Georges Dumas
email: gdumas@chu-grenoble.fr

Haoyue Tan

Laurent Dumas
email: dumaslauurent@gmail.com

Philippe Perrin
email: philippe.perrin@univ-lorraine.fr

Alexis Lion
email: alexis.lion@crp-sante.lu

MD; PhD Sébastien Schmerber
email: sschmerber@chu-grenoble.fr

Skull vibration induced nystagmus in patients with superior semicircular canal dehiscence

Keywords: superior canal dehiscence 3 superior canal dehiscence, severe unilateral vestibular lesion, skull vibration induced nystagmus, high frequencies stimulations, SVIN optimal frequency, SVIN optimal location BCV, Bone Conducted Vibrations, SCC, semi-circular canal, SCD, Superior canal dehiscence, uSCD, Unilateral superior canal dehiscence, bSCD , Bilateral superior canal dehiscence, UVL, Unilateral vestibular loss, SUVL, Severe unilateral vestibular loss, SVIN, Skull Vibration Induced Nystagmus, SVINT, Skull Vibration Induced Nystagmus Test, SPV, Slow Phase Velocity of the Nystagmus, cVEMP, cervical Evoked Myogenic Potentials, CaT, Caloric Test, VHIT, Video Head Impulse Test, HST, Head Shaking Test

Skull vibration induced nystagmus in

Introduction

Bone conducted vibrations (BCV) applied to the cranium, a new modality of stimulation of vestibular receptors are now more clearly documented [START_REF] Curthoys | Neural basis of new clinical vestibular tests: otolithic neural responses to sound and vibration[END_REF]. They can provoke otolith stimulations at frequencies around 200-500 Hz [ocular vestibular evoked myogenic potentials (oVEMP) or cervical vestibular evoked myogenic potentials (cVEMP)] [START_REF] Todd | A utricular origin of frequency tuning to lowfrequency vibration in the human vestibular system?[END_REF] and induce at 100 Hz a Nystagmus named the Skull Vibration Induced Nystagmus (SVIN). This new global vestibular test meets the need to find its place (frequency range analysis) among other first line vestibular tests in the vestibule-ocular reflex (VOR) exploration for guidance, orientation to further explorations or targeted imaging and to show its utility in the screening of common unilateral vestibular loss (UVL) or less common vestibular pathologies as a rapid not invasive test with an accurate cost-efficiency rate [START_REF] Lucke | A vibratory stimulus of 100 Hz for provoking pathological nystagmus (author's transl)[END_REF][START_REF] Dumas | Semiologic value and optimum stimuli trial during the vibratory test: results of a 3D analysis of nystagmus[END_REF][START_REF] Dumas | Nystagmus induced by high frequency vibrations of the skull in total unilateral peripheral vestibular lesions[END_REF][START_REF] Dumas | How to perform the skull vibration-induced nystagmus test (SVINT)[END_REF][START_REF] Dumas | Nystagmus and vibration test research of mechanisms, theoretical methods: on 52 cases of unilateral vestibular lesions[END_REF][START_REF] Park | Test-retest reliability of vibration-induced nystagmus in peripheral dizzy patients[END_REF][START_REF] Park | Clinical significance of vibration-induced nystagmus and headshaking nystagmus through follow-up examinations in patients with vestibular neuritis[END_REF]. SVIN occupies the upper part of vestibular frequency spectrum for the vestibule-ocular reflex (VOR) exploration (Caloric test occupies the lower part of VOR frequency spectrum at 0.003Hz; otolith structures are explored at higher frequencies (200-700Hz) with EMG analysis as described above). SVIN at 100Hz acts as a vestibular Weber test and shows usually a nystagmus with a primarily horizontal component beating toward the intact side in different common peripheral UVL as an indicator of asymmetrical vestibular function [START_REF] Dumas | Nystagmus and vibration test research of mechanisms, theoretical methods: on 52 cases of unilateral vestibular lesions[END_REF][START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF]. SVIN may show various pattern of responses (horizontal, vertical, torsional components) at different locations and frequencies of stimulations following the pathologies and we hypothesize that SVIN addresses different structures, i.e. semicircular canals or otolith end organs involved in these pathologies. To our knowledge, this hypothesis has not been investigated in clinic for very high frequencies. In animals (with intact labyrinth), neural evidence shows that the bone conducted vibration stimulates both canal and otolith afferents at 100Hz but only otoliths at 500Hz [START_REF] Curthoys | Neural basis of new clinical vestibular tests: otolithic neural responses to sound and vibration[END_REF][START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF][START_REF] Curthoys | Sustained and Transient Vestibular Systems: A Physiological Basis for Interpreting Vestibular Function[END_REF][START_REF] Curthoys | Bone conducted vibration selectively activates irregular primary otolithic vestibular neurons in the guinea pig[END_REF][START_REF] Curthoys | How does high-frequency sound or vibration activate vestibular receptors?[END_REF][START_REF] Curthoys | The new vestibular stimuli: sound and vibration-anatomical, physiological and clinical evidence[END_REF]. In common vestibular explorations a nystagmus is classically observed when the VOR is stimulated by canal tests (calorics or rotatory test); but a nystagmus may also be observed when stimulating otoliths during the Off-Vertical Axis Rotation (OVAR) test. In clinical practice the stimulus frequency for Skull Vibration Induced Nystagmus test (SVINT) is commonly between 60 to 120Hz [START_REF] Dumas | Semiologic value and optimum stimuli trial during the vibratory test: results of a 3D analysis of nystagmus[END_REF]. One hundred Hz is the most commonly used frequency [START_REF] Lucke | A vibratory stimulus of 100 Hz for provoking pathological nystagmus (author's transl)[END_REF][START_REF] Dumas | How to perform the skull vibration-induced nystagmus test (SVINT)[END_REF][START_REF] Ohki | Vibration-induced nystagmus in patients with vestibular disorders[END_REF] and is accepted as the most efficient stimulation. A previous study of frequency tuning in UVL patients [START_REF] Dumas | Semiologic value and optimum stimuli trial during the vibratory test: results of a 3D analysis of nystagmus[END_REF] used frequencies ranging from 20 to 150 Hz at constant amplitude of 0.2mm vibration and optimal frequencies were observed between 60 to 120 Hz.

SVINT shows usually at 100Hz in severe unilateral vestibular lesions (SUVL) with labyrinths normally encased in bone, a SVIN beating toward the intact side [START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF]. In superior canal dehiscence (SCD), the nystagmus induced by pressure or sound (Hennebert sign, Tullio phenomenon) is ipsilateral torsional and down beating corresponding to the stimulation of the dehiscent superior semi-circular canal (SCC) [START_REF] Cremer | Eye movements in patients with superior canal dehiscence syndrome align with the abnormal canal[END_REF][START_REF] Minor | Superior canal dehiscence syndrome[END_REF]. Similar observation with cranial vibrations have been reported describing a nystagmus with vertical and torsional components [START_REF] White | Vibration-induced nystagmus as an office procedure for the diagnosis of superior semicircular canal dehiscence[END_REF][START_REF] Aw | Three-dimensional vibrationinduced vestibulo-ocular reflex identifies vertical semicircular canal dehiscence[END_REF][START_REF] Manzari | Bone vibration-induced nystagmus is useful in diagnosing superior semicircular canal dehiscence[END_REF]. However, in SCD a horizontal significant component can be observed [START_REF] Dumas | Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test[END_REF][START_REF] Park | Clinical significance of vibration-induced nystagmus[END_REF] and suggests a concomitant stimulation of other vestibular structures than the sole Superior SCC following Flourens and Ewald laws and according to canal nerves [START_REF] Cohen | Eye Movements from Semicircular Canal Nerve Stimulation in the Cat[END_REF] or utricle nerve stimulations [START_REF] Suzuki | Eye movements from single utricular nerve stimulation in the cat[END_REF] . It has been hypothesized a possible contribution of the utricle in animals by Tullio [START_REF] Tullio | Das Ohr und die Entstehung der Sprache und Schrift[END_REF], and in humans [START_REF] Halmagyi | Vestibular responses to sound[END_REF]. Vestibule bony hyper sensitivity to high frequencies has been described in animals with artificially created SCD [START_REF] Curthoys | How does high-frequency sound or vibration activate vestibular receptors?[END_REF] but to our knowledge no systematic clinical trials in SCD patients has so far been reported with SVIN.

The first aim of this study was to design a practical midline stimulation reference (front, vertex, occipital) in order to standardize the results. The second objective was to analyze SVIN responses (Slow phase velocity of the horizontal, vertical and torsional components of the nystagmus) at higher frequencies (up to 800 Hz) to establish the optimal frequency stimulation in SCD patients.

The last aim was to establish SVIN sensitivity when using other vestibular tests such as cVEMP, caloric test (CaT), Head Shaking Test (HST), video head impulse test (VHIT).

Participants and methods

1) Participants

Participants had no history of psychiatric or neurological disorders and neither patients nor control subjects had taken medications during at least one month before recordings. All the participants gave written informed consent before data collection, in accordance with the current ethical laws in France and the declaration of Helsinki. The different procedures stimulations were performed with our CE-marked Skull vibration material which is approved by our local ethical committee.

Fourty patients with a SCD without previous surgery were enrolled b e t w e e n 2 0 0 1 a n d 2 0 1 6 (mean age 54 ±16 years min-max: 32-82; 2 6 women and 1 4 men). Among them twenty seven had a unilateral SCD (uSCD) (the mean age was 59±17 years, min-max :39-82, with 16 women and 11 men). (they were used in experiment 3-4) A Sub class of 14 patients (mean age 53 ± 16 years, min-max: 32-82; 8 women, 6 men) with uSCD were studied in 3D and was used in exp 2.

Thirteen had a bilateral SCD (bSCD) (mean age was 54±16 years, min-max: 32-79, with 10 women and 3 men; experiment 3 & 4).

Eighteen SUVL patients and 11 subjects for the control group were enrolled and studied in 3D.

SCD patients were defined by c o n d u c t i v e h e a r i n g l o s s on low frequencies (under 1000

Hz) with a preserved stapedial reflex and the audiological Weber lateralized toward the lesion. All patients had a temporal bone CT scan reformatted in the P ö s c h l plane of the superior SCC confirming a dehiscence wider than 3 mm (19 had a Cone Beam and 21 a HRCT). The symptoms included hyperacusis, autophony, pulsatile tinnitus and sound or pressure-induced vertigo at different degrees or positional vertigo. The presence of increased amplitude and lower threshold for cVEMP was a favourable argument but not mandatory. Similarly, the observation of a Hennebert sign or a Tullio phenomenon (observed in 3 and 5 of our patients respectively) was characteristic but seldom observed and not mandatory. These inclusion criteria are in accordance with those enacted by Ward et al. [START_REF] Ward | Superior Canal Dehiscence Syndrome: Lessons from the First 20 Years[END_REF].

SUVL were defined with a severe unilateral vestibular loss (UVL): caloric hypofunction higher than 80% (Jongkees formula) and a vestibular lesion dating more than 6 months.

(mean age 60 ±11 years, min-max: 42-80, 10 women and 8 men). Eleven were treated by intratympanic gentamicin, 3 had a vestibular neuritis and 4 a total UVL (trans labyrinthine surgery or vestibular neurectomy). Eleven among them were used in experiment n°1, and the totality of them in experiment 2.

The subjects (control population) were selected among normal volunteers (mean age 55 ±15 years, min-max: 24-70, 7 women and 4 men). The volunteers were collaborators working at the hospital without any medical history of vertigo, with normal hearing, normal caloric test and normal VHIT

2) Stimulation and Vestibular explorations: vestibular evaluation

The characteristics of SVIN stimulation were similar in the different experiments exepted for the topography (exp.1) and frequency (exp.2) and yielded differences adapted to the procedure of each experiment.

The other vestibular tests were used for the systematic inclusion of patients

SVIN

The vibratory stimulation was applied in experiment n°1 in different locations on the midline (front, bregma, vertex, occipital, sub-occipital) to determine optimal midline location for the following experiments. In experiments 2-4 all participants were stimulated to the vertex and successively on the left and right mastoid during 10 seconds for each location (each stimulation being separated by 3 seconds) using the handheld vibrator Minishaker 4810 (Bruel and Kjaer, Naerum Denmark) with the dominant hand. Participants were in an upright sitting position. On vertex and bregma, the force is given by the weight of the vibrator (1 kg) with no additional pressure; the vibrator being simply maintained in place (Force is 1 Kg X 9.81= 9.81 N). For the mastoid location the static force of application evaluated with force sensors in a previous work was approximately 10 N when applied laterally on a manikin simulating mastoid location [START_REF] Dumas | Topographic analysis of the skull vibration-induced nystagmus test with piezoelectric accelerometers and force sensors[END_REF]; on the patients mastoids the stimulation was retro-auricular level to the external auditory meatus on the left and then right side; the recordings were performed under 2D and/or 3D VNG, [i.e. eyes open (direct medial gaze) behind a videoscopic helmet, to identify the possible SVIN occurrence and its slow-phase eye velocity (SPV, in °/s)].

The nystagmus axis can be horizontal, vertical or torsional and its direction can be right or left, upward or downward, rotatory clockwise or counter-clockwise. This procedure has already been described in detail previously [START_REF] Dumas | Nystagmus induced by high frequency vibrations of the skull in total unilateral peripheral vestibular lesions[END_REF][START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF].

In experiments 1, 3 and 4 frequency was 100Hz and for experiment 2 frequency varied from 10 to 2.2 Caloric test (CaT) This test was performed using VNG according to the bithermal ( 3 0 ° a n d 4 4 °C ) caloric test protocol, with water infusion of the ear canal for 30 s. A hypofunction >20% was considered significant.

Head-shaking test (HST)

The examiner shook the patient's head in the horizontal plane for 20 s at a frequency of 2 Hz, and rotation amplitude of 45 ⸰ on both sides and VNG measured the response. The test was positive when at least one eye flick or nystagmus was observed.

Video Head impulse test (VHIT)

This test was performed on a sitting upright subject with the VHIT Ulmer device [Synapsys Inc., France] at 100 Hz image sampling. This device records eye position and shows possible covert saccades. It also analyses the vestibulo-ocular reflex (VOR) gain. The examiner exerted head impulses (10-20 ⸰ of amplitude) at velocities higher than 200 °/s in the horizontal, anterior, and posterior SCC planes. The results were considered abnormal for the Horizontal canal when the ocular VOR response gain was < 80% and for the vertical canals when the gain was <70 % [START_REF] Mcgarvie | The Video Head Impulse Test (vHIT) of Semicircular Canal Function -Age-Dependent Normative Values of VOR Gain in Healthy Subjects[END_REF].

Cervical Vestibular Evoked Myogenic Potentials (cVEMP)

Patients were positioned supine on a stretcher and were asked to turn their head contralaterally to the stimulated ear. The protocol has previously been described in detail in a previous work [START_REF] Dumas | Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test[END_REF].

The stimuli delivered with a headphone (TDH 39) were short-tone bursts at a frequency of 500 Hz (from 105 dB to 70 dB nHL, rise/fall time 1 ms, plateau time 2 ms). cVEMPs were recorded with a Racia Centor (Racia Biomedical Inc., France). One hundred to 200 stimulations were averaged on each side. The percentage of cVEMP asymmetry in patients with unilateral lesions was measured by calculating the evoked potential ratio (EPR) as follows EPR=AL-AS/AL+AS X 100, where AS is the smaller P13-N23 peak-to-peak amplitude and AL is the larger P13-N23 peak-to-peak amplitude. In unilateral cases, the test was considered positive in our clinic when the difference in amplitude between both sides was greater than 50%. In bilateral cases, the test was considered positive when the cVEMP thresholds were lower than 80 dB nHL.

The four experiments were performed by the same examiner (GD) and were conducted in the following order:

3 Experiment 1: Midline location stimulus optimization at 100 Hz.

Participants

Eleven severe unilateral vestibular lesion (SUVL) out of 18 patients were included: 7 had been treated by intratympanic gentamicin, 3 had a vestibular neuritis, one underwent vestibular neurectomy. The mean age was 62 ± 16 years, min-max: 43-80, with 6 women and 5 men.

Procedure

To identify the optimum site for midline stimulation, experiment n°1 was conducted at 100 Hz in SUVL: stimulation during 10 seconds was applied without additional pressure else that the vibrator own weight on the cranium midline at frontal (Fz), Bregma (Br), vertex (Vx), and with the usual hand held pressure for occipital (Occ) and sub occipital (SOcc) regions. SVIN SPV was recorded on a 3D video nystagmograph (VNG) (Synapsys, Marseille, Inc, France). This experiment was performed before the following experiments to give optimal midline location stimulation.

Experiment 2: comparison between uSCD, SUVL patients and normal subjects stimulated at different frequencies and locations.

In this experiment a 3D analysis was used to verify the influence of stimulation frequency and location on horizontal torsional or vertical components.

Participants

-Twenty seven had a unilateral SCD (uSCD): 14 cases (mean age 53 ± 1.6 years, min-max: 32-82; 8 women, 6 men) were studied in 3D recording (Table I) at different frequencies (10-800 Hz).

They were compared to eighteen SUVL patients and to eleven normal volunteers analyzed in Twenty seven uSCD and 13 bSCD patients were included.

Procedure

The stimulation was performed at 100 Hz on the vertex and each mastoid. SVIN was recorded on 2D VNG and the SVIN SPV was analysed (left and right side averaged value). The SVIN horizontal response for both populations was compared. Among the 27 uSCD, 14 were studied in experiment n°2. Results were expressed in mean ± SD.

Experiment 4: SVIN sensitivity in uSCD and bSCD vs other vestibular tests.

SVINT, CaT, HST, VHIT and cVEMP were performed in uSCD (n=27) and bSCD (n=13).

The percentages of positive results (abnormal results) for those vestibular tests were compared in both groups of patients

Statistical analysis

Statistical analysis was performed using a ANOVA (Experiment 1-3) and Cochrane Q test (Experiment 4) with GraphPad Prism software (GraphPad, Inc., La Jolla, CA, USA). In experiment 2, ANOVA test followed by running post-hoc Tukey's test was performed to assess optimal frequency and location in the 3 populations. The results are presented as the mean ± s.e.m. Statistically significant differences were accepted for a probability level of p < 0.05.

Results

Experiment 1 -Optimal location on the midline (SUVL, n =11)

Horizontal slow phase velocities of the SVIN were normally distributed. No significant difference was observed whatever the midline locations at 100 Hz (Repeated measures ANOVA: F=0.52, p=0.87). Vertical slow phase velocities of the SVIN were abnormally distributed and logtransformation of the data was not possible (several 0 values). No significant difference was observed whatever the midline locations at 100 Hz (Friedman test: χ 2 =3.54, p=0.47). Similar results were observed for the torsional component which showed low SPV responses.

Therefore, for midline stimulation, the vertex location, which is in clinical practice the most often used midline location, was arbitrary chosen as the midline stimulation reference for experiments n°2-4.

Experiment 2

-Optimal frequency SUVL/uSCD/Controls (Figure 1) o In SUVL (n=18) -The quick phases of SVIN always beat away from the affected ear (Table 1).

-For the horizontal component, different frequencies caused different SPV values (p< 0.0001).n= 18 (ANOVA) Comparisons showed that 100 Hz was the optimal frequency to reveal the greatest slowphase velocity of the horizontal SVIN component: for the right mastoid location, the SVIN SPV was higher at 100 Hz (12.33 ± 1.81°/s) than all the other frequencies (p<0.001) . SVIN-SPV 60Hz= 6.52 ± 1.05°/s (60Hz vs 100Hz p<0.01); 200Hz SVIN-SPV= 3.43 ± 0.83°/s (200Hz vs 100Hz p<0.0001); 500Hz SVIN SPV = 0.28 ± 0.05°/s (500Hz vs 100Hz p<0.0001). Similar results were obtained for the left mastoid at 100Hz (13.76 ± 2.28°/s), 30Hz (6.65 ± 1.84°/s), 200Hz (3.87 ± 0.86°/s), 500Hz (0.39 ± 0.06°/s) and with less velocity for the vertex location (4.5 ± 1.06 °/s) at 100Hz (Fig. 1).

-For the vertical component, the different frequencies caused differences in vertical SVIN SPV (p = 0.0001). There was a tendency to show higher responses (as for the horizontal component) at 100Hz than at lower (60Hz) or higher frequencies (200-400Hz) (Fig. 1) However, the comparisons (ANOVA test) did not show significant differences (SVIN SPV values in this condition were small and the population was small). At 100 Hz for the right mastoid SVIN -SPV was 1.25. ± 0.63°/s. Similar values were observed for LM (0.94 ± 0.37°/s) and smaller for VX (0.72 ± .0.27°/s).

At 60 Hz,for the right mastoid, SVIN-SPV values were 0.34 ± 0.06°/s, at 200 Hz 0.69 ± 0.23°/s, at 500 Hz 0.12 ± 0.01°/s -For the torsional component, at 100 Hz on the left mastoid, SVIN-SPV was 2.44 ±0.72 °/s. It was 1.44 ± 0.24°/s at 60Hz; 2.06 ± 0.42°/s at 200Hz and 0.25 ± 0.07°/s at 500Hz

The SVIN-SPV at 100HZ was significantly greater for the horizontal component than for the vertical and torsional components which are small (13.76 ± 2.28°/s; 0.94 ± 0.37°/s; 2.44 ± 0.72°/s respectively, p<0.01). SUVL patients signal usually, when stimulated, a sensation of latero-pulsion toward the safe side (16 patients among 18).

o In uSCD (n=14)

The SVIN direction beats toward the lesion side in 92% of cases (Table 1).

A wider and higher range of frequency responses up to 700 Hz or 800 Hz was observed without a clear cut significant optimal frequency for the horizontal and vertical components of SVIN SPV (ANOVA was not significant) (Fig 1).

-For the horizontal component, a tendency to higher SVIN SPV was observed at 400 and 500 Hz but was not significantly different from responses to other frequencies. The average mean value at 500 Hz for the LM was 4.09 ± 2.51 °/s. The average value for RM at 400 Hz was 4.52 ± 1.78 °/s. The average mean value at 100Hz for the LM was 2.46 ± 0.67°/s and for RM was 2.96 ± 0.87°/s.

For vertex stimulations, greater responses were observed at 300 Hz [8.09 ± 4.46°/s].

-For the vertical component, the SVIN SPV on the RM at 400 Hz was 4.46 ± 2.12°/s and on the vertex at 300 Hz was 8.21 ± 3.97°/s. It was on the RM at 100Hz 1.93 ± 0.21°/s and on the vertex at 100Hz 1.40 ± 0.27°/s. In 4 patients, the down beating nystagmus observed under videoscopy was enhanced when the gaze was directed toward the plane of the dehiscent canal and when the record was performed on the eye ipsilateral to the lesion.

-For the torsional component, a tendency to higher SVIN SPV was observed at 400 and 500 Hz but was not significantly different from responses to other frequencies. The average mean value at 500 Hz for the LM was 5.64 ± 3.27°/s. The average value for RM at 400 Hz was 5.57 ± 3.03°/s. For vertex stimulations, the average mean value at 300 Hz was 6.60 ± 2.70°/s. There was no significant difference whether the stimulation or the record were performed ipsilaterally or contralaterally.

There was no significant difference between horizontal, vertical, and torsional components for SVIN-SPV. Figure 2 shows a 3D recording (direct tract) in a uSCD patient. In uSCD a tendency of sensitivity extension toward higher frequencies than 100Hz is observed in 65% of cases (9 patients among 14). Frequencies lower than 100Hz show a tendency to lower SPV.

Patients with uSCD (16 patients out of 27) signal usually after repeated stimulations a sensation of dizziness with nausea and symptoms commonly attributed to otolith signs.

o In control subjects (n=11)

No significant difference for SVIN SPV was observed when comparing results at different frequency stimulation (Fig. 1). No nystagmus was observed in 62% of cases. A low-intensity SVIN, seldom observed in 38% of cases, was not reproducible, changed direction following the side of stimulation (inconsistency) or was observed in only one location. Its SPV (only observed for the horizontal and vertical components) was < 2°/ s in 30% and <3°/s in the other 8% of normal subjects.

The criteria of a significant SVIN and a positive test are as follow:

-Consistency: the SVIN must have the same direction in at least 2 on 3 cranial location (left mastoid, right mastoid, vertex) (e.g. a SVIN beating rightward after right mastoid stimulation, and leftward after left mastoid stimulation is not valid: negative test.

-Reproducibility: a SVIN direction changing (rightward and then leftward on the same location) after 2 trials or the SVIN disappearance at the second trial makes the test negative.

-An intensity or SVIN SPV < 2°/s makes the test result doubtful or negative.

o Comparison of frequency sensitivity in uSCD and SUVL (Fig. 1)

For the horizontal component, the SVIN SPV in uSCD was significantly higher than in SUVL at 400 Hz for RM stimulation (p<0.01) and at 500 Hz for LM stimulations (p<0.05). For vertex stimulations in uSCD, the SVIN horizontal SPV at 300 Hz was significantly higher than in SUVL (p<0.001). Similar results showing a higher sensitivity to high frequencies in uSCD were observed for the torsional component for mastoids stimulations at 400 and 500 Hz (p<0.05). Similar results were observed for the vertical component and greater responses were obtained in uSCD than in SUVL at high frequencies between 400 to 700 Hz for mastoid and vertex stimulations (p<0.05).

Conversely, the SVIN SPV at 30, 60 and 100 Hz was higher in SUVL than in uSCD for both mastoid stimulations for the horizontal component (p<0.001).

-Optimal location in uSCD vs SUVL (Figure 1).

In uSCD, vertex stimulation was significantly more efficient than mastoid stimulation for the horizontal, vertical and torsional components at 300 Hz (p<0.05) but not for higher frequencies.

In SUVL, mastoid stimulation at 30, 60 and 100 Hz was significantly more efficient for horizontal and torsional components than vertex stimulations (p<0.001). The value of mastoids SVIN SPV were significantly higher in SUVL vs. uSCD at 30, 60 and 100 Hz (p<0.001, ANOVA).

The values of vertex SVIN SPV were significantly higher in uSCD vs. SUVL for the horizontal component at 300Hz (p<0.001), for the vertical component at 60Hz (p<0.01), 300Hz (p<0.001) and 400Hz (p<0.05) and for the torsional component at 300Hz (p<0.001).

In controls, no optimal location could be identified since no clear acceptable responses could be identified. When a SVIN is identified the direction changes with the side of stimulation (inconsistency) and the Horizontal SVIN -SPV mean value is lower than 2°/s.

Experiment 3: Comparison of SVIN results in uSCD and bSCD (Figure 3 & Table 2)

During vertex stimulation, SVIN was more commonly observed in uSCD (88%) than in bSCD (50%) (p=0.009). In uSCD, SVIN beat mostly toward the lesion side (95%). The vertical component was mainly up beating (60%). During vertex and mastoid process stimulations in uSCD patients a coherent SVIN beating toward the same direction accordingly to previously enacted criteria (positive test) was observed in 70%.

The SVIN SPV was significantly higher in uSCD than in bSCD (p=0.0082):

The vertex stimulation showed a main effect of the pathologies, with SPV being higher in uSCD [5.66±8.40°/s] than bSCD [1.50±3.95°/s] (F=7.5; p = 0.0082, ANOVA).

The mastoid stimulation showed a main effect of the pathologies, with SPV being higher in uSCD[4.09±6.93°/s] than bSCD [0.84±2.03°/s] (F=6.24; p = 0.0147, ANOVA).

Experiment 4: Comparison of SVIN results in uSCD with other vestibular tests (Table 2).

In uSCD (n = 27) the SVIN sensitivity was higher than the Caloric, head shaking test, and VHIT sensitivity (p<0.001, Cochrane test), SVIN was positive in 24/27 cases, CaT in 3/23 , HST in 5/25 and VHIT in 6/21) but was not different from cVEMP (19/26) (p>0.5) (Table 2). In bSCD, no difference of sensitivity between the tests SVIN (7 positive cases among 13), CaT (3/12), HST(5/11), VHIT (3/11, cVEMP (9/12)) was observed (p=0.88).

Discussion

The skull vibration induced nystagmus test can predict the vestibular asymmetry in unilaterally vestibular lesioned patients [START_REF] Dumas | Nystagmus induced by high frequency vibrations of the skull in total unilateral peripheral vestibular lesions[END_REF][START_REF] Park | Clinical significance of vibration-induced nystagmus and headshaking nystagmus through follow-up examinations in patients with vestibular neuritis[END_REF][START_REF] Hamann | Vibration-induced nystagmus -A sign of unilateral vestibular deficit[END_REF] and is used as a vestibular Weber Test [START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF][START_REF] Dumas | Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test[END_REF]. Neural evidence shows that the bone conducted vibration stimulates both canal and otolith afferents [START_REF] Curthoys | How does high-frequency sound or vibration activate vestibular receptors?[END_REF][START_REF] Curthoys | The new vestibular stimuli: sound and vibration-anatomical, physiological and clinical evidence[END_REF]. This test has a potential utility to orientate further examination, vestibular exploration or targeted imagery in order to enhance diagnosis accuracy and surgical decision.

In conductive hearing loss with CT-verified SCD, we previously reported that SVIN horizontal and torsional components beat toward the lesion side (in relation to the bone conducted facilitation of the inner ear favored by the existence of a third window) [START_REF] Dumas | Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test[END_REF] and is associated to a "bony hyperacousis" [START_REF] Cremer | Eye movements in patients with superior canal dehiscence syndrome align with the abnormal canal[END_REF][START_REF] Minor | Superior canal dehiscence syndrome[END_REF]. Unlike severe unilateral vestibular lesions where the SVIN is of the lesional type beating toward the intact side [START_REF] Dumas | Nystagmus induced by high frequency vibrations of the skull in total unilateral peripheral vestibular lesions[END_REF][START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF], a SVIN beating toward the lesion side is strongly suggestive of SCD [START_REF] Dumas | Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test[END_REF]. However, it can also be observed in other labyrinthine malformations associated to a third window (e.g. enlarged vestibular aqueduct) [START_REF] White | Nystagmus in Enlarged Vestibular Aqueduct: A Case Series[END_REF]. In SUVL (normally encased labyrinth), greater responses are observed at 100 Hz for the horizontal component (there were poor responses for the vertical and torsional component) and no responses at 500 Hz. In contrast, uSCD patients show greater sensitivity to high frequencies; higher responses were observed at approximately 500 Hz without clear cut specific frequency and the SPV values of the vertical and torsional components were higher than in SUVL. The utility of very high frequency stimulations in SCD has already been signaled for oVEMP [START_REF] Manzari | An indicator of probable semicircular canal dehiscence: ocular vestibular evoked myogenic potentials to high frequencies[END_REF] . Our results suggest that different anatomical structures may be stimulated by SVIN in these 2 populations, mainly horizontal canal and at a less degree utricle at 100 Hz in SUVL, while both canal (mainly superior canal) and utricular neurons are activated in uSCD at 500 Hz. In uSCD, the most often observed component is torsional and horizontal and the vertical component is most often up beating suggesting that the superior SCC is probably not the only stimulated structure. However, we have observed in 23 % of our patients a down beating SVIN when the gaze was directed toward the lesion side at vertex stimulation and the eye axis placed in the same plane of the dehiscent canal; this sign was more often observed in our series than the Hennebert sign which we seldom noted. The usual torsional ipsilateral and down beating nystagmus induced by sound (Tullio phenomenon) or pressure (Hennebert sign) attributed to the dehiscent superior canal activation [START_REF] Cremer | Eye movements in patients with superior canal dehiscence syndrome align with the abnormal canal[END_REF][START_REF] Minor | Superior canal dehiscence syndrome[END_REF] does not explain the totality of the SVIN components here observed. The horizontal component may be explained by the concomitant utricle stimulation as suggested by Halmagyi [START_REF] Halmagyi | Vestibular responses to sound[END_REF] and by physiology [START_REF] Suzuki | Eye movements from single utricular nerve stimulation in the cat[END_REF]. In addition, Tullio in alert animal's studies with artificially created SCD described head movements or muscles contractions. In pigeons ear he observed the membranous wall of the utricle oscillate and in a few animals (rabbits) eye modifications equivalent to an ocular tilt reaction response.

These results are consistent with the response of primary semicircular canal afferent neurons in guinea pigs in response to BCV stimulation: in animals with normally encased bony labyrinths, canal neurons can be activated by BCV only at low frequencies (100-200 Hz) but not at frequencies of 500 Hz [START_REF] Curthoys | How does high-frequency sound or vibration activate vestibular receptors?[END_REF]. This low frequency tuning of canal neurons is consistent with the low frequency tuning of SVIN in SUVL patients found here. In SUVL patients, the direction of the quick phases of nystagmus is away from the affected side since only neurons on the remaining healthy side are activated. After an uSCD, canal neurons can be activated by BCV at low frequencies but now also up to high frequencies, even above 745 Hz [START_REF] Curthoys | Neural basis of new clinical vestibular tests: otolithic neural responses to sound and vibration[END_REF][START_REF] Curthoys | How does high-frequency sound or vibration activate vestibular receptors?[END_REF]. This finding is consistent with the upward frequency shift of SVIN reported here in uSCD patients. In uSCD patients, the direction of the nystagmus is toward the affected side since canal neurons on the affected side will be activated, resulting in nystagmus with slow phases away from the affected side. In this way, we conclude that SVIN acts as a vestibular Weber test [START_REF] Dumas | The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review[END_REF][START_REF] Dumas | Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test[END_REF].

The observation that SVIN sensitivity is lower in bSCD than in uSCD may be related to the fact that SVIN acts as an indicator of vestibular asymmetry (vestibular Weber test). In case of partial bilateral symmetrical or slightly asymmetrical lesion, the test remains negative or shows a very low SVIN SPV. Therefore, in bSCD with both sides affected, the asymmetry may be small and so cVEMP seem to be more relevant since it analyzes separately each side.

In clinical practice SVIN, a first-line examination test for VOR exploration, may help the clinician to discriminate and make a decision in ambiguous cases (true dehiscence or thin bone over the SCC) with disabling vertigo. Radiological results have shown possible discrepancies in SCD between CT scanner results and real anatomically verified lesions [START_REF] Ward | Superior Canal Dehiscence Syndrome: Lessons from the First 20 Years[END_REF][START_REF] Williamson | Coronal computed tomography prevalence of superior semicircular canal dehiscence[END_REF][START_REF] Sequeira | Accuracy of computed tomography detection of superior canal dehiscence[END_REF], as well as similar symptoms in near dehiscent superior canals [START_REF] Ward | Superior Canal Dehiscence Syndrome: Lessons from the First 20 Years[END_REF]. It has been suggested that cVEMP is the best clinical indicator in SCD [START_REF] Govender | Properties of 500Hz air-and bone-conducted vestibular evoked myogenic potentials (VEMPs) in superior canal dehiscence[END_REF]. Here we show that SVIN in uSCD yields responses as efficient as cVEMP, but more efficient than other common vestibular tests. Govender et al. 2016 [START_REF] Govender | Properties of 500Hz air-and bone-conducted vestibular evoked myogenic potentials (VEMPs) in superior canal dehiscence[END_REF] showed that cVEMP were modified significantly in only 82% of SCD. Zuniga et al. [START_REF] Zuniga | Ocular versus cervical VEMPs in the diagnosis of superior semicircular canal dehiscence syndrome[END_REF] showed in 29 surgically verified SCD that cVEMP threshold had a sensitivity of 80% (specificity of 100%) and the study of oVEMP amplitude showed a sensitivity of 90 %. In our study, we observed a SVIN sensitivity of 88 % (vertex stimulation) and specificity of 62% (total absence of nystagmus).

Conclusion

In patient with unilateral conductive hearing loss and normal ear drum, a Skull Vibration Induced Nystagmus observed preferentially on Vertex location and with a torsional and horizontal component beating toward the lesion side at 100 Hz and higher frequencies up to 700 Hz is strongly suggestive of a Superior canal dehiscence. Skull Vibration Induced Nystagmus reveals instantaneously a characteristic nystagmus and acts as a vestibular Weber test. It is more sensitive to reveal unilateral than bilateral superior canal dehiscence. A primarily down beating nystagmus is preferentially observed in patients when the gaze is directed toward the plan of the superior dehiscent canal. We propose that Skull Vibration Induced Nystagmus test should be considered as a useful indicator for unilateral superior canal dehiscence diagnosis in clinical practice.

Disclosure Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The estimated dimension of the dehiscence is given in mm. SVIN [horizontal and torsional components] always beats toward the intact side in SUVL and most often toward the lesion side in uSCD. An up beating VIN is commonly observed in uSCD.

Aknowledgments

The SVIN results on mastoid and vertex marked + or ++ correspond to a semi-quantitative evaluation of the nystagmus intensity. In uSCD higher responses were observed at 500 Hz without significance (tendency) and there was a much wider range of sensitivity spread from 60 Hz up to 800 Hz. The average mean value at 500 Hz for the LM was 4.10 ± 2.51 °/s. Significantly higher responses are obtained on vertex than on mastoids at 300Hz (p<0.05).

In controls, no or few significant responses [VIN inconsistent direction] with a mean value lower

  patients, 14 uSCD patients and 11 controls (volunteers) were stimulated with 10-800Hz vibration (Minishaker 4810, Bruel & Kjaer; Naerum; Denmark) on each mastoid process successively and on the cranium midline vertex. SVIN Horizontal, Vertical and Torsional components were recorded with a 3D VNG (Synapsys Inc., France) and SVIN-SPV was analyzed. 5 Experiment 3: SVIN Sensitivity in unilateral SCD (uSCD) vs. bilateral SCD (bSCD) 5.1 Participants

.

  The authors thank Dr. M. Dols from the department of Statistics, Patrice Jousse for providing drawings and figures (University Grenoble Alpes) and Pr. IS Curthoys for his advices and documentation.

  uSCD: Unilateral Superior canal dehiscences; bSCD: bilateral canal dehiscences. The estimate width of dehiscence is given in mm; Side of lesion (R=right; L=left) Results of different vestibular tests compared to SVIN are given as follows: -CaT caloric test: N= no hypofunction; RH= right hypofunction; LH= left hypofunction. -HST: 0= no HSN; L= left HSN; R= Right HSN -VHIT: N=normal; LA= hypofunction on the left anterior canal; LP= hypofunction on the left posterior canal; LLat=hypofunction on the left lateral canal; RL Lat= Dysfunction of both lateral canals on the right and left side. -cVEMP: += result positive ipsilaterally to the lesion; -= normal result (no asymmetry); ….= no data -SVIN H horizontal component: R beating toward the right; L beating toward the left V vertical component: up= up beating; dw= down beating T torsional component: R= the upper part of the eye is beating toward the patient's right; L= the upper part of the eye is beating toward the patient's left.

Figure 1 .

 1 Figure 1. SVIN horizontal, vertical and torsional components Slow phase velocity (SPV) at different frequencies and locations (Exp.2).

  than 1 or 2°/s at 100 or 200 Hz were observed. B, E, H. Vertical component observed on LM, RM and VX in the 3 populations. In SUVL, the SVIN-SPV at 200 Hz was small on LM [1.81 ± 0.65 °/s]. In uSCD higher values were observed at 400 Hz on RM [4.46 ± 2.12 °/s]. C, F, I. Torsional component on LM, RM, and Vx in the 3 populations. In SUVL SVIN-SPV at100 Hz on LM was very low [2.44 ± 0.72°/s]. In uSCD, the SVIN-SPV on RM at 500 Hz was 6.64 ± 3.27 °/s. *; **; *** indicates significance at p<0.05, <0.01, and <0.001 respectively, when comparing LM/Vx. †; † †; † † † indicates significance at p<0.05, <0.01, and <0.001 respectively, when comparing RM/ Vx. ‡; ‡ ‡; ‡ ‡ ‡ indicates significance at p<0.05, <0.01, and <0.001 respectively, when comparing LM/RM.

Figure 2 .

 2 Figure 2. SVIN in a right uSCD.

Figure 3 .

 3 Figure 3. Comparison of horizontal SVIN in uSCD and bSCD.

  3 A : Percentage of positive VIN in patients with uSCD and bSCD after vertex stimulation. 3B : Horizontal VIN SPV (in °/s) between uSCD and bSCD collected after vertex or mastoids stimulations. The value for mastoid stimulations is the mean value of right and left mastoid stimulation. uSCD, unilateral superior canal dehiscence (n=27); bSCD , bilateral superior canal dehiscence (n=13) ** p < 0.01. Results are expressed as mean value ± SD.. For fig 3A fisher test; and Fig3B Mann and Whitney test.

Figure 2a

 2a Figure 2a

  Figure 2b 100 Hz

Figure 3

 3 Figure 3 A.

Table 1 SVIN in SUVL and uSCD at 100 Hz (Experiment 2).

 1

	Population and SVIN 3D results at 100 Hz stimulation for different SVIN components [ H:
	horizontal component; V: vertical; T : torsional] and directions (Up : up beating; Dw : down
	beating).
	SUVL=severe unilateral vestibular lesion; uSCD=unilateral superior semicircular canal dehiscence.
	ItG: intratympanic gentamicin; VN: vestibular neuritis; VNrct: vestibular neurectomy
	R=right side; L=left side; …= no data.
	CaT= Caloric Test; HST= Head Shaking Test (L= HSN beating toward lhe left; R= HSN toward the
	right); VHIT= Video Head Impulse Test (RA=Right anterior canal dysfunction; RH=right
	Horizontal canal dysfunction; RP=right posterior canal dysfunction; LA, LH, LP= same
	signification for the left side)

Table 2 SVIN in uSCD and bSCD at 100Hz (Experiment 3 & 4).

 2

	SVIN results at 100Hz stimulation for different SVIN components recorderd either in 2D or 3D [ H:
	horizontal component; V: vertical; T : torsional] and directions (Up : up beating; Dw : down
	beating).


Jehanne Calves
email: jehanne.calves@gmail.com

Maxime Thoulouzan

Marie-Aimée Perrouin-Verbe

Vincent Joulin

Antoine Valeri

Georges Fournier

Long-term Patient-reported Clinical Outcomes and Reoperation Rate after Photovaporization with the XPS-180W GreenLight Laser

Keywords: Benign prostatic hyperplasia MESH, Laser therapy MESH, GreenLight XPS, Prostate MESH: Long-term outcomes

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Studies reporting the favorable results of GreenLight laser XPS (GL-XPS) for the treatment of benign prostatic hyperplasia (BPH) are growing, with noninferior functional results, less morbidity, shorter catheterization, and hospitalization time compared with transurethral resection of the prostate (TURP) [START_REF] Brunken | A systematic review of experience of 180W XPS GreenLight laser vaporization of the prostate in 1640 men[END_REF][START_REF] Bachmann | 180-W XPS GreenLight laser therapy for benign prostate hyperplasia: early safety, efficacy, and perioperative outcome after 201 procedures[END_REF]. However, to become an alternative treatment to TURP or open retropubic prostatectomy, GL-XPS must demonstrate its efficiency for the treatment of medium to large glands and also the durability of the functional results, with a low rate of reoperation for recurrent BPH or complications such as bladder neck or urethral strictures. Studies published to date offer only short-term follow-up [START_REF] Bachmann | 180-W XPS GreenLight laser therapy for benign prostate hyperplasia: early safety, efficacy, and perioperative outcome after 201 procedures[END_REF][START_REF] Meskawi | Multicenter international experience of 532 nm-laser photo-vaporization with Greenlight XPS in men with large prostates (prostate volume > 100 cc)[END_REF][START_REF] Hueber | 180 W vs 120 W lithium triborate photoselective vaporization of the prostate for benign prostatic hyperplasia: a global, multicenter comparative analysis of perioperative treatment parameters[END_REF] and studies with long-term follow-up are lacking. The GOLIATH study has a maximum follow-up of 24 mo and the inclusion criteria for prostate volume was <100 ml and patients taking anticoagulants were excluded [START_REF] Bachmann | A European multicenter randomized noninferiority trial comparing 180 W GreenLight XPS laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the GOLIATH study[END_REF]. Studies utilizing the 80-W and 120-W lasers are available with a maximum follow-up of 3-5 yr. In these studies, redo procedure rates vary from 6.8% to 11% at 3 yr and 8.9% at 5 yr of follow-up. Reoperation rates for urethral or bladder neck strictures are reported in 7.4% and 8% in two studies with 3-yr follow-up [START_REF] Al-Ansari | GreenLight HPS 120-W laser vaporization versus transurethral resection of the prostate for treatment of benign prostatic hyperplasia: a randomized clinical trial with midterm follow-up[END_REF][START_REF] Ruszat | GreenLight laser vaporization of the prostate: singlecenter experience and long-term results after 500 procedures[END_REF] and in 1.2% of cases in another series with 5-yr follow-up [START_REF] Hai | Photoselective vaporization of prostate: five-year outcomes of entire clinic patient population[END_REF].

Since the beam geometry of the MoXy fiber and maximum available power of the GL-XPS console are different to previous lasers and fibers, this may have an impact on long-term clinical outcomes and reoperation rate. The aim of this study was to assess both the long-term reported clinical outcomes and reoperation rate at 1 mo, 3 mo, 12 mo, and 57 mo of follow-up, in a prospective cohort of men treated with GL-XPS, without limitations of the prostate volume. To our knowledge, this is the first study of GL-XPS reported clinical outcomes with at least 48 mo of follow-up for all patients and a mean follow-up of 57 mo.

Materials and methods

2.1.Study population

Prospective data were collected on consecutive men undergoing photovaporization of the prostate (PVP) with the GL-XPS laser (American Medical System/Boston Scientific, Marlborough, MA, USA) between 2010 and 2012 in our center. Indication for surgery was bothersome lower urinary tract symptoms associated with prostate enlargement as measured with transrectal ultrasound (TRUS). Large prostate volume (> 100 cc) was not a contraindication and men with indwelling catheters at the time of surgery were included, as well as men taking oral anticoagulant therapy or antiplatelet drugs. Men with prostate cancer or evidence of neurogenic bladder dysfunction were excluded. All patients provided written consent. Our protocol was approved by the Ethics Committee of our University Hospital. All PVP procedures were performed by a single surgeon (GF), with transrectal ultrasonography monitoring according to the technique previously reported [START_REF] Fournier | Usefulness of real time transrectal ultrasonography to monitor the Greenlight XPS (180W) laser prostatectomy[END_REF]. Surgical technique-a standardized technique-was used for all procedures regardless of volume. Briefly, the operation started with the creation of a centroprostatic channel and the bladder neck and apex were treated with a maximum energy of 80 W. During the next step, a posterior vaporization was performed from the bladder neck up to the veru montanum with a maximum power of 120 W at the level of the bladder neck and lateral to the veru montanum. Lateral lobes were vaporized without limitation of power. Energy settings were titrated for optimum vaporization and safety.

2.2.Assessments

Participating men completed patient-reported outcome measures preoperatively, including the International Prostate Symptom Score (IPSS), International Continence Society (ICS), and International Index of Erectile Function short-form (IIEF5) questionnaires. We recorded the patient's American Society of Anesthesiologists score and additional urological comorbidity or prior surgery. Prostate volume was measured by TRUS and uroflowmetry, post residual urine measurement, and prostate-specific antigen (PSA) were assessed preoperatively. Patients treated with antiplatelet drugs had the treatment maintained or stopped according to the advice of the cardiologist. In case of coumadin or warfarin therapy, patients underwent perioperative bridging with low molecular weight heparin. Intraoperative lasing time, total operative time, numbers of fibers used for each procedure, and energy delivered were recorded.

Postoperatively, the TRUS volume measurements were repeated at 3 mo and 12 mo. IPSS, ICS, and IIEF5 questionnaires were collected at 1 mo, 3 mo,12 mo, and after 48 mo. Flow rate and postvoid residual volume were measured at 1 mo, 3 mo,12 mo, and 57 mo. Patient satisfaction was assessed by a specific nonvalidated questionnaire with a Likert scale (Supplementary data). PSA level was assessed at 3 mo, 12 mo, and 57 mo, respectively. The reoperation rate was recorded at the last visit during the 1st yr of follow-up, and by questionnaires and phone calls after 48 mo.

2.3.Statistical analysis

The statistical analysis was done with R (R Foundation for Statistical Computing, Vienna, Austria). Quantitative results were analyzed by Student t test with an alpha risk of 5%. Results are given as mean value plus or minus standards deviations.

Results

3.1.Patients characteristics

The preoperative parameters of 84 patients (82% [84/102] of original cohort) who completed the long-term questionnaire are shown in Table 1.

Patient mean age was 68 ± 7.2 yr (range: 51-85). Eight patients out of 84 were under anticoagulant therapy by warfarin or coumadin, and 24 patients out of 84 were treated with antiplatelet medication (19 aspirin, 3 clopidogrel, 2 bitherapy). Patients were operated under aspirin but clopidogrel was switched to aspirin. Moreover, warfarin was switched to low molecular weight heparin before surgery and stopped a day before surgery.

Mean preoperative prostate volume was 73 ± 38 ml. Nineteen patients out of 84 had a prostate larger than 100 cc. Mean preoperative PSA was 4.5 ± 4.3 ng/ml.

3.2.Perioperative data 3.2.1. Long-term clinical outcomes

Response rate for long-term functional questionnaires was high 82%(84/102). Mean follow-up was 57.4 ± 6.8 mo. Mean IPSS decreased by 80% at 12 mo compared with baseline. The mean decrease in IPSS was 8.2 ± 5.7 at 1 mo, and then went on to decline further at 12 mo to 3.9 ± 3.4, and after reaching this plateau remained stable at 57 mo (5.9 ± 5.8). Mean ICS was 1.7 ± 2.7 before surgery, 1.1 ± 2.7 after 1 mo, and remained stable at 3 mo, 12 mo, and 57 mo of followup. Qmax was improved at 12 mo from 9.6 ml/s before surgery to 21.8 ml/s, 23.9 ml/s, 25.2 ml/s, 19 ml/s at 1 mo, 3 mo, 12 mo, and 57 mo, respectively. Postvoid residual volume was reduced significantly from 96.6 ml to 25ml, 17.3 ml, 27 ml, and 39 ml at 1 mo, 3 mo, 12 mo, and 57 mo of follow-up. Prostate volume, measured by TRUS, decreased by 53%. Mean prostate volume was 73 ml before surgery and 34.7 ml at 12 mo postoperatively (Tables 2 and3).

3.3.Erectile function

There was no significant change in mean IIEF5 following surgery (Table 3).

3.4.Long-term satisfaction

Eight-eight percent (74/84) of the patients were at least mostly satisfied after a mean follow-up of 57 mo (Table 4).

3.5.Long-term complications and reoperation rate

Long-term complications are summarized in Table 5. Three patients experienced de novo urinary incontinence with one requiring pads. Five patients had alphablockers prescribed by their general practitioners and another one an anticholinergic drug. The overall reoperation rate was 4.8% (4/84). Two patients were reoperated on for bladder neck stricture at 15 d and 4 mo after the procedure. Two patients had urethral strictures, managed by dilatation under local anesthesia. Finally, two patients underwent a second PVP for recurrent lower urinary tract symptoms, hematuria, or prostate regrowth at 40 mo and 48 mo of follow-up, respectively. Both of these men had large glands with preoperative prostate volumes of 120 ml and 220 ml, respectively, and the latter patient had an incomplete treatment performed during the initial procedure because of the necessity to perform a short anesthesia due to his comorbidities (respiratory failure secondary to emphysema and heart failure).

3.6.PSA

Mean PSA level fell postoperatively to a nadir of 2 ± 2.13 ng/ml (reduced by 56% from baseline) at 3 mo, 2.2 ± 2.0 at 12 mo, and 2.6 ± 2.2 ng/ml at 57 mo (Table 3). To date, no prostate cancer has been detected.

Discussion

This study reports good and durable clinical reported outcomes by patients experiencing a PVP in an unselected cohort of men undergoing GL-XPS PVP. PSA level declined postoperatively and remained low at a mean 57.4 mo of follow-up. Most of the men were satisfied with the clinical outcomes of PVP.

If we consider the long-term outcomes of previous 80-W or 120-W GLs, our reoperation rate for recurrent BPH is markedly lower (2.4% vs 6.8-11%), suggesting a more complete removal of adenoma [START_REF] Al-Ansari | GreenLight HPS 120-W laser vaporization versus transurethral resection of the prostate for treatment of benign prostatic hyperplasia: a randomized clinical trial with midterm follow-up[END_REF][START_REF] Ruszat | GreenLight laser vaporization of the prostate: singlecenter experience and long-term results after 500 procedures[END_REF][START_REF] Hai | Photoselective vaporization of prostate: five-year outcomes of entire clinic patient population[END_REF]. Our reoperation rate is close to the result of the GOLIATH study performed with the same 180-W GL device (redo for BPH or bladder neck and urethral strictures). Indeed, in this series, the overall reoperation rate was 10.37% after 2 yr of follow up, including regrowth of adenoma in 2.2%, urethral stricture in 2.2%, or bladder neck contracture in 5.9% [START_REF] Bachmann | A European multicenter randomized noninferiority trial comparing 180 W GreenLight XPS laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the GOLIATH study[END_REF].

Our results also look favorable if we consider the reoperation rate reported after TURP, quoted at around 1-2%/yr [START_REF] Oelke | EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction[END_REF]. Finally, we also have to consider the long-term results of the holmium laser treatment which is the main challenger of PVP for BPH treatment today. In a holmium laser series reporting long-term follow-up (mean: 6.1 yr) by Gilling in 2008 [START_REF] Gilling | Holmium laser enucleation of the prostate: results at 6 years[END_REF], the reoperation rate for BPH recurrence was 1.2% and only one patient had a urethral stricture needing urethrotomy.

Moreover, the level of satisfaction was as high as 92% (88% in our series). However, 47% of patients were lost to follow-up and the median preoperative prostatic volume was lower than in our cohort (58 cc vs 73 cc) [START_REF] Gilling | Holmium laser enucleation of the prostate: results at 6 years[END_REF]. The reoperation rate at 7.6 yr of follow-up in another study from the same institution comparing holmium laser to TURP was 0% versus 18% [START_REF] Gilling | Long-term results of a randomized trial comparing holmium laser enucleation of the prostate and transurethral resection of the prostate: results at 7 years[END_REF]. In another series of 118 patients treated by holmium laser, Elzayat and Elhilali [START_REF] Elzayat | Holmium laser enucleation of the prostate (HoLEP): long-term results, reoperation rate, and possible impact of the learning curve[END_REF] reported a higher reoperation rate of 4.2% at 49 mo of follow-up. Finally, Kuntz et al [START_REF] Kuntz | Holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial[END_REF] compared holmium laser treatment to open prostatectomy in large volume BPH, superior to 100 cc at 5 yr of follow-up, and reported a reoperation rate of 5%, similar to ours for urethral or bladder neck strictures, but no reoperation for BPH recurrence.

The decrease rate of the PSA at 12 mo of follow-up is 56% in our series. This was considered as a good landmark for favorable long-term results by Valdivieso et al [START_REF] Valdivieso | Assessment of energy density usage during 180W lithium triborate laser photoselective vaporization of the prostate for benign prostatic hyperplasia. Is there an optimum amount of kilo-Joules per gram of prostate[END_REF].

No erectile dysfunction was reported in our study and the mean IIEF5 remained stable during the follow-up after GL XPS. This is similar to the results reported after TURP or holmium laser treatment [START_REF] Klett | Patient-reported sexual outcomes after holmium laser enucleation of the prostate: a 3-year follow-up study[END_REF][START_REF] Cornu | A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update[END_REF].

Our study is the first reporting long-term clinical outcomes of the GL-XPS PVP, demonstrating the durability of the reported clinical outcomes at a mean follow-up of 57.4 mo. The low rate of patients lost to follow-up in our series decreases the influence of this bias often met in long-term studies. If we consider the results of the published studies of the previous version of the GL, our series reports a decrease in the reoperation rate due to the completeness of the procedure. In our opinion, the TRUS monitoring during the procedure is useful to check the quality of the vaporization through a visible TURP-like cavity at the end of the operation. Because this is a single center, single surgeon series, more objective data such as urodynamic parameters will be needed from other centers to demonstrate the reproducibility of the procedure. Moreover, the long-term outcomes of the GOLIATH study are waiting by providing objectives parameters and multicentric data. More experience is also needed for large prostates, because in our series only 19 patients out of 84 had a prostate volume over 100 cc and the two recurrences belong to this subgroup.

Conclusions

This study is the first to demonstrate the durability of reported clinical outcomes at a mean follow-up of 57 mo. Results remain comparable to TURP and other laser modalities at this length of follow up. Further studies are required to confirm this result with a multicentric design and objectives data including urodynamics parameters.

Table 1 -Baseline characteristics of the 84 patients who underwent photovaporization of the prostate with GreenLight-XPS ASA

 1 = American Society of Anaesthesiologists; BMI = body mass index; BPO = benign prostatic obstruction; PSA = prostate-specific antigen; PVP = photovaporization of the prostate; PVR = postvoid residual; SD = standard deviation.

	Variable	Baseline PVP
	Age mean ± SD (yr)	68 ± 7.2
	BMI mean ± SD (kg/m 2 )	27 ± 4.3
	ASA mean score	2
	N (%)
	Patients with catheter, n (%)	16/84 (19)
	5-Alpha reductase inhibitors, n (%)	15/84 (17.8)
	Alpha blockers, n (%)	60/84 (71.4)
	Phytotherapy, n (%)	27/84 (32)
	Bitherapy for BPO, n (%)	23/84 (27)
	Anticoagulants, n (%)	29/84 (34.5)
	Antiplatelet drugs, n (%)	23/84 (27.4)
	Qmax, mean ± SD (ml/s)	9.6 ± 3.8
	PVR, mean ± SD (ml)	96 ± 87.9
	PSA level, mean ± SD (ng/m)	4.5 ± 4.3

Table 2 -Perioperative data photovaporization of the prostate with GreenLight-XPS

 2

	Variable	PVP
	Mean ± SD (range)
	Operative time (min)	80 ± 35(30-195)
	Vaporization time (min)	48 ± 25(17-147)
	Total applied energy (kJ)	381 ± 220(92-1200)
	Prostate size (ml)	73 ± 38 (17-220)
	Applied power rate
	(kJ/cc)	5.3
	PVP = photovaporization of the prostate; SD = standard deviation.

Table 3 -Long-term outcomes after photovaporization of the prostate with GreenLight- XPS

 3 International Continence Society; IIEF5 = International Index of Erectile Function short-form 5; IPSS = International Prostate Symptom Score; ND = not determined; PSA = prostate-specific antigen; PVR = postvoid residual; SD = standard deviation.

	Baseline	1 mo	3 mo	12 mo	57 mo
	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD
	p value	p value	p value	p value	p value
	Range	Range	Range	Range	Range
	Median	Median	Median	Median	Median
	N		N	N	N	N
	IPSS	19.9 ± 6.47	8.2 ± 5.76	6.1 ± 5.67	3.9 ± 3.4	5.9 ± 5.86
		-	2*10 -17	0.0003	0.0001	0.007
		(4-35)	(1-30)	(0-34)	(0-20)	(0-32)
		19	7	5	3	4
		68	75	77	71	84
	ICS	1.73 ± 2.73	1.1 ± 2.79	0.9 ± 2.44	0.4 ± 1.09	0.6 ± 1.76
		-	0.09	0.3	0.14	0.61
		(0-12)	(0-21)	(0-17)	(0-8)	(0-11)
		0	0	0	0	0
		68	75	77	71	84
	IIEF5	12.5 ± 8.4	10.7 ± 9.59	11.7 ± 9.42	12.3 ± 9.23	10.6 ± 8.97
		-	0.44	0.52	0.11	0.001
		(1-25)	(1-25)	(1-25)	(1-25)	(0-25)
		13	5	13	13	9
		68	73	77	71	84
	PSA	4.5 ± 4.31	ND	2 ± 2.13	2.2 ± 2.08	2.6 ± 2.27
	(ng/ml)	-		1.4*10 -9	0.06	0.04
		(0.38-20.9)		(0.19-13.6)	(0.36-10.8)	(0.35-10.9)
		2.88		1.165	1.6	1.9
		84		70	66	78
	Qmax	9.66 ± 3.86	21.8 ± 11.30	23.9 ±	25.2 ± 9.25	ND
	(ml/s)	-	4.8*10 -11	11.55	0.85
		(3.5-24.8)	(4.5-66.7)	0.16	(8.7-45.7)
		9.1	20.7	(8.8-75.4)	27
		68	78	22.9	70
				73
	PVR (ml)	96.6 ± 87.9	25 ± 30.72	17.3 ±	25.22 ±	ND
		-	6.8*10 -10	22.37	9.25
		(0-567)	(0-161)	0.09	0.11
		83	16	(0-76)	(8.7-45.7)
		68	78	0	19.5
				73	70

Table 4 -Long-term satisfaction after GreenLight-XPS (evaluation by questionnaire) at a mean follow-up of 57 mo

 4

		N (%)
	Delight	41/84 (49)
	Pleased	18/84 (21)
	Mostly satisfied	15/84 (18)
	Mixed	5/84 (6)
	Mostly dissatisfied	3/84 (3.6)
	Unhappy	2/84 (2.4)
	Terrible	0

Table 5 -Long-term complications (evaluation by questionnaire) at a mean follow-up of 57 mo

 5

	N (%)

Funding/Support and role of the sponsor: None.

Author contributions: Jehanne Calves had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Calves, Thoulouzan, Fournier. Acquisition of data: Calves, Thoulouzan, Perrouin-Verbe.

Analysis and interpretation of data: Calves.

Drafting of the manuscript: Calves, Fournier. Critical revision of the manuscript for important intellectual content: Calves, Fournier. Statistical analysis: Calves. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Fournier, Joulin, Valeri. Other: None.

Financial disclosures:

Jehanne Calves certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Fournier is a trainer for GreenLight laser in France and other countries.