Trigeminal neuralgia (TN) is a debilitating neuropathic disorder defined by paroxysmal, electric shock-like facial pain. TN is broadly classified into primary TN (PTN), which includes classical TN caused by neurovascular compression (NVC) with morphological changes (e.g., nerve atrophy) and idiopathic TN with no compression or simple contact, and secondary trigeminal neuralgia (STN) resulting from underlying pathologies such as tumors or cysts (Cephalalgia, 2018; Ashina et al., 2019; Heinskou et al., 2019; Ujihara et al., 2020). While neuroinflammation is increasingly recognized as a key contributor to the pathophysiology across all TN types, marked by elevated pro-inflammatory cytokines that correlate with pain severity (Ostertag et al., 2023; Lai et al., 2025), the specific inflammatory signatures of different etiologies remain poorly understood.

Current TN subtyping relies heavily on magnetic resonance imaging (MRI) and clinical phenotyping, but those can be ambiguous, particularly when distinguishing between different causes of STN, especially between meningiomas and epidermoid cysts–two common causes of STN (Cruccu et al., 2016; Ujihara et al., 2020). Both pathologies trigger inflammatory responses, but through distinct mechanisms: meningiomas actively secrete pro-inflammatory cytokines (e.g., IL-6, TNF-α) that promote chronic perineural inflammation, whereas epidermoid cysts induce mechanical compression combined with intense focal inflammation when cyst contents (e.g., keratin) leak, activating immune cells and releasing localized cytokines (Haslund-Vinding et al., 2022; Zhang et al., 2022; Huang et al., 2024). This raises a question: can these distinct local inflammatory processes produce unique, measurable signatures in systemic circulation? Prior research on systemic inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), has focused on immune dysregulation in conditions like diabetic neuropathy (Liu et al., 2017; Baka et al., 2021; Huang et al., 2024), leaving a gap regarding their utility in differentiating TN subtypes.

To address this gap, we hypothesized that the systemic inflammatory profiles reflected by NLR and PLR would differ significantly among PTN, meningioma-induced STN (STN-M), and epidermoid cyst-induced STN (STN-E). This study aimed to: (1) compare NLR and PLR levels across these three pathologically confirmed TN etiologies, and (2) evaluate the diagnostic accuracy of these hematological indices for discriminating TN subtypes. To our knowledge, this is the first study to investigate the potential of routine hematological markers to stratify TN etiologies, aiming to provide an objective, cost-effective, and universally available tool to enhance preoperative diagnostic precision.

To our knowledge, this is the first study to compare systemic inflammatory markers, NLR and PLR, across distinct etiologies, including primary, meningioma-associated, and epidermoid cyst-associated forms. Our primary finding is twofold. First, after adjusting for age and disease duration, PLR was significantly lower in patients with STN-M than in those with STN-E, whereas NLR showed no intergroup differences. Second, and more importantly, simple patient age emerged as a more powerful discriminator for these two secondary etiologies than the biological marker. ROC analysis confirmed that age (AUC = 0.962) offered higher diagnostic performance compared to PLR (AUC = 0.793), establishing it as the principal predictor.

A particularly intriguing finding of our study was the significantly lower PLR in patients with STN-M compared to those with STN-E. This result is compelling, as one might intuitively hypothesize that a neoplastic process would elicit a stronger systemic inflammatory response. This observation leads to several potential pathophysiological mechanisms. For meningiomas, one plausible mechanism is the local consumption of platelets within the tumor microenvironment. Meningiomas are well-documented to express and secrete high levels of vascular endothelial growth factor (VEGF), a potent pro-angiogenic mediator (Ding et al., 2008; Schmid et al., 2010). Given that VEGF directly induces platelet activation and aggregation, it is conceivable that tumor-derived VEGF in meningiomas leads to localized platelet sequestration and consumption at the tumor site, thereby leading to a relative decrease in circulating platelets which lowers systemic PLR (Liao et al., 2023; Huang et al., 2024; Le Chapelain et al., 2024).

In stark contrast, the inflammatory stimulus from an epidermoid cyst may drive a systemic increase in platelets. The keratin debris within these cysts acts as a potent foreign body, capable of triggering a chronic inflammatory cascade that systemically stimulates thrombopoiesis. This process is likely mediated via an interleukin-6 (IL-6) dominant signaling cascade, which is known to increase hepatic thrombopoietin production and subsequent platelet generation (Liao et al., 2023; Köse et al., 2025; Lai et al., 2025). Therefore, the opposing effects on PLR likely reflect two fundamentally different host-tumor interactions: localized, VEGF-mediated platelet consumption in meningiomas versus systemic, cytokine-driven platelet overproduction triggered by epidermoid cysts.

The lack of a significant difference in NLR among the TN subtypes is also a noteworthy finding, particularly as NLR is often considered a reliable marker in other neuropathic pain conditions, such as diabetic neuropathy. This discrepancy may be attributable to the underlying pathology of TN, especially in cases secondary to benign tumors and cysts. The core mechanism in these conditions is often a combination of chronic mechanical compression and localized perineural inflammation, rather than a robust, systemic inflammatory state characterized by massive neutrophil mobilization. Unlike severe systemic infections or metabolic disorders where a systemic neutrophilic response is prominent, the inflammatory signature in these TN subtypes may be too localized to significantly alter the systemic neutrophil-to-lymphocyte ratio. This is consistent with evidence that NLR is more responsive to acute systemic inflammatory states than to chronic or localized processes (Buonacera et al., 2022; Li and Shao, 2025). Therefore, it is plausible that NLR, a marker more reflective of acute systemic inflammation, lacks the sensitivity to differentiate between TN etiologies that are primarily defined by localized structural and inflammatory changes.

A pivotal finding of this study was the strong diagnostic performance of patient age in distinguishing between secondary etiologies, with its AUC of 0.962 surpassing that of PLR (AUC = 0.793). This result aligns with the established epidemiological profiles of these pathologies: epidermoid cysts are congenital lesions that typically manifesting in younger adults, whereas meningiomas are most prevalent in middle-aged and older populations–a demographic distinction clearly reflected in our cohort. The influential role of age was further confirmed by the multivariable logistic regression analysis. When both age and PLR were included in the model, PLR lost its independent predictive significance (p = 0.197). In contrast, age remained the most influential variable, showing a strong trend toward statistical significance (p = 0.051). This suggests that the diagnostic utility observed for PLR in the univariable analysis is largely confounded by its intrinsic association with the age-dependent nature of the underlying pathologies.

Within the context of our cohort, our findings offer a pragmatic heuristic for the preoperative differential diagnosis of STN. Patient age emerged as the most powerful, zero-cost initial screening tool. Our data indicate that an age greater than 47.5 years is a strong predictor for a meningioma over an epidermoid cyst, a finding that can immediately guide clinical suspicion. PLR, in turn, serves as an auxiliary biomarker, particularly in diagnostically ambiguous scenarios. For instance, in an older patient whose imaging findings are atypical and could suggest an epidermoid cyst, a PLR value below the 117.28 cut-off provides additional evidence for a meningioma diagnosis, owing to its high specificity of 92.3%. It is crucial to emphasize that these parameters are not intended to replace MRI as the gold standard for diagnosis. Rather, they should be regarded as inexpensive and widely available auxiliary tools that can enhance diagnostic confidence, particularly in cases with atypical imaging findings, or assist in preoperative planning.

This study possesses several strengths, including its novel design as the first to systematically compare NLR and PLR across pathologically confirmed TN subtypes. The accuracy of our group categorization was ensured by postoperative pathological verification, and the robustness of our statistical approach was enhanced by adjusting for key confounders. Furthermore, all procedures were performed by a consistent, senior surgical team, minimizing operator-related bias. Nevertheless, we must acknowledge several limitations. First and foremost, the relatively small sample size (n = 53), particularly within the STN-M subgroup (n = 13), limits statistical power and the generalizability of our findings. And this study also lacks external validation or internal cross-validation procedures to confirm the robustness of the regression model. Given the relatively small sample size, especially within the STN subgroups, the reported classification accuracy of 89.7% may be inflated due to overfitting. Future studies should incorporate k-fold cross-validation or independent test sets to ensure the generalizability and stability of the model across diverse patient populations. Second, the retrospective, single-center design introduces inherent risks of selection bias. Furthermore, a key limitation of this study is that it included only surgically treated patients, which may also introduce selection bias and limit the generalizability of our findings. As such, the results primarily apply to patients with surgically confirmed TN subtypes. Future studies should aim to validate these findings in broader TN populations, including non-surgical cases, to assess whether the observed hematological trends are consistent across treatment modalities. Finally, this study relied on peripheral hematological markers as proxies for the local inflammatory state. While these markers are highly accessible, they can be influenced by unmeasured subclinical confounders, and they preclude the establishment of a direct causal link between the specific pathologies and the observed systemic inflammatory profiles without analysis of the local milieu.

Building upon these findings and limitations, future research should prioritize the validation of our results through large-scale, multi-center prospective studies to confirm the diagnostic thresholds for age and PLR. Furthermore, mechanistic studies are warranted to elucidate the precise link between systemic inflammatory markers and the local pathological microenvironment. Such investigations should ideally involve the simultaneous analysis of peripheral blood markers with local inflammatory mediators in CSF or resected tissue, focusing on cytokines previously implicated in TN pathophysiology, such as IL-6 and TNF-α (Ericson et al., 2019; Lai et al., 2025; Xu et al., 2025), to bridge the gap between systemic and local inflammation.

This study demonstrates that while the PLR shows potential for differentiating STN-M versus STN-E, its diagnostic value is substantially surpassed by the simple demographic feature of patient age. These findings underscore the potential of leveraging inexpensive, widely available clinical and hematological parameters as auxiliary tools to enhance diagnostic precision. However, they also affirm that a patient’s classic demographic profile and standard neuroimaging remain the cornerstone of clinical decision-making. Future research is required to elucidate the complex pathophysiological mechanisms that underlie these biomarker associations and to validate these findings in larger, prospective cohorts.