Mélanie Fettig

Wissam El-Hage

Irina Klemina

Julien Biberon

Bertrand De Toffol

Anne Thiriaux

Jean François Visseaux

Martine Lemesle Martin

Jean François Visseaux

Martine Lesmeles

Raymund Schwan

Fatiha Bechiri

Alice Cohn

Mylene Meyer

Louis Maillard

Coraline Hingray
email: coralinehingray@chru-nancy.fr

Adherence to mental health care and caregiver-patient relationship after diagnosis of psychogenic non-epileptic seizures: Longitudinal follow-up study

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

1.

INTRODUCTION

The World Health Organization defines therapeutic adherence as "the extent to which the patient's behaviour matches the prescriber's recommendations" [START_REF] Sabaté | Adherence to long-term therapies: evidence for action[END_REF]. It is therefore a dynamic, complex and multifactorial phenomenon for which patients and healthcare professionals share responsibility. Non-adherence to long-term therapies is a key issue as it concerns around half of all chronically ill patients [START_REF] Sabaté | Adherence to long-term therapies: evidence for action[END_REF]. Poor adherence severely compromises therapeutic effectiveness and therefore impacts the quality of life of these patients and the economics of health care. Accordingly, Haynes et al. stated that "increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments" [START_REF] Haynes | Interventions for helping patients to follow prescriptions for medications[END_REF].

Howlett et al. conducted a study in a population of patients with neurological functional disorders [START_REF] Howlett | Engagement in psychological treatment for functional neurological symptoms-Barriers and solutions[END_REF] to describe how many patients complete a psychological treatment program and whether recorded demographic or clinical factors predict which patients were more likely to engage in treatment. Even though they excluded patients who were initially hostile to the link between their symptoms and a psychological origin, nearly a quarter of the patients did not attend their first appointment, 20.8% unilaterally discontinued therapy, and only 41.6% completed the treatment. The only factor identified as being related to a greater likelihood of engagement was a higher age.

Among neurological functional disorders, psychogenic non-epileptic seizures (PNES) is a common but still relatively unknown chronic condition. It is recognized in ICD-11 (International Classification of Diseases 11th Revision) as an acute dissociative disorder with neurological symptoms [START_REF]ICD-10 Classifications of Mental and Behavioural Disorder: Clinical Descriptions and Disgnostic Guidelines[END_REF]. For DSM-5, PNES is classified in the section "somatic symptom disorders", under the heading of "conversion disorder " [START_REF]Statistical Manual of Mental Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition[END_REF].

Psychiatric evaluation and follow-up should be systematically offered to PNES patients (who are often subject to other psychiatric comorbidities). It is recognized that a standardized explanation can improve the prognosis of patients [START_REF] Lafrance | Multicenter pilot treatment trial for psychogenic nonepileptic seizures: a randomized clinical trial[END_REF]. Some studies have shown an association between psychological follow-up and a better prognosis, particularly in terms of quality of life [START_REF] Jones | Correlates of health-related quality of life in adults with psychogenic nonepileptic seizures: A systematic review[END_REF]. However, there is still no consensus to validate the unconditional requirement of psychotherapies.

Adherence to care in patients with PNES is fragile. Despite the extent of the issue, only a few studies have focused on the quality of adherence to mental health care in these patients and most of these are of a short-term design or quantitative approach. Even fewer studies have investigated the key factors affecting adherence both from the caregiver and patient perspective. [START_REF] Baslet | Initial treatment retention in psychogenic non-epileptic seizures[END_REF] [START_REF] Baslet | Initial treatment retention in psychogenic non-epileptic seizures[END_REF] conducted an observational retrospective study comparing initial levels of adherence to a standardized clinical protocol in subjects with PNES and sought to identify determinants of retention in care at 2 months. They found that being married or having a living partner was associated with higher initial treatment retention. However, in this same study, no differences in specific clinical or psychopathological factors (frequency of PNES, time since diagnosis, neurological or psychiatric comorbidities, psychopathology severity) were identified between adherent and non-adherent subgroups. In 2018, Tolchin et al. conducted a prospective cohort study over four standardized visits, measuring adherence to psychiatric follow-up for up to 17 months following the initial PNES diagnosis [START_REF] Tolchin | Long-term adherence with psychiatric treatment among patients with psychogenic nonepileptic seizures[END_REF]. Adherence to psychiatric treatment was found to be poor overall. Risk factors for nonadherence included a history of a prior diagnosis of PNES, and a lower level of concern about the illness.

Studies are focusing on ways to improve adhesion to care. For instance, Tolchin et al [START_REF] Tolchin | Motivational Interviewing Techniques to Improve Psychotherapy Adherence and Outcomes for Patients With Psychogenic Nonepileptic Seizures[END_REF] conducted a randomized trial of motivationnalmotivational interview (MI) as an intervention to improve adherence and outcomes among 60 PNES patients. Participants were randomly assigned to receive a single session of MI prior to the initiation of psychotherapy or to receive psychotherapy alone. At the 16-week follow-up, those who received the MI session had higher rates of psychotherapy adherence (65% versus 31%), lower PNES frequency (mean reduction of 76% versus 35%), and higher quality of life.

The studies mentioned above suggest that long-term adherence to mental health care in patients with PNES is poor. However, more detailed descriptions of the factors affecting adherence over time are few and far between. Thus, the first aim of our study was to describe the status of adhesion to mental health care at 6, 12, 18 and 24 months after PNES diagnosis in patients who started follow-up and in those who did not. The second aim was to describe the reasons given by non-adherent patients. The third aim was to compare the perception of the quality of the caregiver-patient relationship in patients who started mental health care follow-up.

METHOD

Study protocol

We conducted an ancillary study of a multicentermulticentre prospective study (PHRC EDUQ-CPNE ClinicalTrials.gov Identifier: NCT02311829, Agreement of the French Ethics Committee: 2012-A01580-43). Subjects were recruited according to a standardized protocol between January 2014 and June 2017, in the departments of neurology of four French university hospitals (Nancy, Tours, Dijon, Reims). All the participants gave their written informed consent after receiving fully detailed information about the study.

Population

The inclusion criteria were as follows: patients aged > 18 years, with a clear diagnosis of PNES (with or without epilepsy) by a neurologist after a video-EEG, and having experienced repetitive PNES episodes for > 3 months.

Recruitment was performed during hospitalization for a video-EEG examination by a neurologist and a psychiatrist or a neuropsychologist. All the clinicians had with expertise in epileptology and PNES.

All the patients underwent a standardized diagnostic explanation according to a validated protocol approved by trained practitioners [START_REF] Hall-Patch | Acceptability and effectiveness of a strategy for the communication of the diagnosis of psychogenic nonepileptic seizures[END_REF].

The patients were referred to their community mental health consultation centerscentres and/or to a private psychiatrist/psychologist. The clinicians had variable inequal training, competence in treating PNES, reflecting the reality of current practice. Letters were sent out to the psychiatric care facilities informing them of the patient's participation in the study and requesting their cooperation in assessing adherence to care. An information leaflet on PNES was also sent to mental health caregivers to explain the pathology and treatment possibilities, in order to standardize a minimum level of knowledge about the pathology. Everydisorder. 6 months , patients had a neurologist appointement. Study participants returned for follow-up interviews with neurologist every 6 months.

2.3.

Procedure and collected data

Descriptive data

We collected the sex and age of the patients, the number of PNES they had experienced during the previous 3 months, the duration of the illness since the beginning of PNES (in months) and if they have both PNES and epilepsy.

Status of adherence to mental health care

The adhesion status of each patient was collected through cross-referenced data from both mental health caregivers and the patients themselves at 6, 12, 18 and 24 months.

The clinical research associate called the mental health structures (designated at inclusion and who had received information about the study) to find out whether the patient had started a care program, how many consultations had been attended and if the leaflet had been received . The patient was also contacted by telephone to ensure that he/she had not started another program in a different structure.

Six months after inclusion (M6), the patients were classified into one of two groups: a "no follow-up started" group including patients who had not started any follow-up care (i.e., one appointment or less); and a "follow-up started" group including patients who had started follow-up care (i.e., at least two appointments).

From 12 months (M12) to 24 months (M24) after inclusion, the "follow-up started" group was divided into three subgroups: an "ongoing follow-up" subgroup comprising patients who were still in follow-up at the time of the phone call; a "consensual withdrawal" subgroup comprising patients who had discontinued the program with the agreement of the mental health caregiver; and a "nonconsensual withdrawal" subgroup comprising patients who had decided to discontinue the program unilaterally without prior agreement of the mental health caregiver.

The initial recommendations given to patients were to begin a psychological follow-up. We do not give any recommendations of duration, leaving it up to the patients and their therapists to decide . On this basis, we defined a "not following initial recommendations" group consisting of patients from the "no follow-up started" and "nonconsensual withdrawal" groups, and an "following initial recommendations" group included patients from the "ongoing follow-up" and "consensual withdrawal" groups.

Qualitative data about adherence to care at M24

A psychiatrist called all the patients and their mental health caregivers (when possible) at M24 to obtain qualitative data on adherence to care as well as on the quality of the caregiver-patient relationship.

Reasons of stopping or not beginning follow-up care:

Patients who had not started or who had discontinued follow-up care at the time the data was collected, were invited to give their reason(s) from the following list: -I was not interested/I did not see the need for follow-up -I was feeling better -I did not know who to turn to (lack of information) -

The waiting time for an appointment with a specialist was too long -

The clinic or specialist refused to see me -I had serious health problems (surgery, hospitalization) -For financial reasons -No specific reason -Other (please specify).

Data on caregiver-patient relationship:

We created a qualitative assessment questionnaire to measure adherence and the caregiver-patient relationship, inspired by tried-and-tested scales such as the Working Alliance Inventory (WAI) [START_REF] Horvath | Development and validation of the Working Alliance Inventory[END_REF]. It was completed by both the patients and their mental health caregivers. The questionnaire (Appendix A) contained the same five items for patients and caregivers. Subjects were invited to score each item from 0 to 10 (0 = "not at all satisfied/comfortable", 10 = "extremely satisfied/comfortable"). The items were related to: -feeling comfortable in the relationship or with the care provided, -continuity of care content of the sessions effectiveness of the sessions the patient's overall assessment of the follow-up care.

2.4.

Statistical analysis.

Sociodemographic and clinical characteristics are presented using means and standard deviations (SD) for continuous variables and frequency distributions for categorical variables. Statistical comparisons between groups of patients were done by using non-parametric tests due to the size of the sample, namely Mann-Whitney test for continuous variables. A p < 0.05 was considered significant.

RESULTS

3.1.

Description of the patients and mental health caregivers.

Patient baseline characteristics

The mean age of the 108 patients was 34 years (± 10.8) and 78 were females (72.2%). Seventy-eight of the patients were followed in the Nancy area, 15 in the Tours area, eight in the Dijon area, and seven in the Reims area. Overall, they had been diagnosed an average of 77 months prior to inclusion (± 86 months), and had an average of 59 seizures per patient over the previous 3 months (± 67 months). 45 of 108 patients (41.7%) had a dual diagnosis of epilepsy and PNES at the time of inclusion. Three patients left the study before M6 and were not included in the analysis.

Mental health caregivers

We interviewed 56 mental health caregivers (39 females, 69.6%), including psychiatrists (54.3%), psychologists (32.9%) and nurses (12.9%). Forty-one of the caregivers (72.9%) worked in community mental health centerscentres (42.9% psychiatrists, 36.7% psychologists, 20.4% nurses), and 15 (27.1%) in private practice (88.3% psychiatrists and 11.7% psychologists).

In the community mental health centerscentres, a dual follow-up (i.e., involving two caregivers working together) was initially planned for 41.3% of the patients: 62.4% of psychiatrist-nurse pairs, 27.4% of psychiatrist-psychologist pairs, and 10.2% of psychologist-nurse pairs. The type of follow-up was sometimes modified according to the patient's needs.

Status of adherence to mental health care

Figure 1 summarizes the distribution of the patients in the different follow-up groups throughout the study period. At M6, one-third (35.2%) of the 105 patients had not started any follow-up. At M24, only one quarter (25.8%) of the patients were still in a follow-up program. At M12, 2% of the patients in the "follow-up started" group were in the "consensual withdrawal" subgroup (i.e., discontinuation in agreement with the mental health caregiver). This percentage increased to 9.3% at M24.

Figure 2 shows the changes in adhesion status over time for the "not following initial recommendations" and "following initial recommendations " subgroups. From M6 to M24, adherence decreased progressively from two thirds (64.8% of patients at M6) to one third (35.1% at M24).

Reasons for discontinuing the care program

At M24 we managed to contact 49 of the 63 patients (response rate 77.8%) in the "not following initial recommendations " group (i.e., "no follow-up started" group and "non-consensual withdrawal" subgroup). The first reason was "lack of interest" (47.7% of cases) and the second was "feeling better" (36.6% of cases). Thus, 18 patients (18.5% of the M24 cohort) reported to feel better without any additional follow-up after diagnosis of PNES. These data are summarized in Figure 3.

More specifically, in the "no follow-up started" group (n=23) the causes cited by the patients were lack of interest / usefulness (60.9%), feeling better (30.4%), followed by lack of confidence in mental health professionals / structures (8.6%), long waiting times / refusal of the structures and without reason (4.8%). 2.6% of patients cited two causes.

In the "non-consensual withdrawal" group (n=26), the causes cited were feeling better (42.9%), lack of interest / usefulness (33.3%), lack of confidence in mental health professionals / structures (23.8%), followed by long waiting times, serious health problem, and no reason (4.8% per reason). 1.3% of patients cited two or three causes. These data are summarized in Figure 3.

In the "consensual withdrawal" group, all the patients (100%) cited feeling better as reasons for discontinuing the care program.

3.4.

Caregiver-patient relationship 60 patients and 56 mental health care providers were contacted by phone to answer the 5-item questionnaire about the caregiver-patient relationship. Patient response rate for the caregiverpatient relationship (iei.e., subgroups non-consensual, consensual withdrawal, and ongoing folluwfollow-up) was 77.8%%. Mental health caregiver response rate was 92.3% The results are described in Figure 4.

In the "nonconsensual withdrawal" subgroup, the average perception of the therapeutic relationship was similar for most items for both the patients and mental health caregivers including overall perception of follow-up (p=0.91). The session content was more positively perceived by the professionals (p=0.035). Both the patients and mental health caregivers perceived the quality of the therapeutic relationship as poor (overall score of 4.9/10).

In the "consensual withdrawal" subgroup, the patients' and mental health caregivers' perception of the quality of the therapeutic relationship was different for all items (p<0.001). The average patient rating of the follow-up was high (8.5/10 ±3.6), compared to moderate (5.4/10 ±3.6) for the mental health caregivers. Patients in this group perceived the sessions as particularly effective (9/10 ±3.6).

Compared to the patients, the mental health caregivers reported being less comfortable, perceived less continuity of care, and rated the content and effectiveness of therapeutic sessions less positively.

In the "ongoing follow-up" subgroup, patients rated their follow-up (6.9/10 ±1.9) similarly to the caregivers (6/10 ±3.0) on average. The perception of the effectiveness of the sessions was moderate for both (p=0.455). Once again, professionals reported being less comfortable, perceived less continuity of care, and assessed the session content less positively.

More specifically, we compared the "consensual withdrawal" and "non-consensual withdrawal" groups in patients on the one hand and mental health caregivers on the other.

Among patients, 3 of the 5 items of the therapeutic sessions were perceived differently between the 2 groups (p<0.05), and the 2 other items have a strong statistical tendency to significance. Thus, patients in the "consensual withdrawal" group had a more positive perception of the sessions than patients in the "non-consensual withdrawal" group.

In contrast, among mental health caregivers, the sessions were perceived in the same way in both groups. These results can be seen in Figure 5.

DISCUSSION

Our study confirms how difficult it is for patients diagnosed with PNES to engage in psychiatric care as reflected by the poor adherence to health care programs initiated after diagnosis: between 6 and 24 months after diagnosis the number of patients engaged in ongoing follow-up decreased progressively from two-thirds to one-quarter, while the number of not totally adherent patients increased from one-third to two-thirds.

These results are consistent with those of the literature. Tolchin et al. [START_REF] Tolchin | Long-term adherence with psychiatric treatment among patients with psychogenic nonepileptic seizures[END_REF] also reported that adherence with psychiatric treatment is initially reasonably good but worsens rapidly. In this study, the subjects were recruited and followed for up to 17 months. Eighty percent of the subjects attended the first outpatient visit, 42% attended the second, 24% attended the third, and only 14% remained adherent for the fourth visit. Mckenzie et al. [START_REF] Mckenzie | Early outcomes and predictors in 260 patients with psychogenic nonepileptic attacks[END_REF] conducted a cohort study relating treatment outcome to attendance at two follow-up visits post-PNES diagnosis: 71.9% of the patients attended at least one follow-up visit (6 months), while 40.4% of them attended two visits (6 and 12 months). Baslet et al. [START_REF] Baslet | Initial treatment retention in psychogenic non-epileptic seizures[END_REF] found an initial adherence rate of 54% for psychotherapeutic treatment conducted in the same institution.

According to our data, the top two qualitative reasons given by patients for discontinuing follow-up were lack of interest or need for follow-up, and spontaneous subjective clinical improvement after diagnosis. The lack of interest in mental health follow-up may partly reflect the patients' poor acceptance of their PNES diagnosis. Patients often reject the psychological nature of PNES and view the condition primarily as a physical issue [START_REF] Stone | Illness beliefs and locus of control[END_REF]. More generally, several studies have demonstrated that patients with functional neurological symptoms are often hostile to the idea of psychological treatment for their symptoms, which they typically attribute to an undiscovered physical cause [START_REF] Stone | Functional symptoms in neurology: Management[END_REF]. Nevertheless, it is well recognized that psychoeducation is crucial in the context of PNES to help the patient understand that neurological dysregulation is treatable through psychological work on emotion management.

More than a third of the patients (36.6%) in the "not following initial recommendation " group cite "feeling better" as the second reason for non-adherence and as many as 42.9% as the first reason in the "non-consensual withdrawal". It is thus important to note that a significant proportion of these patients report to feel well. This could be due to the well-known therapeutic effectiveness of a standardized diagnostic explanation. Indeed, several retrospective studies suggest that about one third of patients report improvement of their PNES when asked 3-6 months after diagnosis with no further intervention [17;18]. Most patients who became PNES-free stopped having seizures immediately after the explanation of the condition [15; 19]. Although we did not collect this data in the present ancillary study, it would be interesting to use it in a future analysis of the cohort. It would also be interesting to compare this feeling of clinical improvement with objective data such as the frequency of seizures or the severity of the psychopathological profile. Patients reporting that they feel better may just mean they were out of crisis, but could still be having comorbidities or other events which were not tallied in this study. It is also possible that patients with a good caregiverpatient relationship reported feeling better even if they were no't. And those who did no't have a fine therapeutic relationship reported they were worse.

We initially had the subjective impression that the care pathway was a true barrier to initiating follow-up (long waiting lists, refusal of mental health caregivers to manage patients with PNES…). However, these difficulties were not reflected in our results possibly because the study was not specifically designed to explore this point. It can also be assumed that having specifically informed the mental health caregivers about the patient's participation in a study is a bias that prompted effective management. And yet, it remains difficult today to refer PNES patients to psychologists or psychiatrists in France for several reasons including long waiting-lists and financial constraints: patients are not reimbursed for psychotherapy with a psychologist in private practice, and only partly reimbursed for most private practice psychiatrists; and healthcare public structures are increasingly overloaded and understaffed. These classic obstacles are also found at an international level, with even greater difficulties in the poorer countries [START_REF] Hingray | Access to diagnostic and therapeutic facilities for psychogenic nonepileptic seizures: An international survey by the ILAE PNES Task Force[END_REF]. A recent cohort study [START_REF] Stone | Predicting first attendance at psychiatry appointments in patients with dissociative seizures[END_REF] showed that a first attendance at a psychiatry appointment after a diagnosis of PNES delivered by was not associated with any predictors, including patient confidence in the diagnosis.

Unfortunately, only 9.2% (at the most) of the withdrawals were consensual, i.e., the patient decided to discontinue the program in agreement with his/her caregiver. The originality of this study was to provide some insights about a possible reason for the high rate of non-consensual withdrawals by comparing the dual perspective from both patients and caregivers about the therapeutic relationship. Patients in the "non-consensual withdrawal" group generally rated their relationship less satisfactory than in the other groups: they appeared less confident and unsatisfied with the content of the sessions. This was made clear during the data collection, through multiple changes of therapists and with patients "testing" one or two sessions before stopping. In this subgroup, the discordance with the caregivers is obvious; the caregivers themselves had a much more positive view of the content of their sessions.

One approach to improve this discordant point of view would be to focus on communication between patients and caregivers (a topic which was not directly investigated in our study). It is well known that communication is a challenging issue with PNES patients. Tolchin et al [START_REF] Tolchin | Motivational Interviewing Techniques to Improve Psychotherapy Adherence and Outcomes for Patients With Psychogenic Nonepileptic Seizures[END_REF] suggested that motivational interwiewinterview (MI) as a complement to psychotherapy can improve the interviewer's commitment to collaborating with the patient and thus the patient' engagement in care.

Regardless of the level of adherence to care, overall professionals expressed a more negative vision of care than their patients.

They reported being less comfortable, perceived less care continuity, tended to underestimate the value of the sessions' content and effectiveness compared to their patients. One possible explanation of the discomfort the caregivers feel could be because of their lack of knowledge of PNES. Almost half of French psychiatrists have never dealt with PNES patients, and 75% have never been trained on this disorder [START_REF] Aatti | A crosssectional survey on French psychiatrists' knowledge and perceptions of psychogenic nonepileptic seizures[END_REF].

Caregivers also have a negative perception of PNES patients (and more generally patients with functional disorder), as well as the prognosis of the disease [START_REF] Kanner | Psychiatric and neurologic predictors of psychogenic pseudoseizure outcome[END_REF]. This is unfortunately well described in the literature as the reactance theory: some caregivers see a patient in a distrustful way, leaving the patient feeling defensive or confused about the cause of the symptoms for which he was sincerely seeking help [24 ;25] .

In addition, PNES treatment requires effective collaboration between neurologists and psychiatrists, which appears to be difficult to achieve in routine practice. PNES patients are known to be at the crossroads of neurology and psychiatry, leading to a chaotic patient pathway and therapeutic nomadism [START_REF] Robson | Blaming, shaming, humiliation": stigmatising medical interactions among people with non-epileptic seizures[END_REF]. The majority of authors agree on the value of setting up a multidisciplinary consultation center comprising both neurologists and psychiatrists [START_REF] Haynes | Interventions for helping patients to follow prescriptions for medications[END_REF]. A recent paper [START_REF] Fogarty | Reactance theory and patient compliance[END_REF] described several reasons: poor psychiatry training of neurologists and poor neurology training of psychiatrists, lack of interest in neurologic literature by psychiatrists and vice versa, lack of communication between neurologists and psychiatrists, not enough time in the neurology consultations to explore psychiatric comorbidities. To address this, the authors propose a series of measures to strengthen inter-specialty knowledge. The development of a real "Epi-Psy" sub-discipline would be very interesting [START_REF] Hingray | Stop playing ping-pong! Epi-Psy, an effective discipline to promote" Comment on "Psychiatric comorbidities go unrecognized in patients with epilepsy: 'You see what you know[END_REF].

Our The study's main limitation is that we used a qualitative questionnaire that we developed to explore the caregiver-patient relationship. Even though it is not a validated questionnaire, it is based on recommendations on best practices. An assessment questionnaire is a straightforward, low-cost way of measuring the quality of the caregiving relationship, and is therefore widely used in research [START_REF] Benoit | Comment évaluer la qualité de l'observance ?[END_REF]. During data collection, we realized that the item "not interested/ i I did not see the need for follow-up" could include several different reasons, including anger or disagreement with the diagnosis, which has been shown to be relevant to prognosis.

A possible bias in our study is patient recruitment. It can be assumed that, as in other trials, patients who agree to participate are different from those who do not, for examplenamely in terms of belief in their diagnosis, trust in the medical establishment, empowerment or feeling of self-efficiency.

We can assume that the 3 patients who left the study before M6 would have increased the statistics of the "not following initial recommendations" patient group. However, they represent only 2.7% of the initial population.

In the consensual withdrawal, it was not possible to distinguish the precise given reasons given. It is possible, for example, that the therapist " gives up " the treatment because he or she believes that the treatment is not efficient enough .

Data on caregiver knowledge about PNES included in the study is lacking. We know that the level of knowledge of French psychiatrists is fairly average [START_REF] Aatti | A crosssectional survey on French psychiatrists' knowledge and perceptions of psychogenic nonepileptic seizures[END_REF]. However, the sending of the brochures allowed a common minimum base of knowledge on PNES. We cannot exclude a recruitment bias: caregivers who accept to take care of PNES patients in a research project could be more comfortable with the pathology.

Another limitation is that we were not able to report on the average number of consultations made by patients due to high variability among patients, differences between health care services and various follow-up lengths within the subgroups. Data collection was certainly limited by recall difficulties and desirability response bias of patients and mental health caregivers.

CONCLUSION

Our results highlight the difficulties for adherence to mental health care follow-up after diagnosis of PNES and points up that non-adherence remains a serious problem that tends to increase over time in this population. The lack of interest in follow-up highlighted by the patients, demonstrates the need for better psycho-educative actions to increase a sense of empowerment.

And since adherence is a phenomenon that involves the caregiver as much as the patient, it might be difficult for caregivers to keep patients engaged in care. In fact, the relatively negative view of mental health caregivers on follow-up should also be a target of future training to improve their knowledge and feeling of effectiveness. Finally, interdisciplinarity must be promoted by creating links between the various caregivers.

Nevertheless, a major positive point to retain is the finding that a third of the patients remained in therapy for 24 months following diagnosis, and that they felt satisfied overall and comfortable in the therapeutic relationship.

Future studies are still needed to draw parallels between adherence profiles and factors such as the severity of the disorder and the psychopathological profile.

6.

Figure 1 .Figure 2 .Figure 3 .

 123 Figure 1. Distribution of the different follow-up groups. LS: Left study; LTFU: Lost to follow-up. MO: Inclusion and standardized diagnosis announcement

Figure 4 .

 4 Figure 4. Comparison of qualitative scores between patients and mental health caregivers in the three groups of patients: non-consensual withdrawal, consensual withdrawal, ongoing follow-up.

  DISCONTINUATION QUALITY of CAREGIVER-PATIENT RELATIONSHIP Overall view of therapy (score on 10) -Standardized explanation of PNES diagnosis -Referral to psychiatric care • 5-items questionnaire • Item « overall view of therapy » : -0 : unsatisfactory at all -10 : highly satisfactory

; MHC: Mental health caregivers Score from 0 to 10 (10 >0) P: comparisons between patient and Mental Health Caregivers Figure

  5: Comparison of qualitative scores between patients and mental health caregivers in the two groups of patients: "non-consensual withdrawal" and "consensual withdrawal".

	Non-consensual withdrawal (n=26) P MHC(n =24) 4.9 ± 2.7 4.9 ± 2.4 0.911 p 5.6 ± 2.6 5.0 ± 2.1 0.058 5.2 ± 3.3 5.4 ± 3.4 0.498 4.7 ± 2.6 5.4 ± 2.3 0.035 5.2 ± 3.3 4.8 ± 2.7 0.261 Consensual Feeling of being comfortable, Overall score, M±SD M±SD Continuity of care, M±SD Content of sessions, M±SD Effectiveness of sessions, M±SD withdrawal (n=9) nonconsensual withdrawal (n=26) Overall score 9.0 ± 3.6 5.2 ± 3.3 Feeling of being comfortable 8.5 ± 3.6 4.9 ± 2.7 Continuity of care 7.0 ± 1.4 5.6 ± 2.6 Content of sessions 7.4 ± 2.8 5.2 ± 3.3 Effectiveness of sessions 7.7 ± 1.6 4.7 ± 2.6 P: Patients; MHC: Mental health caregivers Score from 0 to 10 (10 >0) P: PatientsPATIENTS p: comparisons between patient and Mental Health Caregivers Consensual withdrawal P (n=9) MHC(n =8) p 8.5 ± 3.6 5.4 ± 3.6 0001 7.0 ± 1.4 5.6 ± 3.1 0.001 7.4 ± 2.8 4.7 ± 3.9 0.001 7.7 ± 1.6 5.7 ± 2.8 0.001 9.0 ± 3.6 6.6 ± 3.5 0.001 MENTAL HEALTH CAREGIVERS Ongoing follow-up P (n=25) MHC(n =24) p 6.9 ±1.9 6.0 ±3.0 0.001 7.2 ±1.9 6.1 ±2.8 0.001 7.3 ±2.5 6.6 ±3.7 0.001 6.9 ±2.0 6.0 ±2.9 0.001 6.0 ±2.6 5.8 ±2.9 0.455 P consensual withdrawal (n=8) nonconsensual withdrawal (n=24) P 0.004 6.6 ± 3.5 4.8 ± 2.7 0.470 0.059 5.4 ± 3.6 4.9 ± 2.4 0.810 0.055 5.6 ± 3.1 5.0 ± 2.1 0.265 0.004 4.7 ± 3.9 5.4 ± 3.4 0.259 0.001 5.7 ± 2.8 5.4 ± 2.3 0.837

Janssen, Lundbeck, Otsuka, UCB. She received grants from the French National Hospital Program for Clinical Research (PHRC) Wissam El Hage reports personal fees from EISAI, Janssen, Lundbeck, Otsuka, UCB, Roche and Chugai. He received grants from the Fondation de France, and from the French National Hospital Program for Clinical Research (PHRC), unrelated to the submitted work.


Jean-Paul Abecassis

Nadia Ghazzar

Michael Peyromaure

Philippe Giraud
email: philippe.giraud@aphp.fr

Prostate imaging: contribution of PET PSMA and MRI Imagerie de la prostate : apport de la TEP utilisant l'antigène membranaire spécifique de la prostate et de l'IRM

Keywords: Prostate cancer, radiotherapy, Clinical oncology, Functional imaging, Magnetic resonance imaging, Positron-emission tomography-computed tomography, Image-guided radiation therapy Résumé cancer de la prostate, radiothérapie, oncologie médicale, imagerie fonctionnelle, imagerie par résonnance magnétique, tomoscintigraphie par

Prostate cancer is the most common malignant tumour and represents the third cause of cancermortality in men. The management of prostate cancer has dramatically changed over the last decades, mainly due to improvement of diagnostic modalities and development of new therapeutic strategies.

Imaging plays a key role in all the steps of prostate cancer management. In recent years, magnetic resonance imaging (MRI) and positron-emission tomography (PET)-computed tomography (CT) have emerged as two major tools for the detection of prostate cancer, tumour staging and treatment choice.

Both MRI and PET-CT -using choline or prostate-specific membrane antigen (PSMA) as radiotracer -have become mandatory. This article presents the contribution of the latest advances in these two imaging techniques of prostate cancer and their future developments.

Introduction

In western countries, prostate cancer is the most common malignant tumour and represents the third cause of cancer-mortality in men. The management of prostate cancer has dramatically changed over the last decades, due to prostate-specific antigen screening, improvement of diagnostic modalities and development of new therapeutic strategies. Imaging plays a key role in all the steps of prostate cancer management. In recent years, magnetic resonance imaging (MRI) and positron-emission tomographycomputed tomography (PET-CT) have emerged as two major tools for prostate cancer detection, tumour staging and treatment choice.

From an oncologist point of view, the most frequent and challenging questions regarding prostate cancer are: has this patient a potentially aggressive tumour? Is it possible to treat his cancer curatively? Is it possible to perform minimally invasive treatment? Is the tumour recurring? If yes, where is the location of recurrence? Both MRI and PET-CT -using choline or prostate specific membrane antigen as radiotracer -have become unavoidable to answer these questions.

Multiparametric MRI is now widely used by urologists and general practitioners to assess the risk of aggressive prostate cancer in patients with elevated prostate-specific antigen serum concentration. Not only the use of MRI-targeted biopsies improves tumour detection rates, but it also spares patients from unnecessary biopsies when imaging shows no suspicion of cancer. Moreover, MRI findings are correlated to the Gleason score of prostate cancer in 70% of patients [START_REF] Lanz | Gleason score determination with transrectal ultrasound-magnetic resonance imaging fusion guided prostate biopsies--Are we gaining in accuracy?[END_REF]. In patients with newly diagnosed clinically localized prostate cancer, MRI has also become the gold standard for tumour staging. It helps the clinician to make a choice between radical prostatectomy, external beam radiation, brachytherapy, focal treatment or even active surveillance.

In case of locally advanced or high-risk prostate cancer (with prostate-specific antigen serum concentration [PSA] > 20 ng/ml, Gleason score ≥8, clinical stage ≥ T2c), MRI and PET-CT are very helpful to detect small pelvic lymph nodes or seminal vesicles invasion [START_REF] Pinaquy | Comparative effectiveness of ( 18 F)-fluorocholine PET-CT and pelvic MRI with diffusion-weighted imaging for staging in patients with high-risk prostate cancer[END_REF]. Such findings will indicate a combination of radiation and hormone therapy rather than local treatment.

In case of prostate-specific antigen serum concentration elevation following primary local treatment, MRI and PET-CT now represent the optimal modalities to detect locoregional recurrence and/or distant micrometastases. After radical prostatectomy, for instance, MRI shows a sensitivity of 98% and a specificity of 94% for the detection of local recurrence when [PSA] is above 1 ng/ml [START_REF] Panebianco | Prostate cancer recurrence after radical prostatectomy: the role of 3-T diffusion imaging in multi-parametric magnetic resonance imaging[END_REF].

PET-CT using prostate membrane-specific antigen as a tracer (PSMA PET-CT) shows better performances than choline PET-CT for low levels of prostate-specific antigen serum concentration.

PSMA PET-CT has detection rates of 51%, 55%, 70% and 93% for [PSA] < 0.5 ng/ml, 0.5-1 ng/ml, 1-2 ng/ml and 2-5 ng/ml, respectively [START_REF] Evangelista | New clinical indications for ( 18 F)/( 11 C)-choline, new tracers for positron emission tomography and a promising hybrid device for prostate cancer staging: a systematic review of the literature[END_REF].

In such setting, MRI and PET-CT help to distinguish patients who are candidates for secondary local treatment (salvage external radiation or surgery, cryoablation, CyberKnife) and those who require systemic approach (androgenic deprivation and/or chemotherapy). It is acknowledged that they show better accuracy than conventional CT-scan and bone scintigraphy for initial tumour staging, as well as for the detection and evaluation of disease recurrence after primary treatment. However, due to cost issue their real place in routine practice need to be further clarified.

Multiparametric magnetic resonance imaging

Over the past ten years, multiparametric MRI has become an essential tool in the diagnosis, the evaluation and follow-up of prostate cancer. Its widespread has been encouraged by the publication in 2012 of guidelines and scoring system, the Prostate Imaging-Reporting and Data System (Pi-Rads).

The Pi-Rads classification

This system, promoted by the European Society of Urogenital Radiology and the American College of Radiology, aims to a standardization of both acquisition and reporting in the evaluation of prostate cancer, installing a 5-point scale assessment of cancer likelihood, from Pi-Rads 1, very low, to Pi-Rads 5, very high likelihood [START_REF] Turkbey | Prostate Imaging Reporting and Data System Version 2.1: 2019 update of Prostate Imaging Reporting and Data System Version 2.1[END_REF]. Since 2012, two newer versions have been published, currently leading to the utilisation of Pi-Rads v2.1.

Prostate MRI is composed of morphologic sequences (T2) and functional sequences, diffusionweighted imaging and dynamic contrast enhancement. Recent updates have acknowledged the decreasing role of dynamic contrast enhancement in the initial evaluation of prostate cancer, leading to progressive abandonment of gadolinium injection (biparametric MRI) in that clinical scenario. Quality of the results is dependent on the field strength of the magnet (1.5 T or 3 T) and the type of coil used (surface coil or endorectal coil). Although the Pi-Rads Steering Committee has not given definitive recommendations, it is largely admitted among uroradiologists that prostate MRI should be achieved using either 1.5 T-magnet with endorectal coil, or 3 T-magnet, resulting in good spatial resolution and high b values diffusion-weighted imaging (β ≥ 1000).

Reading and reporting with Pi-Rads is based on the concept of a key sequence, which differs with the anatomical region, the peripheral zone or the transition zone. In the peripheral zone, diffusionweighted imaging is almost the only determining factor. In the transition zone, T2 plays a major role, assisted by diffusion-weighted imaging in some cases (Fig 1).

Role of multiparametric MRI

The main indication of multiparametric MRI is the clinical suspicion of prostate cancer, with elevated prostate-specific antigen serum concentration and/or abnormal digital rectal examination, in biopsynaive men and in those with negative standard 12-core systematic biopsy. Expected results in that setting is, besides an accurate estimation of prostate volume, the presence of one or several target lesions, their size and their localisation in order to direct biopsies. Overall sensitivity in detection of significant prostate cancer (Gleason score equal or greater than 7, lesions larger than 1 cm) is 83% [START_REF] Wibulpolprasert | Detection and localization of prostate cancer at 3-T multiparametric MRI using Pi-Rads Segmentation[END_REF].

Multiparametric MRI will also assess the risk of extraprostatic extension of a target lesion with a sensitivity of 57% and a specificity of 91% [START_REF] Mehralivand | A grading system for the assessment of risk of extraprostatic extension of prostate cancer at multiparametric MRI[END_REF]. It will be a valuable tool to determine organconfinement in the setting of positive systematic biopsies or after incidental discovery of prostate cancer during prostatic resection; signs of extraprostatic extension are bulging or disruption of the prostatic capsule, invasion of the anterior fibromuscular stroma, of the periprostatic fat plane or T2 hypointense signal of the seminal vesicles (Fig 2 ); multiparametric MRI will participate in the evaluation of the pelvic lymph nodes.

In the recent years, active surveillance has become an increasingly chosen option after prostate cancer diagnosis; although, the respective role of multiparametric MRI and biopsies is not yet been definitely determined, change in size, modification of signal on diffusion-weighted imaging or lowering of the apparent diffusion coefficient signs a progression of cancer.

After surgery, radiotherapy or brachytherapy, in the presence of rising prostate-specific antigen serum concentrations, multiparametric MRI can be used to assess local recurrence, showing a hypointense focal mass in T2, with restricted diffusion and uptake of contrast after injection of gadolinium-based agent or suspicious pelvic lymph nodes (Fig 3).

Whole-body MRI

When advanced prostate cancer is discovered, exploration of the skeletal system is essential with metastasis disease confined to the bones in 62% of patients at first presentation [START_REF] James | Survival with newly diagnosed metastatic prostate cancer in the "docetaxel era": data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019[END_REF]. Whole-body MRI outperforms bone scan, with a sensitivity of 95% that reach 100% with diffusion-weighted imaging and a specificity of 97% [START_REF] Jambor | Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, ( 18 F)-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial[END_REF]. Whole-body MRI will also detect metastatic lymph nodes based on morphologic criteria but mostly by showing hyperintense signal on diffusion-weighted imaging, with a sensitivity of 72% and a specificity of 86% [START_REF] Thoeny | Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging[END_REF].

Ultrasound-MRI imaging fusion techniques

While detecting area suspicious for prostate cancer is the primary goal of imaging, accurate localisation of target lesions has then become an increasing challenge, either for biopsies or for fiducial markers positioning. While cognitive targeting lacks precision for small lesions, two approaches have been developed in the past years, in bore-MR localisation and ultrasound-MR fusion techniques. Each method has its advantages and drawbacks [START_REF] Verma | The current state of MR imaging-targeted biopsy techniques for detection of prostate cancer[END_REF]. In-bore-MR targeting is the more precise, with direct visualisation of the target and the needle but has a restricted availability and long procedure duration; ultrasound-MR fusion targeting requires a steep learning curve but easily available and allows systematic 12-core biopsies at the same time.

PET/CT for prostate cancer

Positron emission tomography/computed tomography (PET/CT) has recently emerged as a promising diagnostic imaging platform for prostate cancer. Several radiolabelled tracers have demonstrated efficacy for cancer detection in various clinical settings.

In patients diagnosed with intermediate-to high-risk prostate cancer and those with biochemical recurrence, current guidelines recommend disease staging using conventional imaging modalities including CT or MRI of the abdomen and pelvis as well as whole-body bone scintigraphy [START_REF] Thompson | Guideline for the management of clinically localized prostate cancer: 2007 update[END_REF][START_REF] Hovels | The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a metaanalysis[END_REF].

Unfortunately, these methods frequently underestimate the stage of the metastatic disease. As anatomical imaging techniques such as CT or MRI depend solely on morphological features for identifying metastatic disease, lesions smaller than the 8-10 mm threshold are frequently missed [START_REF] Mottet | EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent[END_REF][START_REF] Heesakkers | MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study[END_REF]. On the other hand, malignant lytic bone lesions may have little uptake on bone scan, whereas areas of benign degenerative changes can be mistaken for osteoblastic osseous metastases [START_REF] Horiuchi-Suzuki | Skeletal affinity of Tc(V)-DMS is bone cell mediated and pH dependent[END_REF].

Increased proliferation-based PET imaging: ( 11 C)-choline and ( 18 F)-fluorocholine

Choline is the precursor for phosphatidylcholine, a major component of the cellular membrane. Accumulation of choline is observed in prostate cancer as it is increasingly incorporated into the proliferating tumour cell membranes. Choline analogues radiolabelled with 11 C and 18 F have been used with similar efficacies. Both have shown clear superiority over ( 18 F)-fluorodeoxyglucose. While the ( 18 F)-choline tracer has a much longer half-life (T1/2 = 109.8 min; compared to T1/2 = 20.4 min for 11 C), making its use possible in PET centres without an onsite cyclotron, it is also excreted in the urine within minutes of injection, making assessment of the prostatic bed difficult. Currently, choline PET/CT has been the most extensively studied modality. Although having superior specificity, choline PET/CT suffers from low sensitivity, especially at low prostate-specific antigen serum concentrations.

Nevertheless, choline PET/CT was found to significantly improve upon conventional imaging modalities in the detection of metastatic lesions at biochemical recurrence.

Local detection and primary staging

The shortcomings of choline-based PET/CT radiotracers for the local detection and the ability to detect extraprostatic extension have been well documented. The sensitivity of choline PET/CT for detecting nodal metastases on primary staging was equally poor; however, choline PET/CT has consistently been demonstrated to have higher accuracy for lymph node metastases detection than CT scan and improved sensitivity was demonstrated in patients with high D'Amico risk prostate cancer as well as for lymph node metastases larger than 5 mm [START_REF] Beheshti | F)-choline PET/CT in the preoperative staging of prostate cancer in patients with intermediate or high risk of extracapsular disease: a prospective study of 130 patients[END_REF][START_REF] Evangelista | Comparison between conventional imaging (abdominal-pelvic computed tomography and bone scan) and ( 18 F)-choline positron emission tomography/computed tomography imaging for the initial staging of patients with intermediate-to high-risk prostate cancer: a retrospective analysis[END_REF].

Choline PET/CT has repeatedly shown superior accuracy than bone scan due to its higher image resolution and ability to detect bone marrow metastases at early metabolic stage.

Recurrent staging

Upon biochemical recurrence, choline PET/CT was only able to detect 54 to 73% of local relapsing lesions, clearly underperforming multiparametric MRI. Where choline PET/CT has demonstrated diagnostic value is in the detection of nodal metastases after primary therapy failure (Fig 4). More importantly, choline PET/CT findings at biochemical recurrence have been effectively used to direct site-specific therapy.

The value of recurrent staging by choline PET/CT is augmented by its improved recognition of skeletal metastases. Upon biochemical recurrence after radical prostatectomy, choline PET/CT detected occult bone lesions in 14.6% of patients with negative bone scans (Fig 5).

Strategies for improvement

Choline PET/CT is likely to be useful when prostate-specific antigen serum concentration is above 2 ng/mL and/or its doubling time is less than 6 months. At levels above 2 ng/mL, the majority of the reported sensitivities were above 80% [START_REF] Giovacchini | Predictive factors of ( 11 C)-choline PET/CT in patients with biochemical failure after radical prostatectomy[END_REF]. However, to be useful in guiding salvage radiotherapy within the therapeutic window, choline PET/CT also needs to demonstrate efficacy at low prostatespecific antigen serum concentration ranges after radical prostatectomy failure.

Despite its low sensitivity, choline PET/CT is a good option for prostate cancer staging, most helpful when used to detect recurrent cancer after primary treatment failure. Choline PET/CT has been quickly adopted into clinical practice throughout the world. However, caution must be exercised in interpreting the data until prospective evaluation determines whether the enhanced disease detection can be translated into improved patient outcomes.

Receptor targeted PET imaging: prostate-specific membrane antigen

Newer methods using prostate-specific membrane antigen-targeted radiotracers have preliminarily demonstrated great promise in primary and recurrent staging of prostate cancer. This is based on that over 90% of prostate cancer overexpress prostate-specific membrane antigen, which can be actively targeted by ( 68 Ga)-PSMA PET/CT imaging. The overexpression of prostate-specific membrane antigen in prostate cancer makes it an interesting target for molecular imaging, with normal tissue having almost no expression of this molecule further enhancing delineation between malignant and healthy tissue. On the other hand, prostate-specific membrane antigen expression had been linked to increased cancer aggressiveness as well as progression to androgen independence [START_REF] Cuccurullo | Nuclear medicine in prostate cancer: a new era for radiotracers[END_REF].

As seen with choline PET/CT, detection rates correlated with increasing prostate-specific antigen serum concentration.

The main strength of PSMA PET/CT is its ability to identify small (less than 8 mm) pathological lymph nodes, upstaging nodal status in up to two-thirds of cases. Additionally, PSMA PET/CT, detects bone and bone marrow metastases missed by conventional bone and CT imaging. Thus, PSMA PET/CT has major impact on patient management, with studies reporting overall changes in 39 to 76% of cases.

PSMA PET/CT remains an emerging modality that has not yet been endorsed in the guidelines for the management of prostate cancer pending more established evidence to prove its efficacy.

Additional tracers

Additional ( 18 F)-labelled PET tracers are currently under investigation. Of these, ( 18 F)-PSMA-1007 has already shown efficacy in humans. ( 18 F)-labelled triazolylphenylurea and ( 18 F)-10a are just two of the myriads ( 18 F)-labelled prostate-specific membrane antigen targeted compounds in preclinical development today [START_REF] Treglia | Detection rate of ( 18 F)labeled PSMA PET/CT in biochemical recurrent prostate cancer: a systematic review and a metaanalysis[END_REF].

Conclusions

Multiparametric MRI and PET/CT have emerged as a promising staging modality for both primary and recurrent prostate cancer. Newer tracers for PET/CT have increased detection accuracies for small, incipient metastatic foci. The clinical implications of these occult PET/ CT detected disease foci require organized evaluation.

Depending on the clinical status of the patient at presentation, the following strategies could be suggested:

Figures legendsFig 1 .

 1 Figures legends

Fig 2 .

 2 Fig 2. Prostate cancer imaging: extraprostatic extension. Axial T2-weighted image of a 67-yearold man, with a prostate-specific antigen serum concentration of 42 ng/ml, showing large hypointense lesion with disruption of the prostatic capsule and invasion of the periprostatic fat.

Fig 3 .

 3 Fig 3. Prostate cancer imaging: post-therapeutic relapse. a,b: MRI in a 67-year-old man with rising prostate-specific antigen serum concentration 3 years after prostatic radiotherapy; a: T2-weighted MRI showing diffuse hypointense aspect of the prostate; b: hypersignal of the posterior part of the right lobe on diffusion-weighted MRI, consistent with relapse; c,d: MRI in a 63-year-old man, with a prostate-specific antigen serum concentration of 3 ng/ml after radical prostatectomy; c: T2-weighted MRI showing a 5 mm-hypointense nodule at the right anterior aspect of vesicoureteral anastomosis; d: with corresponding hypersignal on diffusion-weighted MRI.

Fig 4 .

 4 Fig 4. Prostate imaging in a 73-year-old male with prostate adenocarcinoma status post-radiotherapy and biochemical relapse (prostate-specific antigen serum concentration 4.7 ng/mL). Sagittal fused positron-emission tomography-computed tomography (PET-CT) and CT images demonstrating four focal increased 18 F-choline uptake in lombar metastatic lymphe nodes (arrows).

Fig 5 .

 5 Fig 5.Prostate imaging in a 68-year-old male with prostate adenocarcinoma status postradical prostatectomy and radiotherapy and biochemical relapse (prostate-specific antigen serum concentration 6.7 ng/mL). Axial fused positron-emission tomography-computed tomography (PET/CT) image demonstrating bone focal increased ( 18 F)-choline uptake in thoracic vertebra, highly

suspicious of bone metastasis at early metabolic stage because without morphological lesion in the corresponding CT.