Clinical Significance of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Acute Unilateral Vestibulopathy

Abstract

Background and Purpose

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been identified as useful biomarkers for assessing the inflammatory response and for predicting the prognosis of various diseases. This study aimed to determine the clinical significance and effects on prognostic prediction of NLR and PLR in acute unilateral vestibulopathy (AUV).

Methods

We retrospectively recruited 128 patients who were diagnosed with AUV from July 2016 to April 2021, and compared NLR and PLR values between these patients with AUV and age- and sex-matched healthy subjects. We also analyzed the correlations of various clinical parameters with NLR and PLR.

Results

NLR and PLR in the AUV group were 3.41±2.80 (mean±standard deviation) and 128.86±67.06, respectively, with only NLR being significantly higher than that in the control group (1.55±0.60, p<0.001). The gain asymmetry of the horizontal vestibulo-ocular reflex (VOR) was slightly larger in patients with high NLR (n=52) than in those with normal NLR (n=76) (41.9%±20.2% vs. 33.6%±17.4%, p=0.048). However, the hospitalization period, preceding infection, canal paresis, and absolute horizontal VOR gain did not differ between patients with high and normal NLR and PLR values. The correlation analyses also revealed that none of the clinical parameters were significantly correlated with NLR or PLR. At 3-month follow-up examinations, NLR and PLR did not differ significantly between patients with and without function recovery of the horizontal VOR.

Conclusions

This study found a high NLR in AUV, suggesting an acute inflammatory status in the vestibular organ. However, the usefulness of NLR and PLR as prognostic markers remains unclear.

Graphical Abstract

INTRODUCTION

Acute unilateral vestibulopathy (AUV), also called vestibular neuritis, is characterized by an acute unilateral loss of peripheral vestibular function.¹ The main clinical symptom is the acute onset of sustained rotatory vertigo with unsteadiness and nausea/vomiting. The distinctive signs of AUV are spontaneous horizontal-torsional nystagmus, which is direction-fixed and enhanced by removal of visual fixation, and pathological results in a head impulse test on the affected side. Diagnostic criteria recently proposed by the Committee for the Classification of Vestibular Disorders of the Bárány Society imply that the diagnosis of AUV is heavily dependent on the patient history, a bedside examination, and, if necessary, a laboratory evaluation.² Several hypotheses have been proposed for the etiology of AUV, and the most-probable cause is reactivation of herpes simplex virus type 1 (HSV-1), which resides in a latent state in the vestibular ganglia.¹,²,³,⁴ However, the evidence to support a viral etiology remains circumstantial.⁵

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily measurable and available markers from routine blood tests. They have been identified as useful biomarkers for assessing the inflammatory response and for predicting the prognosis of various diseases such as stroke and various kinds of cancer.⁶,⁷,⁸ Likewise, both NLR and PLR have been considered inflammatory biomarkers in patients with vestibulopathies such as benign paroxysmal positional vertigo and Meniere’s disease.⁹,¹⁰,¹¹ Previous studies have also investigated the role of NLR and PLR in AUV to determine its pathogenesis, but the results were inconsistent.¹²,¹³,¹⁴,¹⁵,¹⁶ In addition, there have been no assessments of the significance of NLR and PLR in the short-term prognosis of AUV. This study aimed to determine the clinical significance and effects on prognostic prediction of NLR and PLR in AUV.

METHODS

Subjects

We retrospectively recruited 182 patients who were diagnosed with AUV from July 2016 to April 2021 based on the following criteria: 1) acute onset of sustained rotatory vertigo and unsteadiness with a tendency to fall toward the side of the affected ear; 2) the presence of spontaneous horizontal-torsional nystagmus beating toward the nonaffected ear, which was enhanced by removal of visual fixation; 3) pathological vestibulo-ocular reflex (VOR) function of the affected horizontal canal (HC) documented in a caloric test (canal paresis [CP] >25%) or a video head impulse test (vHIT; gain of the HC VOR <0.89 obtained from normal controls); 4) no evidence for acute central neurological symptoms or acute audiological symptoms such as hearing loss or tinnitus; and 5) not better accounted for by another disease. Among 182 initially enrolled patients, we excluded 27 patients whose vestibular symptoms/signs disappeared within 1 day after symptom onset because transient AUV might not be associated with an inflammatory pathophysiology. We excluded a further 27 patients who had conditions affecting complete blood count (CBC) such as the taking of anticancer or immunosuppressant drugs (n=11), systemic or inflammatory diseases (n=9), fever (n=4), or a postvaccination state (n=3). Therefore, 128 patients were finally enrolled in the study.

Data collection

All patients were hospitalized in the acute phase of AUV. During hospitalization, the patients underwent detailed neurological and neuro-otological examinations by the authors (E.H.O. and J.H.C.) every day. They received conservative treatments such as hydration and medical treatments for vertigo control, but none of the patients were prescribed steroids.

The CBC with differential was applied to peripheral venous blood samples in the acute phase of AUV. The absolute counts of neutrophils, lymphocytes, monocytes, and platelets were obtained using an automated cell counter (XN-9000, Sysmex, Kobe, Japan), and NLR and PLR were calculated. NLR and PLR were classified as high (>2.76 and >203.55, respectively) when they exceeded two standard deviations (SDs) from the means as obtained from 128 age- and sex-matched healthy subjects with no history of AUV.

The following clinical information was obtained: demographic data, past medical history, preceding infections, and hospitalization period.

Clinical outcome

The severity of AUV was assessed based on VOR function at baseline and in follow-up examinations. The VOR was evaluated using bithermal caloric and head impulse tests, as described previously.¹⁷ Briefly, bithermal caloric tests were performed by applying constant flows of warm (46.5℃) and cold (27℃) air to each ear. Horizontal eye movements were recorded binocularly using video-oculography (3D VNG Oculography System, SLMED, Seoul, Korea), and the maximum slow phase velocity of the induced nystagmus was measured. CP was defined as a response difference of >25% between the ears according to Jongkees’ formula. Quantitative head impulse tests were assessed using video-based equipment (SLVNG, SLMED). The VOR gain was calculated as the ratio of the area under the entire eye-velocity response relative to the area under the entire head-velocity response. Gain asymmetry (GA) was calculated as follows: GA=(R-L)/(R+L), where R and L are the mean gain values for impulses to the right and left sides, respectively. We defined a vHIT response as being abnormal when the mean VOR gains exceeded two SDs from the mean as obtained from 31 normal controls (normal gains were 0.89–1.02 for the HCs, 0.80–1.18 for the anterior canals, and 0.88–1.09 for the posterior canals), and when there were corrective catch-up saccades. To evaluate short-term recovery of VOR functions, follow-up caloric tests and vHITs were performed at 3 months after the onset of AUV.

Statistical analysis

Statistical analyses were performed using IBM SPSS software (version 22.0, IBM Corp., Armonk, NY, USA). Results for continuous variables (age, hospitalization period, CBC parameters, CP, vHIT gain, and GA) were expressed as mean±SD values. We compared the CBC parameters between the two groups (AUV vs. control) using Student’s t-test, and clinical data including VOR function between groups with high and normal NLR and PLR values using Student’s t-test or the chi-square test. The Pearson correlation test was also used to assess the associations of clinical parameters with NLR and PLR. Finally, we compared the baseline NLR and PLR between the patients with and without VOR recovery at 3-month follow-up examinations to estimate the effects of NLR and PLR on the risk of an unfavorable outcome. Statistical significance was defined as p<0.05.

Ethics statement

All experiments followed the tenets of the Declaration of Helsinki, and this study was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (05-2023-099).

RESULTS

The 128 finally enrolled patients comprised 58 males and 70 females who were aged 60.8±10.1 years and had a hospitalization period of 5.2±2.7 days. The CBC parameters in the AUV group and normal controls are presented in Table 1. The absolute counts of white blood cells and neutrophils were significantly higher in the AUV group than in the control group, whereas the hematocrit and platelet count were lower in the AUV group. The lymphocyte count did not differ significantly between the groups. NLR and PLR in the AUV group were 3.41±2.80 and 128.86±67.06, respectively, with only NLR being significantly higher than that in the control group (1.55±0.60, p<0.001) (Fig. 1).

Table 1. CBC parameters in the acute unilateral vestibulopathy (AUV) group and the control group.

Variable		AUV (n=128)	Control (n=128)	p
Hemoglobin (g/dL)		13.93±1.35	14.20±1.50	0.125
Hematocrit (%)		40.10±3.43	42.28±4.08	<0.001
WBC (×103/mL)		8.14±2.54	5.66±1.42	<0.001
	Neutrophils	5.46±2.55	3.01±1.04	<0.001
	Lymphocytes	2.10±1.04	2.03±0.56	0.533
Platelets (×103/mL)		224.22±52.95	244.09±54.71	0.003
MPV		9.90±0.82	10.06±0.79	0.113
NLR		3.41±2.80	1.55±0.60	<0.001
PLR		128.86±67.06	126.91±38.32	0.776
CRP (mg/dL)		0.26±0.82	0.11±0.18	0.054

Data are mean±standard deviation values.

CBC, complete blood count; CRP, C-reactive protein; MPV, mean platelet volume; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; WBC, white blood cells.

Fig. 1. Comparison of the neutrophil-to-lymphocyte ratio (NLR) (A) and platelet-to-lymphocyte ratio (PLR) (B) between patients with acute unilateral vestibulopathy (AUV) and normal controls.

An analysis of clinical parameters according to NLR and PLR revealed that the GA of the horizontal VOR was slightly larger in patients with high NLR (n=52) than in those with normal NLR (n=76) (41.9%±20.2% vs. 33.6%±17.4%, p=0.048) (Table 2). However, the hospitalization period, preceding infection, CP, and horizontal VOR gain in vHIT did not differ between patients with high and normal NLR and PLR values. Correlation analysis also revealed that none of the clinical parameters (hospitalization period, CP, or vHIT gain) were significantly correlated with NLR or PLR (p>0.05) (Table 3). In addition, NLR and PLR did not differ significantly between patients with and without function recovery of the horizontal VOR at 3-month follow-up examinations (Fig. 2).

Table 2. Clinical parameters according to NLR and PLR.

Variable		NLR			PLR
		High (n=52)	Normal (n=76)	p	High (n=13)	Normal (n=115)	p
Age (yr)		62.1±11.9	59.8±9.4	0.240	62.7±13.5	60.5±10.2	0.484
Sex				0.073			0.079
	Male	19	40		3	56
	Female	33	36		10	59
Hospitalization period (days)		5.36±2.25	5.94±3.18	0.253	5.46±1.61	5.61±2.77	0.851
Preceding infection		6	7	0.720	2	11	0.510
CP (%)		44.2±12.4	44.3±14.6	0.976	41.3±11.6	44.5±13.5	0.488
HC VOR gain in vHIT		0.66±0.19	0.58±0.29	0.126	0.65±0.46	0.63±0.20	0.802
Gain asymmetry (%)		41.9±20.2	33.6±17.4	0.048	46.0±25.7	35.9±18.0	0.230

Data are n or mean±standard deviation values.

CP, canal paresis; HC, horizontal canal; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; vHIT, video head impulse test; VOR, vestibulo-ocular reflex.

Table 3. Correlations between clinical parameters and laboratory data.

Variable	NLR		PLR
	r *	p	r *	p
CP	-0.135	0.187	-0.048	0.64
vHIT gain	-0.027	0.804	0.119	0.283
Hospitalization period	0.102	0.25	0.073	0.411

^*Pearson correlation coefficient.

CP, canal paresis; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; vHIT, video head impulse test.

Fig. 2. Comparison of NLR and PLR according to the horizontal vestibulo-ocular reflex function at 3-month follow-up examinations. A and B: Bithermal caloric tests. C and D: Video head impulse tests (vHITs). CP, canal paresis; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio.

DISCUSSION

This study found that NLR was higher in patients with AUV than in controls, suggesting an acute inflammatory status in the vestibular organ in AUV. However, neither NLR nor PLR was correlated with clinical parameters such as the hospitalization period, CP, or absolute vHIT gain. Moreover, we did not observe a significant effect of NLR or PLR on the short-term outcome of AUV.

A viral infection has long been suggested as the etiology of AUV by analogy with Bell’s palsy. There are several lines of evidence for a viral etiology, such as the presence of concurrent infectious illness, the demonstration of HSV-1 DNA in vestibular ganglia, and the detection of single-nucleotide polymorphisms associated with HSV-1 replication and the severity of herpes labialis.¹,²,³,⁴,⁵,¹⁸,¹⁹ Despite these findings, a viral etiology has not yet been proved due to the lack of compelling structural evidence for a consistent inflammatory component.⁵ A viral infection usually increases lymphocyte counts and decreases neutrophil counts, and hence leads to a low NLR. However, contrary to this expectation, NLR was significantly higher in the AUV group than in the control group, which is similar to the findings of previous studies.¹²,¹³,¹⁴,¹⁵,¹⁶ Lymphocyte subset quantifications have also revealed decreases in total and CD8 T-lymphocytes in approximately 50% of AUV patients.²⁰ Combining gene expression profiling with bioinformatics analysis has recently detected numerous differentially expressed genes associated with the neutrophil-mediated immune pathway in patients with AUV.¹⁵ All of these findings may contradict a direct viral infection along the vestibular nerve as the pathogenesis of AUV.

While the exact etiology remains unclear, it may be obvious that the inflammatory response plays a crucial role in the pathogenesis of AUV based on the elevation of proinflammatory proteins in the acute phase.²¹ Since neutrophils are one of the first responders to acute inflammation, NLR has been proposed as a prognostic predictor as well as an inflammatory marker in many diseases such as stroke, coronary artery disease, and various kinds of cancer.⁶,⁷,⁸,²² Several studies have found high NLR and PLR values to be associated with a worse prognosis in neuro-otological diseases including Bell’s palsy and sudden sensorineural hearing loss.²³,²⁴,²⁵ Although NLR has been considered an inflammatory biomarker in peripheral vertigo, the usefulness of this parameter as a prognostic predictor remains inconclusive in AUV.⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶ One study found a significant relationship between NLR and the clinical severity of AUV, but those authors evaluated the disease severity using the duration of subjective dizziness requiring antivertigo drugs, rather than using an objective questionnaire.¹² Another study found a positive correlation between NLR values and the period of spontaneous nystagmus in pediatric AUV patients, but this was only in a small number of patients.¹⁶ A recent study found no correlation between the hospitalization period and NLR.¹⁴

In the present study we evaluated the disease severity using various objective parameters such as vestibular signs, caloric tests, and vHITs, and found that none of the clinical parameters other than the GA of the horizontal VOR differed significantly between high- and normal-NLR groups. In addition, NLR was not substantially related to the short-term outcome of AUV. These findings suggest that NLR is not a reliable parameter for predicting the severity or prognosis of AUV. Instead, the clinical outcome of AUV may be determined by various factors such as age and neuro-otological or psychological comorbidities.²⁶,²⁷,²⁸

PLR is another inflammatory marker that has been used to assess the risk of microcirculatory thromboembolism. Previous studies have found PLR to be significantly higher in patients with AUV than in normal controls, and one of them revealed an increased mean platelet volume (MPV) in the AUV group.¹²,¹⁴,¹⁶ Based on these results, those authors have proposed the vascular theory to explain the pathogenesis of AUV.¹⁴,²⁹ However, the results for PLR or MPV have varied among studies, and neither PLR nor MPV was elevated in the AUV group in the present study. Although several factors such as differences in normal CBCs and no standardization of MPV measurements could contribute to inconsistent results, it is also possible that the inflammatory process in AUV does not result from thrombotic changes in the vestibular organ.³⁰

This study was subject to some potential limitations. Because the study had a retrospective case–control design, there were missing data such as from follow-up VOR examinations. The CBC parameters of the control group were obtained from age- and sex-matched subjects who underwent health medical examinations, but it was not certain that they were really healthy. Finally, we did not measure serial NLR and PLR values, which might have enabled more-reliable predictions.

In conclusion, this study found high NLR values in patients with AUV, but neither NLR nor PLR was correlated with the severity and prognosis of AUV. Although CBC parameters can show the acute inflammatory status in AUV, their usefulness as prognostic markers remains unclear. To clarify this issue, future research with a prospective design and serial measurements of CBC parameters or neutrophil-derived cytokines is needed.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.