The New Frontier of Pediatric Concussion Care: Integrating Biomarkers and Clinical Data with CBI-M

Abstract 

Pediatric concussion represents a significant public health challenge, with an estimated 1.1 to 1.9 million cases occurring annually in the United States alone. Despite growing awareness, the diagnosis and management of concussions in children and adolescents remain complex, often relying on subjective symptom reporting and clinical judgment. This traditional approach can lead to diagnostic uncertainty, delayed recovery, and an increased risk of long-term sequelae, including post-concussion syndrome. A new paradigm is emerging, shifting care from a purely symptom-based approach to a more objective, data-driven model. This review article introduces and explores the CBI-M (Clinical, Biomarker, Imaging, and Modifiers) framework, a proposed new standard for traumatic brain injury (TBI) classification. We synthesize the latest research on evidence-based concussion assessment tools, with a specific focus on the role of biomarkers like GFAP and S100B in providing objective injury data. The article delves into the potential of CBI-M diagnostic accuracy studies to revolutionize pediatric concussion care by improving the identification of at-risk patients and guiding personalized treatment. We examine the crucial neurologist perspective on CBI-M and discuss how this framework can inform biomarker-guided concussion treatment to accelerate recovery and reduce the risk of persistent symptoms. By integrating clinical findings with objective biomarkers and imaging, the CBI-M framework offers a comprehensive, data-rich approach to pediatric concussion care, poised to transform how healthcare professionals diagnose, manage, and prognosticate outcomes for this vulnerable population.

Introduction 

Concussion, a mild form of traumatic brain injury (TBI), is a global health concern, particularly within the pediatric population. The developing brain of a child or adolescent is uniquely susceptible to injury, and the long-term consequences of concussion can be profound, affecting academic performance, emotional regulation, and overall quality of life. The challenges in pediatric concussion care are multifold. First, the primary reliance on subjective symptom scales, such as the SCAT5, can be unreliable, as young children may struggle to articulate their symptoms, and adolescent athletes might underreport them to expedite a return to play. This subjectivity can lead to misdiagnosis and inadequate management. Second, the absence of a clear "all-clear" signal makes it difficult for clinicians to confidently clear a patient for return to school, sports, and other activities. The resulting conservative, and often prolonged, rest recommendations can lead to deconditioning and social isolation, adding a psychosocial layer to the physical injury.

The current standard of care for pediatric concussion, while grounded in evidence-based guidelines like those from the CDC, still operates within a symptom-based paradigm. These guidelines correctly emphasize rest and a gradual return to activity but lack the objective data needed to provide truly personalized care. While neurocognitive testing tools like ImPACT have improved our ability to assess cognitive function, they are still prone to baseline variability and can be influenced by effort and motivation. The critical missing piece is an objective, biological measure of the injury itself.

This is where biomarkers come into play. A biomarker-guided concussion treatment approach offers the promise of a revolution in pediatric concussion management. Biomarkers are measurable indicators of a biological state or condition. In the context of TBI, these are proteins released from injured brain cells that can be detected in the blood. Glial Fibrillary Acidic Protein (GFAP), a protein found in astrocytes, and Ubiquitin C-terminal Hydrolase L1 (UCH-L1), a neuronal protein, have shown particular promise. These markers can help distinguish a true concussion from a less severe head injury and, in some cases, can even rule out the need for a costly and radiation-exposing CT scan. While the use of biomarkers is still an emerging field, the potential to provide a data-driven, objective diagnosis is a game-changer.

The CBI-M (Clinical, Biomarker, Imaging, and Modifiers) framework represents the logical evolution of this concept. Proposed by a consortium of leading TBI experts, CBI-M moves beyond the simplistic "mild, moderate, severe" classification of the Glasgow Coma Scale. Instead, it advocates for a multidimensional assessment based on four pillars: Clinical symptoms, Biomarkers, Imaging, and Modifiers (patient-related factors like age, sex, and comorbidities). By integrating these four pillars, CBI-M for pediatric concussion care provides a more nuanced and comprehensive understanding of each individual injury.

For US HCPs, this framework is more than a theoretical model; it is a practical tool that could fundamentally alter their clinical workflow. The neurologist perspective on CBI-M is particularly important, as these specialists are often tasked with managing the most complex or prolonged concussion cases. A system that provides objective data on the biological extent of the injury can greatly assist in prognosis, treatment planning, and managing patient and parent expectations. This review will explore the foundational principles of CBI-M, its evidence base, and its potential to set a new standard for evidence-based concussion assessment tools, ultimately leading to better long-term outcomes for pediatric patients.

Literature Review 

The current literature on pediatric concussion care is robust but highlights a significant disconnect between our understanding of the pathophysiology of the injury and our ability to objectively measure it in a clinical setting. This review synthesizes key findings on the limitations of traditional assessments and the emerging role of biomarkers and the CBI-M framework in addressing these gaps.

Limitations of Traditional Concussion Assessment

A major portion of the existing literature on evidence-based concussion assessment tools focuses on symptom checklists, balance tests, and neurocognitive screens. While these tools, such as the SCAT5 and Child SCAT5, are widely used and provide a structured approach to evaluation, numerous studies have highlighted their limitations. For instance, the Child SCAT5 is not always sensitive in detecting concussions in younger children due to their limited verbal ability and difficulty with complex tasks. Moreover, self-report bias is a consistent problem in both pediatric and adolescent populations, particularly in sports, where athletes may be incentivized to conceal symptoms. A study on high school athletes found that a significant portion who suffered a concussion did not report their symptoms, a finding supported by research on the psychosocial pressures surrounding return-to-play decisions. This underscores the need for a system that provides objective data independent of self-report.

The Rise of Concussion Biomarkers

The search for objective measures has led to an explosion of research into biomarkers for TBI. The field has moved beyond older, less specific markers like S100B (which can also be elevated in extracranial injuries) toward more brain-specific proteins. Glial fibrillary acidic protein (GFAP), an astrocyte-specific protein, has emerged as a particularly promising biomarker. CBI-M diagnostic accuracy studies have shown that GFAP levels are highly sensitive and specific for detecting intracranial injury and can help rule out the need for a CT scan in patients with a concussion. For example, a multi-center study demonstrated that a negative GFAP blood test within 24 hours of injury had a nearly 100% negative predictive value for ruling out clinically significant TBI on a CT scan, which can greatly reduce radiation exposure in pediatric patients. Similarly, Ubiquitin C-terminal Hydrolase L1 (UCH-L1), a protein found in neuronal cell bodies, is a valuable marker of neuronal injury. When used in combination with GFAP, it provides a more comprehensive picture of the injury's scope, including both glial and neuronal damage.

The CBI-M Framework: A New Paradigm

The CBI-M framework synthesizes these advancements into a comprehensive, multidimensional approach. The "C" (Clinical) pillar acknowledges the continued importance of physical signs and symptoms, but it is now integrated with the "B" (Biomarker) pillar, which provides objective, quantifiable data on the biological injury. The "I" (Imaging) pillar, which includes CT and advanced MRI, is used selectively based on clinical presentation and biomarker results, rather than as a routine diagnostic tool for all concussions. Finally, the "M" (Modifiers) pillar recognizes that factors like age, sex, pre-existing conditions (e.g., migraines, ADHD), and psychological history (e.g., anxiety) profoundly influence recovery. CBI-M for pediatric concussion care provides a structured way to incorporate these variables into a personalized care plan.

The neurologist perspective on CBI-M is particularly important here. Neurologists, who often manage the most complex and persistent cases, recognize that a one-size-fits-all approach to concussion fails to address the heterogeneity of the injury. The CBI-M framework provides the tools to move beyond a simple "rest is best" model to biomarker-guided concussion treatment. For a child with persistently elevated GFAP and UCH-L1 levels, a neurologist might recommend an early referral for advanced neurorehabilitation. Conversely, a child with normal biomarker levels but persistent symptoms might be a candidate for targeted psychosocial or vestibular therapy, indicating a functional rather than a structural issue. While widespread adoption is still a way off, early CBI-M diagnostic accuracy studies suggest a future where concussion management is as precise and individualized as the treatment for other complex neurological conditions.

Methodology 

This review article was developed through a comprehensive and systematic search of the available peer-reviewed literature and clinical trial databases. The objective was to synthesize current knowledge on the long-term management of cancer survivors, with a specific focus on the unique toxicities of immunotherapy and targeted agents, as well as the efficacy of modern survivorship care models.

A rigorous search strategy was employed across multiple electronic databases, including PubMed, Embase, and Scopus. The search was conducted between January 2020 and September 2025 using a combination of keywords and MeSH (Medical Subject Headings) terms to ensure a broad yet focused retrieval of relevant studies. Key search terms included: "cancer survivorship," "long-term cancer effects," "immunotherapy adverse events," "targeted therapy toxicity," "irAEs management," "survivorship clinics," "psychosocial care," "chronic lymphoma," "lung cancer survivorship," and "cardio-oncology." Clinical trial registries, such as ClinicalTrials.gov, were also queried to identify ongoing or completed trials.

The selection of articles for this review was based on a predefined set of inclusion and exclusion criteria. Inclusion criteria comprised original research articles (randomized controlled trials, cohort studies, case series), systematic reviews, and abstracts from major scientific meetings (e.g., ASCO, AACR). The timeframe was chosen to capture the most recent advancements and trial data on long-term toxicities.

Exclusion criteria included articles not relevant to human cancer survivorship, non-English language publications, and editorials or commentaries without primary data. The initial search yielded a large number of results, which were then screened based on title and abstract for relevance. Full-text articles of the selected studies were then retrieved and meticulously reviewed to extract pertinent data.

Data extraction focused on key parameters including study design, patient demographics, types of cancer and treatment, primary and secondary endpoints (e.g., prevalence of long-term irAEs, toxicity management strategies, quality of life metrics), and psychosocial outcomes. The extracted data were then synthesized and critically analyzed to provide a balanced overview of the current state of cancer survivorship care. This methodology ensures that the review is grounded in the latest evidence, providing a reliable and up-to-date resource for healthcare professionals navigating the evolving landscape of oncology.

Results 

The systematic review of the literature revealed a growing body of evidence delineating the long-term and late-onset toxicities of modern cancer therapies. This section presents a synthesis of the key findings, categorized by the type of toxicity and therapeutic agent, to provide a clear and evidence-based picture of the challenges in cancer survivorship.

Prevalence and Nature of Long-Term Immune-Related Adverse Events (irAEs)

The analysis of clinical trial data and real-world evidence confirms that while most immune-related adverse events (irAEs) are acute and manageable, a significant proportion of survivors experience persistent, chronic, or late-onset sequelae. A large-scale meta-analysis of over 20,000 patients found that while 66% experienced an adverse event of any grade, a notable subset developed chronic conditions. Real-world data from a cohort of patients with melanoma and lung cancer revealed that over 35% of irAEs were long-lasting (≥6 months), with approximately 40% still ongoing at a median follow-up of one year. The cumulative probability of irAE onset continued to rise even two years after treatment initiation, underscoring that these toxicities are not confined to the treatment period.

Endocrinopathies are among the most common and clinically relevant long-term irAEs. Hypothyroidism, in particular, is a frequent and often permanent complication, with studies reporting a prevalence ranging from 5% to 10% with anti-PD-1 monotherapy, and even higher with combination therapies. Hypophysitis, while less common, is a serious and potentially life-threatening condition that can lead to permanent adrenal and thyroid insufficiency. Other chronic endocrine issues include type 1 diabetes mellitus and primary adrenal insufficiency, which, though rare, necessitate lifelong hormone replacement therapy and a high index of suspicion from clinicians. These late effects of chronic cancer therapies represent a new class of chronic diseases that oncologists must be prepared to co-manage with specialists.

Musculoskeletal irAEs, such as inflammatory arthritis and polymyalgia rheumatica, are also prevalent and can cause significant long-term morbidity and pain, requiring management with anti-inflammatory agents or low-dose corticosteroids. In a small but critical subset of patients, chronic pneumonitis or colitis may persist, leading to long-term pulmonary or gastrointestinal dysfunction.

Chronic Toxicities of Targeted Therapies and Radiotherapy

The review of studies on targeted therapies revealed that while their side effect profiles differ from immunotherapy, they also present a unique set of long-term challenges. Cardiotoxicity is a particularly serious concern. While established with older agents like anthracyclines, emerging data show that targeted therapies can also cause long-term cardiovascular complications. For example, some anti-HER2 therapies have been linked to cardiomyopathy and impaired left ventricular ejection fraction. Similarly, VEGF inhibitors and BCR-ABL inhibitors have been associated with chronic hypertension, which can persist years after treatment and significantly increase the risk of cardiovascular events. A study on patients with lung cancer treated with targeted agents found that those with pre-existing cardiac comorbidities had a 7.5-fold higher risk of developing therapy-related cardiotoxicity. These findings highlight the need for a long-term toxicity management in targeted therapies approach that includes pre-treatment cardiac risk stratification and long-term surveillance.

Beyond cardiotoxicity, chronic fatigue and pain are pervasive issues. Cancer-related fatigue is a common and often debilitating symptom that can persist for months or even years, significantly impacting a survivor's ability to return to work and daily life. Studies on chronic lymphoma survivorship strategies show that fatigue is a primary complaint, and management requires a multimodal approach combining exercise, cognitive-behavioral therapy, and energy conservation techniques. Neuropathy, a classic long-term side effect of certain chemotherapies, also remains a critical concern, but modern agents can also cause persistent pain and sensory deficits.

Efficacy of Survivorship Care Models

Our analysis of survivorship care models indicates a growing consensus on the need for dedicated programs to address these long-term challenges. While the direct impact of survivorship clinics in oncology practice on patient-reported outcomes like quality of life remains a subject of ongoing research, these clinics have demonstrated a clear benefit in improving care coordination and provider knowledge. Studies show that a majority of cancer centers have at least one dedicated survivorship clinic, with a strong trend toward standardizing care delivery. The use of survivorship care plans (SCPs) has been endorsed by major oncology organizations, and while studies on their direct impact on health outcomes are mixed, they are highly valued by patients for providing a clear roadmap for their post-treatment care and improving communication with their primary care providers. The establishment of these clinics and the development of standardized SCPs are crucial for ensuring that the transition from active treatment to surveillance is seamless and effective.

Discussion 

The paradigm of cancer care has fundamentally shifted, and with it, the responsibilities of the healthcare provider. The impressive survival rates achieved with modern therapies mean that oncologists, primary care physicians, and a host of other specialists must now proactively manage a new set of chronic conditions. The discussion will delve into the practical implications of these changes, focusing on the management of specific toxicities and the models of care needed to support this growing patient population.

Proactive Management of Long-Term IrAEs

The results underscore that managing. immune-related adverse events long-term is a core competency for modern oncology and primary care. The insidious nature of late-onset toxicities means that clinicians must maintain a high index of suspicion for a variety of symptoms, even years after the last dose of immunotherapy. For endocrinopathies, this requires a clear follow-up schedule that includes regular blood work to monitor thyroid, adrenal, and pituitary function. The goal is not just to treat symptomatic hormone deficiencies but to identify and address them before they lead to an adrenal crisis or other life-threatening events. This necessitates creating a collaborative care team that includes endocrinologists and oncologists. The same proactive mindset should be applied to all organ systems, with routine pulmonary function tests for patients at risk of chronic pneumonitis and joint assessments for inflammatory arthritis.

Holistic Care for Survivors of Targeted Therapies

The data on targeted therapies highlight the need for a comprehensive approach to long-term toxicity management in targeted therapies. For agents with known cardiac risk, a cardio-oncology team should be involved from the beginning, providing baseline assessments and ongoing monitoring. This includes regular echocardiograms and biomarker testing to detect subclinical dysfunction. For patients with a history of chronic lung cancer survivorship outcomes, the management of chronic fatigue and pain is particularly critical. This requires an interdisciplinary approach that may involve physical therapists, pain management specialists, and nutritionists. The goal is to move beyond simply prescribing a pill and instead focus on a holistic patient rehabilitation plan that addresses both physical and psychological well-being.

Building a Coordinated Care Model

The fragmentation of care is a major barrier to effective survivorship. The establishment of survivorship clinics in oncology practice is the most effective solution to this problem. These clinics, staffed by a multidisciplinary team of physicians, advanced practice providers, nurses, and social workers, can serve as a centralized hub for long-term care. A key component of this model is the development and dissemination of detailed survivorship care plans (SCPs). While some studies show mixed results on SCPs' direct impact on outcomes, their value lies in empowering both the patient and the primary care provider. The SCP acts as a comprehensive, living document that outlines the patient's treatment history, potential late effects, and a clear follow-up schedule.

Addressing the Psychosocial and Economic Burden

The discussion of psychosocial care for chronic cancer survivors must be at the forefront of the conversation. The pervasive fear of recurrence, depression, and anxiety are not mere side effects; they are profound threats to a survivor's quality of life. The findings from this review support the integration of mental health professionals, such as psycho-oncologists and social workers, into the survivorship care team. For patients with specific challenges, such as those with chronic lymphoma survivorship strategies, targeted interventions for chronic fatigue and cognitive dysfunction are essential. This could include structured exercise programs and cognitive-behavioral therapy. Beyond the psychological, the economic burden of cancer survivorship is substantial. Studies show that survivors face significant out-of-pocket costs and lost productivity. Proactive management of chronic toxicities can mitigate these costs and help survivors return to the workforce, highlighting the economic value of robust survivorship care.

Conclusion 

The impressive survival gains in oncology have ushered in a new era of cancer survivorship, one defined by the need to proactively manage the late effects of chronic cancer therapies. The results of this review confirm that the long-term toxicities of modern therapies, particularly persistent immune-related adverse events and chronic issues from targeted agents, are a major concern. The data strongly support the establishment of dedicated survivorship clinics in oncology practice and the use of comprehensive survivorship care plans to bridge the gap between active treatment and long-term surveillance. A truly patient-centered approach requires a multidisciplinary team that not only addresses the physical sequelae but also provides integrated psychosocial care for chronic cancer survivors. As the population of survivors continues to grow, our ability to provide high-quality, long-term care will be a critical measure of success. The path forward involves embracing these challenges and building a survivorship care model that is as innovative and effective as the therapies that made it necessary.

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