---
title: "Otolin-1 lacks diagnostic discrimination for central versus peripheral acute continuous dizziness"
id: "plos-one-9-otolin-1-for-differentiating-central-and-peripheral-causes-of-acute-continuous"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-9-otolin-1-for-differentiating-central-and-peripheral-causes-of-acute-continuous"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361036"
published_at: "2026-10-22T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Otolin-1 lacks diagnostic discrimination for central versus peripheral acute continuous dizziness
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-9-otolin-1-for-differentiating-central-and-peripheral-causes-of-acute-continuous
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361036)
- **Published At:** 2026-10-22T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Prospective multicenter analysis of 245 ED patients with isolated acute-onset continuous dizziness (**iAOCD**) compared 179 peripheral diagnoses to 66 central diagnoses using blinded expert adjudication. - Blood samples were collected within 24 hours of symptom onset and plasma **otolin-1** measured by a commercial ELISA; final diagnosis combined clinical assessment, diffusion-weighted MRI and 3-month follow-up. - Median otolin-1 did not differ: 517.6 pg/mL (peripheral) versus 487.9 pg/mL (central); reported p = 0.349, indicating no statistically significant separation. - Time-window analyses (hyperacute <4.5 hours and acute 4.5–24 hours) showed no significant differences in median concentrations between groups; substantial overlap in ranges was observed. - ROC analyses produced poor discrimination: overall **AUC** 0.539 (95% CI 0.455–0.623); subgroup AUCs similarly non-diagnostic with confidence intervals including 0.50. - Otolin-1 concentrations also did not separate central iAOCD from specific peripheral diagnoses (vestibular neuritis, BPPV, Ménière’s disease); peripheral elevations noted in some cases but without reliable specificity. - The study used stratified sampling from the PROVIDE cohort, pre-specified power calculations, blinded laboratory analysis, and an expert panel blinded to otolin-1 results to determine final diagnoses. - Authors concluded that, despite biological plausibility linking **otolin-1** to inner ear pathology, it lacks sufficient discriminatory value as a stand-alone biomarker for differentiating central and peripheral causes of **iAOCD** in the ED.
## Clinical Analysis & Structured Key Points
Otolin-1 for differentiating central and peripheral causes of acute continuous dizziness | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Peer Review Reader Comments Figures Figures Abstract Background Patients with isolated acute-onset continuous dizziness (iAOCD) are commonly seen at the emergency department (ED). Distinguishing peripheral vestibular disorders from central causes remains challenging. Existing diagnostic tools, including bedside examination and neuroimaging, have important limitations. Otolin-1, an inner ear–specific glycoprotein, has been proposed as a biomarker of peripheral vestibular pathology. This study evaluated whether otolin-1 could serve as a diagnostic biomarker for this differentiation. Methods This study analyzed samples from a prospective multicenter cohort of adult patients who were seen at the ED with acute onset, continuous dizziness without focal neurological deficits. Patients were included within 24 hours of symptom onset. Otolin-1 plasma concentrations were measured using an enzyme-linked immunosorbent assay. Final diagnoses (central versus peripheral) were determined by an expert panel based on clinical assessment, diffusion-weighted magnetic resonance imaging and 3-month follow-up. Results We analyzed 245 patients (179 peripheral, 66 central). Median otolin-1 concentrations did not differ significantly between peripheral and central causes (517.6 [IQR 443.7–592.8] pg/mL vs 487.9 [424.9–644.4] pg/mL; p = 0.349). No significant differences were observed in hyperacute (<4.5 hours after symptom onset) or acute (4.5–24 hours after symptom onset) subgroups. Similarly, otolin-1 concentrations did not differ between central iAOCD and specific peripheral diagnoses. Substantial overlap in concentration ranges was observed across all comparisons. Receiver operating characteristic analysis similarly showed no useful discrimination (AUC 0.539, 95% CI 0.455–0.623). Conclusions Otolin-1 does not differentiate between central and peripheral causes of iAOCD in the ED setting. Although biologically linked to inner ear pathology, otolin-1 lacks sufficient discriminatory value as a stand-alone diagnostic biomarker. Citation: Klokman VW, Verhagen MJJ, Ros AAJ, de Laat KF, Jellema K, de Kleijn DPV, et al. (2026) Otolin-1 for differentiating central and peripheral causes of acute continuous dizziness. PLoS One 21(10): e0361036. https://doi.org/10.1371/journal.pone.0361036 Editor: Gauri Mankekar, LSU Health Shreveport, UNITED STATES OF AMERICA Received: July 22, 2026; Accepted: October 5, 2026; Published: October 22, 2026 Copyright: © 2026 Klokman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: An updated de-identified dataset has been added as suporting information S1 Dataset as part of the submitted article. Funding: Funding was received from the Jeroen Bosch Hospital Stipendium, the spoedeisendegeneeskunde onderzoeksfonds (SGO), Dutch Organization for knowledge and innovation in health, healthcare and well-being (ZonMw): 10330022010010, St. Jacobusstichting and the Stichting Researchfonds Bronovo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction Acute dizziness or vertigo is a common reason for presentation to the emergency department (ED) [ 1 , 2 ]. In patients with acute vestibular syndrome (AVS), the underlying cause is most often a peripheral vestibular disorder, such as vestibular neuritis or labyrinthitis. However, approximately 20% of patients have central causes, particularly posterior circulation stroke [ 3 ]. Acute vestibular syndrome (AVS) is a term used to describe acute-onset, severe dizziness, imbalance or vertigo lasting more than 24 hours, with exam findings of nystagmus or gait unsteadiness [ 1 ]. However, not all patients with acute dizziness present with a visible or spontaneous nystagmus, and patients in the ED are often evaluated within the first hours after symptom onset, before this duration and nystagmus criterion can be fulfilled. For this reason, we use the term isolated acute-onset continuous dizziness (iAOCD) to describe patients presenting with acute, ongoing dizziness without focal neurological deficits, representing a clinically relevant umbrella population that includes patients with evolving AVS. In this setting, early differentiation between peripheral vestibular disorders and central causes, particularly posterior circulation ischemia, remains challenging. Bedside examination techniques, specifically the Head-Impulse test, Nystagmus, Test-of-Skew and hearing (HINTS+) examination, have demonstrated high diagnostic accuracy when performed by experienced clinicians [ 4 ]. However, their performance is reduced when applied by non-specialized physicians [ 5 ]. Neuroimaging also has recognized limitations. Non-contrast computed tomography (CT) has low sensitivity for acute ischemic stroke [ 6 ], while diffusion-weighted magnetic resonance imaging may fail to detect up to 15% – 20% of posterior circulation infarctions within the first 24–48 hours, particularly in small lesions [ 7 – 9 ]. These limitations have prompted interest in circulating biomarkers as adjunctive tools for differentiating central from peripheral causes of iAOCD in the acute setting. However, current evidence remains insufficient to support their routine clinical use [ 10 ]. Biomarkers that are specific to inner ear pathology may be particularly informative, as they could provide objective evidence supporting a peripheral vestibular origin and thereby reduce the clinical likelihood of a central cause. Among these, the inner ear–specific protein otolin-1 has emerged as a promising candidate with potential diagnostic utility [ 11 ]. Otolin-1 is a secreted glycoprotein expressed in the supporting structures of the cochlear and vestibular sensory organs, where it contributes to the structural organization of the otoconial matrix [ 12 , 13 ]. Given its expression is mainly in otolithic structures, the presence of otolin-1 in peripheral blood has been proposed as a marker of inner ear injury [ 14 ]. Circulating otolin-1 levels have been shown to be increased in patients with benign paroxysmal positional vertigo (BPPV), consistent with otoconia degeneration and displacement [ 14 – 17 ]. Elevated otolin-1 levels have also been reported in other peripheral vestibular disorders, including Ménière’s disease [ 18 , 19 ] and acute unilateral vestibulopathy [ 18 , 20 ], suggesting that otolin-1 reflects inner ear injury rather than a disease-specific process. While this supports its role as a sensitive biomarker of peripheral vestibular pathology, it also limits its specificity for individual disease entities. The potential role of otolin-1 in differentiating central from peripheral causes of acute dizziness has not been investigated. Given that central causes do not directly involve otoconial damage, it is plausible that circulating otolin-1 concentrations differ between these groups. Conversely, if otolin-1 is a marker of chronic turnover rather than acute injury, no difference would be expected. The objective of the present study was therefore to evaluate the diagnostic utility of otolin-1 in distinguishing central from peripheral causes of iAOCD in patients presenting to the ED. Materials and methods Ethical approval This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Medical Ethics Committee Leiden The Hague Delft of the Dutch Central Committee on Research Involving Human Subjects (protocol number NL76143.058.21; registration number P21.029). Written informed consent was obtained from all participants. Study design and population This study was conducted using blood samples from patients who were included in the PROVIDE study (Providing Diagnostic Accuracy in Acute Onset, Continuous Dizziness), a prospective multicenter cohort study. The PROVIDE study enrolled adult patients who were seen at the ED with acute onset, continuous dizziness in the absence of focal neurological deficits. Between August 1, 2021, and July 1, 2024, a total of 800 patients were included across 11 hospitals in the Netherlands (2 academic and 9 non-academic teaching hospitals). Blood samples were collected from 645 patients. The primary endpoint of the PROVIDE study was the final diagnosis established after 3 months of follow-up. For the present analysis, 245 subjects were selected from the PROVIDE cohort using a stratified sampling approach based on diagnostic group. To ensure adequate representation of central causes, 66 patients with a central diagnosis and available neuroimaging were selected first. Thereafter, patients with a peripheral diagnosis, including vestibular neuritis, BPPV or Ménière’s disease, were randomly selected from the remaining eligible PROVIDE samples. A priori power calculations, based on a pooled effect size from a prior meta-analysis (standardized mean difference: 1.53) [ 11 ], indicated that at least 128 patients with peripheral iAOCD and 64 patients with central iAOCD, using a 2:1 ratio, would provide more than 90% power (α = 0.05) to detect a clinically relevant medium effect size (Cohen’s d = 0.5) in otolin-1 plasma concentrations. Fig 1 depicts the study in a STARD flow diagram. Download: PNG larger image TIFF original image Fig 1. STARD flow diagram. https://doi.org/10.1371/journal.pone.0361036.g001 Inclusion and exclusion criteria Patients were eligible for inclusion if they met the following criteria: (1) acute onset continuous dizziness still present at ED arrival as the primary complaint; (2) presentation within 24 hours of symptom onset; and (3) age ≥ 18 years. Exclusion criteria were: (1) recurrent peripheral AVS or symptoms compatible with a previously established diagnosis (e.g., Ménière’s disease or vestibular migraine); (2) new focal neurological deficits on examination (e.g., ataxia, dysarthria, spontaneous skew deviation, gaze palsy, or reduced level of consciousness defined as Glasgow Coma Scale less than 14); (3) Clear signs of BPPV (i.e., iAOCD successfully treated by canalith repositioning) (4) known pregnancy; (5) contraindications to magnetic resonance imaging (MRI), such as claustrophobia or non-compatible implanted devices; (6) a clear alternative medical condition explaining symptoms (e.g., hypotension, sepsis, or medication-related causes); (7) prior inclusion in the PROVIDE study; (8) inability to complete follow-up (e.g., life expectancy less than 3 months, severe cognitive impairment, or lack of permanent residence in the Netherlands); (9) inability to provide informed consent; or (10) insufficient command of the Dutch language. The presence of nystagmus and gait imbalance or instability was permitted but not required. Clinical data and outcome assessment Baseline data collected at presentation included demographic characteristics, medical history, and symptom characteristics. The final diagnosis (peripheral vestibular disorder vs central cause) was established by an expert panel consisting of experienced neurologists in this field. The diagnosis was based on clinical findings, including HINTS (plus) examination results, diffusion-weighted MRI and outpatient clinical follow-up at 3 months. The expert panel were blinded to the otolin-1 concentration results. Sample collection and biochemical analysis Blood samples were collected in 4 mL K3-EDTA tubes at ED presentation. Samples were centrifuged at 2500 × g for 10 minutes, and the supernatant was aliquoted and stored at −80°C until analysis. Otolin-1 concentrations were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (catalog number MBS167289; MyBiosource, San Diego, CA, USA), based on a biotin double-antibody sandwich technique. All assays were performed in accordance with the manufacturer’s instructions. General laboratory values were carried out by each participating institution per local protocol. Laboratory personnel were blinded to clinical data and final diagnoses during sample analysis. Statistical analysis Statistical analyses were performed using R (version 4.4.0). Continuous variables are presented as mean ± standard deviation (SD) for normally distributed data, or as median with interquartile range [IQR] for non-normally distributed data. Categorical variables are presented as counts and percentages. Normality of continuous variables was assessed using the Shapiro–Wilk test. Group comparisons were performed using the independent samples t-test for normally distributed data and the Wilcoxon rank-sum test (Mann–Whitney U test) for non-normally distributed data. Baseline characteristics were summarized descriptively using available observations; missing data were not imputed. No formal statistical testing was performed for baseline characteristics, as the diagnostic groups were not randomized and were expected to differ clinically. A p-value <0.05 was considered statistically significant. As a secondary analysis, receiver operating characteristic (ROC) curves were constructed to assess the ability of plasma otolin-1 concentrations to discriminate peripheral from central iAOCD. Peripheral etiology was defined as the positive outcome, consistent with the hypothesis that higher otolin-1 concentrations indicate peripheral vestibular pathology. Areas under the ROC curve (AUCs) were calculated with 95% confidence intervals. ROC analyses were performed for the overall cohort and separately for the hyperacute (0–4.5 hours) and acute (4.5–24 hours) subgroups. Results Study population Following the stratified selection procedure, the final study population consisted of 245 patients: 66 patients with central iAOCD and 179 randomly selected patients with peripheral iAOCD. Baseline characteristics are shown in Table 1 . Patients with central iAOCD more frequently had vascular risk factors, including hypertension, hypercholesterolemia and prior ischemic stroke, whereas age and sex distribution were comparable between groups. Median duration of symptoms at blood sampling was also comparable between patients with a peripheral or central cause (6.75 [3.08–13.50] vs 7.08 [3.19–15.31] hours). Download: PNG larger image TIFF original image Table 1. Clinical characteristics of subjects. https://doi.org/10.1371/journal.pone.0361036.t001 Otolin-1 concentrations Median otolin-1 concentrations did not differ significantly between patients with peripheral and central causes (517.6 [443.7–592.8] pg/mL vs 487.9 [424.9–644.4] pg/mL, p = 0.349; Table 2 ). Fig 2 shows the distribution of otolin-1 concentrations in peripheral and central iAOCD. Several peripheral cases had otolin-1 concentrations above the range observed in central cases; however, substantial overlap in concentrations remained between the two groups. Subgroup analyses regarding sampling time were carried out correlating to the thrombolysis window of less than 4.5 hours (i.e., hyperacute subgroup) and between 4.5 and 24 hours (i.e., acute subgroup). In patients presenting within 4.5 hours of symptom onset median otolin-1 concentrations were 522.1 pg/mL (IQR 443.7–592.8) in peripheral iAOCD and 535.3 pg/mL (451.2–668.5) in central iAOCD (p = 0.711). In patients who were seen between 4.5 and 24 hours after symptom onset, median concentrations were 508.1 pg/mL (444.1–592.7) and 484.4 pg/mL (420.3–554.0), respectively (p = 0.155) ( Table 2 ). Figs 3 and 4 show the distribution and concentration ranges of otolin-1 in the hyperacute and acute onset subgroups, respectively. Download: PNG larger image TIFF original image Table 2. Comparison of otolin-1 concentrations between central iAOCD and peripheral diagnostic subgroups. https://doi.org/10.1371/journal.pone.0361036.t002 Download: PNG larger image TIFF original image Fig 2. Otolin-1 concentration distributions in patients with peripheral and central isolated, acute onset, continuous dizziness. https://doi.org/10.1371/journal.pone.0361036.g002 Download: PNG larger image TIFF original image Fig 3. Otolin-1 concentration distributions in patients with peripheral and central isolated, acute onset, continuous dizziness within 4.5 hours of symptom onset. https://doi.org/10.1371/journal.pone.0361036.g003 Download: PNG larger image TIFF original image Fig 4. Otolin-1 concentration distributions in patients with peripheral and central isolated, acute onset, continuous dizziness between 4.5 and 24 hours after symptom onset. https://doi.org/10.1371/journal.pone.0361036.g004 Secondary ROC analysis confirmed poor discriminatory performance. In the overall cohort, the AUC was 0.539 (95% CI 0.455–0.623; S1 Fig ). The AUC was 0.474 (95% CI 0.328–0.618) in the hyperacute subgroup sampled within 4.5 hours ( S2 Fig ) and 0.574 (95% CI 0.467–0.677) in the acute subgroup sampled between 4.5 and 24 hours after symptom onset ( S3 Fig ). All confidence intervals included 0.50. Otolin-1 concentrations in peripheral iAOCD subgroups Median otolin-1 concentrations did not differ significantly between central iAOCD and individual peripheral vestibular diagnoses ( Table 2 ). Fig 5 shows the distribution and concentration ranges of otolin-1 across central iAOCD and the peripheral diagnostic subgroups. Download: PNG larger image TIFF original image Fig 5. Otolin-1 concentration distributions in patients with central isolated, acute onset, continuous dizziness and the individual peripheral etiologies*. * From left to right: central isolated, acute onset, continuous dizziness, vestibular neuritis, BPPV, and Ménière’s disease. https://doi.org/10.1371/journal.pone.0361036.g005 Discussion In this prospective multicenter cohort, plasma otolin-1 concentrations did not differ significantly between patients with peripheral and central iAOCD, neither overall, stratified by symptom duration, nor within subgroups of specific peripheral vestibular diagnosis. These findings suggest that circulating otolin-1, despite its biological plausibility as a marker of peripheral vestibular pathology, does not provide discriminatory value for distinguishing peripheral from central causes of iAOCD in the emergency setting. This study addresses a clinically relevant and previously unexplored question. Although otolin-1 has been proposed as a biomarker of peripheral vestibular pathology, particularly BPPV [ 14 , 15 , 17 , 21 , 22 ], to our knowledge no prior study has evaluated its ability to differentiate central from peripheral causes of dizziness. Multiple studies have reported increased otolin-1 concentrations in BPPV compared with asymptomatic controls, and a recent meta-analysis demonstrated a pooled association between elevated otolin-1 levels and peripheral vestibular syndromes [ 11 , 21 ]. Similar findings have been reported in vestibular neuritis and Ménière’s disease, suggesting broader relevance of otolin-1 as a marker of peripheral vestibular injury [ 11 , 18 ]. However, those studies primarily addressed disease-versus-control discrimination rather than the more clinically demanding question of central versus peripheral differentiation. Our findings suggest that while otolin-1 may reflect otoconial turnover or inner ear pathology, this signal is not sufficiently disease-specific to distinguish peripheral from central iAOCD in acute clinical presentations. Several biological explanations may account for these findings. One possibility is that otolin-1 reflects chronic otolithic degeneration or susceptibility rather than acute-state i
## Related Clinical Research

- [Multimodal extraction of heart disease risk factors from free-text and structured records using Li](https://medichelpline.com/clinical-feed/plos-one-0-leveraging-free-text-clinical-records-for-heart-disease-classification-through.md)
- [Iron-related Parameters and Sepsis-associated Acute Kidney Injury — Source Content Not Available](https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-association-of-iron-related-parameters-with-the-development-of-sepsis.md)
- [Neural-Immune-Cardiovascular Axis: Mechanisms and Therapeutic Targets in Cardiovascular Disease](https://medichelpline.com/clinical-feed/frontiers-in-immunology-13-neural-immune-cardiovascular-axis-from-mechanistic-crosstalk-to-therapeutic.md)
- [Rising national stroke incidence and deaths in Uganda, 2016–2028 forecasts](https://medichelpline.com/clinical-feed/plos-one-5-rising-stroke-burden-in-uganda-a-national-time-series-analysis-and-forecasts.md)
- [Amlodipine versus nifedipine after ischemic stroke/TIA: 5-year functional outcomes](https://medichelpline.com/clinical-feed/plos-medicine-0-comparative-effectiveness-of-amlodipine-versus-nifedipine-prescribed-at.md)

## Navigation
- [← Back to Neurology Feed](https://medichelpline.com/clinical-feed/neurology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.