Relationship between trigeminal neuralgia and the C-reactive protein/albumin ratio

Abstract

Objectives: This study aimed to assess whether the C-reactive protein/albumin ratio (CAR) is a risk factor for trigeminal neuralgia (TN) development and the relationship between the CAR and TN pain frequency.

Patients and methods: In this retrospective study, 100 patients (51 females, 49 males; mean age: 58.6±14.1 years; range, 31 to 88 years) with idiopathic TN and 70 healthy controls (38 females, 32 males; mean age: 54.1±15.7 years; range, 21 to 89 years) were included between January 2020 and December 2022. Patients were divided into two groups by weekly and monthly pain frequency. The laboratory findings and CARs were compared.

Results: The CAR values were significantly different between the patient and control groups (p<0.05) and were significantly different among TN subgroups divided according to attack frequency (p<0.05).

Conclusion: Since there was a significant relationship between TN and CAR as a prognostic predictor, this relationship demonstrated once again that inflammation plays a role in the etiopathogenesis of TN. As opposed to previous studies that investigated the effect of only inflammation, the effects of both inflammation and malnutrition could be investigated by evaluating CAR in this study.

Introduction

Trigeminal neuralgia (TN) is a chronic, neuropathic, trigeminal nerve pain syndrome. It is the most common form of facial pain, associated with burning, stinging, and repetitive paroxysmal problems in the orofacial region.[1,2] It is subclassified as primary or idiopathic and secondary or symptomatic, depending on the cause. Idiopathic TN (approximately 10% of all cases) is diagnosed when no obvious cause is apparent.[3-5] Inflammation plays a role in TN pathogenesis. Proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor (TNF), modulate neuronal activity;[6] both are nociceptor activators that increase trigeminal neuron excitability and sensitivity.[7,8] Interleukin-1b, TNF, IL-6, and CCL2 trigger neuropathic pain.[9-14] One study that investigated the relationship between the neutrophil-to-lymphocyte ratio, the monocyte-to-lymphocyte ratio, and TN reported that elevated levels of inflammatory markers might be risk factors for TN.[15]

C-reactive protein (CRP) is a positive acutephase reactant secreted by the liver. The blood level of CRP increases within hours after inflammation and infection commence.[16] Albumin (Alb) is a negative acute-phase reactant secreted by the liver[17] and is the most abundant protein in plasma, maintaining the plasma osmotic pressure and modulating fluid distribution among the various bodily compartments.[18] It has antioxidant and anti-inflammatory properties.[19] The CRP/Alb ratio (CAR) is a new prognostic marker of inflammation severity and mortality.[20] An increased CAR is associated with poor prognosis of migraine, Crohn’s disease, and Guillain-Barré syndrome.[21-23] Hematological and biochemical tests are simple, inexpensive, and readily interpretable; the CRP and Alb levels are routinely assayed. It is also important that it is more easily accessible than inflammatory cytokines such as IL-6, IL-1β, and TNF-alpha.[24-26]

Since inflammation can play a role in nerve damage and pain pathways, a higher CAR might suggest a more pronounced inflammatory response in individuals with TN. In other chronic conditions, the CRP/Alb ratio has been used to predict outcomes and disease progression. While specific studies on TN are limited, the CRP/Alb ratio might offer similar prognostic information, helping to identify patients at higher risk of severe disease or complications. No study has yet reported a relationship between TN and the CAR. Hence, this study aimed to explore whether a high CAR increased the risk for TN and whether the CAR was associated with the TN pain frequency.

Material and Methods

All medical records of patients who visited the neurology outpatient clinic of Inonu University Medical Faculty who were diagnosed with idiopathic TN between January 2020 and December 2022 were retrospectively analyzed. One hundred patients (51 females, 49 males; mean age: 58.6±14.1 years; range, 31 to 88 years) diagnosed with idiopathic TN using the criteria of the ICHD-3 (third edition of the International Classification of Headache Disorders) were included.[27] The inclusion criteria were primary TN, specific TN treatment, absence of hematological or current infectious disease, hyperpyrexia, metabolic disorder, severe heart disease, severe kidney or liver dysfunction, a neoplasm, an autoimmune or inflammatory disease, and not being on medication to treat an inflammatory condition. Positive stool culture, positive blood culture, positive urine culture, infiltrates on chest X-ray, documented skin infection, fever over 38°C, and patients with otitis symptoms were not included in the study. Each patient underwent magnetic resonance imaging using a 1.5 T superconductive scanner (Siemens Magnetom® Avanto; Siemens AG, München, Germany). Patients with symptomatic TN attributable to meningiomas, multiple sclerosis, or epidermoid cysts in the cerebellopontine angle were excluded. All patients were divided into two groups by pain frequency: those with pain at least weekly (Group 1; n=58) and those with pain once a month or less (Group 2; n=42). A control group of 70 healthy individuals (38 females, 32 males; mean age: 54.1±15.7 years; range, 21 to 89 years) was included. Healthy controls were frequency-matched to the patients by age, sex, educational level, and comorbidities.

Fasting peripheral blood samples were collected from all patients. Hematological parameters, including erythrocyte sedimentation rate (ESR), were measured using an automated nephelometric system (Sysmex Corporation 1-5-1, Wakinahama-kai Gandari Chuo-ku, Kobe, Japan) and kits from the same company. C-reactive protein levels were assayed employing another automated nephelometric system (BNII; Dade Behring, Deerfield, IL, USA), and kits from that company. Total serum levels of protein and Alb were measured via automatic spectrophotometry (Abbott Laboratories Diagnostics, Abbott Park, IL, USA) using kits from that company. The CAR was calculated. Patients with TN and control subjects were compared in terms of demographics, laboratory findings, and CARs.

Statistical analysis

Statistical analyses were performed using IBM SPSS version 26.0 (IBM Corp., Armonk, NY, USA). The normality of continuous variables was verified using the Shapiro-Wilk test (n<50) and Kolmogorov-Smirnov test (n≥50). Differences between patients with TN and healthy controls were assessed using the Mann-Whitney U test for independent nonnormally distributed variables and independent t-tests for normally distributed variables. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff values for CARs in terms of predicting TN and TN attack frequency. All statistical tests were two-tailed, and p-values <0.05 were assumed to indicate statistical significance.

Results

The levels of total protein, CRP, Alb, and CARs, significantly differed (p<0.05 unless stated otherwise) between patients and controls. All values were significantly higher than those of controls, except for Alb, whose levels were significantly lower. There were no significant differences in age or ESR between patients and controls (Table 1).

The mean CRP and Alb levels, and the CARs of TN patients, significantly differed by pain frequency; all were significantly higher in Group 1 than Group 2, but ESR, total protein level, and disease duration did not differ between the groups (Table 2).

Receiver operating characteristic curve analysis and the Youden index were used to determine the optimal CAR that could distinguish patients from controls. The area under the ROC curve for CAR was 78.6 (95% confidence interval [CI]: 0.700-0.831; Figure 1). For patients, the optimum CAR cutoff was 0.075, with a sensitivity and specificity of 55.7% and 92%, respectively; the accuracy was 77.1% (Table 3). Furthermore, ROC curve analysis and the Youden index were used to determine the CAR that could distinguish Groups 1 and 2. For Group 1, the area under the ROC curve for CAR was 65.4 (95% CI: 0.239-0.431; Figure 2). For Group 1, the optimum CAR cutoff was 0.105, and the sensitivity and specificity were 52.4% and 77.6%, respectively; the accuracy was 33% (Table 4).

Figure 1. Control/patient CAR ROCs.
CAR: C-reactive protein/Alb ratio; ROC: Receiver operating characteristic.

Figure 2. Group 1/Group 2 CAR ROCs.
CAR: C-reactive protein/Alb ratio; ROC: Receiver operating characteristic.

Discussion

We found that CAR values were significantly higher in patients with TN than in healthy controls. Furthermore, the CAR values significantly increased with TN pain frequency. To the best of our knowledge, this is the first study to show that the CAR is a novel marker of TN inflammation.

Trigeminal neuralgia is the most common form of facial pain in those aged 50 years or more. It is thought to be of neuropathic origin, caused by demyelination or remyelination associated with damage to the roots or ganglia of the trigeminal axons.[28,29] The nerve fibers become overexcitable and trigger paroxysmal pain.[29] However, the molecular mechanisms of pain generation and transmission remain unclear. It has been suggested that inflammation may be in play. Demyelination of the root entrance regions of the primary sensory trigeminal afferents may trigger secretion of inflammatory factors.[30-32] Tumor necrosis factor-alpha, IL-6, IL-8, and IL-1β contribute to neural pain.[33-36] Inflammatory mediators, including prostaglandins, proinflammatory cytokines, and chemokines, directly induce pain by increasing the sensitivities of the nociceptors that serve as the primary sensory neurons perceiving noxious stimuli.[37-39] Some studies found that proinflammatory cytokines, including IL-1, IL-2, IL-6, IL-8, TNF, and interferon, produced during inflammation activate the nerve endings of polymodal nociceptors.[40-42] Studies that used animal models of TN found many macrophages and mast cells in trigeminal root regions undergoing focal demyelination.[43,44] Thus, there may be a very close relationship between inflammation and TN.

The CAR is a new marker that is prognostic of the severity of inflammation and mortality; it was first used to identify patients with severe disease.[45] In the literature, there are studies on CAR and many diseases that are known to play a role in the etiology of inflammation.[23,46,47] There are studies showing that CAR is a prognostic factor for cancer patients.[48,49] Moreover, CAR was associated with mortality in patients with antineutrophil cytoplasmic autoantibody-related vasculopathies[50] and was significantly increased and prognostic for patients with autoimmune diseases such as Crohn’s disease, Behçet’s disease, and Takayasu arteritis.[23,46,47] Olgun Yazar et al.[51] reported a significant difference in the CARs of patients with restless legs syndrome and controls; the CAR significantly increased with disease severity. In another study, no significant differences were found between patients with migraine and controls, but the CAR significantly increased during migraine attacks.[22] Our findings are consistent with previous reports; the CAR was significantly higher in TN patients than in controls, particularly in those with more pain attacks.

Few studies have investigated the relationship between TN and inflammation in the literature. Yao et al.[15] showed that the white blood cell, neutrophil, and monocyte counts, the neutrophil-to-lymphocyte ratio, and the monocyte-to-lymphocyte ratio were higher in the peripheral blood of TN patients compared to controls. It was suggested that these inflammatory markers might be risk factors for TN and that they played a predictive role in diagnosing TN. Ericson et al.[52] found that the levels of many proteins that affect the immune system, particularly TNF-beta, were elevated in the cerebrospinal fluid of TN patients after surgery compared to controls. Another study reported that the serum levels of IL-1β, IL-6, IL-8, and TNF-alpha in TN patients were significantly higher than those of controls and that IL-6 concentrations were positively correlated with TN severity.[53] We found that the CAR, a new inflammatory marker, was significantly higher in TN patients than in controls.

We found that the CAR levels achieved a diagnostic accuracy of 77.1% in TN. In our study, the sensitivity and specificity of the CAR ROC analysis for the distinction between control and patient were found to be 55.7% and 92%, respectively. Although we were aware that the diagnostic accuracy was not very high, no reports in the literature were found to compare our results. Therefore, we decided to present this paper as a contribution to the literature.

There are several limitations to our study. First, not all inflammatory biomarkers were evaluated in detail. In addition, this was a retrospective cross-sectional study with a rather low number of patients. Future prospective large-scale studies are required.

In conclusion, there was a significant relationship between TN, the etiology of which is still unclear, and CAR, an inflammatory marker. The CAR could be an inflammatory prognostic marker for TN etiology and disease severity. Additionally, this study contributed to the literature by investigating the effects of both inflammation and malnutrition using the CAR. It is thought that this study will provide a new perspective to the literature in this respect.

Cite this article as: Algul FE, Unver FB. Relationship between trigeminal neuralgia and the C-reactive protein/albumin ratio. Turk J Neurol 2024;30(3):134-140. doi: 10.55697/ tnd.2024.134.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The study protocol was approved by the İnönü University Faculty of Medicine Ethics Committee (date: 24.01.2023, no: 2023/4389). The study was conducted in accordance with the principles of the Declaration of Helsinki.

A written informed consent was obtained from each patient.

Conceptualization, resources: F.E.A., F.B.U.; Data curation: F.B.U.; Methodology, project administration, supervision, writing-original draft, writingreview & editing: F.E.A. All the authors contributed to the study conception and design.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

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