Olfactory Bulb Volume and Function Recovery in Eosinophilic Chronic Rhinosinusitis

ABSTRACT

Objective

To evaluate perioperative changes in olfactory bulb volume (OBV) and olfactory function in patients with eosinophilic chronic rhinosinusitis (ECRS) using 3T magnetic resonance imaging (MRI) with fast imaging employing steady‐state acquisition (FIESTA) sequence and to assess their associations.

Methods

This single‐center, retrospective observational study included 32 patients with ECRS who underwent functional endoscopic sinus surgery. Olfactory function was assessed pre‐ and postoperatively using the Alinamin test, T&T olfactometer, Open Essence (OE), Odor Stick Identification Test for Japanese (OSIT‐J), Visual Analog Scale (VAS), and Self‐Assessment Olfactory Questionnaire (SAOQ). OBV was manually measured from FIESTA images. Logistic regression was used to identify preoperative predictors of OBV change.

Results

Postoperative OE, OSIT‐J, VAS, and SAOQ scores improved significantly. Mean OBV increased by 10.3% postoperatively, although not statistically significant (p = 0.095). OBV change correlated with improvements in olfactory identification (OE: r = 0.404, p = 0.022; OSIT‐J: r = 0.402, p = 0.022), which should be interpreted as exploratory. Multivariate analysis revealed that longer odor duration on the Alinamin test (≥ 50 s) and higher SAOQ scores predicted smaller OBV increases.

Conclusion

OBV measurement using 3T MRI with FIESTA may provide a structural correlate of olfactory changes in ECRS. The observed correlation between OBV changes and olfactory identification suggests a potential relationship with postoperative functional recovery.

Level of Evidence

4.

This study investigated perioperative changes in olfactory bulb volume (OBV) in patients with eosinophilic chronic rhinosinusitis using high‐resolution 3T MRI. Postoperative increases in OBV were associated with improvements in olfactory identification, suggesting a potential link between olfactory bulb structural plasticity and functional recovery after endoscopic sinus surgery.

1. Introduction

Olfactory function is vital for daily life, influencing food enjoyment, hazard detection, and social interactions. Its impairment significantly reduces quality of life (QOL) [1, 2, 3] and is highly prevalent in chronic rhinosinusitis (CRS), affecting over 80% of patients [4]. Notably, CRS with nasal polyps (CRSwNP) causes more severe olfactory dysfunction than CRS without nasal polyps, likely due to olfactory cleft obstruction by polyps and diffuse epithelial inflammation [5]. CRS represents a heterogeneous inflammatory disorder of the sinonasal mucosa. CRSwNP encompasses multiple endotypes, among which eosinophilic chronic rhinosinusitis (ECRS) constitutes a subtype characterized by dominant type 2 inflammation. In Japan, ECRS is defined according to the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria, which incorporate clinical findings, peripheral blood eosinophilia, computed tomography (CT) scores, and tissue eosinophil infiltration [6]. The prevalence [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17] and diagnostic criteria [6, 18] of ECRS differ across regions. ECRS is a distinct CRS subtype characterized by marked eosinophilic inflammation and responsiveness to biologics [19].

The olfactory bulb (OB) is the first central relay for sensory input from the olfactory epithelium [20] and is critical for odor processing, discrimination, and memory integration [21]. The OB exhibits structural plasticity, with volume changes reported in response to aging [22], sensory deprivation [23, 24], infections, trauma [25, 26, 27], and neurodegenerative diseases [28, 29, 30]. Conversely, olfactory training and sensory recovery can increase OB volume (OBV) [31, 32, 33]. Therefore, OBV can be regarded as a reversible structural indicator that may reflect aspects of olfactory function and may aid in understanding olfactory dysfunction and treatment outcomes.

In CRS, OBV correlates with olfactory improvement following endoscopic sinus surgery (ESS). Longitudinal studies [34, 35] have reported significant OBV increases post‐ESS, supporting OB plasticity. However, OB structural changes in ECRS—a CRSwNP subtype characterized by severe olfactory dysfunction—remain underexplored. Studying OBV in ECRS may yield important insights. Traditional olfactory assessments (questionnaires, psychophysical tests) are subjective and influenced by compliance and cognition. Magnetic resonance imaging (MRI), particularly 3T MRI, with high‐resolution T2‐weighted sequences such as fast imaging employing steady‐state acquisition (FIESTA), enables direct, reproducible visualization of central olfactory structures, including the OB. As a noninvasive adjunct, MRI enhances assessment of olfactory impairment and therapeutic response.

This study aimed to investigate pre‐ and post‐ESS OBV changes in ECRS using 3T MRI to clarify the relationship between OBV and olfactory function recovery and to improve understanding of ECRS pathophysiology and prognosis.

2. Methods

2.1. Patients and Methods

This retrospective study included 32 patients treated at Sapporo Medical University Hospital (Sapporo, Japan) between February 2019 and January 2025 (Figure 1). ECRS was diagnosed according to JESREC criteria: a total score ≥ 11 and an average of > 70 eosinophils per HPF in three eosinophil‐rich areas [6]. Exclusion criteria were patients who had received systemic steroids within 2 months before or after olfactory testing or who had conditions affecting olfaction, including head trauma, claustrophobia, or MRI‐incompatible metal implants/pacemakers. The study was approved by the Sapporo Medical University ethics board (No. 342‐83). An opt‐out consent process was employed through public disclosure of the study purpose and procedures. To minimize the risk of selection bias, all consecutive patients who met the JESREC‐based eligibility criteria and underwent ESS during the study period were included, as illustrated in the CONSORT‐style flow diagram (Figure 1).

FIGURE 1.

Flowchart of the included patients. ECRS, eosinophilic chronic rhinosinusitis; MRI, magnetic resonance imaging.[Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

All patients underwent bilateral ESS (full‐house functional ESS), unifying all sinuses into a single cavity. Polyps and edematous mucosa within the olfactory cleft were resected with a microdebrider. A single otolaryngologist (the first author) performed all surgeries. Patients received topical steroid spray Mometasone furoate nasal spray (Alamist, 110 μg/day) was administered for at least 3 months preoperatively and continued postoperatively until the time of olfactory testing and daily saline irrigation both pre‐ and postoperatively. Low‐dose, long‐term clarithromycin (200 mg/day) was administered for 3 months postoperatively.

All patients underwent preoperative CT imaging. ECRS diagnosis and severity were assessed using the JESREC scoring system, involving four clinical parameters: bilateral disease, nasal polyps, ethmoid‐dominant opacification on CT, and peripheral blood eosinophilia (≥ 5%). A score of ≥ 11 confirmed ECRS. Severity was further classified: Factor A was positive if both (i) blood eosinophils ≥ 5% and (ii) ethmoid‐dominant shadowing on CT were present. Factor B was positive if any of the following were present: (i) bronchial asthma, (ii) aspirin intolerance, or (iii) nonsteroidal anti‐inflammatory drug intolerance. Patients with JESREC scores ≥ 11 were categorized as follows: mild ECRS: Factor A (−), Factor B (−); moderate ECRS: Factor A (+), Factor B (−); and severe ECRS: Factor A (+), Factor B (+) [6].

Pre‐ and postoperative olfactory assessments included the prosultiamine (Alinamin; Takeda Pharmaceutical Co., Osaka, Japan) intravenous olfaction test assessing retronasal olfaction and neurogenic dysfunction [36], T&T olfactometer (Daiichi Yakuhin Sangyo, Tokyo, Japan) assessing odor threshold and identification [37], Open Essence (OE; Fujifilm Wako Pure Chemical Corp, Osaka, Japan) [38] and Odor Stick Identification Test for Japanese (OSIT‐J; Daiichi Yakuhin Sangyo, Tokyo, Japan) assessing odor threshold and identification [39], and Visual Analog Scale (VAS) and the Self‐Administered Odor Questionnaire (SAOQ) representing subjective olfactory perception [40]. The Alinamin test evaluates olfactory nerve function via intravenous prosultiamine, which produces a garlic‐like odor. Latency and duration of odor perception are measured, with mean values of ~8 and 70 s, respectively in healthy individuals [36]. The T&T olfactometer uses five standard odorants. The detection threshold reflects perception; while the recognition threshold reflects identification. The severity of olfactory dysfunction is classified by the average recognition threshold: < 1.0 is normal, 1.1–2.5 is mild hyposmia, 2.6–4.0 is moderate hyposmia, 4.1–5.5 is severe hyposmia, and ≥ 5.6 is anosmia [36]. Both OE and OSIT‐J assess the recognition of 12 familiar odors. OE uses microcapsule‐embedded paper strips that patients open and sniff independently. OSIT‐J involves an examiner applying stick‐based odors to paraffin paper. Correct identifications are scored, with 7–8 or more considered to be normal olfaction [38, 39]. The VAS was used for the subjective assessment of olfaction, with ratings obtained directly from patients. Patients were instructed to rate their current olfactory ability on a 10‐cm horizontal line, where 0 indicated “no sense of smell” and 10 indicated “normal sense of smell.” The SAOQ is a questionnaire consisting of 20 odor items familiar to Japanese individuals. A higher percentage score indicates better olfactory ability, and the statistically normal reference level of the SAOQ was determined as more than 70% [40].

In line with clinical trial guidelines recommending a 6‐month endpoint for evaluating postoperative QOL after ESS [41], all olfactory tests (Alinamin, T&T, OE, OSIT‐J, VAS, and SAOQ) were repeated at approximately 6 months, along with MRI. T&T recognition thresholds were evaluated per Japanese criteria: cured, threshold ≤ 2.0; improved, ≥ 1.0 point decrease; worsened, ≥ 1.0 point increase; and no change, all other cases [36]. VAS scores were similarly classified: Cured, score ≥ 9.0; improved, ≥ 2.0 point increase; worsened, ≥ 2.0 point decrease; no change, not meeting other criteria [42]. The “Overall Judgment” was used as a composite indicator to summarize postoperative olfactory improvement based on predefined criteria for changes in both T&T olfactometry and VAS scores. In this study, postoperative changes were first calculated for each patient, and the mean changes across all patients were then used to represent the overall trend of olfactory improvement.

2.2. Scanning Protocol

High‐resolution T2‐weighted imaging of the OB was performed using a three‐dimensional FIESTA (3D‐FIESTA) sequence on a 3T MRI scanner (3.0‐T GE Signa, HDx version 16.0; GE Healthcare) with eight‐channel head coils and two sets of gradient field coils. Imaging parameters were: TR/TE = 5.7/2.3 ms, flip angle = 60°, field of view (FOV) = 160 × 160 × 51.2 mm, matrix = 320 × 320 × 124, voxel size = 0.5 × 0.5 × 0.4 mm, bandwidth = 195 Hz/pixel, and NEX = 1. Total acquisition time was approximately 5 min and 50 s. The FOV included the anterior and middle skull base. Standard axial T2‐weighted images of the brain were also acquired to rule out central causes of olfactory dysfunction.

2.3. Volumetric Analysis

OBVs were measured on FIESTA images using a dedicated medical imaging workstation (Ziostation2, Ziosoft, Tokyo, Japan; Figure 2A). Measurements followed established anatomical landmarks and manual segmentation techniques. Slices with clear visualization of the OB were selected (Figure 2B–D). A 3D graphical model is generated based on the following procedures (Figure 2E). OB boundaries were manually traced on each coronal slice (Figure 2F), with the proximal OB defined at the point of abrupt diameter change marking the transition to the olfactory tract [43, 44]. OB limits were further delineated by adjacent cerebrospinal fluid and the anterior cribriform plate [45]. Sagittal (Figure 2G) and axial (Figure 2H) views were reconstructed from the coronal tracings, allowing volumetric calculation based on contour data and voxel dimensions. To ensure measurement reliability, OBVs were independently measured for all patients by two experienced neuroimaging technologists (each with > 15 years of experience), who were blinded to clinical information and surgical outcomes. All measurements were performed according to a standardized protocol. Inter‐rater reproducibility was assessed using the intraclass correlation coefficient ICC(2,1) with a two‐way random‐effects model. To evaluate intra‐rater reproducibility, the same rater repeated OBV measurements in seven randomly selected cases, and ICC(1,1) was calculated. When vascular structures were visible near the OB, bulb margins were identified by tracking continuous slices in which the OB was clearly distinguishable. Slices with unclear boundaries between the OB and adjacent vessels were excluded, and contours were interpolated using the preceding and following slices. Margins were further verified by cross‐referencing axial, coronal, and sagittal planes. If measurements differed by < 10%, the mean was recorded. If the difference was > 10%, a radiologist performed a third measurement, and the two closest values were averaged per published protocols [35].

FIGURE 2.

Visualization and volumetric assessment of the olfactory bulbs using 3T MRI. (A) Coronal FIESTA sequence MRI image showing bilateral olfactory bulbs (white arrowheads). (B–D) Representative coronal (B), sagittal (C), and axial (D) slices in which the olfactory bulbs were clearly delineated. (E) A three‐dimensional reconstruction of the olfactory bulbs (yellow) based on the manually segmented contours and voxel dimensions. Two experienced radiologic technologists independently performed olfactory bulb volume measurements. If the measurements differed by < 10%, their average was recorded. If the difference was > 10%, a radiologist conducted a third measurement, and the average of the two closest values was used. (F) Manual tracing of the outer boundaries of the olfactory bulbs on consecutive coronal slices using Ziostation2 (G, H). Sagittal (G) and axial (H) views generated from the segmented coronal slices, demonstrating the same olfactory bulb regions. Small orientation labels: S: superior; I: inferior; A: anterior; P: posterior; L: left; R: right. FIESTA, fast imaging employing steady‐state acquisition; MRI, magnetic resonance imaging.[Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

2.4. Statistical Analysis

Statistical analyses were performed using EZR (version 1.64), a graphical user interface for R (version 4.3.1). Normality of all continuous variables was assessed using the Shapiro–Wilk test, and homogeneity of variances between pre‐ and postoperative values was confirmed using the F‐test. As all variables, including T&T and SAOQ scores, met both assumptions of normality and equal variance, parametric paired t‐tests were used to compare preoperative and postoperative scores from the prosultiamine (Alinamin) test, T&T olfactometer, OE, OSIT‐J, VAS, SAOQ, and OBVs. Pearson's correlation coefficient was used to assess associations between changes in subjective olfactory scores (VAS, SAOQ, OE, OSIT‐J) and postoperative MRI interval (days from surgery to MRI) and changes in OBV. The significance of these correlations was evaluated using t‐tests. Two‐sided p < 0.05 was considered statistically significant. For descriptive purposes, olfactory test results were presented as median values with 95% confidence intervals (CIs) to intuitively represent central tendency and variability. To account for multiple testing, the false discovery rate (FDR) was controlled using the Benjamini–Hochberg procedure, and both uncorrected and adjusted p values were reported. A sensitivity analysis using Cook's distance (threshold: 4/n ≈ 0.125) was performed to assess the influence of potential outliers on correlation coefficients.

2.5. Logistic Regression Analyses

Logistic regression analyses were performed to identify factors associated with postoperative increases (> 10%) in OBV. Age and sex—known determinants of OBV [46]—were included as covariates in all multivariate models. Variables with p < 0.20 in univariate analysis were considered for inclusion, and given the limited sample size, each multivariate model included only three predictors (age, sex, and one additional variable) to minimize overfitting. All predictors were entered simultaneously, and multicollinearity was evaluated using the variance inflation factor (VIF), which was < 1.3 for all variables. Continuous variables were analyzed as raw values, whereas categorical variables were dichotomized. For each model, the regression coefficient (β), standard error, odds ratio (OR), 95% CI were determined, and model fit was evaluated using the Hosmer–Lemeshow goodness‐of‐fit test.

3. Results

Baseline demographic and clinical characteristics of the 32 patients with ECRS, including 13 (40.6%) men and 19 (59.4%) women, are presented in Table 1. The median age was 59.5 years (range, 28–72). Based on JESREC classification, 16 (50.0%), 9 (28.1%), and 7 (21.9%) patients had severe, moderate, and mild ECRS, respectively. Bronchial asthma was present in 22 patients (68.8%), and 13 (40.6%) had a history of smoking. Prior sinus surgery was performed in five patients (15.6%). Peripheral blood eosinophil levels were < 5%, 5%–10%, and > 10% in 6 (18.8%), 21 (65.6%), and 5 (15.6%) patients, respectively. The interval from surgery to MRI was 83–265 days, with a mean of 142.7 days. The correlation between MRI interval and changes in OBV was negligible and not significant (r = 0.009, p = 0.959). Inter‐rater reliability for manual OBV segmentation was excellent, with ICC(2,1) = 0.92 (95% CI: 0.78–0.98). Intra‐rater reproducibility was also outstanding, with an ICC(1,1) = 0.99, confirming very high measurement consistency.

TABLE 1.

Baseline characteristics of patients with ECRS.

	Patients with ECRS
N	32
Age (years), median (range)	59.5	(28, 72)
Sex
Male, n (%)	13	40.6
Female, n (%)	19	59.4
JESREC score severity
Severe, n (%)	16	50
Moderate, n (%)	9	28.1
Mild, n (%)	7	21.9
Bronchial asthma, n (%)	22	68.8
Smoking habit, n (%)	13	40.6
Previous surgery, n (%)	5	15.6
Proportion of blood Eos.
< 5%, n (%)	6	18.8
5%–10%, n (%)	21	65.6
> 10%, n (%)	5	15.6
Days from surgery to MRI, mean (range)	142.68	(83–265)

Note: Baseline demographic and clinical characteristics of patients with eosinophilic chronic rhinosinusitis. Values are presented as median (range) for continuous variables and number (%) for categorical variables. JESREC score was used to classify disease severity.

Abbreviations: ECRS, eosinophilic chronic rhinosinusitis; Eos., eosinophil; JESREC, Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis; MRI, magnetic resonance imaging.

Figure 3 illustrates changes in olfactory function before and after surgery, assessed via the Alinamin test, T&T olfactory detection and recognition tests, OE, OSIT‐J, VAS, and SAOQ. Median Alinamin test latency significantly improved from 20.0 s (95% CI: 19.3–31.6) preoperatively to 13.0 s (95% CI: 11.7–16.8) postoperatively (p = 0.001; Figure 3A). No significant change was observed in median Alinamin test duration (p = 0.853; Figure 3B). The median T&T olfactory score improved from 5.2 (95% CI: 2.6–4.5) to 0.5 (95% CI: 0.1–1.8) (p < 0.001; Figure 3C), and the recognition score improved from 5.7 (95% CI: 2.8–6.0; scale range: 0–5.8) to 2.2 (95% CI: 1.8–3.1) (p < 0.001; Figure 3D). The OE scores increased from 2.0 (95% CI: 1.0–4.0) to 5.3 (95% CI: 4.2–6.3) (p < 0.001; Figure 3E), and OSIT‐J scores from 1.0 (95% CI: 2.0–3.0) to 6.5 (95% CI: 4.5–6.9) (p < 0.001; Figure 3F). VAS scores significantly increased from 0.0 (95% CI: 0.6–2.1) to 6.5 (95% CI: 4.9–7.1) (p < 0.001; Figure 3G). SAOQ scores also improved markedly from 2.5 (95% CI: 9.5–28.3) to 79.0 (95% CI: 54.0–77.8) (p < 0.001; Figure 3H).

FIGURE 3.

Comparison of preoperative and postoperative olfactory function using multiple assessment tools. Changes in olfactory function before and after endoscopic sinus surgery (ESS) are assessed using the following methods: The Alinamin test (latency and duration times), T&T olfactometer (detection and recognition thresholds), Open Essence (OE), the Odor Stick Identification Test for Japanese (OSIT‐J), Visual Analog Scale (VAS), and Self‐Assessment Olfactory Questionnaire (SAOQ). Significant improvements were observed in Alinamin test latency (A), T&T detection (C), and recognition (D) scores, OE (E), OSIT‐J (F), VAS score (G), and SAOQ score (H). No significant change was observed in Alinamin test duration (B). Preop, preoperative; Postop, postoperative.

Table 2 summarizes the improvement status and perioperative changes in T&T recognition scores and VAS assessments. In the T&T test, 59.4% of patients were classified as “Cured” (25.0%) or “Improved” (34.4%), with a mean score improvement of 1.87 ± 1.84 (95% CI: 1.21–2.53). Based on the VAS score, 81.3% of patients were deemed “Cured” (18.8%) or “Improved” (62.5%), with a mean score improvement of 4.91 ± 3.55 (95% CI: 3.63–6.18). Overall, both tests indicated improved olfactory function.

TABLE 2.

Distribution of improvement categories and perioperative changes in T&T and VAS scores.

Test	Judgment category	n	%	Mean difference ± SD	95% CI	Overall judgment
T&T	Cured	8	25.0
	Improved	11	34.4	1.87 ± 1.84	1.21–2.53	Improved
	No change	12	37.5
	Worsened	1	3.1
VAS	Cured	6	18.8
	Improved	20	62.5	4.91 ± 3.55	3.63–6.18	Improved
	No change	5	15.6
	Worsened	1	3.1

Note: Classification of olfactory improvement and the corresponding changes in T&T and VAS scores pre‐ and postoperatively, based on Japanese clinical criteria.

Abbreviations: CI, confidence interval; SD, standard deviation; T&T, T&T recognition score; VAS, Visual Analog Scale.

No significant differences were observed in OBVs pre‐ and postoperatively (Figure 4A; Table 3). Mean total OBV increased from 77.2 ± 19.5 (95% CI: 68.2–82.2) to 81.1 ± 23.9 mm³ (95% CI: 72.5–89.7; p = 0.095). Right OBV increased from 37.6 ± 11.2 to 41.1 ± 12.2 mm³ (p = 0.106), and left OBV from 39.7 ± 10.4 to 43.6 ± 12.7 mm³ (p = 0.155), although the difference was not statistically significant. The average postoperative OBV change was 10.3% ± 25.3% (95% CI: 1.2%–19.5%) (Figure 4B; Table 3).

FIGURE 4.

Changes in olfactory bulb volume (OBV) before and after endoscopic sinus surgery. (A) Right, left, and total OBVs measured preoperatively and postoperatively using 3T‐magnetic resonance imaging. No statistically significant differences were observed between pre‐ and postoperative OBVs for right (p = 0.106) and left (p = 0.155) sides or total (p = 0.095). (B) Percentage change in total OBV from preoperative to postoperative measurements. The mean perioperative change was 10.3% (±25.3%). Periop: perioperative; Postop: postoperative; Preop: preoperative.

TABLE 3.

Changes in OBV pre‐ and postoperatively.

OBV	Timepoint	Mean ± SD (mm3)	95% CI (mm3)	p
Right OBV	Preop.	37.6 ± 11.2	33.5–41.6	—
	Postop.	41.1 ± 12.2	36.7–45.5	0.106
Left OBV	Preop.	39.7 ± 10.4	35.9–43.4	—
	Postop.	43.6 ± 12.7	39.0–48.2	0.155
Total OBV	Preop.	77.2 ± 19.5	68.2–82.2	—
	Postop.	81.1 ± 23.9	72.5–89.7	0.095
Perioperative volume change (%)	—	10.3 ± 25.3	1.2–19.5	—

Note: Volume change (%) was calculated as (postop. − preop.)/preop. × 100.

Mean OBVs before and after endoscopic sinus surgery. Data are expressed as mean ± SD; 95% CIs (in parentheses) are shown for total OBV. No statistically significant differences were observed. Perioperative changes were calculated as the percentage difference between preoperative and postoperative values.

Abbreviations: CI, confidence interval; OBV, olfactory bulb volume; Postop., postoperative; Preop., preoperative; SD, standard deviation.

Figure 5 shows correlations between the percentage change in (ΔOBV%) and various olfactory tests. ΔOBV% was not significantly correlated with Alinamin test latency (r = 0.009, p = 0.620; Figure 5A), duration (r = 0.153, p = 0.620; Figure 5B), T&T detection (r = 0.219, p = 0.229; Figure 5C), or recognition (r = 0.166, p = 0.364; Figure 5D). However, significant correlations were observed with OE (r = 0.404, p = 0.022; Figure 5E) and OSIT‐J scores (r = 0.402, p = 0.022; Figure 5F). Nonsignificant correlations were observed with VAS (r = 0.329, p = 0.066; Figure 5G) and SAOQ (r = 0.297, p = 0.099; Figure 5H). After FDR correction using the Benjamini–Hochberg procedure, the correlations between ΔOBV and OE (r = 0.40, uncorrected p = 0.0218, adjusted p = 0.09) and ΔOBV and OSIT‐J (r = 0.40, uncorrected p = 0.0224, adjusted p = 0.09) did not remain statistically significant. Sensitivity analysis using Cook's distance revealed that excluding influential cases reduced the correlation coefficients to r = 0.24 for ΔOBV‐OE and r = 0.22 for ΔOBV‐OSIT‐J, while preserving the positive direction of association.

FIGURE 5.

Correlation between percentage change in olfactory bulb volume (ΔOBV%) and changes in olfactory function. Scatter plots showing the relationship between ΔOBV% and pre‐to‐postoperative changes in olfactory test results: Alinamin test latency (A), Alinamin test duration (B), T&T detection threshold (C), T&T recognition threshold (D), Open Essence (E), Odor Stick Identification Test for Japanese (OSIT‐J) (F), Visual Analog Scale (VAS) (G), and Self‐Assessment Olfactory Questionnaire (SAOQ) (H). Significant positive correlations were observed for Open Essence and OSIT‐J scores. Pearson's correlation coefficients (r) and p values are indicated for each plot. p < 0.05 was considered statistically significant.

Multivariate logistic regression was conducted to identify factors associated with postoperative OBV increase > 10% (Table 4). Longer odor perception on the Alinamin test (≥ 50 s) was negatively associated with OBV increase (OR = 0.16, 95% CI: 0.01–1.12, p = 0.049), and this association remained significant in the multivariate model (adjusted OR = 0.08, 95% CI: 0.0096–0.70, p = 0.022). An SAOQ score > 0—indicating better self‐reported olfactory function—was also significantly associated with lower odds of OBV increase (adjusted OR = 0.19, 95% CI: 0.035–0.99, p = 0.049). All logistic models demonstrated acceptable calibration with Hosmer–Lemeshow goodness‐of‐fit p values ranging from 0.087 to 0.974, indicating no evidence of lack of fit. These results suggest that patients with relatively intact olfaction—reflected by longer Alinamin odor duration and higher SAOQ scores—exhibit less OB volume change and remodeling of the OB, consistent with limited structural neuroplastic changes following surgery. OBV increase may therefore reflect compensatory neuroplasticity in patients with poorer baseline olfactory function.

TABLE 4.

Univariate and multivariable logistic regression analyses of factors associated with greater perioperative olfactory bulb volume change (> 10%).

Variable	Univariate OR	95% CI (lower–upper)	p	β	SE	Multivariable OR	95% CI (lower–upper)	p	Reference category	H–L p
Age (> 50)	0.34	0.05–1.76	0.166
Sex (male)	2.71	0.46–20.6	0.265
Intravenous alinamin test (latency < 30 s)	0.62	0.12–3.06	0.723
Intravenous Alinamin test (duration ≥ 50 s)	0.16	0.01–1.12	0.049	−2.50	1.09	0.08	0.02–0.70	0.022	Duration < 50 s	0.495
T&T recognition score (severe hyposmia, anosmia)	2.98	0.57–18.4	0.166	0.81	0.82	2.24	0.45–11.2	0.326	Moderate, mild hyposmia	0.180
OE score (≥ 4 correct answers)	0.38	0.03–2.89	0.402
OSIT‐J score (≥ 4 correct answers)	0.18	0.02–1.22	0.06	−1.39	0.97	0.25	0.04–1.68	0.154	< 4 correct answers	0.974
VAS score (> 0)	0.27	0.04–1.39	0.087	−1.36	0.82	0.26	0.05–1.28	0.096	VAS = 0	0.946
SAOQ score (> 0)	0.22	0.03–1.16	0.07	−1.68	0.85	0.19	0.04–0.99	0.049	SAOQ = 0	0.087
OBV (≥ 50 mm3)	0.42	0.01–8.87	0.589

Note: Univariate and multivariate logistic regression analyses were conducted to identify predictors of perioperative OBV increase (> 10%). In the multivariate model, longer odor perception in the Alinamin test (≥ 50 s) and SAOQ score > 0 were significantly associated with reduced odds of OBV increase. ORs, 95% CIs, and p values are reported. Variables with clinical or statistical relevance in the univariate analyses were included in the multivariate model with age and sex as covariates.

Abbreviations: CI, confidence interval; H–L, Hosmer–Lemeshow; OBV, olfactory bulb volume; OE, Open Essence; OR, odds ratio; OSIT‐J, Odor Stick Identification Test for Japanese; SAOQ, Self‐Assessment Olfactory Questionnaire; SE, Standard error; VAS, Visual Analog Scale; β, regression coefficient.

4. Discussion

This study assessed perioperative changes in OBV and their relationship with olfactory function in patients with ECRS using 3T MRI. Notably, T&T, OE, OSIT‐J, and VAS scores improved postoperatively, and OBV changes significantly correlated with OE and OSIT‐J improvements. However, these associations did not remain significant after correction for multiple comparisons and should therefore be interpreted as exploratory, suggesting a possible structural correlate of olfactory recovery in ECRS. Patients with preoperative Alinamin test durations > 50 s or SAOQ scores ≥ 1 were less likely to show OBV increases postoperatively.

Olfactory dysfunction is common in ECRS, but its recovery trajectory remains unclear. In this study, postoperative T&T, OE, OSIT‐J, and VAS scores all improved, supporting the potential for olfactory recovery. Olfactory improvement in CRS varies by assessment method, with approximately 50% of patients showing improvement and one‐third achieving complete normalization [47]. A study on ECRS reported improvement in 76% of patients at 3 months postoperatively using the T&T test [48]. In our cohort, 59.4% of patients demonstrated T&T score improvement, and 81.3% showed VAS improvement at 3–6 months postoperatively. Multiple olfactory tests were employed in this study to comprehensively assess distinct physiological and perceptual domains of olfactory function. The Alinamin test reflects retronasal and neurogenic components and serves as an objective neurophysiological indicator of olfactory nerve function. T&T evaluates odor threshold and identification, OE and OSIT‐J assess odor identification, and VAS/SAOQ capture subjective perception. These tests are therefore complementary rather than redundant.

The variability in postoperative improvement across tests likely reflects differences in the underlying mechanisms of olfactory dysfunction among patients. In cases where orthonasal airflow obstruction predominates, FESS improves nasal airflow by removing polyps and inflamed mucosa, resulting in early recovery of odor identification and subjective awareness [49]. In contrast, the Alinamin test evaluates olfactory epithelial and neural function via the retronasal route. Experimental studies have demonstrated that olfactory receptor neuron loss prolongs Alinamin latency, whereas excessive mucus secretion increases odor duration time without affecting latency [50]. Clinically, prolonged latency has been associated with neurogenic olfactory dysfunction and poorer postoperative prognosis. In our cohort, latency improved, while duration time remained unchanged, suggesting partial neural recovery but persistent physiological factors such as mucus retention in the olfactory cleft. In our cohort, we did not quantitatively assess disease duration or polyp volume, and no significant associations were observed between postoperative olfactory improvement and age, sex, or eosinophilic inflammation (data not shown). Because previous studies have suggested that factors such as age and sex may influence olfactory outcomes [47] and that eosinophilic inflammation can affect postoperative olfactory recovery [51], incorporating these variables into future analyses will be important for clarifying the mechanisms and timelines of olfactory recovery in ECRS. The difference between T&T and VAS improvements likely reflects the distinct function assessed by each measure. T&T primarily evaluates psychophysical olfactory performance, whereas VAS patients' subjective self‐assessment of olfactory perception. These two measures do not necessarily change in parallel, and discrepancies between subjective ratings and psychophysical test results have been reported [52].

Previous studies have reported significant increases in OBV after ESS in patients with CRS [32, 33]. In this study, no statistically significant OBV change was observed in patients with ECRS; however, the mean volumetric increase of approximately 10% was comparable to previously reported postoperative OBV changes in CRS cohorts (approximately 3%–15%) [33, 35, 53]. Several factors may account for this discrepancy. Even within CRSwNP, disease subtypes and inflammatory profiles are heterogeneous [54, 55]. Compared with previous studies that included broader CRSwNP populations—such as the longitudinal [34] and prospective cohorts [35]—our ECRS cohort likely differed in patient characteristics and inflammatory profiles. Our cohort was strictly defined using blood markers, tissue pathology, and established clinical criteria [6]. In this population, persistent olfactory cleft obstruction from polyps or viscous secretions, along with sustained eosinophilic inflammation, may have limited olfactory input and, consequently, OBV plasticity. Persistent inflammation within the olfactory cleft in ECRS may limit OB recovery through both inflammatory and structural mechanisms. Local upregulation of type‐2 cytokines such as IL‐5, IL‐13, and IgE has been linked to olfactory loss in CRS [56], and eosinophil‐derived neurotoxins in olfactory cleft mucus correlate with olfactory dysfunction [57]. Chronic inflammation can reduce olfactory stem cell regeneration [58] and induce epithelial remodeling, including thinning and fibrosis [59, 60], thereby attenuating afferent input to the OB. Although OB atrophy may be partially reversible after inflammation control, persistent epithelial changes could still limit postoperative OBV improvement [33, 61, 62]. From a translational perspective, longitudinal OBV assessment may offer a promising direction for future investigation—particularly as biologics targeting type‐2 inflammation are increasingly introduced for ECRS. With further validation, OBV changes could complement psychophysical olfactory tests and patient‐reported outcomes as a noninvasive structural correlate of treatment response.

In this study, postoperative increases in OBV were correlated with improvements in odor identification ability (OE and OSIT‐J) in patients with ECRS, although these associations did not remain significant after correction for multiple comparisons. Given that these associations did not remain significant after FDR correction, they should be regarded as exploratory rather than definitive. Accordingly, postoperative OBV change is better interpreted as an exploratory structural correlate of olfactory improvement, and routine OBV measurement cannot yet be recommended for daily practice. In contrast, no significant association was found between OBV changes and olfactory threshold. Specifically, greater threshold improvement postoperatively is linked to more pronounced OB volume, possibly reflecting enhanced survival and synaptic density of olfactory neurons due to restored peripheral input [33]. Furthermore, resolution of inflammation may allow newly generated, mature olfactory sensory neurons (OSNs) to form synapses, enhancing sensory transmission and contributing to both threshold recovery and OBV enlargement [32]. However, the relationship between OBV and odor identification varies across conditions and studies. In healthy individuals, OBV correlates with overall olfactory performance—threshold, discrimination, and identification—independent of age [46]. In postinfectious olfactory dysfunction, OBV is significantly associated with odor identification bilaterally [27]. Conversely, studies on traumatic olfactory dysfunction report no correlation between threshold scores and discrimination or identification [62]. If postoperative OBV increases neuroplastic changes—such as neurogenesis, synaptic remodeling, or glial alterations—within these regions, the observed correlation with identification performance supports this interpretation. In contrast, olfactory threshold may depend more on peripheral factors, including OSN receptor sensitivity, mucosal integrity, and nasal airflow, rather than bulb volume [3]. In our cohort, mucosal edema, viscous nasal discharge, and reduced olfactory cleft patency were common and may have masked any association between OBV and threshold. Improvements in odor identification likely reflect recovery of central olfactory processing and neuroplasticity.

Logistic regression analysis showed that patients with relatively preserved preoperative olfaction (Alinamin test > 50 s and SAOQ score ≥ 1) were significantly less likely to exhibit a > 10% postoperative increase in OBV. These findings are consistent with more pronounced volumetric OBV change in patients with poorer baseline olfaction, which may reflect greater structural neuroplastic remodeling elicited by substantial sensory changes.

Previous studies in humans and animals have shown that olfactory deprivation reduces OBV, whereas sensory reintroduction promotes volumetric recovery [63, 64]. In this study, OBV changes likely reflect a neural response to surgical restoration of olfactory input. In patients with relatively preserved preoperative olfaction, smaller OBV changes may reflect a ceiling effect rather than reduced neuroplastic potential. Normative OBV thresholds (< 58 mm³ under 45 years, < 46 mm³ at ≥ 45 years) [46] were derived mainly from non‐Asian populations, and postoperative values in this study were still below these references. Further studies are warranted to clarify potential ethnic and methodological influences on OBV interpretation. ECRS causes prolonged sensory deprivation via olfactory cleft obstruction from viscous secretions, nasal polyps, and chronic eosinophilic inflammation [18, 48]. Surgery resolves these obstructions, improving airflow and reintroducing olfactory stimuli, thereby promoting OBV plasticity.

Our findings suggest that MRI‐based OBV measurement can capture a structural remodeling for the olfactory pathway in patients with ECRS. Olfaction is closely associated with QOL [3, 18, 65, 66], and predicting its recovery supports realistic patient counseling and tailored rehabilitation strategies [3, 18, 55]. Traditional olfactory tests rely on subjective responses, limiting their reproducibility and objectivity. In contrast, MRI‐based OBV assessment provides a noninvasive, objective method of visualizing neuroplastic changes [33, 35, 67]. The observed correlation between postoperative olfactory improvement and increased OBV supports further investigation of OBV as a structural correlate of treatment response and prognosis in ECRS. Incorporating MRI‐based OBV analysis into olfactory assessment may enhance personalized clinical decision‐making.

This study has certain limitations. The sample size was small, and the retrospective single‐center design may introduce selection and center bias. To mitigate these issues, all consecutive eligible patients were included, surgeries were performed using a standardized technique by a single surgeon, and all MRI scans were obtained with a uniform 3T protocol. Postoperative MRI timing varied among patients; however, its correlation with OBV change was negligible (r = 0.009, p = 0.959), suggesting that interval variability was unlikely to confound the results. The correlations between ΔOBV and olfactory function were modest and did not remain statistically significant after FDR correction, indicating that these associations should be regarded as exploratory. Moreover, multiple olfactory outcomes were examined without formal correction for multiple comparisons, which increases the risk of false‐positive findings. Given the exploratory nature of this study and the comprehensive assessment of several olfactory measures, the results should be interpreted with caution and considered hypothesis‐generating rather than confirmatory. Future prospective studies with predefined primary endpoints and appropriate statistical adjustment for multiple testing are warranted to validate these associations and clarify their clinical significance. Sensitivity analysis using Cook's distance showed that although the strength of the correlations decreased (ΔOBV‐OE: r = 0.24; ΔOBV‐OSIT‐J: r = 0.22), the positive direction was preserved, suggesting that the findings are not driven solely by outliers but remain weak overall. Given the limited sample size, the stability of multivariate models may have been constrained despite efforts to minimize overfitting by limiting the number of predictors and checking for multicollinearity (VIF < 1.3). To further evaluate the performance of the logistic regression models, calibration was assessed using the Hosmer–Lemeshow goodness‐of‐fit test, which showed no evidence of poor model fit (all p > 0.05). However, given the small sample size, these findings should still be interpreted with caution. Disease duration may have been an unmeasured confounding factor in our cohort, potentially influencing the extent of OBV recovery [32, 68]. Additionally, a post hoc power analysis based on the observed correlation coefficient (r = 0.40, n = 32, α = 0.05) indicated an achieved power of 0.73, suggesting that the study had a moderate ability to detect true associations. Future large‐scale, multicenter prospective studies including appropriate control groups are necessary to elucidate longitudinal OBV changes and their clinical significance in ECRS. Comparative studies with other neuroplasticity markers—such as functional MRI, Positron emission tomography, or olfactory event‐related potentials—are also essential. Clinically, recent advances in 3T MRI with FIESTA sequences allow high‐resolution, noninvasive imaging of the OB [28] with shorter scan times and no radiation. This technique aids in preoperative exclusion of central olfactory dysfunction and postoperative evaluation of the olfactory and sinonasal structures. However, challenges remain, including difficulty distinguishing the OB from adjacent vasculature, the labor‐intensive nature of manual volumetric analysis, and cost [3]. In addition, because OBV was measured using manual segmentation, the potential influence of observer bias cannot be completely eliminated. Although high inter‐rater and intra‐rater reproducibility was confirmed in the present study, the use of manual segmentation itself remains an inherent limitation. Simplified, rapid OBV measurement methods are emerging and show clinical promise [69]. Currently, OBV is primarily measured manually, with concerns about inter‐rater variability and workload. Artificial intelligence‐assisted automated OBV identification and quantification could improve standardization and efficiency, enhancing diagnostic reliability. Integrating OBV data with olfactory testing and cytokine profiles may enable predictive modeling of clinical outcomes. These advances may support personalized postoperative rehabilitation and contribute to the development of artificial olfaction technologies.

5. Conclusions

This study presents the first detailed evaluation of OBV changes and postoperative olfactory function in patients with ECRS using 3T MRI. Our results showed positive associations between postoperative OBV and improvement in olfactory identification, as measured using OE and OSIT‐J. However, these associations did not remain significant after correction for multiple comparisons and should therefore be interpreted as exploratory. These findings are compatible with the presence of OB neuroplasticity in humans and suggest that MRI‐based OBV measurement may serve as a structural correlate of such neuroplastic changes. Our results enhance understanding of olfactory dysfunction in ECRS and highlight the potential role of MRI‐based assessments in prognosis and personalized treatment planning.

Funding

The authors have nothing to report.

Ethics Statement

This study was conducted in accordance with the Ethical Guidelines for Life Sciences and Medical Research Involving Human Subjects in Japan and approved by the ethics board of Sapporo Medical University (No. 342‐83), the opt‐out ensured that information about the purpose and conduct of the research was made public and that the participants could opt out of the research. The opt‐out consent process was considered appropriate for a retrospective study using anonymized clinical information, as approved by the institutional review board. Study information was disclosed publicly, and all patients were provided with the opportunity to decline participation.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.