Keywords: levothyroxine, hypothyroidism, bariatric surgery, sleeve gastrectomy Mots-clés : lévothyroxine, hyperthyroïdie, chirurgie de l'obésité, gastrectomie longitudinale

Levothyroxine dose adjustment in hypothyroid patients following gastric sleeve surgery Ajustement de la dose de Lévothyroxine pour les patients hypothyroïdiens après une gastrectomie longitudinale

Résumé

Introduction : Les patients euthyroïdiens présentent un niveau de thyréostimuline (TSH) diminué après une gastrectomie longitudinale. Cependant, des études sur l'absorption de la Lévothyroxine après une chirurgie de l'obésité rapportent des résultats contradictoires et les données sur l'ajustement de la dose de lévothyroxine en fonction du poids sont éparses. L'objectif de cette étude est d'évaluer l'ajustement de la dose de lévothyroxine au cours de la perte de poids qui suit la gastrectomie longitudinale. Méthodes : Cette étude rétrospective évalue les changements de doses de la lévothyroxine chez les patients bénéficiant d'une gastrectomie longitudinale au centre hospitalier universitaire de Nîmes (France) entre janvier 2010 et mars 2016. Les patients ont reçu un suivi post-opératoire standard après une chirurgie de l'obésité ainsi qu'un traitement à la lévothyroxine pour l'hypothyroïdie. Résultats : Cinquante-deux des 271 patients ayant bénéficié d'une gastrectomie longitudinale (19,2 %) ont été traités avec de la lévothyroxine. Vingt-deux d'entre eux ont été exclus ; 31 ont été suivis pendant 12 mois dont 12 qui ont été suivis au total pendant 24 mois. La perte de poids moyenne était de 35 ± 11 kg à 12 mois et de 41,8 ± 10,2 kg à 24 mois. La dose quotidienne de lévothyroxine a été diminuée de 108 µg/jour à 94 [63-125] µg/jour à 12 mois puis, à 69 [44-134] µg/jour à 24 mois, avec une corrélation positive entre la dose de lévothyroxine et la perte de poids à 12 mois (p = 0,03). La dose ajustée en fonction du poids était de 1,04 [0,81-1,24] µg/kg/jour au début de l'étude, de 1,14 [0,85-1,66] µg/kg/jour à 12 mois et de 0,85 [0,53-2,10] µg/kg/jour à 24 mois, ne montrant aucune corrélation avec la perte de poids. La médiane du niveau de TSH a diminué jusqu'à 1,30 [0,63-2,27] mUI/l à 12 mois puis 1,48 [START_REF] Inserm | enquête épidémiologique nationale sur le surpoids et l'obésité[END_REF]42] mUI/l à 24 mois.

Introduction

Obesity is rising in France, in 2012, 32.3% of population was overweight and 15% obese [START_REF] Inserm | enquête épidémiologique nationale sur le surpoids et l'obésité[END_REF]. By the way bariatric surgery is increasing : 30 513 procedures were carried out in 2011 (44 % were sleeve gastrectomy). Between 10.9 % and 12.3 % of patients receiving bariatric surgery are taking levothyroxine [START_REF] Fierabracci | Prevalence of Endocrine Diseases in Morbidly Obese Patients Scheduled for Bariatric Surgery : Beyond Diabetes[END_REF]. The dose is adapted to the body weight ; therefore obese patients require a higher dose due to their higher plasmic volume, a longer delay in intestinal absorption of levothyroxine (3) and the increased of lean body mass [START_REF] Santini | Lean Body Mass Is a Major Determinant of Levothyroxine Dosage in the Treatment of Thyroid Diseases[END_REF].

Obese patients have increased levels of TSH (5) [START_REF] Pearce | Thyroid hormone and obesity[END_REF], which reduce or even return to normal after weight loss through dietary control(6)(7) [START_REF] Lips | Roux-en-Y gastric bypass and calorie restriction induce comparable time-dependent effects on thyroid hormone function tests in obese female subjects[END_REF]. Previous studies looking at the variation of thyroid function following bariatric surgery have concentrated on either euthyroid patients or hypothyroid patients treated with levothyroxine. Thyroid function seems to improve (TSH reduction or lower levothyroxine dose) after weight loss following bariatric surgery, to the same extent as weight loss through dietary interventions.

Only three studies have investigated sleeve gastrectomy(17)(20) [START_REF] Bevan | Thyroxine malabsorption following intestinal bypass surgery[END_REF]. (Table 1 and2) In healthy non-operated patients, a normal gastric acid secretion is important for the absorption of levothyroxine [START_REF] Pabla | A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry[END_REF] who is largely absorbed in the jejunum-ileum [START_REF] Hays | Localization of Human Thyroxine Absorption[END_REF]. However, data from surgery patients is contradictory : several cases of malabsorption following bypass have been reported [START_REF] Padwal | A systematic review of drug absorption following bariatric surgery and its theoretical implications[END_REF] [START_REF] Bevan | Thyroxine malabsorption following intestinal bypass surgery[END_REF] [START_REF] Topliss | Increased requirement for thyroid hormone after a jejunoileal bypass operation[END_REF] [START_REF] Azizi | Malabsorption of thyroid hormones after jejunoileal bypass for obesity[END_REF], although one more recent study instead showed an improvement in pharmacokinetics following sleeve gastrectomy and bypass [START_REF] Gkotsina | Improved Levothyroxine Pharmacokinetics After Bariatric Surgery[END_REF].

There is currently little data relating to treatment with levothyroxine and thyroid function following sleeve gastrectomy. The aim of this study was to analyse the change in levothyroxine dose against weight loss in hypothyroid patients having undergone sleeve gastrectomy. Weight loss would be expected to result in a decrease in daily levothyroxine dose (µg/day) and a stabilisation of the weight-adjusted dose µg/kg/day. If there is an improvement in thyroid function, the weight-adjusted dose will decrease, whilst malabsorption of the product will result in an increased weight-adjusted dose.

Method

Participants :

This is a retrospective observational study. Participants were recruited from patients hospitalised between January 2010 and March 2016 in the Maladies Métaboliques et Endocriniennes department of the CHU Nîmes. Participants included were males or females over the age of 18 years, having received sleeve gastrectomy at the CHU Nîmes prior to March 2016 in order to have a minimum follow-up of 12 months, treated with a substitutive dose of levothyroxine for peripheral hypothyroidism. Participants were excluded if they had a central hypothyroidism, a poor compliance to levothyroxine, took oral liquid levothyroxine, a follow-up of less than 12 months after surgery, or were pregnant.

The recruitment and the follow up of the population is described in the Figure 1 and the characteristics of the population is described in the Table 3.

Progression of patients pursuing a bariatric surgical program :

Following acceptance at the multidisciplinary team meeting, surgery was performed under general anaesthetic by the same surgeon for all patients by coelioscopy : a complete gastrolysis was conducted with removal of the His angle and exposure of the left diaphragmatic crus. The stomach was then cut and stapled from 4-5cm above the pylorus to the angle of His. Intraoperative methylene blue testing was conducted to ensure the integrity of the seal.

Patients were then registered, and followed every 3 months for 1 year (M3-M6-M9-M12), then every 6 months the following year (M18 -M24), and subsequently once per year. At each visit, blood samples were taken to test TSH levels to confirm euthyroid status. Patients met with their doctor who recorded their body weight, treatment (levothyroxine dose) and any related events. Vitamin supplements were prescribed if any deficiencies were discovered and the dose of levothyroxine was modified according to TSH level.

Data collection pre-surgery (M0) :

Body weight and height were recorded at the multidisciplinary team meeting, which took place on average 2-3 months prior to surgery. There was frequently a difference of ± 2-3kg between the body weight recorded at the RCP and the body weight recorded on the day of the surgery, although this difference was no considered to be significant for our study. Levothyroxine dose was recorded from the consultation or hospital letters preceding surgery to ensure that there was no variation in the 3 months prior to surgery.

TSH measurement :

Serum TSH levels were measured by enzyme-linked immunosorbent assay from January 2010 to March 2013 (Beckman Coulter®, sensitive to 0.015 mUI/l, reference values 0.40 mUI/l to 4 mUI/l), and by electrochemiluminescent immunometric assay from March 2013 (Elecys Roche Cobas®, sensitive to 0.014 mUI/l, reference values 0.40 mUI/l to 3.77 mUI/l).

Judgment Criteria:

The main judgment criterion was the change in daily levothyroxine dose (µg/day) between M0 and M12 or M24. Other judgment criteria were change in weight-adjusted dose (µg/kg/day) between M0 and M12 or M24, change in weight-adjusted dose (μg/kg/day) between M0 and each follow-up visit at M6-M12-M24 and change in body weight (kg) between M0 and each follow-up visit at M6-M12-M24. TSH levels were observed at each hospital visit at M6-M12-M24 to confirm euthyroid status. The normal level of TSH value was defined as TSH between 0.40-3.77 mUI/l.

Data analysis:

The correlation between dose alteration and change in body weight between M0 and M12 or M24 was calculated by Kendall ranking coefficient with a p ≤ 0.05 considered statistically significant. The Kendall coefficient was chosen as the dose was a discrete variable, not following a normal law, and often presented equivalent values.

Results

Between January 2010 and March 2016, 271 patients received sleeve gastrectomy at the CHU Nîmes. Fifty-two patients (19.2%) were taking levothyroxine. Twenty-one (40.4%) patients were excluded and 31 included in the study (Fig. 1). The pre-surgery patient characteristics are described in table 1.

The average weight loss was 35 ± 11 kg at 12 months (Graph 1A) and 41.8±10.2kg at 24 months (Graph 1B).

The median daily dose of levothyroxine dropped for all 31 patients followed for 12 months from 108[88-144] to 94[63-125] µg/day (Graph 2A) at 12 months, and for the 12 patients followed to 24 months, from 125[84-153] to 69[44-134] µg/day (Graph 2B).

Weight-adjusted levothyroxine dose went from 1.04[0.81-1.24] to 1.14[0.85-1.66] μg/kg/day (Graph 3A) for the 31 patients followed for 12 months, and from 1.033[0.69 -1.34] to 0.90[0.53-2.10] μg/kg/day (Graph 3B) for the 12 patients followed for 24 months.

A significant positive correlation was found between weight loss and decrease in daily levothyroxine dose (Ԏ Kendall = 0.29; p = 0.03) (Graph 4) and between the decrease in BMI and decrease in daily levothyroxine dose (Ԏ Kendall = 0.34; p = 0.01) (Graph 5) at 12 months. This correlation was not significant in the group followed for 24 months.

There was no significant correlation between weight loss and the decrease in weightadjusted dose of levothyroxine.

Discussion

Thyroid function in obese patients is different than in normal weight patients, the major difference is a higher TSH, and peripheral hormones level in serum [START_REF] Michalaki | Thyroid Function in Humans with Morbid Obesity[END_REF] [START_REF] Pearce | Thyroid hormone and obesity[END_REF]. This is due to an activation of the hypothalamic-pituitary-thyroid axis due to the accumulation of fat mass. There is a complex interaction between adipose tissue and the hypothalamic pituitary thyroid axis by the action of various adipocytes cytokines. Any authors talk about "acquired resistance to thyroid hormone" in obesity.

Hypotheses as to why include a possible role as an adaptive mechanism to compensate for weight gain, or partially inactive TSH or resistance to TSH or a perturbation of the hypothalamic-pituitary system with a likely role of leptin [START_REF] Svare | Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway[END_REF]. Further studies have shown that after weight loss the regulation of the hypothalamic-pituitary-thyroid axis was improved.

A decrease in ghrelin is observed after by-pass and sleeve gastrectomy [START_REF] Langer | Sleeve Gastrectomy and Gastric Banding : Effects on Plasma Ghrelin Levels[END_REF] as it is mainly secreted in the gastric fundus which is removed by this surgery. Ghrelin has appetite stimulating properties and also plays a role in thyroid function: Emami A et al. showed a negative correlation between ghrelin and TSH and a positive correlation between ghrelin and T4 and T3 in both hypothyroid and hyperthyroid patients [START_REF] Emami | Is association between thyroid hormones and gut peptides, ghrelin and obestatin, able to suggest new regulatory relation between the HPT axis and gut? RegulPept[END_REF]. A two-way regulation between the hypothalamic-pituitary and peptides secreted by the digestive system appears to exist, although mechanisms have not yet been elucidated [START_REF] Langer | Sleeve Gastrectomy and Gastric Banding : Effects on Plasma Ghrelin Levels[END_REF].

After weight loss in euthyroid bariatric surgery parties, it is possible to see an improvement in thyroid function by a decrease of TSH (8)(13)(12). To our knowledge, only one study has analysed the change of TSH after sleeve gastrectomy (38 patients): a modest yet significant decrease (-0.63mUI/l) was observed, not correlated to loss of weight [START_REF] Ghanem | Effect of Sleeve Gastrectomy on Thyroid Hormone Levels[END_REF].

We know that after oral administration 30-90% of levothyroxine dose is absorbed within 3h of ingestion, a majority of the absorption takes place in the jejunum and ileum. Absorption is maximal when administered on an empty stomach, reflecting the importance of gastric acidity in the process.

Following sleeve gastrectomy, we saw a decrease in daily dose of levothyroxine with a positive correlation at 12 months between weight loss and decrease in dose. This correlation was not retained at 24 months, most likely due to the lack of power associated with the smaller group. These results confirm the importance of adapting dose to the body weight (3)(4). However, when removing the 'weight effect' by studying the weight-adjusted dose, this correlation between dose and weight loss is not found. In all, this suggests that there is no modification of thyroid function after sleeve gastrectomy. Several individual factors could induce a variation in adjusted levothyroxine dose. Any treatments can cause an increase in available levothyroxine. Proton pump inhibitors (PPI) increase gastric pH through inhibition of the parietal gastric cell H + /K + ATPase pump and therefore the dissolution of levothyroxine (18)(25) [START_REF] Centanni | Thyroxine in Goiter, Helicobacter pylori Infection, and Chronic Gastritis[END_REF]. Iron salts taken orally chelate levothyroxine in the digestive tract, preventing its absorption [START_REF] Campbell | Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism[END_REF]. Calcium carbonate and cholestyramine also decrease the absorption of levothyroxine [START_REF] Liwanpo | Conditions and drugs interfering with thyroxine absorption[END_REF]. In our study, 13 patients out of 33 (39.4%) received PPI at least once over the course of the study ; 5 (15.2%) receiving ferrous sulfate and 8 (24.3%) taking other supplements containing calcium carbonate (Alvityl®, Azinc®, Protenplus®). As not all patients received these treatments, and those that did were given different dosages and varying lengths of treatment, variations in absorption could well arise causing knock-on effects on levothyroxine dose.

Certain digestive disorders can alter levothyroxine absorption: coeliac disease, gastritis, lactose intolerance, digestive tract inflammatory disease (Crohn) (31) [START_REF] Liwanpo | Conditions and drugs interfering with thyroxine absorption[END_REF]. We do not have a record of such digestive pathologies in our study.

Eating behaviours change following bariatric surgery. Not only is there a decrease in quantities consumed, but also a change in the types of food : a decrease in appetite for high energy food [START_REF] Miras | Bariatric surgery and taste: novel mechanisms of weight loss[END_REF] which could lead to consumption for food affecting absorption of levothyroxine. Soya, high fibre foods (walnuts, papaya), coffee [START_REF] Benvenga | Altered intestinal absorption of L-thyroxine caused by coffee[END_REF] and grapefruit juice can alter levothyroxine absorption by sequestering it in the digestive tract [START_REF] Benvenga | When thyroid hormone replacement is ineffective ? CurrOpinEndocrinol Diabetes Obes[END_REF] [START_REF] Liwanpo | Conditions and drugs interfering with thyroxine absorption[END_REF]. It was not possible in this retrospective study to examine the eating habits of patients regarding these food products.

Patients had different causes of hypothyroidism. Some were putatively defined as Hashimoto hypothyroid, but without a measure of anti-TPO antibody it was not possible to confirm this diagnosis, and it is possible that this disease was not explored in the other patients. It was evocated that thyroiditis group can have a more fluctuant TSH value during levothyroxine treatment than post-surgical hypothyroidism. In our study five patients (15.2%) had received thyroidectomies, four for benign nodules, and one for a low risk papillary carcinoma. However alteration of levothyroxine dose for these patients was similar to the principal cohort in this study.

In hypothyroid patients taking levothyroxine, improved thyroid function with weight loss could result in a decrease in levothyroxine dose. Analysis of the alteration in levothyroxine dose following sleeve gastrectomy in 19 patients showed a decrease in daily dose in the majority of patients (13/19, 68.4%), or a stabilisation of dose [START_REF] Aggarwal | Laparoscopic Sleeve Gastrectomy Leads to Reduction in Thyroxine Requirement in Morbidly Obese patients With Hypothyroidism[END_REF]. There was a positive correlation between daily dosage and percentage of excess weight lost. However this dose was not adjusted for body weight, and as we have seen above, it is logical that daily dose would decrease with body weight. Another study analysed the change in levothyroxine dose following sleeve gastrectomy in a small cohort : eight patients out of 93 undergoing sleeve gastrectomy with a similar result to the main cohort (by-pass + band + sleeve) : there is not a significant correlation between weight loss and decrease in levothyroxine dose [START_REF] Fierabracci | Weight Loss and Variation of Levothyroxine Requirements in Hypothyroid Obese Patients After Bariatric Surgery[END_REF]. The correlation with weight-adjusted dose (which rose in this study) was not examined. In our study there was no correlation between decrease in weight-adjusted dose and the loss of weight. Weight loss varied hugely between patients : between eight and 54kg at 12 months and between 26 and 58 kg at 24 months. It would be interesting to study the change in TSH activity and the leptin concentration in patients compared with this weight loss. Fierabracci et al. saw an average drop of 60% in leptin following bariatric surgery ; but without correlation with weight loss. In addition, the decrease in levothyroxine dose was proportional to the decrease in lean body mass evaluated by absorptiometry [START_REF] Fierabracci | Weight Loss and Variation of Levothyroxine Requirements in Hypothyroid Obese Patients After Bariatric Surgery[END_REF].

In summary, it appears that the pharmacokinetics of levothyroxine are improved following sleeve gastrectomy : Gkotsina M et al. have shown that the AUC (area under curve) of plasmic concentration of levothyroxine administered to euthyroid patients was improved after biliopancreatic derivation and after sleeve gastrectomy [START_REF] Gkotsina | Improved Levothyroxine Pharmacokinetics After Bariatric Surgery[END_REF]. This paradoxical result is difficult to explain: levothyroxine is less in contact with bile secretion, therefore there is less glucourono-conjugation and thus a better absorption. Modification of the intestinal microbiota and proliferation of digestive mucus is also likely.

The advantage of our study is that the analysis of weight-adjusted dose changes (μg/kg/day) allowed us to dissect the effect of weight.

Nevertheless, our study had certain limitations: as a retrospective observational study with a small cohort size, there was a lack of power particularly for the analyses at 24 months. However, the previous largest study in the literature studying the changes in dose of levothyroxine following sleeve gastrectomy comprised 19 patients, compared to 31 in ours. Finally, the adaptation of levothyroxine over the course of the study was not protocoled; it was based upon TSH value, but the dose changes were at the discretion of the doctor, and the value was large between 0.40-3.77 mUI/l.

Similarly, it was difficult to evaluate patient compliance in terms of taking the medication in this observational study.

Another limit of this study is the only descriptive character, it will be interesting to have a control group in order to compare the result, with thyroid function in obese patient with weight loss and no surgery.

Finally the median adjusted dose of levothyroxine is lower than expected with value between 1.04 to 1.03 µg/kg/day who correspond more with subclinical hypothyroidism than real hypothyroidism. This fact underline the difficulty to evaluate the thyroid function in obese population in general.

In conclusion, after weight loss following sleeve gastrectomy, the daily dose of levothyroxine decreases, but not regarding adjusted weight dose. Confusing factors are multiple and prevent us from proving incontestably a variation in dose adjusted for weight. This results must encourage to a regular follow-up of TSH level in the years following bariatric surgery in patients treated with levothyroxine in order to adapt treatment. Further protocoled studies on larger cohorts including absorption observations are necessary, with control groups in order to confirm this results.

Table 1. Variation of TSH following weight loss due to bariatric surgery in euthyroid patients

Graph 1 .

 1 Evolution of body weightGraph2. Change in daily dose of levothyroxine Graph 3. Change in weight-adjusted dose of levothyroxine Graph 4. Correlation between weight loss and daily dose of levothyroxineDecrease in daily levothyroxine dose at 12 month (µg/j) Graph 5. Correlation between BMI and daily dose of levothyroxineDecrease in daily levothyroxine dose at 22 month (µg/j)

Figure 1 .

 1 Figure 1. Recruitment and follow-up of patients receiving sleeve gastrectomy

Table 3 . Pre-surgery patient characteristics Total = 31 patients 12 patients followed 24 months (38.7%)

 3

	Ratio males/females	2/29	1/11
	Age average(years)	50.9 ± 9.07	46.2 ± 8.9
	Body weight average(kg)	112.1±16.7	117.3± 17.2
	BMI average(kg/m 2 )	42.6 ± 5.4	43.9 ± 6.3
	Number patients BMI< 35(kg/m 2 )	2 (6.5%)	1 (8.3%)
	Number patients BMI [35-39] (kg/m 2 )	9 (29%)	3 (25%)
	Number patients BMI ≥ 40 (kg/m 2 )	20 (64.5%)	8 (66.7%)
	Median daily dose of levothyroxine (µg/day)	108 [88 -144]	125 [84 -153]
	Median adjusted dose of levothyroxine µg/kg/day)	1.04 [0.81 -1.24]	1.03 [0.69 -1.34]


Mylène Meyer
email: my.meyer@chru-nancy.fr

Sophie Colnat-Coulbois

Solène Frismand
email: s.frismand@chru-nancy.fr

Pierre Vidailhet
email: pierre.vidailhet@chru-strasbourg.fr

MD Pierre-Michel Llorca
email: pmllorca@chu-clermontferrand.fr

Elisabeth Spitz
email: elisabeth.spitz@univ-lorraine.fr

Raymund Schwan
email: raymund.schwan@univ-lorraine.fr

Meyer Mylène

Colnat-Coulbois Sophie

Frismand Solène

MD Vidailhet Pierre

Llorca Pierre- Michel

PhD Spitz Elisabeth

MD Schwan Raymund

MD Sophie

Parkinson's Disease and Bilateral Subthalamic Nuclei Deep Brain Stimulation: Beneficial Effects of Preoperative Cognitive Restructuration Therapy on Postoperative Social Adjustment

Keywords: cognitive restructuration, Parkinson's disease, social adjustment, subthalamic nucleus deep brain stimulation

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

Introduction

Bilateral subthalamic nuclei (STN) deep brain stimulation (DBS) is known to greatly improve motor symptoms and dopa-linked dyskinesia, and reduce dosage of dopaminergic treatments in patients with Parkinson's disease (PD) [START_REF] Benabid | Deep brain stimulation of the subthalamic nucleus for the treatment of parkinson's disease[END_REF] . However, many studies report that social adjustment and mental aspects of quality of life (QOL) do not improve after STN DBS. This is true even when the PD patient undergoing STN DBS has been identified as eligible, i.e., they fulfil surgical criteria of dopamine responsiveness, age, and are free of cognitive alteration or psychiatric disorders [START_REF] Benabid | Deep brain stimulation of the subthalamic nucleus for the treatment of parkinson's disease[END_REF] .

Social adaptation [START_REF] Weissman | The assessment of social adjustment: a review of techniques[END_REF] can be defined as "the interplay between the individual and the environment", i.e. the individual's behaviour in terms of socially-accepted roles: "Social adjustment is a reflection of the patient's interactions with others, satisfactions and performances in roles, which are more likely modified by previous personality, cultural and family expectations". Weissman [START_REF] Weissman | The assessment of social adjustment: a review of techniques[END_REF] added that the individual's assumed roles are dependent on age and, potentially, on psychopathology. The notion of social adjustment contrasts with QOL, which refers more generally to the consequences of PD on daily living activities.

Various causal hypotheses have been put forward to explain the lack of improvement in postoperative social adjustment and mental QOL in patients with PD, highlighting "unrealistic" expectations following neurosurgery [START_REF] Houeto | Behavioural disorders, parkinson's disease and subthalamic stimulation[END_REF][START_REF] Houeto | Subthalamic stimulation in Parkinson Disease : Behavior and social adaptation[END_REF][START_REF] Schüpbach | Neurosurgery in Parkinson's disease : A distressed mind in a repaired body[END_REF][START_REF] Agid | Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so?[END_REF][START_REF] Meyer | Neurosurgery in Parkinson's disease : social adjustment, quality of life and coping strategies[END_REF] , a lack of positive anticipation of DBS outcome, and destabilization of the familial structures [START_REF] Meyer | Neurosurgery in Parkinson's disease : social adjustment, quality of life and coping strategies[END_REF][START_REF] Montel | Coping and quality of life of patients with parkinson's disease who have undergone deep brain stimulation of the subthalamic nucleus[END_REF] . Lin et al. [START_REF] Lin | Patients' expectations and satisfaction in subthalamic nucleus deep brain stimulation for Parkinson disease : 6-year follow-up[END_REF] explored STN DBS result expectations and related satisfaction, preoperatively and at 6 months and 6 years postoperatively. Firstly, they showed that patients' expectations change over time: preoperative expectations were different than 6 month's postoperative ones, suggesting that patients may adapt expectations to their actual healthstatus during the postoperative phase, and these expectations seemed to influence the satisfaction of the neurosurgery outcome, particularly in case of unrealistic expectations [START_REF] Geraedts | Selecting candidates for deep brain stimulation in Parkinson's disease : the role of patients' expectations[END_REF] . It seems that the postoperative evolution of motor symptoms severity influences the rank order of symptoms goals, which dynamic was not observed for behavioural goals, less related to postoperative improvements [START_REF] Kubu | Patients' shifting goals for deep brain stimulation and informed consent[END_REF] . Secondly, they proposed that the management of pre and postoperative expectations seems to be fundamental in maintaining optimal PD patients' care, hypothesizing that adjustment of expectations allows patients to remain satisfied of the DBS result in the postoperative phase [START_REF] Lin | Patients' expectations and satisfaction in subthalamic nucleus deep brain stimulation for Parkinson disease : 6-year follow-up[END_REF] . However, while this lack of improvement in postoperative social adjustment is now generally recognised, it is rarely taken into account in patients' follow-up and management. Furthermore, although many authors recommend focusing on "unrealistic" expectations for neurosurgery, pre [START_REF] Schüpbach | Neurosurgery in Parkinson's disease : A distressed mind in a repaired body[END_REF][START_REF] Meyer | Neurosurgery in Parkinson's disease : social adjustment, quality of life and coping strategies[END_REF][START_REF] Montel | Coping and quality of life of patients with parkinson's disease who have undergone deep brain stimulation of the subthalamic nucleus[END_REF][START_REF] Castelli | Neuropsychiatrics symptoms three years after subthalamic DBS in PD patients. A case control study[END_REF][START_REF] Schrag | Young-versus older-onset Parkinson's disease: Impact of disease and psychosocial consequences[END_REF][START_REF] Schüpbach | Psychosocial adjustment after deep brain stimulation in Parkinson's disease[END_REF] and postoperatively [START_REF] Lin | Patients' expectations and satisfaction in subthalamic nucleus deep brain stimulation for Parkinson disease : 6-year follow-up[END_REF] non specific psychosocial interventions have been developed to help manage this specific point. It would thus appear necessary to evaluate expectations preoperatively, and include assessment in the routine psychosocial follow-up of patients, to better prepare and support the patients for the changes induced by neurosurgery.

The purpose of this study was to investigate whether a preoperative cognitive restructuration therapy would improve postoperative social adjustment for PD patients undergoing STN DBS.

Cognitive restructuration consisted of a discussion about the dysfunctional cognition for the result of the neurosurgery in which the psychologist encouraged the patient to understand that the cognition was distorted and to consider alternative cognitions through various approaches including: decentration (e.g., "Do you think that every neurostimulated patient is able to…?"); managing the degree of belief in the cognition (e.g., "To what extent, on a scale of 0 to 100, do you think that this idea is true?"); or describing the cognition in detail (e.g., "Why do you expect this result?" "How will you reach this goal?" "Do you think you will be able to do this, and why?"). We describe both motor and psychiatric data in our PD population.

Patients and methods

Design

This was a prospective, controlled, multicentre study (Clinical Research Program, N°IDRCB 2008-A00655-50) which was approved by the local ethics committee (CPP EST III, N° CPP: 08.07.03, first version date: 04/01/2008) and registered on the ClinicalTrials.gov website (NCT02893449). All included patients gave written informed consent. The detailed methodology of our study has been described in a previous paper [START_REF] Meyer | A methodology to improve social adjustment after bilateral subthalamic deep brain stimulation in Parkinson's disease[END_REF] . Briefly, PD patients eligible for bilateral STN DBS after careful selection according to the criteria reported by Benabid et al. [START_REF] Benabid | Deep brain stimulation of the subthalamic nucleus for the treatment of parkinson's disease[END_REF] were randomised through a computer implemented method into three groups at the inclusion visit (M-2): a cognitive restructuration therapy group (CRTG) consisting of two preoperative interviews including a cognitive restructuring method for unrealistic expectations [START_REF] Meyer | Presentation of a consensual-dialogue methodology as a support of a "cognitive restructuration" : The Heidelberg's structure formation technique[END_REF] ; a clinical interview group (CIG) consisting of two nondirective psychiatric interviews; and a control group (CG) without preoperative preparation. Patients had to be capable to understand consent form and to give written consent. Exclusion criteria were PD patients without social protection, or under tutorship or guardianship. All the patients were followed pre-and postoperatively by a neurologist, a neurosurgeon, a psychologist and a psychiatrist. Psychometric questionnaires proposed at inclusion and at the two postoperative visits (at 3 (M+3) and 6 months (M+6) post-surgery) were performed by psychiatrists blinded to the patient group allocation.

Measurements

All the included patients underwent one preoperative (M-2) and two postoperative (M+3 and M+6) evaluations performed by a trained psychiatrist or psychologist. The patients were assessed for social adjustment by the Social adjustment scale-self-report (SAS-SR [START_REF] Weissman | Assessment of social adjustment by patient self-report[END_REF] ).

The SAS-SR is a 54-item scale, measuring social adjustment over the two previous weeks through six dimensions: work, social life and leisure, family, children, marital situation, and material situation.

The items are rated on a 0-5 or 0-8 scale, depending on the relevance of the item with an item scoring 8 inferring an irrelevant question. A higher total or subscale score indicates greater social impairment.

For the psychiatric dimensions, all the patients were assessed for: i. depression by the Montgommery and Arsberg Depression Rating Scale (MADRS) [START_REF] Montgomery | A new depression scale designed to be sensitive to change[END_REF] with a cut-off score of 15 indicating depression; ii.

anxiety by the Hamilton Anxiety Rating Scale (HARS) [START_REF] Hamilton | The assessment of anxiety-states by rating[END_REF] with a score between 6 and 14 indicating minor anxiety and a score over 15 indicating major anxiety; iii. apathy by the Apathy Scale (AS, Starkstein) [START_REF] Starkstein | Reliability, validity and clinical correlates of apathy in Parkinson's disease[END_REF] with a cut-off score of 14 evoking apparent apathy; and, iv. for global functioning by the Evaluation of Global Functioning (EGF) [START_REF]Diagnostic and statistical manual of mental disorders[END_REF] with a higher score indicating adapted functioning and lower scores altered functioning in the psychological, social and professional life. These psychiatric data are important for the interpretation of social adjustment, indeed, these dimensions could negatively impact social adjustment and the benefit of cognitive restructuration.

Neurologist assessed at each of the three visits the Unified Parkinson's Disease Rating Scale (UPDRS [START_REF] Fahn | UPDRS Development Committee. Unified Parkinson's Disease Rating Scale[END_REF] ), exploring daily living activities (UPDRS II), motor disability (UPDRS III) and treatment side-effects (UPDRS IV). The UPDRS was proposed preoperatively in "ON-medication" condition and postoperatively in "ON-medication, ON-DBS" condition. The medical treatment was recorded for each patient. These medical data are fundamental to consider the effectiveness of STN-DBS, and the link between postoperative motor increasing, decreasing of treatment side-effects and postoperative social adjustment.

Statistical analysis

All statistical analyses were conducted using the software IBM SPSS V.20.0. (SPSS, Chicago, Illinois, USA). All data are reported as mean ± standard deviation. A value of p ≤0.05 was considered as statistically significant. The means were compared using ANOVA for repeated measurements.

Results

Sample

Of the 73 patients enrolled, 62 performed all three visits -the initial inclusion visit (M-2) and the two postoperative visits (M+3, M+6) -these 62 patients were retained for analysis. The overall mean age (52% men) was 59±6.13 (Table 1a) and mean disease duration was 9.44±3.62 years. Additional data concerning educational level, professional status and marital status are also presented (Table 1b): 55% of the patients had secondary school education, 68% were married, 68% were retired, and 15% were still working at the time of neurosurgery.

Table 1a

Table 1b

Neurological data

The pre-and postoperative neurological motor scores are presented in Table 2a.

The daily-living activities (UPDRS II) were similar between the three visits: 8±5.7 for M-2; 5.79±3.5 for M+3; 6.33±3.9 for M+6. The motor scores (UPDRS III) improved postoperatively (20.99±13.4 at M-2 and 15.39±8.6 at M+3) without reaching significance (p=.091). The M+6 UPDRS III was similar to the first postoperative score (14.94±8.7). The scores for UPDRS IV decreased significantly (p=.001) from baseline (M-2: 6.98±3.4) to M+3 (3.10±2.6) and remained stable at the M+6 visit (2.81±1.9).

Table 2a

UPDRS: Unified Parkinson's Disease Rating Scale Additional data concerning STN-DBS stimulation parameters are presented in Table 2b.

Psychiatric data

Psychiatric data concerning depression, anxiety, apathy, and global functioning are presented in Table 3. No significant differences were found either between the groups or the visits for depression, anxiety, apathy or global functioning scores. Furthermore, the scores for these items were within the normal values for each group and at all three evaluations.

Social adjustment

Social adjustment data are presented in Table 4. No significant differences were found between the groups or between the visits (M-2, M+3, M+6) for the SAS-SR total score or subscores. However, a significant interaction effect was found at M+6 between patients from the CRTG and CIG (p=.042) for the "family" dimension: the patients from the CIG had higher scores than those in the CRTG, and for CRTG group, the scores decreased progressively between M-2 and M+6. Furthermore, at M+6, the CIG patients presented lower scores than the CRTG patients without reaching significance (p=.056).

Discussion

It is now well established that STN DBS does not always result in improved social adjustment scores in patients with PD [START_REF] Houeto | Subthalamic stimulation in Parkinson Disease : Behavior and social adaptation[END_REF][START_REF] Schüpbach | Neurosurgery in Parkinson's disease : A distressed mind in a repaired body[END_REF][START_REF] Agid | Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so?[END_REF][START_REF] Meyer | Neurosurgery in Parkinson's disease : social adjustment, quality of life and coping strategies[END_REF][START_REF] Schüpbach | Psychosocial adjustment after deep brain stimulation in Parkinson's disease[END_REF] even in the context of good motor improvement. This has been attributed to "unrealistic" expectations [START_REF] Montel | Coping and quality of life of patients with parkinson's disease who have undergone deep brain stimulation of the subthalamic nucleus[END_REF][START_REF] Castelli | Neuropsychiatrics symptoms three years after subthalamic DBS in PD patients. A case control study[END_REF] that the patients have about the surgery, as well as the impact of non-motor variables such as depression and apathy [START_REF] Castelli | Neuropsychiatrics symptoms three years after subthalamic DBS in PD patients. A case control study[END_REF][START_REF] Porat | Association of preoperative symptom profile with psychiatric symptoms following subthalamic nucleus stimulation in patients with Parkinson's disease[END_REF][START_REF] Soulas | Depression and coping as predictors of change after deep brain stimulation in Parkinson's disease[END_REF][START_REF] Maier | Patients'expectations of deep brain stimulation, and subjective perceived outcome related to clinical measures in Parkinson's disease : a mixed-method approach[END_REF] . However, although preoperative preparation is recommended, to our knowledge, no study has attempted to evaluate the interest of preoperative psychosocial preparation focusing on these unrealistic expectations [START_REF] Castelli | Neuropsychiatrics symptoms three years after subthalamic DBS in PD patients. A case control study[END_REF][START_REF] Maier | Patients'expectations of deep brain stimulation, and subjective perceived outcome related to clinical measures in Parkinson's disease : a mixed-method approach[END_REF] . This paper is thus the first to present data concerning the impact of a preoperative cognitive restructuration therapy on social adjustment, compared to clinical interviews and to a control group, in a population of patients meticulously selected for neurosurgery eligibility (i.e., no major depressive disorder, pathological apathy or anxiety).

The concept of "burden of normality" [START_REF] Gilbert | The burden of normality : from "chronically ill" to "symptom free". New ethical challenges for deep brain stimulation postoperative treatment[END_REF] , initially developed to support patients following neurosurgery for seizures, has recently been introduced for patients with PD who undergo DBS [START_REF] Houeto | Subthalamic stimulation in Parkinson Disease : Behavior and social adaptation[END_REF][START_REF] Schüpbach | Neurosurgery in Parkinson's disease : A distressed mind in a repaired body[END_REF] . This syndrome highlights the need to adjust after successful surgery when the patient transforms from a "chronically ill" person to a "well" person. This "burden of normality" may also play a role in the limitation of improvement of mental aspects of social maladjustment [START_REF] Baertschi | The burden of normality as a model of psychosocial adjustment after deep brain stimulation for Parkinson's disease : a systematic investigation[END_REF] . Despite a lack of group effect on the SAS-SR, we observed that our patients presented appropriate functioning in social adjustment both pre-and postoperatively. However, in the last postoperative visit (M+6), patients from the CRTG presented better social adjustment in the family dimension than those from the CIG. This could be due to the fact that cognitive restructuring helped patients to accept the family roles, that the perception of these roles remains unchanged compared to the preoperative period, or that the role is modified according to the new health status of the patient. This is an important data, considering that more than 70% of our sample lives as a couple.

During the preoperative cognitive restructuration therapy, cognitions from different spheres of life (social roles, family roles, marital relationship, professional situation and leisure activities) were assessed according to the Heidelberg Structure-formation-technique [START_REF] Meyer | A methodology to improve social adjustment after bilateral subthalamic deep brain stimulation in Parkinson's disease[END_REF][START_REF] Meyer | Presentation of a consensual-dialogue methodology as a support of a "cognitive restructuration" : The Heidelberg's structure formation technique[END_REF] . The cognitions were written down and organised into three dimensions corresponding to the patient's perceived life before PD, the perceived life with PD and the expected life after neurosurgery. Cognitive restructuring then focused on dysfunctional cognitions concerning the patient's social role, and more specifically on their preoperative social position with PD, and their postoperative social role expectations with PD. During this restructuring phase, the patients were progressively made aware of the fact that even if neurostimulation improves their motor symptoms, it is unlikely that their environment will necessarily change or that they will find themselves back in the same state as many years ago before the onset of major motor limitations and before the familial-social-professional structures were disrupted by PD. In other words, the patients from the CRTG were brought to the understanding that, after neurosurgery, they will return to their preoperative environment as neurostimulated patients.

Concerning social adjustment as measured by the SAS-SR, we did not observe any group effect either on the global scale score or the subscale score. However, this does not necessary mean that our preoperative therapy did not have any impact on social adaptation variables. On one hand, we only considered patients for neurosurgery who were free from major depressive disorder, major apathy and invalidating anxiety. Furthermore, they presented globally realistic expectations about the outcome of the neurosurgery, i.e., adapted behaviour in terms of social adjustment at the SAS-SR.

We can therefore imagine that even if the patients had a specific "dysfunctional" cognition about the surgery, this may have been modulated through the preoperative visit and psychoeducation, but not necessarily confirmed through more adapted behaviours of social adjustment, which were fully adapted at baseline. On the other hand, the SAS-SR is constructed for participants to complete only the items corresponding to their situation, for example, single patients without children and out of work do not complete the subscales entitled "marital relation", "interaction with children", or "work". Therefore, even if the whole sample completed the SAS-SR, not all the subscales were completed by each participant. Consequently, our sample may have been underpowered to demonstrate the impact of our cognitive restructuration therapy on social adjustment. This lack of data concerning specific subscales may also have had an impact on statistics.

It has been suggested that a multidisciplinary education of patients confronted to unrealistic expectations of the result of neurosurgery and adapted to its individual problematic could improve postoperative efficiency [START_REF] Geraedts | Selecting candidates for deep brain stimulation in Parkinson's disease : the role of patients' expectations[END_REF][START_REF] Knoop | Bridging the gaps in patient education for DBS surgery in Parkinson's disease[END_REF] and patient's satisfaction. In line with this and with previous hypothesis [START_REF] Santos | Tackling psychosocial maladjustment in Parkinson's disease patients following subthalamic deep-brain stimulation : A randomised clinical trial[END_REF] , our results suggest that it could be important that psychoeducation associated with preoperative cognitive restructuration therapy focusing on expectations could be included for all patients with PD undergoing neurosurgery.

One of the strengths of our study is the blinded methodology: the neurologists, psychologists and psychiatrists were blinded as to the patient groups for the pre-and postoperative psychometric evaluation. However, some limitations are apparent. As mentioned above, our sample was relatively small which may have modulated the statistical effect of the impact of the preoperative cognitive restructuration therapy on social adjustment dimensions. The follow-up period of 6 months is also limited and it is possible that greater improvement in the social adjustment dimensions emerge over time as patients adjust to their new situation, as described by Lin et al. [START_REF] Lin | Patients' expectations and satisfaction in subthalamic nucleus deep brain stimulation for Parkinson disease : 6-year follow-up[END_REF] .

Conclusion

The specific or « unrealistic » expectations of patients with PD following STN DBS have been well identified in recent literature. We present here the first data concerning preoperative cognitive restructuration therapy to improve non-motor aspects such as social adjustment in the context of PD neurosurgery. While our results do not present an increase in overall social maladjustment scores but only in the family sphere, they contribute to support the idea that it could be important that preoperative cognitive restructuration therapy focusing on patient' specific expectations be included for all patients with PD undergoing neurosurgery, and maybe associated with psychoeducation. This approach could be effective even in the context of brief therapies (as in our methodology) which are easily adaptable to patient management in a hospital setting, constituting a suggestion for future research.

Table 3

 3 MADRS: Montgommery and Arsberg Depression Rating Scale; HARS : Hamilton Anxiety Rating Scale; AS : Apathy Scale; EGF : Evaluation of Global Functioning

Table 4

 4 SAS-SR : Social Adjustment Scale-Self Report

Table 1a : Patient demographic data

 1a

			Mean	Standard deviation
	n		62
	Age (years)	59	6.13
	Disease duration (years)	9.44	3.62
	Table 1b: Additional patient demographic data
			n	percentage (%)
	Gender	male	38	52%
		female	35	48%
	Educational Level	no school	2	3%
		primar	11	15%
		secondar	40	55%
		superior	20	27%
	Social status	single	10	14%
		married	50	68%
		widowed	2	3%
		living together	6	8%
		divorced	8	11%
	Professional status	working	11	15%
	active pensioner	25	34%
	inactive pensioner	25	34%
		invalidity	10	14%
		sick leave	2	3%

Table 2a : Neurological data for the patients Group n Preoperative evaluation (M-2) Postoperative evaluation (M+3)

 2a

				Mean	SD	Mean	SD	Postoperative evaluation (M+6) Mean SD	Group Effect	Time Effect
	Daily levodopa equivalent dose (mg)	CRTG CIG CG total	21 20 21 64	1192.50 1279.10 1322.55 1264.27	471.08 623.42 377.14 491.58	839.07 791.21 706.23 778.45	371.78 425.27 433.14 407.81	811.57 707.59 699.43 740.53	385.11 370.71 406.79 385.66	ns ns ns ns	.000 .000 .000 .000
		CRTG	14	7.64	5.27	6.14	3.46	7.29	5.12	ns	ns
	UPDRS II	CIG CG	13 16	6.62 9.44	6.46 5.33	6.47 4.94	4.01 3.21	5.38 6.25	3.43 3.15	ns ns	ns ns
		total	43	8.00	5.66	5.79	3.53	6.33	3.95	ns	ns
		CRTG	14	21.07	12.80	16.32	9.34	17.93	9.78	ns	ns
	UPDRS III	CIG CG	15 18	19.23 22.39	15.67 12.36	15.90 14.25	8.04 8.84	12.53 14.61	8.16 8.15	ns ns	ns ns
		total	47	20.99	13.39	15.39	8.60	14.94	8.75	ns	ns
		CRTG	14	7.36	2.34	2.79	1.67	2.21	1.53	ns	ns
	UPDRS IV	CIG CG	13 15	6.77 6.80	4.23 3.59	3.54 3.00	2.14 3.66	3.46 2.80	1.85 2.33	ns ns	ns ns
		total	42	6.98	3.38	3.10	2.63	2.81	1.97	ns	.001
	UPDRS: Unified Parkinson's Disease Rating Scale

Table 2b : STNDBS stimulation parameters data concerning PD patients

 2b

	Stimulation parameters	Group	Postoperative evaluation (M+3) means SD	Postoperative evaluation (M+6) means SD	Time Effect
	Right frequency (Hz)	1 2 3 total	131,59 132,75 117,86 127,38	13,04 9,39 31,57 21,27	131,59 132,75 121,43 128,57	13,04 9,39 26,51 18,37	ns ns ns ns
	Right pulse-width (µS)	1 2 3 total	61,43 63 62,86 62,42	6,55 9,23 13,09 9,87	58,57 63 61,43 60,97	14,93 9,23 6,55 10,82	ns ns ns ns
		1	2,21	0,87	2,45	0,67	ns
	Right voltage	2	2,26	0,73	2,6	0,69	ns
	(V)	3	2,22	0,67	2,82	0,78	ns
		total	2,23	0,75	2,62	0,72	.000
		1	131,67	13,35	134,29	17,7	ns
	Left frequency	2	130,75	3,35	130,75	3,35	ns
	(Hz)	3	117,86	31,57	121,43	26,51	ns
		total	126,69	20,72	128,79	19,16	ns
	Left pulse-width (µS)	1 2 3 total	62,86 64,5 62,86 63,39	9,02 10,99 13,09 11,01	61,43 65,5 61,43 62,74	6,55 11,46 6,55 8,53	ns ns ns ns
		1	2,31	0,97	2,31	0,97	ns
	Left voltage	2	2,31	0,90	2,31	0,90	ns
	(V)	3	2,29	0,78	2,29	0,78	ns
		total	2,3	0,87	2,3	0,87	.042

Table 3 : Pre-and postoperative scores for depression, anxiety, apathy and global functioning Group n

 3

				Preoperative evaluation (M-2) Mean SD	Postoperative evaluation (M+3) Mean SD	Postoperative evaluation (M+6) Mean SD	Group Effect	Time Effect
		CRTG	21	8.14	5.28	6.00	6.31	7.19	6.00	ns	ns
	MADRS	CIG CG	19 22	7.47 7.00	7.76 5.77	5.68 5.27	4.75 3.44	7.00 6.45	6.47 7.24	ns ns	ns ns
		total	62	7.53	6.22	5.64	4.89	6.87	6.51	ns	ns
		CRTG	21	7.52	4.65	5.38	3.44	6.00	4.59	ns	ns
	HARS	CIG CG	19 22	8.63 6.27	8.46 4.90	6.05 5.68	3.84 4.44	7.00 5.32	7.65 6.77	ns ns	ns ns
		total	62	7.42	6.12	5.69	3.89	6.06	6.36	ns	ns
		CRTG	21	11.52	6.34	10.71	7.31	13.9	6.98	ns	ns
	AS	CIG CG	19 22	9.47 12.45	5.80 6.43	10.79 12.50	3.73 5.03	10.53 13.36	6.56 5.89	ns ns	ns ns
		total	62	11.23	6.24	11.37	5.58	12.68	6.54	ns	ns
		CRTG	21	74.76	12.49	76.48	12.77	76.57	13.18	ns	ns
	EGF	CIG CG	19 22	78.58 80.09	14.28 10.40	79.95 81.50	11.47 9.75	80.47 85.09	9.98 8.38	ns ns	ns ns
		total	62	77.82	12.40	79.32	11.39	80.79	11.11	ns	ns
	MADRS: Montgommery and Arsberg Depression Rating Scale;
	HARS: Hamilton Anxiety Rating Scale;
	AS: Apathy Scale;
	EGF: Evaluation of Global Functioning

Table 4 : Pre-and postoperative SAS-SR scores for the 3 patient groups

 4

	SAS-SR	Group	n	Preoperative evaluation (M-2) Mean SD	Postoperative evaluation (M+3) Mean SD	Postoperative evaluation (M+6) Mean SD	Group Effect	Time Effect
		CRTG	21	1.51	0.30	1.51	0.39	1.55	0.36	ns	ns
	Total score	CIG CG	19 22	1.62 1.69	0.30 0.33	1.65 1.55	0.28 0.18	1.67 1.64	0.37 0.45	ns ns	ns ns
		total	62	1.61	0.32	1.57	0.30	1.62	0.39	ns	ns
		CRTG	11	1.94	0.67	1.76	0.60	1.98	0.68	ns	ns
	Work	CIG CG	10 8	1.91 2.03	0.65 0.66	1.68 1.62	0.87 0.21	1.45 1.58	0.67 0.36	ns ns	ns ns
		total	29	1.95	0.64	1.69	0.62	1.69	0.63	ns	ns
		CRTG	21	1.83	0.49	1.86	0.69	2.02	0.86	ns	ns
	Social life-	CIG	19	1.78	0.46	1.85	0.82	1.77	0.57	ns	ns
	leisures	CG	22	1.99	0.68	1.99	0.31	2.08	0.82	ns	ns
		total	62	1.87	0.55	1.90	0.62	1.96	0.77	ns	ns
	Family life	CRTG CIG CG	20 19 22	1.62 1.83 1.88	0.53 0.46 0.56	1.59 1.89 1.81	0.59 0.57 0.44	1.53 1.89 1.78	0.43 0.60 0.57	0.42 ns	ns ns ns
		total	61	1.78	0.52	1.76	0.54	1.73	0.55	ns	ns
		CRTG	1	1.50	-	1.25	-	1.00	-	ns	ns
	Interaction	CIG	4	1.31	0.24	1.25	0.29	1.31	0.47	ns	ns
	with children	CG	11	1.42	0.31	0.98	0.58	1.29	0.82	ns	ns
		total	16	1.39	0.28	1.06	0.50	1.34	0.71	ns	ns
		CRTG	15	1.37	0.50	1.26	0.78	1.40	0.54	ns	ns
	Marital	CIG	16	1.64	0.73	1.67	0.83	1.63	0.84	ns	ns
	relation	CG	16	1.66	0.52	1.56	0.54	1.75	0.81	ns	ns
		total	47	1.56	0.60	1.50	0.73	1.60	0.75	ns	ns
		CRTG	21	1.00	0.00	1.05	0.22	1.05	0.22	ns	ns
	Material	CIG	19	1.11	0.32	1.00	0.00	1.26	0.93	ns	ns
	situation	CG	21	1.24	0.54	1.05	0.22	1.14	0.36	ns	ns
		total	61	1.11	0.37	1.03	0.18	1.15	0.57	ns	ns
	SAS-SR: Social Adjustment Scale-Self Report

Acknowledgement

The authors thank PD patients for their motivated participation to the study.

Formatting of funding sources

This work was supported by the French Clinical Research Program (N°IDRCB 2008-A00655-50).


Augustin Coisne
email: augustin.coisne@chru-lille.fr

Samy Aghezzaf

Jean-Louis Edmé

Anne Bernard

Iria Ma

Chloé Yohann Bohbot

Di Lena

Yoan Martin Nicol

Lavie Badie

Damien Eyharts

Jean-Louis Edme

Chloé Di Lena

Yoan Lavie Badie

Aurélien Seemann

Claire Falaise

Julien Ternacle

Annabelle Nguyen

Geraldine Montier

Arnaud Hubert

David Montaigne

Erwan Donal

Julien Dreyfus

Reproducibility of reading echocardiographic parameters to assess severity of mitral regurgitation. Insights from a French multicentre study

Keywords: Mitral regurgitation, Agreement, Transthoracic echocardiography EACVI, European Association of Cardiovascular Imaging, EROA, effective regurgitant orifice area, κ, Kappa, LA, left atrium, LV, left ventricle, MR, mitral regurgitation, PISA, proximal 4 isovelocity surface area, RVol, regurgitant volume, SPAP, systolic pulmonary artery pressure, TTE, transthoracic echocardiography

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

Introduction

Mitral regurgitation (MR) is the most prevalent valvular heart disease in Western countries, with an age-dependant prevalence, affecting up to 10% of people older than 75 years [START_REF] Iung | A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease[END_REF][START_REF] Nkomo | Burden of valvular heart diseases: a population-based study[END_REF]. Despite recent progress in MR evaluation by cardiac magnetic resonance imaging, transthoracic echocardiography (TTE) remains the backbone for exploration of both the mechanism of MR and its severity, and thus guides patient management [START_REF] Bax | Advanced imaging in valvular heart disease[END_REF]. Several quantitative and semiquantitative parameters are currently recommended for quantifying MR severity [START_REF] Lancellotti | Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging[END_REF][START_REF] Zoghbi | Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation: A Report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance[END_REF]. Although these methods are routinely used in daily practice worldwide, their reliability was questioned in 2010 [START_REF] Grayburn | Grading severity of mitral regurgitation by echocardiography: science or art?[END_REF]. The dynamic nature of MR throughout systole as well as the complexity of MR mechanisms were thought to be partly responsible for the suboptimal interobserver agreement in MR evaluation [START_REF] Grayburn | Grading severity of mitral regurgitation by echocardiography: science or art?[END_REF][START_REF] Biner | Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity[END_REF]. We hypothesized that the poor reproducibility in MR assessment was related to the poor image quality previously offered by sonographs, alongside insufficient skills of cardiologists in the 2000s, and this issue had to be addressed at the time of mitral-dedicated percutaneous intervention. We thus investigated interobserver agreement in parameters used in daily practice to quantify MR severity within and between junior and senior cardiologists specialized in echocardiography.

Methods

Study population

We prospectively included 25 consecutive patients referred to five tertiary French hospitals (Creteil, Lille, Rennes, Toulouse and Tours) for MR exploration during a 1-month period (May to June 2018).

Senior cardiologists specialized in echocardiography at each centre enrolled 4 patients with primary (due to mitral valve prolapse) and 1 patient with secondary MR into the study, according to a standardized acquisition protocol. Thus, 20 primary MRs due to mitral valve prolapse and 5 secondary MRs were included. The distinction between primary and secondary MR was given by the senior cardiologist performing the TTE.

Patients with MR ≥ moderate, according to European Association of Cardiovascular Imaging (EACVI) guidelines, were included [START_REF] Lancellotti | Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging[END_REF]. Patients with previous mitral surgery, poor echogenicity, another valvular heart disease ≥ moderate or a congenital heart disease were excluded.

The local ethics committee approved the protocol and all patients gave informed consent.

Cardiac imaging acquisition and analysis

Two-dimensional TTEs were performed using a commercially available ultrasound machine (Vivid E9 or E95, GE Healthcare, Little Chalfont, UK). Each patient underwent comprehensive TTE according to American Society of Echocardiography (ASE) or EACVI guidelines, with particular attention given to the mitral valve [START_REF] Lang | Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF][START_REF] Galderisi | Standardization of adult transthoracic echocardiography reporting in agreement with recent chamber quantification, diastolic function, and heart valve disease recommendations: an expert consensus document of the European Association of Cardiovascular Imaging[END_REF]. Echocardiographic data were stored for off-line analysis using dedicated software (EchoPAC version 201.0.0; GE Vingmed Ultrasound, Horten, Norway).

Cardiological review

The echocardiographic data were analysed off-line by junior and senior physicians specialized in echocardiography, as follows: quantification of MR severity and evaluation of its mechanisms and consequences were done in eight tertiary public and private hospitals (Amiens, Creteil, Lille, Rennes, Saint Denis, Toulouse and Tours) by one junior and one senior physician in each centre (i.e. 16 physicians). A junior physician was defined as a final-stage cardiology resident and a senior physician as a cardiologist specialized in cardiac imaging, who graduated more than 2 years earlier. All physicians were provided with the entire echocardiographic study, reviewed all images, and were blinded to the patient's medical history, previous MR evaluation, and MR classification (primary or secondary) by the centre that enrolled the patient.

Mitral regurgitation grading

MR severity was graded using effective regurgitant orifice area (EROA) and regurgitant volume (RVol) according to the latest EACVI guidelines [START_REF] Lancellotti | Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging[END_REF][START_REF] Galderisi | Standardization of adult transthoracic echocardiography reporting in agreement with recent chamber quantification, diastolic function, and heart valve disease recommendations: an expert consensus document of the European Association of Cardiovascular Imaging[END_REF]. Grading was in three categories for primary MR: moderate (RVol between 30 and 44 mL, EROA between 20 and 29 mm²), moderate-to-severe (RVol between 45 and 59 mL, EROA between 30 and 39 mm²) or severe (RVol > 60 mL, EROA > 40 mm²); and in two categories for secondary MR: moderate (RVol < 30 mL, EROA < 20 mm²) or severe (RVol ≥ 30 mL, EROA ≥ 20 mm²). Proximal isovelocity surface area (PISA) radius was classically measured in apical four-chamber view or in parasternal view in case of anterior mitral valve prolapse, as recommended. The area of interest was optimized by lowering imaging depth and reducing the Nyquist limit to 15-40 cm/s. The radius of the PISA was measured at mid-systole using the first aliasing. A multiparametric approach was also performed by each physician using all qualitative, semiquantitative and quantitative parameters available.

Statistical analysis

Continuous variables are presented as means with standard deviations (SD) and qualitative variables as frequencies and percentages. To determine interobserver agreement of binary or ordinal outcome variables, multirater κ statistics were computed using the macro MAGREE with SAS, Version 9.4 (SAS Institute, Cary, North Carolina). This macro implements the methodology of Fleiss et al., measuring the agreement when the number of raters is > 2 [START_REF] Fleiss | Statistical Methods for Rates and Proportions, 3rd Edition[END_REF]. Kappa (κ) values were interpreted according to Landis and Koch, with κ coefficients of 0 = poor; 0.01-0.20 = slight; 0.21-0.40 = fair; 0.41-0.60 = moderate; 0.61-0.80 = substantial; and 0.81-1.0 = almost-perfect agreement. Multirater κ were calculated for each patient using the online κ calculator developed by Randolph.

To determine the interobserver agreement of continuous outcome variables, intraclass correlations and their 95% confidence intervals (CIs) were calculated using the macro ICC9 with SAS [START_REF] Hankinson | Reproducibility of plasma hormone levels in postmenopausal women over a 2-3-year period[END_REF]. Intraclass correlation values were interpreted as κ values.

Results

Study population

The characteristics of the patients are summarized in Table 1. Mean age was 62 ± 18 years, 76% were male (76%), and 76% were symptomatic (NYHA ≥ II); 1 patient had atrial fibrillation (AF).

Agreement to assess MR mechanism and severity

Overall interobserver agreement to distinguish primary from secondary MR was moderate (0.57 ± 0.03) (Table 2). Interobserver agreement was better in case of posterior versus anterior prolapse, especially for the central segments P2 (substantial, 0.66 ± 0.03) and A2 (moderate, 0.52 ± 0.03).

Interobserver agreement was fair or slight to identify a non-central prolapse (A1-P1 or A3-P3). Raw agreement to characterize holo-systolic or end-systolic MR was 0.23 ± 0.03.

Interobserver agreement to assess MR severity using semiquantitative parameters was fair for vena contracta width, moderate for PISA radius and substantial for peak E wave velocity and time velocity integral (TVI) mitral/TVI aortic ratio (Table 2). Interobserver agreement was moderate for all quantitative parameters (EROA, RVol using PISA method, and RVol using volumetric method).

Interobserver agreement was substantial or almost perfect for assessing MR consequences on left ventricular and left atrial dilatation and left ventricular function, but only moderate for systolic pulmonary artery pressure (SPAP).

Agreement according to physician experience

Overall interobserver agreement to assess the MR mechanism was better in senior than in junior physicians, especially to identify a P2 prolapse (substantial vs moderate, respectively), a flail leaflet (moderate vs fair) or end-systolic MR (fair vs slight) (Table 2).

Interobserver agreement was also better in senior than in junior physicians for all parameters used to quantify MR severity, i.e. vena contracta width (fair vs slight, respectively), EROA (substantial vs fair), and RVol with the PISA method (moderate vs fair) (Table 2). Interobserver agreement for the RVol calculated using the volumetric method was similar between the two groups, as well as assessment of left ventricular and left atrial consequences, except for SPAP, with better agreement within the senior than the junior group.

Agreement according to the mechanism of MR

Interobserver agreements of parameters used to quantify MR severity were low and were even lower for secondary versus primary MR (i.e. slight vs fair, respectively, for vena contracta width and RVol using the PISA method) (Table 3). EROA for primary MR used by a senior cardiologist appeared to be the most reproducible parameter, with substantial interobserver agreement (0.61, 95% CI 0.43-0.76).

Global MR quantification

Using a multiparametric individual approach, overall distribution of interobserver agreement for grading MR severity was slight or fair in 56% of cases, and substantial and almost perfect in only 36% (Figure 1). Substantial or almost perfect agreement was more frequently observed in the senior than In the junior group (52% vs 36%, respectively). Overall interobserver agreement for grading MR severity was fair (0.30, 95% CI 0.14-0.44), and was slightly better in the senior group (0.31, 95% CI 0.12-0.42 vs 0.28, 95% CI 0.11-0.40). Of the 400 analyses, discrepancies were apparent between grading from RVol/EROA and the final judgment from the echocardiographist in 78 patients (19.5%), with a tendency to a lower discrepancy in the senior group (17.5% vs 21.5%, respectively; P = 0.31).

Discussion

Exploring parameters used in daily practice to assess MR in 25 patients in eight French tertiary public and private hospitals, we found that interobserver agreement for MR mechanism definition and grading with EROA and RVol was only moderate. However, interobserver agreement for the consequences of MR (left ventricular function and left ventricular and left atrial dilatation) was substantial or almost perfect. Interobserver agreement for a single parameter or for a multiparameter quantification was generally better in senior than in junior physicians, and was better for primary than for secondary MR.

Agreement to assess MR mechanism and severity

Surprisingly, the agreement to distinguish primary from secondary MR was only moderate, both in the senior and the junior group. This lack of substantial agreement is an important issue for clinical decision-making regarding corrective surgery, as cut-offs to define severe MR in European guidelines differ according to the mechanism. Of note, this is not an issue in the American guidelines [START_REF] Nishimura | AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Boekstegers | Percutaneous interventional mitral regurgitation treatment using the Mitra-Clip system[END_REF].

Agreement to define a flail leaflet was only moderate for senior physicians and fair for junior physicians, and was substantial for central prolapse (A2-P2), probably because of its higher prevalence. Conversely, results for medial or lateral prolapse were disappointing in TTE. Overall, the results of the interobserver agreement regarding MR mechanism suggested the importance of transoesophageal echocardiography for a precise analysis of the mechanism to offer the patient the best therapeutic option at the time of development of percutaneous procedures [START_REF] Blanke | Multimodality Imaging in the Context of Transcatheter Mitral Valve Replacement: Establishing Consensus Among Modalities and Disciplines[END_REF][START_REF] Pu | Quantification of mitral regurgitation by the proximal convergence method using transesophageal echocardiography. Clinical validation of a geometric correction for proximal flow constraint[END_REF]. Nevertheless, further studies are needed to analyse interobserver agreement using transoesophageal echocardiography.

Regarding assessment of the severity, our findings highlight the weaknesses of the semiquantitative parameters, especially for vena contracta width, with a very low consistency.

Exploring the PISA and vena contracta measurements of 16 patients with MR interpreted by 18 echocardiologists from 11 academic institutions in 2009, Biner et al. found similar results (0.28) [START_REF] Biner | Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity[END_REF].

Concerning PISA measurement, the moderate agreement can be explained by the difficulty in measuring the PISA radius. Indeed, agreement was only fair for PISA radius, while it was substantial for other parameters used in the PISA method. This may be explained by several pitfalls linked to this method, i.e. variation during systole, non-holosystolic or eccentric jet and containment [START_REF] Baumgartner | ESC/EACTS Guidelines for the management of valvular heart disease[END_REF][START_REF] Buck | Effect of dynamic flow rate and orifice area on mitral regurgitant stroke volume quantification using the proximal isovelocity surface area method[END_REF][START_REF] Topilsky | Mitral valve prolapse with mid-late systolic mitral regurgitation: pitfalls of evaluation and clinical outcome compared with holosystolic regurgitation[END_REF] (Figure 2). Nevertheless, despite these pitfalls, the agreement observed for PISA radius and EROA for primary MR were consistent and acceptable (both substantial) in the senior group in contrast to the junior group, reinforcing the idea of a learning curve for this quantification technique. More strikingly, use of a multiparametric approach to quantify MR severity did not improve the consistency between observers, with only a fair interobserver agreement (0.30), again in perfect agreement with the findings from Biner at al. (0.32).

Conversely, left ventricular and left atrial volumes and function measurements had good interobserver agreement, both for senior and junior physicians, probably reflecting improvements in image quality in recent years. With three-dimensional imaging and automatization of endocardial contouring, the agreement will probably be even better in the near future.

Agreement to assess severity according to physician experience

Our findings clearly show a difference between senior and junior physicians regarding assessment of the mechanism and severity of MR. These results are in line with a recent study from Iung et al. [START_REF] Iung | Educational needs and application of guidelines in the management of patients with mitral regurgitation. A European mixed-methods study[END_REF], which highlighted the importance of the learning curve in the assessment of this valvular heart disease. Of note, EROA agreement within the senior group was better than in the study by Biner et al.

(0.61 vs 0.37, respectively) [START_REF] Biner | Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity[END_REF].

Agreement in the subgroup of secondary MR

Interobserver agreement of parameters used to quantify MR severity were lower in secondary MR. Evaluation of secondary MR is complex even for senior physicians. Recently, Iung et al. found that only 44% of cardiologists evaluated secondary MR appropriately [START_REF] Iung | Educational needs and application of guidelines in the management of patients with mitral regurgitation. A European mixed-methods study[END_REF]. These difficulties in grading secondary MR may be explained by the non-circular shape of the proximal flow convergence region and the absence of angle correction in the calculation of EROA in secondary MR [START_REF] Cape | Three-dimensional surface geometry correction is required for calculating flow by the proximal isovelocity surface area technique[END_REF][START_REF] Yosefy | Proximal flow convergence region as assessed by real-time 3-dimensional echocardiography: challenging the hemispheric assumption[END_REF]. These concerns should be addressed by an improved learning approach in valvular heart diseases with, for instance, a dedicated level-three teaching plan and use of multimodal imaging.

Study limitations

Despite a limited set of TTE variables, each parameter was assessed 16 times (by eight senior and eight junior physicians) and thus 400 analyses per parameter were obtained. Moreover, all TTE evaluations were performed by five senior physicians with the same commercially available ultrasound machine to limit variability due to technical/imaging quality. The definition of MR mechanism was left to the discretion of the senior echocardiographer at inclusion, without referring to a gold standard method. The dataset was restricted to two-dimensional imaging, as based on normal clinical routine.

Three-dimensional TTE, transoesophageal echocardiography and multimodality imaging would have probably increased the consistency of the reviewers. Finally, we choose to include MR ≥ moderate.

The interobserver agreement might have been better with the inclusion of mild MR, even if the clinical relevance to quantify mild MR is questionable.

Conclusions

Robust and reproducible TTE MR quantification and mechanism definition remain challenging despite high-quality images echocardiographic and the expected high skills of echocardiographists regarding MR at the time of dedicated percutaneous intervention surge. The multiparametric approach does not entirely alleviate the substantial dispersion in measurement of MR severity parameters, while reader experience seems to partially address the issue, suggesting the continuing need for education in MR evaluation among cardiologists.

a

  RVol (volume method) = stroke volume (Simpson) -stroke volume (left ventricular outflow tract pulsed Doppler). b LVEDD and LVESD were measured by two-dimensional left ventricular and left atrial volumes by the Simpson biplane method; c Right atrial pressure was estimated using the inferior vena cava diameter and collapsibility [22]. Slight = 0.01-0.20 Fair = 0.21-0.40

Figure 1 .

 1 Figure 1. Distribution of interobserver agreement for grading mitral regurgitation severity using the multiparametric approach.

Figures 2 .

 2 Figures 2. Examples of pitfalls of the PISA method in our population.Non-holosystolic mitral regurgitation with variation in effective regurgitant orifice area.

Table 1

 1 Patient characteristics.

	Variable

Table 2

 2 Interobserver agreement to assess MR mechanism, severity and consequences according to physician experience.

		Overall	Senior	Junior
	MR mechanism
	Posterior prolapse
	P1 prolapse	0.23 ± 0.03	0.25 ± 0.04	0.20 ± 0.04
	P2 prolapse	0.66 ± 0.03	0.76 ± 0.04	0.55 ± 0.04
	P3 prolapse	0.17 ± 0.03	0.19 ± 0.04	0.13 ± 0.04
	Anterior prolapse
	A1 prolapse	0.12 ± 0.03	0.13 ± 0.04	0.08 ± 0.04
	A2 prolapse	0.52 ± 0.03	0.57 ± 0.04	0.47 ± 0.04
	A3 prolapse	0.39 ± 0.03	0.51 ± 0.04	0.16 ± 0.04
	Chordae rupture	0.35 ± 0.043	0.36 ± 0.04	0.31 ± 0.04
	Flail leaflet	0.42 ± 0.03	0.50 ± 0.04	0.32 ± 0.04
	MR mechanism (primary vs	0.57 ± 0.03	0.59 ± 0.04	0.55 ± 0.04
	secondary)
	Carpentier classification
	I	0.06± 0.03	0.00 ± 0.04	0.04 ± 0.04
	II	0.75 ± 0.03	0.86 ± 0.04	0.66 ± 0.04
	III	0.75 ± 0.03	0.87 ± 004	0.63 ± 0.03
	Holo-systolic MR	0.27 ± 0.03	0.39 ± 0.04	0.15 ± 0.04
	End-systolic MR	0.25 ± 0.03	0.37 ± 0.04	0.15 ± 0.04
	MR severity
	E wave velocity (m/s)	0.80 (0.72-0.86)	0.74 (0.60-0.84)	0.87 (0.78-0.92)
	E/A ratio	0.87 (0.81-0.91)	0.90 (0.82-0.94)	0.83 (0.72-0.90)
	Vena contracta width (mm)	0.22 (0.13-0.35)	0.28 (0.14-0.35)	0.18 (0.08-0.37)
	PISA radius (mm)	0.52 (0.40-0.63)	0.62 (0.46-0.75)	0.43 (0.27-0.60)
	MR peak velocity (m/s)	0.67 (0.57-0.76)	0.74 (0.60-0.84)	0.62 (0.46-0.76)
	MR TVI (cm/s)	0.78 (0.70-0.85)	0.77 (0.65-0.86)	0.79 (0.67-0.88)

EROA, effective regurgitant orifice area; LAV, left atrial volume; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter;

LVESV, left ventricular end-systolic volume; MR, mitral regurgitation; PISA, proximal isovelocity surface area; RVol, regurgitant volume; SPAP, systolic pulmonary artery pressure; SV, stroke volume; TVI, time velocity integral.

Table 3

 3 Interobserver agreement to assess MR severity according to MR mechanism.

		Primary	Secondary
	Vena contracta width
	Overall	0.26 (0.16-0.41)	0.06 (0.00-0.57)
	Senior physicians	0.32 (0.16-0.52)	0.04 (0.00-0.91)
	Junior physicians	0.22 (0.09-0.44	0.05 (0.00-0.87)
	Effective regurgitant orifice area
	Overall	0.43 (0.30-0.56)	0.43 (0.20-0.70)
	Senior physicians	0.61 (0.43-0.76)	0.46 (0.15-0.79)
	Junior physicians	0.31 (0.16-0.52)	0.41 (0.41-0.77)
	Regurgitant volume
	Overall	0.39 (0.27-0.53)	0.13 (0.02-0.46)
	Senior physicians	0.48 (0.30-0.66)	0.19 (0.03-0.64)
	Junior physicians	0.35 (0.19-0.55)	0.05 (0.00-0.83)

k values are given for ordinal outcomes variables and intraclass correlations for continuous outcome variables.

Acknowledgement

All participants are members of the French Society of Cardiovascular Imaging.