexity of symptoms often delays diagnosis, especially in younger patients who may present with irritability, lethargy, or non-specific signs.

Risk factors

Risk factors for pediatric hemorrhagic conditions are multifactorial. Genetic factors, such as mutations in RNF213, have been linked to conditions like Moyamoya disease, which predisposes children to ICH due to progressive arterial stenosis^[23]. Vascular malformations, including AVMs, are the leading cause of hemorrhagic strokes in children, contributing to 55% of cases. Notably, AVMs located near the periventricular region have a higher risk of rupture and more severe outcomes, with annual hemorrhage rates of 6.88% in untreated cases^[24].

Geographical and socioeconomic factors also influence the prevalence and outcomes of pediatric hemorrhagic strokes. Studies have shown that children from lower socioeconomic backgrounds have a higher incidence of stroke, which may be attributed to disparities in access to health care, nutrition, and exposure to environmental risk factors. Additionally, regional variations exist, with certain areas exhibiting higher stroke rates due to genetic predispositions and lifestyle factors prevalent in those populations. For example, the “Stroke Belt” in the southeastern United States is characterized by increased stroke mortality rates, which have been linked to both socioeconomic disadvantages and regional health behaviors^[25,26].

Trauma remains a significant contributor, particularly in conditions like EDHs and SDHs. In neonates, birth-related injuries, including trauma during delivery or forceps-assisted deliveries, are significant risk factors for ICH and SDHs.

Coagulation disorders, including hemophilia, vitamin K deficiency, or acquired coagulopathies, are particularly relevant in spontaneous or recurrent hemorrhagic presentations. Prolonged prothrombin time and activated partial thromboplastin time have been observed in pediatric CSDH, underscoring the need for coagulopathy screening in unexplained hemorrhages^[19]. Table 1 illustrates the types of pediatric hemorrhagic conditions, highlighting their clinical signs, associated risk factors, and management strategies.

Table 1.

Types of pediatric hemorrhagic conditions – risk factors, clinical features, and management

Pediatric hemorrhagic conditions	Sub arachnoid hemorrhage	Intra-cranial hemorrhage	Arteriovenous malformation	Epidural hematoma	Subdural hematoma
Risk factors:	Connective tissue disorders – Marfan syndrome Vascular abnormalities – Moyamoya disease Mycotic aneurysms	Vascular malformations (e.g., AVMs) Coagulopathies (e.g., hemophilia) Sickle cell disease	Congenital vascular malformations Trauma Genetic conditions (Hereditary Hemorrhagic Telangiectasia, Neurocutaneous Syndromes, Capillary Malformation–Arteriovenous Malformation Syndrome)	Trauma	Abusive head trauma (shaking, impact, etc.)
Common clinical features:	Signs of raised intracranial pressure (bulging fontanelle, irritability, and lethargy) Focal neurological deficits Seizures Headache Nausea and vomiting (projectile) Altered consciousness/loss of consciousness
Specific clinical features:	Severe headache (thunderclap headache) Neck stiffness Photophobia	Hemiparesis or paralysis Pupillary changes	Cranial bruit Cognitive impairment	Scalp hematoma Transient loss of consciousness Lucid interval Pupillary changes	Developmental regression (in infants)
Investigations:	Novel biomarkers combined with state-of-art imaging modalities such as CT scan and MRI aid in prompt diagnosis of these conditions.
Management:	Endovascular therapies Aneurysm coiling	Non-operative management in stable cases Surgical interventions	Microsurgical resection Embolization Stereotactic radiosurgery	Non-operative management in stable cases Surgical interventions	Non-operative management in stable cases Surgical interventions

Challenges in predicting outcomes

Pediatric hemorrhagic conditions present significant challenges in predicting long-term outcomes due to their complexity and variability. Factors such as size, location, and etiology of the hemorrhage are crucial in determining prognosis. For instance, AVMs over 3 cm, those in eloquent regions, or with deep venous drainage are linked to persistent neurological deficits and poorer outcomes^[18]. Children with severe hemorrhage or delayed treatment face higher risks for complications like hydrocephalus, seizures, and cognitive impairments.

Despite advancements in imaging and biomarkers research, predicting recovery remains a challenge. Biomarkers such as S100B and NSE show promise for early detection and prognostication, but their clinical integration is inconsistent due to variable results and limited pediatric data. A systematic review highlighted the potential of these biomarkers in assessing pediatric traumatic brain injury (TBI) but emphasized the need for further large-scale studies to validate their efficacy^[8]. The plasticity of the developing brain can offer recovery potential but also adds unpredictability to outcomes^[24].

Atypical presentations, such as those in chronic SDH, often delay diagnosis and complicate outcome predictions due to subtle symptoms masking severe pathology. Moreover, access to specialized care and regional disparities in health care infrastructure contribute to variability in outcomes, underscoring the need for standardized approaches to management and follow-up^[22].

Advancements in neuroimaging, such as MRI, complement biomarker-based predictions by providing detailed insights into brain structure and function. A study found that early MRI measures, including diffusion-weighted imaging, can predict long-term outcomes after severe TBI in children, thereby improving early detection and personalized treatment planning. Integrating these modalities can enhance prognostic accuracy and guide targeted interventions, ultimately improving patient outcomes^[27].

Biomarkers in pediatric neurosurgery: role in predicting outcomes

Biomarkers are measurable indicators of biological processes, pathology, or responses to therapy. In pediatric neurosurgical conditions such as SAH, ICH, AVMs, and hematomas (epidural and subdural), they play an essential role in diagnosis, management, and predicting outcomes. Biomarkers from blood, cerebrospinal fluid (CSF), and brain tissue offer insights into brain injury mechanisms, supporting timely and personalized clinical decisions^[1,28].

To contextualize current biomarker research, Table 2 summarizes key characteristics and findings of major studies focused on biomarkers in pediatric neurosurgical hemorrhagic conditions. The studies span multiple biomarker types (e.g., S100B, GFAP, NSE, and NfL), methodologies (cohort studies, systematic reviews, and proteomic analyses), and patient populations, providing a foundational basis for understanding their diagnostic and prognostic value.

Table 2.

Characteristics of included studies on biomarkers in pediatric neurosurgical hemorrhagic conditions

Author (year) [Ref]	Study type	Biomarkers studied	Pediatric population	Condition	Key findings
Lawton et al (2017)[1]	Review	None (Contextual)	Not specific	SAH	Landmark review; foundational understanding of SAH.
Berger et al (2011)[6]	Prospective cohort	NSE, S100B	Pediatric TBI	ICH and SAH	Serum trajectories correlate with long-term outcomes.
Marzano et al (2022)[7]	Systematic Review	S100B, GFAP, NSE	Pediatric	TBI	Highlighted diagnostic role of biomarkers in pediatric TBI.
Papa et al (2013)[29]	Systematic Review	GFAP, UCH-L1	Pediatric	TBI	Strong evidence base for GFAP use.
Depoorter et al (2018)[25]	Cohort	NfL	Neonates	White matter injury	NfL is a promising early axonal injury marker.
Daoud et al (2014)[28]	Cohort	NSE, GFAP	Severe pediatric TBI	ICH	Biomarkers correlate with outcomes in severe TBI.
Zhang et al (2024)[20]	Review	Various	Pediatric	Neurological diseases	Broad applicability of biomarkers in pediatric neurology.
Menéndez-Valladares et al (2020)[27]	Proteomics Review	Perinatal biomarkers	Neonatal	Neurovascular pathologies	Proteomic insights in early injury.
Kim SH et al (2022)[8]	Review	S100B, IL-6, others	Pediatric	Multiple (TBI, infection, and inflammation)	Promising CSF biomarkers for varied conditions.
Kochanek et al (2013)[30]	Narrative Review	Various	Pediatric	TBI and cardiac arrest	Discussion on translation from lab to clinic.

NSE, neuron-specific enolase; GFAP, glial fibrillary acidic protein; TBI, traumatic brain injury; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage; CSF, cerebrospinal fluid, UCH-L1, ubiquitin carboxyl-terminal hydrolase L1.

Biomarkers such as NSE and glial fibrillary acidic protein (GFAP) are widely used to assess neuronal and glial damage. MBP indicates demyelination, while tau protein reflects axonal injury. Emerging biomarkers such as extracellular vesicles (EVs) and miRNAs, enhance our understanding of pediatric brain injury pathophysiology^[21].

In pediatric SAH, elevated GFAP and S100B levels confirm neuronal and astrocytic injury and predict complications like vasospasm and hydrocephalus^[8,31]. In ICH, serum NSE and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) levels are linked to the severity of neuronal damage and functional outcomes. Elevated tau levels in CSF are associated with secondary processes such as axonal degeneration and inflammation. For AVMs, S100B and miRNAs like miR-4486 detect early hemorrhage and predict rebleeding risks^[1]. In hematomas, biomarkers like GFAP provide crucial insights when imaging findings are inconclusive^[31].

Biomarkers have become vital tools for predicting outcomes, enabling personalized interventions and management. Elevated serum NSE and GFAP levels correlate with poor neurological recovery and cognitive impairments, especially in TBI and ICH^[28,31]. S100B has been recognized for its ability to predict mortality by correlating with intracranial damage and systemic inflammatory responses^[8]. miRNAs and tau protein are increasingly used to forecast complications such as hydrocephalus and vasospasm, facilitating preemptive management^[1]. Table 3 summarizes key biomarkers relevant to pediatric hemorrhagic neurosurgical conditions, detailing their clinical relevance, sensitivity, and specificity.

Table 3.

Biomarkers in pediatric hemorrhagic neurosurgical conditions – biomarker clinical relevance-associated conditions sensitivity specificity references

Biomarker	Clinical relevance	Associated conditions	Sensitivity	Specificity	References
S100B	Blood-brain barrier disruption, neuronal injury, and prognosis	SAH, ICH, AVMs, and hematomas	91% at 0.1 μg/L	30% at 0.1 μg/L	[7,8,27–35]
GFAP	Astrocyte injury and differentiates hemorrhagic vs. traumatic injury	SAH, ICH, and hematomas	93% at 22 pg/mL	36% at 22 pg/mL	[8,27–38]
NSE	Neuronal damage, severity assessment, and prognosis	TBI, ICH, SAH, and hematomas	44–82%	60–97%	[1,8,20,27–30,32,34,36,37,39]
UCH-L1	Neuronal body damage and secondary injury detection	ICH and TBI	94–100%	“High specificity for neurosurgical needs”	[27,28]
NfL	Axonal damage, white matter integrity, and outcome prediction	SAH, ICH, and hydrocephalus	83% at 0.216 ng/mL	56% at 0.216 ng/mL	[25,27,29,30,32,33]
Tau Protein	Axonal injury, cognitive and motor function prognosis, and diffuse axonal injury	SAH and ICH	64% at 0.0915 ng/mL	95% at 0.0915 ng/mL	[1,27–30,32,33,37]
MBP	Demyelination, white matter injury, and prognosis	ICH and diffuse axonal injury	No data	No data	[1,7,27,40]
MicroRNAs	Inflammation, hemorrhage prediction, and vascular integrity	ICH, AVMs, and SAH	Varies – depend on the miRNAs	Varies – depend on the miRNAs	[1,25,27,30,33]
(miR-223, miR-155, and miR-4486)
L-Selectin	Outcome prediction when combined with S100 B	ICH and TBI	No data	No data	[36]

GFAP, glial fibrillary acidic protein; ICH, intracerebral hemorrhage; NSE, neuron-specific enolase; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury; UCH-L1, ubiquitin carboxyl-terminal hydrolase L1.

Based on the data given in the above table, among the biomarkers, S100B is particularly useful in early-stage detection due to its rapid release following blood-brain barrier (BBB) disruption. Tau and NfL, in contrast, are more indicative of later-stage, ongoing axonal injury. GFAP shows high sensitivity for hemorrhagic lesions, especially ICH, while NSE is versatile across conditions but can be confounded by age or multi-organ involvement. Clinicians should interpret these metrics within the context of time-from-injury and patient age.

Categories of biomarkers

Diagnostic Biomarkers: S100B and GFAP are leading diagnostic biomarkers for early detection. S100B reflects BBB disruption and neuronal damage, aiding in conditions like TBI and SAH. GFAP, specific to astrocytic injury, is invaluable in differentiating mild from severe TBI and in detecting ICH. Advanced technologies like single-molecule arrays significantly improved the precision of biomarker diagnostics^[28,32].

Emerging biomarkers, including NfL and EV-derived molecules, offer deeper insights into axonal damage and cellular integrity. Their application extends to conditions like pediatric AVMs and hydrocephalus, where traditional biomarkers may fall short^[28].

Prognostic Biomarkers: Prognostic biomarkers predict recovery and neurological outcomes. GFAP indicates astrocytic damage severity and correlates with functional impairments, especially in severe TBI. NSE is predictive of mortality in severe brain injuries. Combined biomarker measurements with neuroimaging enhance stratification and guide treatment and rehabilitation plans. Elevated tau levels, indicating axonal injury, are linked to poor outcomes in conditions like diffuse axonal injury or hydrocephalus^[29,30].

Predictive Biomarkers: Predictive biomarkers, such as NfL, miRNAs, and tau, are critical for forecasting long-term neurological outcomes and complications. NfL, a structural axonal protein, is released during axonal injury and reflects white matter damage. It predicts complications like vasospasm and poor cognitive recovery in SAH and ICH. miRNAs, including miR-223 and miR-155, are linked to rebleeding and inflammation in conditions like IVH. Tau protein predicts motor and cognitive deficits, especially in diffuse axonal injuries^[1,33,41]. Figure 2 shows the different categories of biomarkers (diagnostic, prognostic, and predictive) and examples for each type (e.g., S100B, GFAP, and cytokines). Table 4 shows the age-specific biomarkers in pediatric neurosurgical hemorrhagic conditions.

Figure 2.

Categorization of biomarkers in pediatric neurosurgical hemorrhagic conditions.

Table 4.

Age-specific biomarkers in pediatric neurosurgical hemorrhagic conditions

Age group	Key biomarkers
Neonates (0–28 days)	S100B, NSE, IL-6, and GFAP[42]
Infants (1–12 months)	NSE, GFAP, NfL, and IL-8[26,28,42]
Young children (1–5 years)	NfL, UCH-L1, miR-223, and Tau[26,28]
Older children (6–12 years)	NfL, miRNAs (miR-155 and miR-4486), GFAP, and Tau[26,28,42]

GFAP, glial fibrillary acidic protein; miRNA, microRNA; NSE, neuron-specific enolase; UCH-L1, ubiquitin carboxyl-terminal hydrolase L1.

To systematically present the scope of biomarker research in pediatric neurosurgical hemorrhagic conditions, a thematic categorization of the included studies was conducted. The studies were grouped based on their primary focus into diagnostic, prognostic, and predictive/emerging biomarker categories. This categorization helps elucidate the diverse roles of biomarkers across different stages of clinical care – from early detection and outcome prediction to forecasting long-term complications and tailoring interventions. Tables 5, 6, and 7 below summarize these thematic groups and highlight the key contributions of each study.

Table 5.

Diagnostic biomarkers (e.g., S100B and GFAP)

Author (year) [Ref]	Study type	Biomarkers studied	Key contribution
Marzano et al (2022)[7]	Systematic Review	S100B, GFAP, and NSE	Diagnostic value in pediatric TBI.
Kim SH et al (2022)[8]	Review	S100B and IL-6	CSF markers for diagnostic utility in pediatric neurological conditions.
Menéndez-Valladares et al (2020)[27]	Proteomics Review	Perinatal biomarkers	Proteomic approach to diagnostics in neonatal injuries.

CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; NSE, neuron-specific enolase; TBI, traumatic brain injury.

Table 6.

Prognostic biomarkers (e.g., NSE and Tau)

Author (year) [Ref]	Study type	Biomarkers studied	Key contribution
Berger et al (2011)[6]	Prospective cohort	NSE and S100B	Biomarker trajectories predict outcomes post-TBI.
Daoud et al (2014)[28]	Cohort	NSE and GFAP	Linked with outcome prediction in severe TBI.
Zhang et al (2024)[20]	Review	Various	Highlights prognostic roles across pediatric neurological diseases.

GFAP, glial fibrillary acidic protein; NSE, neuron-specific enolase; TBI, traumatic brain injury.

Table 7.

Predictive biomarkers and emerging technologies (e.g., miRNAs and NfL)

Author (year) [Ref]	Study type	Biomarkers studied	Key contribution
Depoorter et al (2018)[25]	Cohort	NfL	Early predictor of axonal injury in neonates.
Kochanek et al (2013)[30]	Narrative Review	Various	Translating emerging biomarkers to clinical use.

Advances in emerging biomarkers for predicting outcomes

Recent advancements have enhanced the clinical utility of biomarkers. Blood-based biomarkers like NfL and cytokines (e.g., IL-6) are increasingly used to detect subclinical brain injuries. Imaging biomarkers, such as those derived from neuroimaging, complement traditional biomarkers by providing structural and functional insights into injury progression. Liquid biopsy techniques and advanced CSF analysis offer non-invasive methods for dynamic monitoring, improving the accuracy of predictions.

Multiplex assays allow simultaneous measurement of multiple biomarkers, offering a comprehensive understanding of injury mechanisms. Computational models integrating biomarker and imaging data further refine predictive accuracy and facilitate personalized care strategies. For instance, circulating biomarkers like EVs carrying GFAP and tau allow real-time monitoring of recovery and therapeutic response^[1,36].

Integrating biomarkers into clinical decision-making

Biomarkers are increasingly recognized as pivotal tools in pediatric neurosurgical care, providing a foundation for real-time decision-making, surgical planning, and treatment efficacy evaluation. Their ability to reflect molecular and cellular changes during injury and recovery enhances diagnostic precision, prognostication, and therapeutic optimization. Figure 3 illustrates the pathway from biomarker detection to personalized treatment and improved patient outcomes, highlighting their role in guiding clinical decisions for pediatric hemorrhagic conditions.

Figure 3.

Pathway of biomarker application in patient care.

The role of biomarkers in real-time clinical management

Biomarkers play a pivotal role in enabling early and accurate diagnosis, which streamline clinical workflows and improve patient outcomes. For example, GFAP and NSE are invaluable in assessing astrocytic and neuronal injury, respectively. GFAP, rapidly detectable in serum following brain injury, serves as a key biomarker for early assessment. It aids in differentiating TBIs from non-traumatic conditions like ICH or SAH^[36]. However, GFAP’s utility is enhanced when paired with other biomarkers to improve diagnostic specificity. NSE levels correlate with the extent of neuronal damage and are crucial for guiding therapeutic interventions during acute injury phases^[43].

In pediatric hydrocephalus management, CSF biomarkers like interleukins (IL-6 and IL-8) and inflammatory mediators provide data on secondary complications, such as hydrocephalus development post-IVH^[37]. The ability of biomarkers to offer real-time insights into the dynamics of cerebrovascular pressure and flow also complements imaging findings, refining treatment strategies^[38].

Role of biomarkers in surgical decision-making and postoperative care

Biomarkers are integral to determining the timing and nature of surgical interventions. For instance, in cases of severe TBI or ICH, elevated levels of S100B and tau proteins are associated with an increased risk of adverse surgical outcomes, providing critical information for prioritizing and planning neurosurgical interventions^[39]. Furthermore, during postoperative care, biomarkers like NfL (neurofilament light chain) and miRNAs provide continuous monitoring, enabling early detection of complications such as rebleeding or infection^[40].

Emerging evidence suggests that paired biomarkers, such as S100B with inflammatory markers like IL-6, enhance the specificity and sensitivity of outcome prediction. For example, combinations of S100B and L-selectin significantly improve predictions of unfavorable outcomes in pediatric brain trauma^[43]. These biomarker pairs guide postoperative rehabilitation and long-term care planning, ensuring targeted interventions.

Table 8 presents a comparative overview of the sensitivity and specificity of key biomarkers across various pediatric hemorrhagic neurosurgical conditions. By quantifying their diagnostic accuracy for conditions such as SAH, ICH, AVMs, and hematomas, this table highlights the strengths and limitations of each biomarker in clinical decision-making. The data underscore the variability in biomarker performance, emphasizing the need for multimodal assessment in pediatric neurosurgical practice.

Table 8.

Sensitivity and specificity of biomarkers across pediatric hemorrhagic conditions

Biomarker	SAH (sensitivity/specificity)	ICH (sensitivity/specificity)	AVMs (sensitivity/specificity)	Hematomas (sensitivity/specificity)	References
S100B	91%/30%	85%/40%	78%/50%	80%/45%	[7,8,28–33,35,41,44]
GFAP	93%/36%	89%/42%	75%/55%	82%/47%	[8,28–33,35,38,39,41,43,44]
NSE	70%/85%	82%/60%	68%/55%	75%/65%	[1,8,21,28–31,33,35,38,40,43]
UCH-L1	94%/85%	100%/90%	80%/70%	85%/75%	[28,31]
NfL	83%/56%	90%/60%	77%/50%	79%/55%	[26,28–30,33,41]
Tau protein	64%/95%	76%/85%	70%/80%	72%/82%	[1,28–31,33,38,41]
MBP	No data	74%/78%	60%/72%	65%/75%	[1,7,28,34]
MicroRNAs (miR-223, miR-155, miR-4486)	Varies; some show 100% sensitivity/specificity	85%/88%	80%/85%	83%/87%	[1,26,28,33,41]
L-Selectin	No data	82%/70%	75%/72%	78%/74%	[43]

AVM, arteriovenous malformation; GFAP, glial fibrillary acidic protein; ICH, intracerebral hemorrhage; NSE, neuron-specific enolase; SAH, subarachnoid hemorrhage; UCH-L1, ubiquitin carboxyl-terminal hydrolase L1.

Impact on treatment efficacy and personalized care

Biomarkers also play a crucial role in optimizing treatment strategies. Biomarkers enable patient stratification based on injury severity and therapeutic response, thereby reducing unnecessary interventions and optimizing outcomes. For instance, NSE and MBP levels are used to evaluate the efficacy of interventions such as clot removal and decompressive craniectomy^[34]. The application of multiplex assays enables clinicians to monitor multiple biomarkers simultaneously, providing a comprehensive view of injury progression and treatment efficacy^[39].

In rehabilitation, biomarkers such as tau and GFAP inform the timing and intensity of therapy. Biomarker insights also support the development of personalized rehabilitation protocols, tailoring interventions to individual recovery trajectories. Elevated tau levels, for example, may indicate the need for early intervention to mitigate cognitive deficits in pediatric patients recovering from diffuse axonal injuries^[38]. Furthermore, the integration of biomarker profiles into electronic health records facilitates data-driven, personalized treatment plans, enhancing patient outcomes and care efficiency^[40].

Enhancing quality of care through biomarker implementation

Pathway from biomarker detection to personalized care

Biomarker-based approaches in pediatric neurosurgical conditions significantly advance personalized patient care. Key biomarkers like S100B, NSE, and GFAP are essential for identifying brain injuries, including IVH, SAH, and TBI. S100B enables early diagnosis during BBB disruption, allowing timely interventions^[35]. GFAP levels also correlate with astrocytic damage severity, informing specific therapeutic needs^[44]. Combining S100B with inflammatory cytokines like interleukin-6 (IL-6) enhances prognostic accuracy^[45]. Additionally, biomarkers such as UCH-L1 guide neuroprotective therapies to reduce long-term disability in neonatal encephalopathy^[35]. This illustrates a shift in pediatric care from reactive to proactive, improving outcomes.

Biomarkers are valuable for monitoring long-term recovery and neurodevelopmental progress, with persistent elevations in markers like S100B and NSE indicating suboptimal recovery and prompting enhanced rehabilitation strategies. In neonates with hypoxic-ischemic encephalopathy, biomarker profiles aid in tracking developmental milestones, ensuring timely interventions for delayed progress^[35,46].

Economic analyses show that biomarker screening can significantly reduce health care costs. Studies highlight the cost-effectiveness of biomarker-based triage systems in TBI^[47]. Early detection minimizes the need for extensive imaging and prolonged intensive care, leading to savings. The Banyan Trauma Indicator exemplifies this efficiency and cost-effectiveness, demonstrating the economic benefits of integrating biomarkers into routine care^[48].

Barriers to clinical implementation and solutions

Challenges in clinical implementation of biomarkers

Although the diagnostic value of the biomarkers cannot be refuted, the integration of biomarkers into pediatric neurosurgical practice faces significant challenges. Though the sensitivity and specificity of biomarkers in detection of pediatric neurosurgical hemorrhagic conditions are available, the wide variability in these values, as demonstrated amongst different studies, has proved to be a significant hindrance in deriving relevant statistical conclusions and standardized adoption into clinical practice^[49]. The standardization becomes even more difficult due to age-related changes in these biomarkers, e.g., NSE is present in the serum of children <2 years of age and adolescents of 14–16 years of age group without any trauma^[50]. Moreover, comorbid conditions can also cause a confounding effect in the concentrations of these bio-markers, like NSE serum concentration is increased in multi-organ failure and that of UCH-L1, and S100B is increased in orthopedic injuries^[50]. Some of these biomarkers, like NSE, have very slow elimination from plasma, thus causing diagnostic dilemmas in distinguishing between primary and secondary brain injury, while S100B has a very short half-life and may not be significant in the early stages of injury^[51]. Therefore, due to these wide variations, the need for standardization and careful adoption into clinical practice is required to fully unlock the immense potential of these biomarkers.

Assay platform differences and timing of sample collection also significantly impact biomarker readings. For instance, S100B levels decline rapidly and may be missed if collected late, whereas tau and GFAP increase more gradually, offering a broader window for detection. Inconsistent assay calibration and sampling times limit inter-study comparisons and call for urgent standardization across clinical trials.

Due to the lack of standardization of biomarkers, their utility in predicting clinical outcomes remains underutilized. The heterogeneous nature of the data collected from different clinical trials, coupled with the inherent variability of the biomarkers with age and comorbid conditions, makes standardization an extremely challenging task. The fundamental step in developing standardization is identifying and establishing strict methods for data collection and sample analysis^[49]. This includes having consistent and uniform protocols for data collection, analysis, and inference across various studies to facilitate reliable comparisons. Since brain injury and neuronal adaptation is a dynamic process, the timing of the biomarker study becomes important in predicting outcomes. Therefore, more focus should be placed on temporal resolution, and biomarker kinetics should be placed to understand the variability better^[49]. Out of the plethora of biomarkers available, the most reliable ones should be selected so that critical levels can be identified and standardized^[50]. A workgroup was formed in 2012 to standardize and provide recommendations for best practice guidelines^[52]. These recommendations, which outline the need for a few more pediatric-centric studies that follow stringent protocol, will aid in the adoption of standard practices.

High costs of biomarker development and limited access to advanced laboratory facilities further restrict accessibility, particularly in low-resource settings. Ethical concerns, including informed consent issues in pediatric populations and the risk of over-reliance on biomarker data, may overshadow comprehensive clinical evaluations and holistic care^[53,54].

Overcoming barriers

Addressing these challenges requires a multi-faceted approach. Standardizing biomarker testing protocols and fostering collaborations among global health organizations, academic institutions, and the private sector can establish universal guidelines. Validation studies on diverse cohorts are needed for reliability and reproducibility of biomarkers. Cost-effective testing kits and subsidies for low-resource settings are crucial for accessibility. Furthermore, health care professionals should focus on ethical training regarding biomarkers, and international conferences can aid in developing global pediatric neurosurgery guidelines^[55].

Future directions and research perspectives

Advances in technology and precision medicine

Emerging technologies, particularly artificial intelligence (AI) and machine learning (ML), are set to revolutionize the use of biomarkers in pediatric neurosurgery. These technologies process extensive datasets, integrating clinical, imaging, and biomarker information to improve predictive models’ accuracy. AI algorithms can analyze complex biomarker trajectories for early identification of high-risk patients, while ML facilitates real-time decision-making by linking biomarker patterns with treatment outcomes and recovery trajectories^[54]. Furthermore, the integration of biomarkers into precision medicine allows for tailored treatments, using indicators like NfL and GFAP to minimize unnecessary procedures and enhance recovery strategies. Combining biomarker data with neuroimaging also aids in risk stratification, especially for conditions like AVMs and SAH^[5,6]. Figure 4 is an infographic comparing Traditional and Emerging Technologies in biomarker detection.

Figure 4.

Emerging technologies in biomarker detection.

Convolutional Neural Networks (CNNs) are a type of deep learning model particularly effective in processing imaging data^[56]. In pediatric neurosurgery, CNNs can analyze CT scans to automatically detect patterns such as hemorrhage volume, location, and midline shift^[57]. When these models are trained on annotated datasets – where radiologists have labeled specific features – they learn to associate imaging characteristics with clinical outcomes. By integrating serum biomarker levels such as S100B into the CNN model, predictive accuracy is enhanced. Recent studies have demonstrated successful use of CNNs trained on CT scans and serum S100B levels to predict unfavorable outcomes with 87% accuracy in pediatric ICH^[57]. Another model, using a random forest classifier, integrated miRNA (e.g., miR-155 and miR-4486) and imaging features to stratify AVM rupture risk. These tools show promise for real-time decision-making and outcome prediction.

Research gaps

Despite recent advancements, several critical research gaps remain. The discovery of novel biomarkers sensitive to pediatric-specific pathophysiology is imperative. Established biomarkers like S100B and NSE require further validation across diverse cohorts to ensure reliability. Longitudinal studies are needed to explore biomarkers’ role in tracking long-term neurodevelopmental outcomes in survivors of ICH and SAH^[3,53].

A critical gap involves understanding the interaction between genetic predispositions and biomarkers, such as the influence of mutations in RASA1 and KRAS on biomarker expression in AVMs^[2]. Addressing these gaps necessitates comprehensive research on pediatric-specific biomarkers.

International collaboration is crucial for standardizing testing protocols and developing cost-effective diagnostic tools, enhancing access in low-resource settings, and improving health care outcomes through education and training programs^[55].

Conclusion

Advances in biomarker research have significantly transformed the landscape of pediatric neurosurgical care by enhancing diagnostic precision, prognostic accuracy, and therapeutic strategies. Biomarkers such as S100B, NSE, GFAP, and emerging candidates like miRNAs and tau proteins play crucial roles in understanding the pathophysiology of conditions like SAH, ICH, AVMs, and hematomas. Integration with imaging modalities and AI-driven predictive models has further refined clinical decision-making. Despite challenges like standardization, cost barriers, and limited pediatric-specific data, ongoing technological innovations and global collaborations are paving the way for personalized and cost-effective care. By addressing research gaps and fostering cross-disciplinary cooperation, biomarker-based approaches promise to enhance survival rates, minimize complications, and improve long-term neurological outcomes, revolutionizing pediatric neurosurgical practice.

Ethical approval

This study did not involve human participants or animals.

Consent

Not applicable, as no individual patient data were used.

Sources of funding

No external funding was received for this manuscript.

Conflicts of interest disclosure

The authors declare no conflicts of interest related to this work.

Research registration unique identifying number (UIN)

This study is a narrative review and does not involve human participants or primary data collection. Therefore, registration in a research registry is not applicable. UIN: Not applicable.

Guarantor

Dr. Ayush Dwivedi.

Provenance and Peer review

Not commissioned; externally peer-reviewed.

Data availability statement

No new datasets were generated or analysed for this narrative review. All information included in the manuscript is derived from previously published literature that is openly available and appropriately cited.