European Radiology (2022) 32:6900–6909

https://doi.org/10.1007/s00330-022-08889-y

HEAD AND NECK

Optimized 3D-FLAIR sequences to shorten the delay

between intravenous administration of gadolinium and MRI
acquisition in patients with Menière’s disease
Juliette Barlet 1 & Alexis Vaussy 2 & Yohan Ejzenberg 3 & Michel Toupet 4 & Charlotte Hautefort 3 & André Gillibert 5 &
Arnaud Attyé 6 & Michael Eliezer 1

Received: 11 January 2022 / Revised: 6 May 2022 / Accepted: 8 May 2022 / Published online: 27 June 2022
# The Author(s), under exclusive licence to European Society of Radiology 2022

Abstract
Objectives The aim of this study was to shorten the 4-h delay between the intravenous administration of gadolinium and MRI
acquisition for hydrops evaluation using an optimized 3D-FLAIR sequence in patients with Menière’s disease.
Methods This was a single-center prospective study including 29 patients (58 ears), recruited between November 2020 and
February 2021. All patients underwent a 3-T MRI with an optimized 3D-FLAIR sequence without contrast then at 1 h, 2 h, and
4 h after intravenous administration of gadobutrol. The signal intensity ratio was quantitatively assessed with the region of
interest method. We also evaluated the volume of endolymphatic structures (saccule, utricle) then the presence of endolymphatic
hydrops and blood-labyrinthine barrier impairment at each acquisition time.
Results For all ears, the signal intensity ratio was significantly non-inferior at 2 h compared to 4 h, with a mean geometric signal
intensity ratio at 0.83 (95% CI: 0.76 to 0.90, one-sided p < .001 for non-inferiority at −30% margin). Mean volume equivalence of
saccule and utricle between 2 and 4 h was proven at a ± 0.20 standardized deviation equivalence margin. Intra-rater agreements
(Cohen’s kappa) were all greater than 0.90 for all endolymphatic hydrops location and blood-labyrinthine-barrier impairment
between the 2- and 4-h assessments.
Conclusions We demonstrated that using an optimized 3D-FLAIR sequence we could shorten the acquisition from 4 to 2 h with a
high reliability for the diagnosis of endolymphatic hydrops and blood-labyrinthine-barrier impairment.
Clinical trial registration Clinical trial no: 38RC15.173
Key Points
• Magnetic resonance imaging with delayed 3D-FLAIR sequences allows the diagnosis of endolymphatic hydrops in patients
with definite Menière’s disease.
• An optimized 3D-FLAIR sequence with a long TR of 16000 ms and a constant flip angle allows for reducing the delay between
intravenous injection of gadobutrol and MRI acquisition from 4 to 2 h to diagnose endolymphatic hydrops.
• Reducing this delay between intravenous injection and MRI acquisition could have implications for clinical practice for both
patients and imaging departments.

Keywords Magnetic resonance imaging . Endolymphatic hydrops . Gadobutrol

* Michael Eliezer 4
Centre d’explorations fonctionnelles Otoneurologiques, Paris, France
michael.eliezer@aphp.fr
5
1
Department of Biostatistics, Rouen University Hospital,
Department of Neuroradiology, Lariboisière University Hospital, 76000 Rouen, France
75010 Paris, France
2
Siemens Healthcare France, Saint-Denis, France 6
Department of Neuroradiology, Grenoble University Hospital, La
3
Department of Head and Neck Surgery, Lariboisière University Tronche, France
Hospital, Paris, France
European Radiology (2022) 32:6900–6909 6901

Abbreviations using an optimized 3D-FLAIR sequence, since gadolinium

BLB Blood-labyrinthine-barrier agents start to cross the BLB after an hour.
CNR Contrast-to-noise ratio The aim of this study was to investigate the non-inferiority
EH Endolymphatic hydrops of the 2-h acquisition compared to the 4-h acquisition to diag-
FOV Field of view nose EH with reliability in MD patients.
GRAPPA Generalized auto calibrating partially
parallel acquisition
IC Confidence interval Materials and methods
ICC Intraclass correlation coefficient
MD Meniere disease Patients
Nex Number of excitations
SD Standard deviation This was a single-center prospective imaging study that was
SIR Signal intensity ratio registered with clinicaltrialsregister.eu registry (38RC15.173)
SMD Standardized mean difference conducted between November 2020 and February 2021.
TE Echo time Written informed consents were obtained from all participants.
TI Time inversion Inclusion criteria were patients with definite MD recruited by a
TR Repetition time specialist in otolaryngology. Exclusion criteria were patients
κ Cohen’s kappa who could not have an MRI scan or contrast injection. We in-
cluded 30 patients with definite MD, but one of them was ex-
cluded of the study because of severe motions artefacts during
Introduction MRI acquisition (the patient was claustrophobic).
Definite MD was defined by the latest American Academy
Endolymphatic hydrops (EH) has been considered for years as of Otolaryngology-Head and Neck Surgery (AAO-HNS) [12].
the main histological biomarker of Menière’s disease (MD)
[1, 2]. MRI using delayed 3D-FLAIR sequences became a Imaging
useful tool in clinical practice to evaluate the presence of EH
in MD but also in various inner ears disorders [3, 4]. Counter MRI examinations were carried out on a 3T Magnetom Skyra
et al have demonstrated on animals that the gadolinium pen- (Siemens Healthineers) with a Head/Neck 64 coil. All patients
etrates exclusively into the perilymph space by crossing pro- underwent an MRI scan without injection, then three addition-
gressively the blood-labyrinth barrier (BLB) [5]. Based on al MRI scans at 1, 2, and 4 h (gold standard) after a single IV
these findings, Niyazov et al showed that the diagnosis of dose of gadobutrol (Gadovist; Bayer HealthCare), known to
EH was possible in vivo with MRI on guinea pigs [6]. provide a high contrast in the labyrinth [9]. All patients under-
Naganawa et al have demonstrated in humans that the optimal went a heavily T2-weighted sequence for an anatomical ref-
acquisition time to show this perilymphatic space enhance- erence of the labyrinthine fluid then a 3D-FLAIR sequence
ment was 4 h after the intravenous (IV) administration of with gadolinium injection at different acquisition times, using
contrast media, reaching a maximal signal intensity ratio a constant flip angle (Table 1).
(SIR) [7]. Yet, contrast enhancement could be detected on
MRI by 1.5 h post-contrast in the perilymph in healthy volun-
teers but was significantly weaker than 3, 4.5, and 6 h [8]. Table 1 MRI sequences parameters
Since the main limiting factor of the IV administration is the T2-WI FLAIR
low concentration of gadolinium in the perilymphatic space,
many research groups tried to optimize the MRI hydrops pro- Scan mode 3D 3D
tocol. First, Eliezer et al highly recommend the administration Sequence name SPACE SPACE
of gadobutrol that present a high concentration and longitudi- TR (ms) 1470 16000
nal relaxivity (r1) [9]. Additionally, some authors also advised TE (ms) 310 640
to perform a constant flip angle 3D-FLAIR sequence instead TI (ms) 3000
of a variable flip angle, providing a higher contrast-to-noise Nex 2 2
ratio (CNR) [10]. Recently, it has been demonstrated that 3D- Flip angle (degree) 120 165
FLAIR sequences with a long repetition time (TR = 16000 FOV (mm) 160 × 160 154 × 154
ms) have higher SIR and CNR compared to conventional 3D- Matrix 384 × 345 256 × 256
FLAIR sequences with TR of 10000 ms [11]. Slice thickness (mm) 0.4 0.8
We raised the hypothesis that a reduction of the delay be- Acquisition duration 5 min 56 s 8 min 15 s
tween the injection and the MRI acquisition was possible
6902
Imaging analysis
For each patient, MR images were evaluated at 1 h, 2 h, and 4
h after gadolinium administration, with Carestream Vue®
software version 12.1 (Carestream Health) by two radiolo-
gists: one neuroradiologist with 7 years of experience in inner
ear imaging and one junior radiologist. Radiologists assessed
all images, independently and blindly of the timing. To avoid
memorization bias, a wash-out period of at least 10 days was
required between two evaluations of the same patient.
Quantitative assessment
First, we performed the region of interest (ROI) method, as
reported previously [13]. The signal-to-noise also called SIR
was defined as follows:
SIR ¼ SIperilymph =standard deviation of SInoise
Second, the volumetric measurement of the endolymphatic
space was performed by contouring manually the endolym-
phatic structures: the utricle and the saccule. Then, the soft-
ware automatically calculated the volume.
Qualitative assessment
For the diagnosis of EH, we used the anatomical classification
system [14]. The presence or absence (0: absence, 1: presence)
of cochlear hydrops (area of the endolymphatic space
exceeded the area of the scala vestibuli), the saccular hydrops
(saccule appeared larger to the utricle), and the utricular
hydrops (herniation of the utricle in the non-ampullated part
of the lateral semi-circular canal) was assessed. We also eval-
uated the increased signal intensity (ISI) of the cochlea (0:
absence, 1: presence) that was defined as a higher signal in-
tensity (visually assessed) in the basal turn of one cochlea as
compared to the contralateral side.
Statistical analysis
All analyses were performed using R software version 4.0.3
(The R Foundation for Statistical Computing).
Non-inferiority was searched for the SIR, with a − 30%
non-inferiority margin. Equivalence was searched for the sac-
cule and utricle volumes, with non-inferiority margins of ±
0.20 standard deviations. An intra-rater agreement (Cohen’s
kappa) between 2 and 4 h, greater than 0.90, was searched for
the hydrops diagnosis and BLB impairment.
For the evaluation of the signal intensity ratio, rather than
averaging the SIRs of the two readers, the worst SIR was
taken as a reference. The SIRs were compared, after logarith-
mic transformation, between 2 and 4 h in a gaussian linear
mixed effect model with a random patient intercept explaining
European Radiology (2022) 32:6900–6909
the ear-paired differences of 2 h versus 4 h, taking into account
the correlation between the two ears of patients. The geomet-
ric means of the SIRs were compared, with a non-inferiority
margin of − 30% for 2 h versus 4 h.
An equivalence analysis was performed on the arithmetic
mean of the volume of the utricle and saccule between 2 h and
4 h, in a linear mixed-effects model, after averaging the results
of the two readers; the equivalence margin was a standardized
mean difference of ± 0.20, i.e., a systematic underestimation
or overestimation error of 0.20 standard deviation was consid-
ered as the maximum acceptable. All ears with EH diagnosed
by the two readers were excluded from this analysis, because
endolymphatic structures were too large to encircle them pre-
cisely. Subgroup analyses were performed on pathological
and healthy ears. As there was at most one healthy ear per
patient, Student’s paired t tests were performed rather than a
mixed-effects model.
Inter-reader agreements were evaluated with full agreement
intra-class correlation coefficient ICC (2,1), except for EH
which was evaluated with Cohen’s kappa. For EH, as some
Cohen’s kappa were close or equal to one, we used a non-
asymptotic method, conditional to margins, derived from
Fisher’s exact test.
Non-inferiority one-sided p values were computed with a
significance threshold set at 2.5%. No multiple testing correc-
tions were performed.
Results
Population
Twenty-nine patients (15 women and 14 men) were included
in this study, nine with bilateral ear disease, 8 left-sided MD,
12 right-sided MD. A total of 58 ears (20 healthy, 38 patho-
logical) were analyzed. The mean (standard deviation) age
was 50.9 + / − 15.8 years.
MRI data
Signal intensity ratio
The signal intensity ratio (SIR) at 4 h was taken as a reference
for the geometric mean ratio with the value of 1.00. For the 58
ears (n = 29 patients), the geometric mean (geometric SD) SIR
was 17.9 (× /1.5) at 1 h, 25.5 (× /1.4) at 2 h, and 30.8 (× /1.4) at
4 h (Fig. 1). The SIR was slightly lower at 2 h compared to that
at 4 h with a mean geometric SIR ratio at 0.83 (95% CI: 0.76
to 0.90) but was above the −30% non-inferiority threshold
(p = 0.0001 for non-inferiority). For symptomatic (38 ears)
and asymptomatic (20 ears) ears, the SIR ratios at 2 h, as
compared with 4 h, were 0.81 (95% CI: 0.75 to 0.88, p <
European Radiology (2022) 32:6900–6909 6903

Fig. 1 Left ear on Axial 3D-

FLAIR MRI sequence without
contrast, and at 1 h, 2 h, and 4 h
after IV-administration of gado-
butrol. On the non-contrast 3D-
FLAIR sequence, the saccule
seems enlarged, yet no sign of
endolymphatic hydrops is ob-
served at each acquisition time
following contrast media admin-
istration. The contrast between
endolymphatic and perilymphatic
space is better at 2 h and 4 h
compared to that at 1 h. Images A,
C, E, and G at the level of the
Utricle (white arrow). Images B,
D, and F at the level of the
Saccule (white-dotted arrow)

.001 for non-inferiority) and 0.86 (95% CI: 0.76 to 0.97, p =
0.001 for non-inferiority) respectively (Table 2).
Endolymphatic space volume
For 16 ears, none of the two readers could measure the volume
of the saccule and utricle because of significant endolymphat-
ic hydrops. For the 42 other ears (26 patients), the mean (SD)
saccular volume was 3.66 + / − 2.89 mm3 at 1 h, 3.69 + / −
2.93 mm3 at 2 h, and 3.48 + / − 2.58 mm3 at 4 h. The mean
volume at 2 h was 0.21 mm3 (95% CI: + 0.03 to + 0.39 mm3)
higher than that at 4 h with a standardized mean difference
(SMD) estimated at 0.08 SD (95% CI: 0.01 to 0.15), meeting
the prespecified ± 0.20 requirement for equivalence. That was
not the case for the difference of SMD between 1 and 4 h,
because of the upper bound of the 95% CI: + 0.14 SD (95%
CI: 0.05 to 0.23) (Tables 3 and 5).
The mean utricular volume was 13.73 + / − 3.21 mm3 at 1
h, 13.70 + / − 2.98 mm3 at 2 h, and 13.72 + / − 3.04 mm3 at 4
h. By taking the 4-h sequence as the reference for the measure
of the utricular volume, we found equivalent volume for all
ears between 2 and 4 h (− 0.00 SD, 95% CI: − 0.12; + 0.11)
and also between 1 and 4 h (− 0.00 SD, 95% CI: − 0.16 to +
0.15) (Tables 3 and 5).

Table 2 Comparison of SIR

(signal intensity ratio) 1, 2, and Times Geometric mean × / geometric Ratio of geometric One-sided p value
4 h after IV-administration SD of SIR* means of SIR (95% CI) for non-inferiority**

All ears n = 58, N = 29

0h 7.4 × / 1.4 0.24 (0.21 to 0.28) > 0.99
1h 17.9 × / 1.5 0.58 (0.52 to 0.65) > 0.99
2h 25.5 × / 1.4 0.83 (0.76 to 0.90) 0.0001
4h 30.8 × / 1.4 1.00 (reference)
Pathologic ears n = 38, N = 29
0h 7.5 × / 1.4 0.23 (0.20 to 0.27) > 0.99
1h 19.4 × / 1.5 0.57 (0.52 to 0.63) > 0.99
2h 27.3 × / 1.5 0.81 (0.75 to 0.88) 0.0005
4h 33.6 × / 1.4 1.00 (reference)
Healthy ears n = 20, N = 20
0h 7.3 × / 1.3 0.28 (0.24 to 0.33) > 0.99
1h 15.5 × / 1.5 0.59 (0.51 to 0.69) 0.99
2h 22.6 × / 1.3 0.86 (0.76 to 0.97) 0.001
4h 26.2 × / 1.4 1.00 (reference)

n number of ears; N number of patients; SD standard deviation

*the lowest SIR between the two readers was employed
**non-inferiority with − 30% for margin (SIR ratio of 0.70)
6904 European Radiology (2022) 32:6900–6909

Table 3 Comparison of saccule

and utricle volumes 1, 2, and 4 h Mean ± SD volume*, mm3 Difference of means, Standardized mean
after IV-administration mm3 (95% CI) difference (95% CI)

Saccule volume
All ears n = 42, N = 26
1h 3.66 ± 2.89 0.35 (0.13 to 0.58) 0.14 (0.05 to 0.23)
2h 3.69 ± 2.93 0.21 (0.03 to 0.39) 0.08 (0.01 to 0.15)
4h 3.48 ± 2.58 0 (reference) 0 (reference)
Pathologic ears n = 22, N = 20
1h 4.91 ± 3.53 0.35 (0.01 to 0.69) 0.11 (0.00 to 0.22)
2h 5.03 ± 3.52 0.33 (0.02 to 0.64) 0.11 (0.01 to 0.21)
4h 4.70 ± 3.08 0 (reference) 0 (reference)
Healthy ears n = 20, N = 20
1h 2.29 ± 0.71 0.26 (0.08 to 0.44) 0.52 (0.16 to 0.88)
2h 2.21 ± 0.62 0.08 (− 0.06 to 0.23) 0.16 (− 0.13 to 0.45)
4h 2.13 ± 0.50 0 (reference) 0 (reference)
Utricle volume
All ears n = 48, N = 27
1h 13.73 ± 3.21 − 0.01 (− 0.49 to 0.47) 0.00 (− 0.16 to 0.15)
2h 13.70 ± 2.98 − 0.01 (− 0.37 to 0.34) 0.00 (− 0.12 to 0.11)
4h 13.72 ± 3.04 0 (reference) 0 (reference)
Pathologic ears n = 28, N = 24
1h 14.16 ± 3.46 − 0.03 (− 0.59 to 0.53) − 0.01 (− 0.18 to 0.16)
2h 14.00 ± 3.19 − 0.19 (− 0.66 to 0.28) − 0.06 (− 0.20 to 0.09)
4h 14.20 ± 3.25 0 (reference) 0 (reference)
Healthy ears n = 20, N = 20
1h 13.12 ± 2.80 0.07 (− 0.63 to 0.76) 0.03 (− 0.24 to 0.29)
2h 13.29 ± 2.70 0.24 (− 0.38 to 0.85) 0.09 (− 0.14 to 0.32)
4h 13.05 ± 2.64 0 (reference) 0 (reference)

n number of ears; N number of patients; SD standard deviation

*the geometric mean of the two readers was made first. Ears for which both readers found an EH were excluded
from the analyses, leading to a smaller number of cases than in other analyses

Endolymphatic hydrops respectively (Table 4). The senior radiologist overdiagnosed

EH for at least one site was observed in 35/58 ears (60.3%)
at 1 h, 32/58 ears (55.2%) at 2 h, and 32/58 ears (55.2%) at
4 h according to the senior radiologist; 32, 26, and 26 co-
chlear hydrops, 30, 32, and 32 saccular hydrops; and 14, 14,
and 15 utricular hydrops at 1 h, 2 h, and 4 h respectively.
For the junior radiologist, EH was observed in 26/58 ears
(44.8%) at 1 h, 26/58 ears (44.8%) at 2 h, and 26/58 ears
(44.8%) at 4 h (Fig. 2).
The consistency of the senior radiologist between 2 and 4 h
was excellent for the diagnosis of cochlear hydrops (Cohen’s
kappa (κ) = 1.00, 95% CI: 0.85 to 1.00), saccular hydrops (κ =
1.00, 95% CI: 0.85 to 1.00), and utricular hydrops (κ = 0.95,
95% CI: 0.74 to 1.00). Between 1 and 4 h, the κ for the senior
radiologist diagnosis of cochlear, saccular, and utricular
hydrops were estimated at 0.80 (95% CI: 0.62 to 1.00), 0.93
(95% CI: 0.76; 1.00), and 0.95 (95% CI: 0.74; 1.00)
6/58 (10.3%) cochlear hydrops at 1 h after IV-administration
that were not confirmed at 4 h (Fig. 3) and overdiagnosed 2/58
(3.4%) utricular hydrops at 2 h and 4 h that he had not seen at
1 h. The only discrepancy between 2 and 4 h was a utricular
hydrops, only diagnosed at 4 h. The consistency of the junior
radiologist between 2 and 4 h for the diagnosis of hydrops was
good (all κ ≥ 0.93) (Table 4).
Increased signal intensity of the cochlea
According to the senior radiologist, ISI was observed in 16/58
ears (27.6%) at 1 h, 18/58 ears (31.0%) at 2 h, and 18/58 ears
(31.0%) at 4 h after IV-administration. For 2 symptomatic
ears, ISI was not observed at 1 h after IV-administration but
was then observed at 2 h and 4 h after IV-administration (Fig.
4). Compared to 4 h after IV-administration, the senior radi-
ologist had a consistent diagnosis of ISI at 1 h (κ = 0.92, 95%
European Radiology (2022) 32:6900–6909 6905

Fig. 2 Right ear on Axial 3D

FLAIR MRI sequence without
contrast, and at 1 h, 2 h, and 4 h
after IV-administration of gado-
butrol. Cochlear and Saccular
hydrops are easily diagnosed at 1
h, 2 h, and 4 h. Images A, C, E,
and G at the level of the Utricle
(white arrow). Images B, D, F,
and H at the level of the Saccule
(white-dotted arrow) and
Cochlear duct (gray arrow)

CI: 0.72 to 1.00) and 2 h (κ = 1.00, 95% CI: 0.82 to 1.00) after
IV-administration (Table 4). According to the junior radiolo-
gist, ISI was observed in 8/58 ears (13.8%) at 1 h, 9/58 ears
(15.5%) at 2 h, and 8/58 ears (13.8%) at 4 h after IV-admin-
istration. Compared to 4 h after IV-administration, the junior
radiologist consistency for the diagnosis of ISI was acceptable
at 1 h (κ = 0.86, 95% CI: 0.51 to 0.97) and excellent at 2 h (κ =
0.93, 95% CI: 0.63 to 1.00) (Table 4).
Inter-rater agreements
In the 174 (3 times × 58 ears) images assessed, the inter-
reader agreement for the SIR was acceptable for all ears at
1 h (ICC = 0.80), 2 h (ICC = 0.72), and 4 h (ICC = 0.74)
and when pooling the three evaluation times (ICC = 0.78).
For the evaluation of utricular volume, the inter-reader
agreement was poor at 1 h (ICC = 0.45), 2 h (ICC =
0.41), and 4 h (ICC = 0.48); it was better for saccular
volume evaluation at 1 h (ICC = 0.82), 2 h (ICC = 0.84),
and 4 h (ICC = 0.76) (Table 5).
Discussion
We demonstrated that by using an optimized 3D-FLAIR se-
quence with TR 16000 ms and a constant flip angle, we man-
aged to shorten the MRI acquisition time from 4 to 2 h with
very high consistency for the diagnosis of EH and BLB
impairment.
Previous studies demonstrated that the best time to assess
the presence of EH on MRI was between 3 and 6 h after IV-
administration [15]. However, Naganawa et al reported that
MRI could detect the presence of gadolinium 1.5 h following
IV-administration, but significantly weaker than 3, 4.5, and
6 h [8]. For this reason, we hypothesized that by increasing
the sensitivity to low concentration of gadolinium in the
perilymphatic space, the evaluation of the endolymphatic
space and the ISI of the cochlea might be possible earlier.
Firstly, in our study, gadobutrol has been administrated to all
patients while most studies have administrated gadodiamide
and gadoteridol [16, 17]. Yet, it has been demonstrated that,
for inner ear exploration, gadobutrol enables a higher
perilymphatic enhancement in comparison to gadodiamide

Table 4 Intra-reader consistency

for EH diagnosis and BLB
impairment: 1 h vs 4 h and 2 h vs
4h
Diagnosis Senior’s consistency Cohen’s κ (95% CI) Junior’s consistency Cohen’s κ (95% CI)
1 h vs 4 h n = 58, N = 29 n = 58, N = 29
Cochlea EH 0.80 (0.62 to 1.00) 0.96 (0.80 to 1.00)
Saccule EH 0.93 (0.76 to 1.00) 1.00 (0.84 to 1.00)
Utricle EH 0.95 (0.74 to 1.00) 1.00 (0.76 to 1.00)
BLB impairment 0.92 (0.72 to 1.00) 0.86 (0.51 to 0.97)
2 h vs 4 h n = 58, N = 29 n = 58, N = 29
Cochlea EH 1.00 (0.85 to 1.00) 1.00 (0.84 to 1.00)
Saccule EH 1.00 (0.85 to 1.00) 1.00 (0.84 to 1.00)
Utricle EH 0.95 (0.74 to 1.00) 1.00 (0.76 to 1.00)
BLB impairment 1.00 (0.82 to 1.00) 0.93 (0.63 to 1.00)

n number of ears; N number of patients; EH endolymphatic hydrops; BLB blood-labyrinth barrier

6906 European Radiology (2022) 32:6900–6909

Fig. 3 Right ear on Axial 3D

FLAIR MRI sequence at 1 h, 2 h,
and 4 h after IV-administration of
gadobutrol. A. Cochlear hydrops
is seen on the 1-h acquisition after
IV-administration of gadobutrol
with an enlargement of the
Cochlear duct (grey arrow), but
then not confirmed at 2 h (B) and
4 h (C). Saccule (white dotted ar-
row) and Utricle (white arrow)
show no abnormality

Fig. 4 Axial 3D FLAIR MRI

sequence at the level of the basal
turn of both cochlea. Blood-
labyrinthine-barrier (BLB) impair-
ment is observed on the left ear on
the 2-h and 4-h acquisition after
IV-administration of gadobutrol
with a higher signal intensity in the
basal turn of the left cochlea but
was not observed at 1 h
European Radiology (2022) 32:6900–6909 6907

Table 5 Inter-reader agreement

for SIR, Saccule volume, Utricle All ears n = 58, N = 29 Pathologic ears n = 38, N = 29 Healthy ears n = 20, N = 20
volume, and EH diagnosis
SIR, ICC (2,1)
Without injection 0.49 0.46 0.58
1h 0.80 0.79 0.79
2h 0.72 0.72 0.63
4h 0.74 0.75 0.56
Saccule volume, ICC (2,1)
1h 0.82 0.79 0.25
2h 0.84 0.80 0.36
4h 0.76 0.69 0.31
Utricle volume, ICC (2,1)
1h 0.45 0.47 0.42
2h 0.41 0.40 0.45
4h 0.48 0.45 0.54
EH, Cohen’s κ
1h 0.74 0.67 0.38
2h 0.79 0.74 0.49
4h 0.78 0.72 0.49

n number of ears; N number of patients; EH endolymphatic hydrops; SIR signal intensity ratio; ICC intraclass
correlation coefficient

and gadoteridol since it has a higher concentration and
relaxivity coefficient r1 [18]. Secondly, our optimized 3D-
FLAIR sequence used a constant flip angle and a repetition
time of 16000 ms. Some authors reported that constant flip
angle 3D-FLAIR instead of variable flip angle sequences,
provided higher CNR, and allowed to highlight the shortening
of the longitudinal relaxation induced by gadolinium [10].
Furthermore, it has also been speculated that elongation of
the TR up to 16000 ms enables the recovery of longitudinal
magnetization, which was not sufficient with conventional TR
of 9000 ms [11, 19, 20]. As expected, this study showed
higher SIR at 4 h after IV-administration compared to that at
1 h and 2 h after IV-administration, as has been reported
previously [7]. Despite a mean SIR 17% lower at 2 h than at
4 h after IV-administration, the contrast between the endo-
lymph and the perilymph was sufficient at 2 h for the evalu-
ation of the endolymphatic space. Indeed, there was an excel-
lent intra-reader consistency for the diagnosis of EH for all
localization. By contrast, the image quality 1 h after IV-
administration is not good enough to perform a reliable diag-
nosis of EH. We should mention that we observed cochlear
EH for 6/58 ears (10.3%) 1 h after IV-administration that were
not found at 2 h and 4 h. Nevertheless, cochlear hydrops is a
non-specific finding since some healthy subjects could present
EH in histopathology and imaging studies [21].
We also observed another image quality problem at 1 h
after IV-administration, since 2 symptomatic ears with ISI,
observed at 2 h and 4 h were not observed 1 h after IV-ad-
ministration. The hydrops MRI protocol enables the assess-
ment of the endolymphatic space but also the permeability of
the BLB, which might be slightly impaired in MD but also in
various inner ear diseases [12, 22–24]. Therefore, for now, we
do not recommend the use of 1 h after IV-administration to
evaluate the permeability of the BLB.
Naganawa et al did not recommend performing MRI 1.5 h
after IV-administration since they showed that the size of the
endolymphatic space was significantly larger at 1.5 h than at 3,
4.5, and 6 h after IV-administration, which was surprisingly large
for 8 healthy volunteers [8]. Yet, this enlargement of the endo-
lymphatic space might be also explained by the post-processing
technic used, which consists of the multiplication of heavily T2-
weighted and HYDROPS sequences, making the negative abso-
lute pixel values of the endolymphatic space quite large due to
the multiplication of pixel values. In our study, we found vol-
umes within the ± 0.20 SD equivalence margin at 2 h compared
to that at 4 h after IV-administration for the saccule, and equiv-
alent volumes for the utricle at 1 h, 2 h, and 4 h after IV-admin-
istration. Despite the fact that these volume measurements were
not highly reproducible between readers, we should mention that
these volumes were close to those found in a previous histolog-
ical analysis on cadaveric humans [25].
Our study has several clinical implications. Many authors
have reported low image quality using the IV-administration
of gadolinium, which has hampered the broad clinical appli-
cation of this imaging protocol. Here, we showed that despite
the low concentration of gadolinium, an optimized 3D-FLAIR
sequence could detect sufficient contrast between the endo-
lymphatic and the perilymphatic spaces at 2 h after IV-admin-
istration. Another limitation of the widespread use of this pro-
tocol is because of the 4 h delay between the contrast media
6908
administration and the MRI acquisition. However, the appli-
cation of this protocol in the clinical setting has provided new
insights into inner ear disorders and has dramatically changed
the treatment strategy of these patients. Reducing the delay
between MRI acquisition and IV-administration might im-
prove the acceptability for patients and enable additional scan
time slots per week. In our neuroradiology department, ap-
proximately 50 patients undergo inner ear screening MRIs
per week. Ten additional hours of scan time (30 patients) per
week can be gained only by reducing this delay.
Our study has several limitations. First, we had no possi-
bility to quantify the volume of the vestibular endolymphatic
space in vivo. Second, the sample size of our study was small,
limiting the statistical precision. Third, all our patients under-
went 3-T MRI, which is not commonly used in the current
clinical practice. Yet, some studies have already demonstrated
that delayed post-contrast 3D-FLAIR sequences were possi-
ble on 1.5-T for EH evaluation, allowing easier access for
patients to this protocol [26, 27]. Nevertheless, the acquisition
time on 1.5-T MRI is longer; thus, further studies are warrant-
ed to evaluate the possibility of optimized 3D-FLAIR se-
quences with long TR for hydrops evaluation with an accept-
able acquisition time.
In summary, shortening MRI acquisition time to diagnose
EH with confidence is still challenging and requires sequences
with optimal parameters to evaluate the endolymphatic space
accurately. We demonstrated that by using an optimized 3D
FLAIR sequence, we could reduce the delay between IV-
administration and image acquisition from 4 to 2 h for the
diagnosis of EH with high reliability.
Funding The authors state that this work has not received any funding.
Declarations
Guarantor The scientific guarantor of this publication is Michaël
Eliezer.
Conflict of interest One of the authors (Alexis Vaussy) of this manu-
script is an employee of Siemens Healthcare. The remaining authors
declare no relationships with any companies whose products or services
may be related to the subject matter of the article.
Statistics and biometry One of the authors has significant statistical
expertise.
Informed consent Written informed consent was obtained from all sub-
jects (patients) in this study.
Ethical approval Institutional Review Board approval was obtained.
Methodology
• prospective
• diagnostic or prognostic study
• performed at one institution
European Radiology (2022) 32:6900–6909
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