Blood Labyrinth Barrier Waste Clearance as Assessed by GBCAs on MRI: A Scoping Review

ABSTRACT

Objective

The discovery of the glymphatic system in the brain and eye has raised the hypothesis of a similar system in the inner ear. Dysfunctional lymph fluid dynamics may contribute to inner ear conditions such as Meniere's Disease (MD) and endolymphatic hydrops (EH). This scoping review evaluates inner ear waste clearance mechanisms by tracking gadolinium‐based contrast agent (GBCA) signal over time using magnetic resonance imaging.

Data Sources

PubMed, Embase, Cochrane, Web of Science, and Scopus.

Review Methods

A systematic search identified studies reporting inner ear GBCA signal > 4 h after intravenous (IV) administration. Data on study design, cohort characteristics, and time points were extracted.

Results

Fifteen studies (three animal; 12 human) met inclusion criteria. Three studies had a goal of studying clearance. Animal studies demonstrated a decrease in GBCA signal following a 4‐h peak. Of the human studies, three analyzed healthy controls, four studied EH without MD, three focused on MD, and two focused on neurological disorders but provided insight into inner ear enhancement. In healthy and MD ears, the internal auditory canal was enhanced before other inner ear structures. In EH, a reduced superior petrosal sinus area was noted, and delayed excretion rates were observed in MD patients 24 h post‐IV administration. A positive association between endolymph and perilymph signal was identified in EH patients after 24 h.

Conclusions

Most studies were not designed to assess clearance mechanisms. Future in vivo and histopathological studies are needed to clarify the potential presence of glymphatic system involvement in the inner ear.

1. Introduction

Similar in function to the blood–brain barrier (BBB), the blood labyrinth barrier (BLB) separates the blood from the inner ear fluids, notably endolymph and perilymph [1, 2]. This barrier plays a critical role in maintaining ionic homeostasis within the inner ear and protecting it from harmful substances [2, 3]. The capillaries within the BLB are lined with tight junctions [2, 4], like those in the brain, which restrict the passive movement of substances. Consequently, both the brain and inner ear require specialized mechanisms for clearing interstitial fluid and waste independent of the venous system [5]. In the brain, this function is carried out by the glymphatic system, a cerebral lymphatic network that has also been identified in the eye [5, 6, 7]. While the glymphatic system has been shown to manage waste in these immune‐privileged sites, its existence and role in the inner ear remain less well understood. Evidence supporting the presence of a lymphatic system in the inner ear includes the observation of ventral dural lymphatic structures near the orifices of the internal auditory canal (IAC) [8].

While a primary function of the BLB is to maintain separation between the blood and inner ear fluids, it is known that injecting intravenous (IV) administration of gadolinium‐based contrast agents (GBCA) results in delayed entry into the inner ear, as observed on magnetic resonance imaging (MRI) approximately 4 h later [3]. However, the fate of GBCAs within the inner ear after this time remains unclear. Recent reports have shown that intratympanically administered ¹⁷O‐labeled saline demonstrates decreased cochlear and vestibular signal intensity following peak enhancement over 24 h, suggesting a potential clearance mechanism for particles in the inner ear [9]. Additionally, there is increasing recognition of the role lymph fluid dynamics may play in the pathogenesis of poorly understood conditions, such as Meniere's disease (MD) and endolymphatic hydrops (EH).

Taken together, there is a critical need to investigate the potential existence of a glymphatic system in the inner ear to understand better the cause and management of different inner ear pathologies. This scoping review aimed to review existing literature on waste clearance from the inner ear in animals and humans, focusing on assessing GBCA clearance four or more hours after IV injection.

2. Methods

A scoping review was conducted to synthesize existing knowledge regarding waste clearance from the inner ear, focusing on GBCA detected via MRI 4 h after IV administration. A comprehensive search was performed on May 6, 2024, using PubMed, Embase, Cochrane, Web of Science, and Scopus. The search strategy employed a combination of controlled vocabulary (e.g., MeSH terms in PubMed) and keywords related to the concepts of the “inner ear,” “gadolinium,” and “MRI” (see Appendix S1). This strategy was developed with assistance from a staff member (MS) from the Welch Medical Library at Johns Hopkins Medicine. The findings were deduplicated in Endnote and exported into Covidence for review.

Articles were included in the review if they met the following inclusion criteria: they assessed the presence of GBCAs in the inner ear space via MRI 4 h after IV administration, presented original data, and were written in English. Case reports and case series were considered eligible, while systematic reviews, scoping reviews, literature reviews, and meta‐analyses were excluded. Study members (SAA, EH, JSK) independently reviewed the articles; any discrepancies in inclusion decisions were resolved through discussion. A snowballing approach was also employed to ensure a thorough review, wherein references cited in the included articles were screened and evaluated against the inclusion criteria.

For animal and human studies that provided information on clearance by tracking GBCA signal over time, relevant data were extracted on variables including study design, cohort characteristics, dose and type of GBCA used, MRI sequence, static magnetic field strength (measured in Tesla), signal enhancement, time points analyzed, and any correlations with symptoms when appropriate. The study team (SAA, YB, BW) reviewed the included studies, while two team members (SAA and JSK) conducted an evaluation of the quality and risk of bias for each clinical research article using a modified version of the National Institute of Health (NIH) Quality Assessment Tool for Cross‐Sectional Studies [10]; as summarized in Table 1.

TABLE 1.

NIH quality assessment checklist.

Modified NIH quality assessment checklist
Original question	Specific interpretation used
Was the research question or objective in this paper clearly stated?	—
Was the study population clearly specified and defined?	Was the study population specified as a single or multi‐center sample? Was the sampling method described?
Was the participation rate of eligible persons at least 50%?	—
Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study pre‐specified and applied uniformly to all participants?	Were the inclusion criteria specific and applied uniformly?
Was a sample size justification, power description, or variance and effect estimates provided?	Was a power analysis included to justify sample sizes?
For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured?	Were patients included in the study prior to MRI assessment?
Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?	Did participants undergo MRI within a reasonable timeframe from when they received IV contrast?
For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)?	Were both pre‐contrast and post‐contrast MRI evaluated?
Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?	Were the MRI protocol and contrast dose and agent clearly described?
Was the exposure(s) assessed more than once over time?	Was MRI performed and assessed at varying time points following contrast administration?
Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?	Was the measurement of contrast enhancement done with clearly specified and reliable methods?
Were the outcome assessors blinded to the exposure status of participants?	Was it clearly specified that MRI findings were evaluated by individuals blinded to the clinical status of patients?
Was loss to follow‐up after baseline 20% or less?	—
Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?	When appropriate, were reasonable controls used as comparisons to diseased ears?

Note: If no interpretations are specified, the original question was sufficient for our purposes.

Abbreviations: IV, intravenous; MRI, magnetic resonance imaging; NIH, national institute of health.

Given that the objective of this scoping review was to qualitatively describe the current literature and map key concepts in this field, no statistical analyses were performed.

3. Results

3.1. Literature Search

The database search yielded 2050 citations: 432 from PubMed, 806 from Embase, 10 from Cochrane, 276 from Web of Science, and 526 from SCOPUS. After removing duplicate entries, 1124 unique articles remained. Initial title and abstract screening identified 202 full‐text articles for further evaluation. Of these, 25 studies reported on GBCA signal in the inner ear 4 h after IV injection. Among the 25 studies, 12 provided information on clearance from the inner ear by tracking GBCA signal over multiple time points and were included in the final analysis. The remaining 13 studies offered valuable insights into inner ear fluid dynamics but did not meet the criteria for inclusion in the final analysis [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]. An additional review of references from the initially included studies identified three more articles that satisfied the selection criteria, bringing the total number of studies in the final analysis to 15. Variables of interest were formally extracted from these studies (Figure 1).

FIGURE 1.

PRISMA flowchart for the creation of our study cohort.

3.2. Animal Studies

The final review included three animal studies: two involving guinea pigs and one involving mice. These studies varied significantly in their methodologies, including differences in magnetic field strength (1.5–9.4 Tesla), the dose and type of GBCA (gadodiamide, gadopentetate, gadobutrol, etc.), and the duration of observation following IV administration (250 min to 48 h) (Table 2) [24, 25, 26]. The earliest in this review, conducted by Niyazov et al., investigated the signal intensity of gadodiamide in the cochlea across successive images. This study demonstrated that signal intensity appeared to peak approximately 4 h after administration before steadily decreasing over the subsequent hours. Later animal studies provided more localized information. For example, one study employed high‐dose furosemide to disrupt the integrity of the BLB and found that the GBCAs saturated the scala media more prominently than the scala vestibuli and scala tympani [25]. However, attempts to calculate an excretion rate in this study were hindered, as data collection had to be prematurely terminated for many mice at 235 min due to abnormal breathing [25]. The final animal study compared postauricular to IV administration of GBCAs in guinea pigs. Like the earlier studies, this investigation showed that signal intensity peaked at approximately 4 h after administration and gradually declined to undetectable levels over 24 h [26]. Although all included animal studies showed a decrease in signal intensity following a peak, they did not provide detailed information about the localization of the signal as it diminished over time.

TABLE 2.

Summary of findings on animal studies.

Author	n	Animal type	Interventions	Time points analyzed after IV administration	Gd agent (dose)	MRI strength (T)	MRI protocol	Signal assessment	Findings regarding enhancement
Niyazov et al. [24]	9	Guinea Pigs	Surgically induced EH (n = 4)	Immediate post‐contrast, 2, 4, 6, and 8 h	Gadodiamide (1.25 mmol/kg)	1.5	Spin‐echo T1‐weighted	Quantitative	Peaked at 4 h and decreased steadily after
Videhult et al. [25]	20	Mice	No interventions	Every 10 min for 250 min	Gadobutrol (1 mmol/mL), Gadopentetic acid (0.5 mmol/mL), and gadoteric acid (279 g mg/mL)	9.4	GE3D	Quantitative	Giving furosemide leads to highest Gd signal in scala media, but unable to calculate excretion
Li et al. [26]	6	Guinea Pigs	No interventions	0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48 h	Gadopentetate dimeglumine (3 mL/kg [0.5 mmol/mL])	7	T1 and T2 weighted	Quantitative	IV Gd disappeared by 24 h

Note: Quantitative signal assessment methods involve the use of signal intensity measurements with regions of interest within the inner ear as compared to other imaged regions such as the cerebellum.

Abbreviations: EH, endolymphatic hydrops; Gd, gadolinium; GE3D, T1 weighted 3D with Gradient Cho 3D; IV, intravenous; MRI, magnetic resonance imaging; T, Tesla.

3.3. Human Studies

The human studies primarily employed a cross‐sectional study design and investigated a range of conditions, including healthy controls (n = 3), neurological disorders (n = 2), and inner ear pathologies such as EH without MD (n = 4) and EH with MD (n = 3). Most studies administered a single dose of GBCA (0.1 mmol/kg, 67%) and used 3 Tesla MRI scanners (80%), with 91.7% quantifying MRI signal intensity. Gadobutrol was the most commonly used GBCA (50%), followed by gadolinium diethylenetriamine penta‐acetic acid (Gd‐DTPA, 33.3%). However, only one study assessed potential correlations between MRI findings and clinical symptoms, reporting no significant differences [27] (Table 3).

TABLE 3.

Quality assessment of included human studies with the NIH quality assessment tool.

Author	Clear research question	Clearly specified pop.	Participation > 50%	Uniform inclusion criteria	Sample size justification	Exposure measured before outcome	Sufficient timeframe	Varied exposure levels measured	Clearly defined exposure	Expose assessed over time	Clearly define outcome	Assessors blinded	< 20% loss to follow‐up	Confounders addressed
Yoshida et. al [27]	Y	N	NA	Y	N	Y	Y	Y	Y	Y	Y	Y	NA	N
Naganawa et al. [28]	Y	N	NA	N	N	Y	Y	Y	Y	Y	N	N	NA	NA
Naganawa et al. [29]	Y	Y	NA	N	N	Y	Y	Y	Y	Y	Y	N	NA	NA
Naganawa et al. [30]	Y	N	NA	Y	N	Y	Y	Y	Y	Y	Y	N	NA	NA
Hirai et al. [31]	Y	Y	NA	Y	N	Y	Y	Y	Y	Y	N	N	NA	N
Deike‐Hofmann et al. [32]	Y	N	NA	Y	N	Y	Y	Y	Y	Y	Y	Y	NA	NA
Naganawa et al. [33]	Y	N	NA	N	N	Y	Y	Y	Y	Y	Y	N	NA	N
Naganawa et al. [34]	Y	N	NA	N	N	Y	Y	Y	Y	Y	N	N	NA	N
Li et al. [35]	Y	Y	NA	Y	N	Y	Y	N	Y	Y	Y	Y	NA	N
Naganawa et al. [36]	Y	Y	NA	Y	N	Y	Y	Y	Y	Y	Y	N	NA	N
Naganawa et al. [37]	Y	N	NA	Y	N	Y	Y	Y	Y	Y	Y	N	NA	N
Zhang et al. [38]	Y	Y	NA	Y	N	Y	Y	N	Y	Y	Y	Y	NA	N

Note: Details of each quality assessment category is explained in Table 1. NA indicates that assessment was not able to be determined.

Abbreviations: N, no; Y, Yes.

3.4. Healthy Controls

In healthy controls (n = 15), all participants were male, and experiments were conducted by Naganawa et al. [28, 29, 30]. In one of the earliest human studies on this topic, similar to findings in animal studies, the researchers demonstrated that GBCAs could be sequentially tracked in different compartments over 4.5 h. They observed that GBCAs peaked early in blood vessels, such as the subarcuate artery, before decreasing to undetectable levels. Within inner ear structures, the endolymphatic sac showed early and sustained enhancement, remaining enhanced longer than the cochlear aqueduct and cochlear fluids, which exhibited no enhancement at any time [28]. This pattern of peaking around 4 h, followed by a gradual decrease, was subsequently supported in the other two studies, which provided more granular analyses [29, 30]. For instance, signal enhancement was observed in the perilymph of the cochlea and vestibule, with a peak around 4 h. However, there was no significant difference in enhancement between the 3.5‐ and 6‐h time points [30]. Additionally, despite the four‐hour peak in most structures, the IAC showed peak enhancement at 3 h [30]. These findings suggest different rates of uptake for GBCA among various inner ear structures in healthy men that decrease over time and begin to demonstrate that the rate of signal reduction may follow different time courses in different compartments.

3.5. Pathologic Ears

While studies on healthy controls provided insights into baseline GBCA dynamics, those focusing on pathologic ears revealed variations linked to specific diseases. Taken together, these findings suggest that pathological conditions may alter the dynamics of GBCA uptake and clearance in the inner ear, potentially reflecting disrupted fluid regulation or impaired clearance mechanisms.

3.6. Neurological Disorders: FAP and Cerebral Metastases

Two studies provided insights into inner ear fluid dynamics in patients with neurological disorders, specifically transthyretin‐related familial amyloid polyneuropathy (FAP) and cerebral metastases. In patients with FAP (n = 6), the gadolinium signal in the IAC peaked almost immediately compared to controls [31]. Additionally, signal enhancement persisted in the cochlea 24 h after IV administration; however, this prolonged enhancement was observed only in patients with the Tyr114Cys genotype, suggesting a genetic influence on fluid dynamics [31]. For the study on cerebral metastases, researchers observed that signal intensity in the cochlea steadily increased from three to 24 h in both affected and control patients. However, there was no significant difference in signal intensity between the two groups, indicating that metastatic disease may not directly affect GBCA behavior in the inner ear [32].

3.7. Endolymphatic Hydrops in Non‐MD Populations

This finding that signal intensity in the cochlea continued to increase over 24 h contrasts with another study in patients with EH, which demonstrated that the mean cochlear perilymph signal peaked at 4 h but significantly decreased by 24 h [33]. Other studies focusing on EH provide additional insights into clearance mechanisms. For example, a study observed that patients with significant EH in the cochlea and vestibule had a smaller cross‐sectional area of the superior petrosal sinus (SPS) compared to controls but not the inferior petrosal sinus (IPS), suggesting a possible relationship between venous outflow and EH [34]. Another study investigating the optimal scan time for a double dose of GBCAs in patients with EH found that signal intensity in the inner ear peaked at 4 h but declined significantly by 8 h, suggesting active clearance during this period [35]. Similarly, a study examining fluid movement into and out of the perilymph and endolymph found that the perilymph signal peaked at 4 h and declined by 24 h. In contrast, signal intensity in the endolymph remained low but increased gradually over 24 h. Older age was associated with increased perilymph signal intensity at four and 24 h, but not endolymph signal [36].

3.8. Endolymphatic Hydrops in Meniere's Disease

Three studies primarily focused on MD. One study found that high signal intensity in the IAC began around 3.5 h post‐IV administration but was not detectable at 10 min, suggesting a slow permeation process. Although comparisons between groups analyzed at different time points (e.g., 3.5–4 h vs. 4–4.5 h) revealed no significant differences, differences in the cochlear and vestibular perilymph signal at 4 h indicated that clearance mechanisms might be impaired in MD [37]. Similarly, another study demonstrated that signal intensity was higher in ears affected by MD compared to unaffected ears at two, four, and 6 h. Within affected ears, signal intensity increased between two and 4 h and between two and 6 h but showed no significant difference between four and 6 h [38] Taken together, many studies have used proxies for clearance by comparing signal intensity at different time points. In addition, researchers have employed an excretion rate metric, calculated as follows: (signal intensity ratio at 4 h—signal intensity ratio at 24 h) /signal intensity ratio at 4 h. Using this approach, they found delayed excretion rates in patients with EH and older patients (age > 50 years) at the four‐ and 24‐h time points [27].

3.9. Methodologic Limitations

Though valuable for mechanistic insights, animal studies were few (n = 3) and exhibited considerable variability in design, including differences in magnetic field strength (1.5–9.4 Tesla), GBCA types and doses, and observational time frames ranging from 250 min to 48 h. While these studies highlighted important findings, such as the localization of GBCAs in specific inner ear compartments, their small sample sizes and inconsistent methodologies hinder generalizability and their applicability to human physiology. Furthermore, the inability to track the spatial clearance of GBCAs over time remains a significant gap in these studies.

The human studies included in this review also demonstrated notable limitations (Table 4). Blinding of MRI evaluations was not reported in 67% of studies, raising the risk of observer bias, and 58% lacked clarity in describing study populations and sampling methods. Additionally, all studies analyzing pathologic ears failed to include control populations for comparison, and none justified their sample sizes, limiting statistical power. Protocol variability, such as differences in GBCA types, doses, and MRI sequences, further complicated study comparisons. Limited temporal resolution, with few studies extending observations beyond 24 h, also restricted the understanding of long‐term GBCA clearance. Future research should adopt standardized protocols, include well‐defined controls, and provide robust reporting to address these limitations and advance knowledge in this field.

TABLE 4.

Summary of findings on human studies.

Author	n	Sex	Study population	Time points analyzed after IV administration	Gd agent (dose)	MRI strength (T)	MRI protocol	Signal assessment	Findings regarding enhancement	Correlation with symptoms and prognosis
Yoshida et. Al [27]	16	10 M, 6 F	EH, MD, Fluctuating HL	10 min, 4, and 24 h	Gadobutrol (0.1 mmol/kg)	3	MRC, hT2W3D, 3D‐FLAIR	Quantitative	Higher SIR values in older patients and in patients with EH at 24 h	No difference in SIR between PTA < 40 dB and > 40 dB
Naganawa et al. [28]	7	7 M	Healthy Controls	1, 90 min, 180, and 270 min	Gd‐DTPA‐BMA (0.3 mmol/kg)	1.5	T1W fast spin echo based 3D rIR, gradient‐echo‐based 3D SPGR	Quantitative	Endolymphatic sac enhances early and stays enhanced longer compared to cochlear aqueduct and cochlear fluid (no enhancement seen here)	ND
Naganawa et al. [29]	2 (5 total, but only 2 with data after 4 h)	2 M	Healthy Controls	Immediate post‐contrast, 2 h, 4 h, and 6 h	Gd‐DTPA‐BMA (01. Mmol/kg)	3	T1W3D‐FLASH and T2W3D‐CISS, 3D‐FLAIR	Quantitative	Signal intensity increases and peaks at 4 h, slowly starts to lower as it approaches 6 h	ND
Naganawa et al. [30]	6	6 M	Healthy controls	0.5, 1.5, 3, 4.5, and 6 h	Gadoteridol (0.1 mmol/kg)	3	T2W MRC and hT2W‐3D‐FLAIR	Quantitative	Signal peaks in perilymph of cochlea and vestibule around 4 h, but no difference in signal between 3.5 h to 6 h. Gd peaks in IAC at 3 h.	ND
Hirai et al. [31]	6	2 M, 4 F	Transthyretin‐related FAP	Immediate post‐contrast, 3, 6 h, and 24 h	Gd‐DTPA (0.1 mmol/kg)	1.5	Serial T1 and FLAIR	Qualitative	Enhancement in IAC almost immediately after Gd administration, enhancement in inner ear at 24 h still stronger than pre‐contrast	ND
Deike‐Hofmann et al. [32]	40	27 M, 13 F	Neurologically healthy (n = 33) and brain metastases (n = 7)	3 h and 24 h	Gadobutrol (1.0 mmol/mL)	1.5	hT2W‐3D‐FLAIR	Quantitative	Signal increased from 3 h to 24 h in entire cohort	ND
Naganawa et al. [33]	24	15 M, 9 F	Suspected EH	10 min, 4, and 24 h	Gadobutrol (0.1 mmol/kg)	3	3D real IR, 2D MRF	Quantitative	Cochlear perilymph signal peaked at 4 h and decreased significantly by 24 h	ND
Naganawa et al. [34]	34	ND	Suspected EH	Immediate post‐contrast, 4 and 24 h	Gadobutrol (0.1 mmol/kg)	3	MPRAGE, PPI based heavily on T2 weighted FLAIR, PEI, 3D real IR	Quantitative	CSA of SPS associated with EH grade in cochlea and vestibule	ND
Li et al. [35]	22	8 M, 14 F	Unilateral vertigo or SNHL	4, 6, 8 h	Gadobenate dimeglumine (0.4 mL/kg)	3	3D FLAIR	Quantitative	Double‐dose Gd enhancement peaks at 6 h, and seems to be excreted between 6 and 8 h	ND
Naganawa et al. [36]	41	22 M, 19 F	Suspected EH	4 and 24 h	Gadobutrol (0.1 mmol/kg)	3	MRC, hT2W3D, 3D‐FLAIR	Quantitative	Endolymph signal slowly increases over period of 24 h, while perilymph signal peaks at 4 h and decreases as it approaches 24 h	ND
Naganawa et al. [37]	10	6 M, 4F	MD	10 min, 3.5, 4 h, and 4.5 h	Gd‐DTPA‐BMA (0.1 mmol/kg)	3	hT2W‐3D‐FLAIR	Quantitative	High signal in IAC at 3.5 h, but not immediately after contrast. No difference between 3.5 h and 4.5 h but SIR values between groups not same at 4 h	ND
Zhang et al. [38]	17	8 M, 9 F	MD	2, 4, and 6 h	Gadobutrol (0.1 mL/kg)	3	T2 FLAIR, 3D FLAIR	Quantitative	In affected or unaffected ear, SIR higher at 4 and 6 h compared to 2 h, but no significant difference between 4 and 6 h	ND

Note: Data not included by authors in each study are depicted as “not described” (ND). Quantitative signal assessment methods involve the use of signal intensity measurements with regions of interest within the inner ear as compared to other imaged regions such as the cerebellum.

Abbreviations: CISS, constructive interference in steady state; CSA, cross‐sectional area; DTPA‐BMA, diethylenetriamine pentaacetic acid‐ bismethylamide; EH, endolymphatic hydrops; FLAIR, fluid‐attenuated inversion recovery; FLASH, fast low angled shot; Gd, gadolinium; GE3D, T1 weighted 3D with Gradient Cho 3D; HL, hearing loss; hT2W, heavily T2‐weighted; IAC, internal auditory canal; IV, intravenous; MD, meniere's disease; MPRAGE, magnetization prepared gradient rapid echo; MRC, MR cistenography; MRF, MR fingerprinting; MRI, magnetic resonance imaging; PEI, positive endolymph image; PPI, positive perilymph image; PTA, pure‐tone average; SIR, signal intensity ratio; SNHL, sensorineural hearing loss; SPGR, spoiled gradient‐recalled; SPS, superior petrosal sinus; T2W, T2‐weighted.

4. Discussion

The glymphatic system has recently garnered increasing interest due to its role in waste clearance from immune‐privileged sites such as the brain and eye. Whether a similar system exists in the inner ear remains unknown. However, dysfunctions in waste clearance have been implicated in various poorly characterized inner ear conditions, including MD or EH, which are thought to involve disruptions of the BLB [27]. This scoping review investigated GBCA signal dynamics as a proxy for clearance, offering novel insights into waste removal mechanisms in the inner ear across animals and human studies.

Waste accumulation in tissues is known to contribute to a variety of disease processes. For example, impaired clearance of misfolded proteins has been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease [39]. The glymphatic system is thought to play a key role in these conditions, and its function can be broadly influenced by systemic disorders. Conditions such as obesity, diabetes, hypertension, chronic kidney disease, and hepatic encephalopathy have all been shown to significantly affect glymphatic function [40]. Similar mechanisms may be at play in diseases of the inner ear. For instance, elevated T2 FLAIR signal in the cochlea and vestibule of patients with vestibular schwannoma is believed to reflect the accumulation of secreted protein products that are not effectively cleared, and this has been associated with sensorineural hearing loss [41, 42]. These findings, alongside growing recognition of the potential role lymph fluid dynamics may play in disorders such as MD and EH, underscore the need for continued exploration. A better understanding of waste clearance pathways in the inner ear could illuminate the pathophysiology of these poorly understood conditions and inform the development of targeted therapies.

Our review highlighted potential entry points of GBCA into the inner ear. A weak but positive correlation was seen between endolymph and perilymph signals at four and 24 h, suggesting some vasculature involvement [36]. While these studies demonstrated that signal enhancement within the inner ear decreases over time after a peak, they offered limited insights into potential mechanisms for clearance. The IAC has been hypothesized to play a role in the transport and clearance of waste from the inner ear. This suggests that understanding GBCA entry pathways into the inner ear might also provide some understanding of clearance. Human studies provided additional, though still limited, insights into IAC‐mediated clearance. For example, both healthy individuals and MD patients exhibited IAC peak enhancement around 3–3.5 h [30, 37], slightly earlier than the commonly observed four‐hour peak in other inner ear structures [3, 29]. Although the time difference is small, it supports the notion that gadolinium may enter the IAC independently rather than solely as part of waste clearance pathways.

The endolymphatic sac demonstrated earlier and more prolonged enhancement in healthy ears than structures like the cochlear aqueduct, suggesting the endolymphatic sac could play a role in waste clearance [28]. Furthermore, two veins parallel these structures—the vein of the vestibular aqueduct adjacent to the endolymphatic duct draining into the sigmoid sinus and the vein of the cochlear aqueduct alongside the cochlear aqueduct draining into the inferior petrosal sinus [43, 44]. It is, therefore, plausible that gadolinium and other waste products could drain from the inner ear through these venous pathways. Additionally, while a decreased superior petrosal sinus cross‐sectional area has been associated with EH grade, implicating the SPS in clearance mechanisms [34], the inferior petrosal sinus could similarly be involved. Future research is needed to examine anatomical structures' overlapping role in clearance. Lastly, pathologies affecting blood‐labyrinth barrier integrity, such as FAP—known to be associated with hearing issues [45]—may impede clearance due to amyloid deposition within inner ear capillaries, further complicating the clearance process.

However, despite identifying potentially involved structures and a comprehensive search, limited data exist regarding waste clearance from the inner ear. Of the 15 studies that met our inclusion criterion, only three focused explicitly on investigating clearance mechanisms in the inner ear [27, 33, 34]. Additionally, in vivo analyses are sparse, and there is minimal understanding of inner ear histopathology in the context of a potential glymphatic system. This glymphatic system in the brain and eye is thought to rely on the glial water channel aquaporin‐4 (AQP4), which is located at the vascular foot processes of astrocytes [5, 7, 46]. Interestingly, AQP4 is also highly abundant in the inner ear, and its impaired function has been linked to hearing loss [47]. This raises the possibility that disruptions to a similar glymphatic system in the inner ear may contribute to clinical manifestations of conditions like MD.

However, histopathological analysis of the inner ear remains limited due to technical challenges, including the time‐intensive temporal bone decalcification, risks of iatrogenic tissue damage, and the long time intervals between specimen collection and analysis [48, 49, 50]. While continued research is needed to optimize histopathological methods for investigating a potential glymphatic system, in vivo studies specifically designed to assess inner ear waste clearance are critical for advancing our understanding in this area.

Several limitations must be acknowledged. Our quality assessment revealed many unaddressed issues across the studies, including significant variability in methodologies, particularly regarding the types of GBCAs used. This variability reduces the reliability of comparisons across studies [3, 21]. Moreover, as noted in a prior scoping review on the blood‐labyrinth barrier, there remains no consensus on distinguishing between normal and abnormal enhancement patterns [3]. Our review also identified considerable variability in the number and timing of scans analyzed beyond 4 h after IV GBCA administration, further complicating comparisons. Additionally, our initial screening identified a substantial number of studies focused on intra‐tympanic administration of contrast. Future research should explore studies examining clearance patterns beyond 24 h following intra‐tympanic administration, as this corresponds to the time of peak enhancement [51, 52].

5. Conclusion

This scoping review aimed to investigate how waste is cleared from the inner ear in animals and humans by assessing GBCA clearance four or more hours after IV administration. While the studies reviewed were able to track signal intensity over time and propose some anatomical pathways for clearance, the existing literature lacks a focused investigation into inner ear clearance mechanisms through in vivo studies. Future research should specifically explore whether a glymphatic system exists in the inner ear and its potential role in vestibular conditions like MD.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Appendix S1: Supporting Information.

Ahmad S. A., Huang E. Y., Kim J. S., Balhi Y., Spann M., and Ward B. K., “Blood Labyrinth Barrier Waste Clearance as Assessed by GBCAs on MRI: A Scoping Review,” Laryngoscope Investigative Otolaryngology 10, no. 5 (2025): e70240, 10.1002/lio2.70240.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.