# How valid are proxy assessment of mental health and sleep comorbidities of patients with epilepsy using standardized questionnaires?

Chris Serrand, Marie Faucanié, Audrey Jaussent, Arielle Crespel, Marie

Denuelle, Fabrice Bartolomei, Laurent Vercueil, Philippe Derambure, Louise

Tyvaert, Cécile Marchal, et al.

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► To cite this version:

Chris Serrand, Marie Faucanié, Audrey Jaussent, Arielle Crespel, Marie Denuelle, et al. How valid are proxy assessment of mental health and sleep comorbidities of patients with epilepsy using standardized questionnaires?. Seizure - European Journal of Epilepsy, 2023, 111, pp.151-157. 10.1016/j.seizure.2023.08.011. hal-04969182

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# How valid are proxy assessment of mental health and sleep comorbidities of patients with epilepsy using standardized questionnaires?

<figure><img src="image_4.png" /></figure>

Chris Serrand<sup>a,b</sup>, Marie Faucanié<sup>c</sup>, Audrey Jaussent<sup>c</sup>, Arielle Crespel<sup>c</sup>, Marie Denuelle<sup>d</sup>, Fabrice Bartolomei<sup>e</sup>, Laurent Vercueil<sup>f</sup>, Philippe Derambure<sup>g</sup>, Louise Tyvaert<sup>h</sup>, Cécile Marchal<sup>i</sup>, Elisabeth Landre<sup>j</sup>, William Szurhaj<sup>k</sup>, Thibault Mura<sup>a</sup>, Vincent Navarro<sup>l</sup>, Sylvain Rheims<sup>m</sup>, Marie-Christine Picot<sup>b,c,*</sup>

## ARTICLE INFO

**Keywords:**

Verbal autopsy

Inter observer agreement

SUDEP

Psychiatric comorbidities

Sleep disorders

## ABSTRACT

**Background:** The study aimed to determine the level of agreement between patients with epilepsy and their proxies when assessing psychiatric comorbidities, sleep disorders, and medication adherence using standardized questionnaires.

**Methods:** This agreement study is an ancillary analysis of the PRERIES study, a matched case-control study exploring SUDEP risk factors. Controls aged 15 years and older, with active epilepsy or in remission for less than 5 years were recruited between 01/01/2011 and 03/31/2019. An interview was carried out by a trained psychologist on both the patient and a proxy-respondent. During these independent interviews, the following comorbidities were explored: psychiatric comorbidities using the MINI, the STAI- Y₂ and NDDI-E scales, sleep disorders with the SDQ-SA and Epworth scales and medication adherence. Level of agreement between patient and their proxy was estimated using Gwet's AC1&2.

**Results:** Among the 107 patient-proxy dyads recruited, proxy respondents were mainly family members (65.4%) or spouses (30.8%). Exploration of present major depression showed excellent agreement at 0.81 [0.65;0.97], as well as exploration of dysthymia at 0.96 [0.61;1]. Suicidal risk evaluation had a lesser agreement at 0.77 [0.60;0.94]. Agreement on anxiety was moderate 0.5 [0.38;0.62]. For sleep disorder, SDQ-SA presented a better agreement than the Epworth questionnaire with respectively 0.73 [0.51;0.95] and 0.45 [0.26;0.63]. For medication adherence, the overall agreement rate was excellent (0.90 [0.78;1]).

**Conclusion:** Exploration of potential risk factors through families can give valuable and relatively robust information, especially if the respondent lives with the patient, and should be retrieved, when possible, in usual clinical setting.

<footnote><sup>a</sup> Department of Biostatistics, Epidemiology, Public Health and Innovation in Methodology, CHU Nîmes, Univ. Montpellier, Nîmes, France</footnote>

<footnote><sup>b</sup> CESP, Villejuif Paris, France</footnote>

<footnote><sup>c</sup> CHU Montpellier, Univ. Montpellier, France</footnote>

<footnote><sup>d</sup> University Hospital of Toulouse, Toulouse, France</footnote>

<footnote><sup>e</sup> University Hospital of Marseille, Marseille, France</footnote>

<footnote><sup>f</sup> University Hospital of Grenoble, Grenoble, France</footnote>

<footnote><sup>g</sup> University Hospital of Lille, Lille, France</footnote>

<footnote><sup>h</sup> University Hospital of Nancy, Nancy, France</footnote>

<footnote><sup>i</sup> University Hospital of Bordeaux, Bordeaux, France</footnote>

<footnote><sup>j</sup> University Hospital of Paris St Anne, Paris, France</footnote>

<footnote><sup>k</sup> Clinical Neurophysiology Department, CHU Amiens, UR 7516, CHIMERE, University of Picardie Jules Verne, Amiens, France</footnote>

<footnote><sup>l</sup> Sorbonne Université, AP-HP, Pitié-Salpetrière Hospital, Epilepsy Unit, Paris Brain Institute, ICM, Reference Center for Rare epilepsies, 75013, Paris, France</footnote>

<footnote><sup>m</sup> Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and University of Lyon, Lyon, France</footnote>

<footnote>* Corresponding author at: Unité de recherche clinique et épidémiologie, Service de santé Publique, CHU Montpellier - Hôpital La Colombière, 291 avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 05.</footnote>

<footnote>E-mail address: mc-picot@chu-montpellier.fr (M.-C. Picot).</footnote>

<footnote>https://doi.org/10.1016/j.seizure.2023.08.011</footnote>

<footnote>Received 26 April 2023; Received in revised form 6 August 2023; Accepted 18 August 2023</footnote>

<footnote>Available online 19 August 2023</footnote>

<footnote>1059-1311/© 2023 British Epilepsy Association. Published by Elsevier Ltd. This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/).</footnote>
<figure><img src="image_5.png" /><figcaption>Fig. 1. Flow Chart.</figcaption></figure>

# 1. Introduction

In healthcare, medical information should ideally be assessed directly with the patient. However, sometimes this is impossible, for example, when assessing subjective data such as health-related quality of life of very young children or in patients with dementia or with major intellectual disability. This can also be challenging when assessing psychiatric diagnoses that require thorough interview. For such cases, information from a proxy respondents can be valuable [1]. This is particularly true in the case of Sudden Unexpected Death in Epilepsy (SUDEP). This rare event is one of the reason for an up to 5 times higher risk of mortality in patients with epilepsy compared to the general population [2]. Indeed SUDEP represents a challenge for research. Even with well-kept medical records, knowledge about the patient's condition at the time of death is often patchy. Thus, essential clinical information, potentially related to the occurring of the SUDEP, such as the presentation of recent seizures, comorbidities or medication adherence are often derived from previous medical observations although these factors are far from negligible. Psychiatrics comorbidities are highly prevalent in epilepsy patient, with one third of patients presenting mood disorders and one quarter anxiety disorders [3], while sleep apnea can be found in as much as 30% of adult with epilepsy when looking at drug-resistant profiles [4]. For these reasons, using interviews with relatives of deceased patients is an indirect but essential source of information, and has already been established in postmortem research based on verbal or psychological autopsy [5–7].

Verbal autopsy is a survey method seeking information from deceased persons that would otherwise be inaccessible. It consists in questioning one or more relatives (or proxy) in a standardized, and therefore reproducible, interview using a questionnaire. This can be used to assess the cause of death and circumstances of death, but can

also gather otherwise unavailable data. The validity of the reported clinical information in these situations is questionable [6] but has never been explored in epilepsy patients. With the support of the French League Against Epilepsy (LFCE) and the French Foundation for Research on Epilepsy (FFRE), a case-control epidemiological study looking for risk factors of SUDEP (PRERIES study) [8] has been on-going since 2010 in France. The PRERIES study sought potential risk factors for SUDEP such as psychiatric comorbidities, sleep apnea and medication adherence by interviewing the families using the psychological autopsy method, based on INSERM guidelines [9], a technique commonly used in the context of suicide. To check the validity of the retrieved information, the PRERIES study also interviewed both the control patient population and a proxy.

The aim of our study was to investigate the degree of agreement between patients with epilepsy and their proxy. We wished to evaluate the validity of questionnaires in collecting information on the psychiatric comorbidities, sleep disorders and medication adherence using a verbal autopsy technique.

# 2. Methods

This agreement study [10] is an ancillary analysis focused on the matched control group of the national epidemiological PRERIES study (NCT03074279), a paired case-control study exploring SUDEP risk factors. Here, both live control patients and a close proxy were administered a series of questionnaires to assess the validity of information retrieved in the case group (where only the information provided by the family was available).

The population consisted in patients aged 15 years and older, with active epilepsy or in remission with or without treatment for less than 5 years. Eligible control patients were first screened from a national pseudonymized database, the French epilepsy patient registry GRENAT
<table><caption>**Table 1**
Patients characteristics.</caption><thead><tr><th>Socio demographic n (%)</th><th>Missing</th><th>n (%)</th></tr></thead><tbody><tr><td>Sex (Women)</td><td>0</td><td>53 (49.5)</td></tr><tr><td>Age mean (± sd)</td><td>0</td><td>31.7 (± 11.6)</td></tr><tr><td>Alcohol consumption</td><td>0</td><td>77 (72.0)</td></tr><tr><td>Tabaco usage</td><td>0</td><td>48 (44.9)</td></tr><tr><td>Type of accommodation</td><td>0</td><td></td></tr><tr><td>With family</td><td></td><td>35 (32.7)</td></tr><tr><td>Marital Household</td><td></td><td>50 (46.7)</td></tr><tr><td>Alone</td><td></td><td>22 (20.6)</td></tr><tr><td>Employment status</td><td>1</td><td></td></tr><tr><td>Employed</td><td></td><td>47 (44.3)</td></tr><tr><td>Unemployment</td><td></td><td>33 (31.1)</td></tr><tr><td>Student</td><td></td><td>23 (21.7)</td></tr><tr><td>Retired</td><td></td><td>3 (2.8)</td></tr><tr><td>Relationship with the proxy respondent</td><td>0</td><td></td></tr><tr><td>Family member</td><td></td><td>70 (65.4)</td></tr><tr><td>Spouse</td><td></td><td>33 (30.8)</td></tr><tr><td>Other*</td><td></td><td>4 (3.7)</td></tr><tr><td>Close proxy (living with the patient)</td><td></td><td>64 (59.8)</td></tr><tr><td><strong>Comorbidities</strong></td><td></td><td></td></tr><tr><td>Intellectual disability</td><td>7</td><td>5 (5.0)</td></tr><tr><td>Cardiac comorbidity</td><td>8</td><td>7 (7.1)</td></tr><tr><td>Vascular comorbidity</td><td>9</td><td>4 (4.1)</td></tr><tr><td>Respiratory comorbidity</td><td>7</td><td>10 (10.0)</td></tr><tr><td>Sleep apnea</td><td>11</td><td>6 (6.3)</td></tr><tr><td>Anxiety</td><td>12</td><td>37 (40.0)</td></tr><tr><td>Present depression*</td><td>5</td><td>25 (24.5)</td></tr><tr><td>Past depression</td><td>5</td><td>36 (35.3)</td></tr><tr><td>History of suicide attempt</td><td>1</td><td>19 (17.9)</td></tr><tr><td><strong>Epilepsy characteristics</strong></td><td></td><td></td></tr><tr><td>Epilepsy duration median years (Q1;Q3)</td><td>0</td><td>14.8 (10.6;23.6)</td></tr><tr><td>Epilepsy type</td><td>0</td><td></td></tr><tr><td>Focal</td><td></td><td>79 (73.8)</td></tr><tr><td>Generalised or combined</td><td></td><td>28 (26.2)</td></tr><tr><td>Mean number of focal seizures per month (in the last 3 months)</td><td>25</td><td></td></tr><tr><td>&lt; 1</td><td></td><td>14 (17.1)</td></tr><tr><td>between 1 and 4</td><td></td><td>30 (36.6)</td></tr><tr><td>&gt; 4</td><td></td><td>38 (46.3)</td></tr><tr><td>Mean number of generalised seizures per month (in the last 3 months, for patient with generalised seizures)</td><td>3</td><td></td></tr><tr><td>&lt; 1</td><td></td><td>19 (79.2)</td></tr><tr><td>1 or more</td><td></td><td>6 (20.8)</td></tr><tr><td>Usual seizure time</td><td>0</td><td></td></tr><tr><td>Rather at night</td><td></td><td>18 (16.8)</td></tr><tr><td>Rather at day</td><td></td><td>57 (53.3)</td></tr><tr><td>Both night and day</td><td></td><td>32 (29.9)</td></tr><tr><td>Epilepsy surgery</td><td>13</td><td></td></tr><tr><td>Yes</td><td></td><td>9 (9.6)</td></tr><tr><td>No</td><td></td><td>85 (10.4)</td></tr><tr><td>Epilepsy etiology (Focal epilepsy)</td><td>41</td><td></td></tr><tr><td>Cortical malformations</td><td></td><td>14 (36.8)</td></tr><tr><td>Brain tumours</td><td></td><td>7 (18.4)</td></tr><tr><td>Infectious diseases</td><td></td><td>4 (10.5)</td></tr><tr><td>Head injury</td><td></td><td>7 (18.4)</td></tr><tr><td>Surgical adverse event</td><td></td><td>3 (7.9)</td></tr><tr><td>Other*</td><td></td><td>3 (7.9)</td></tr><tr><td>Treatment response</td><td>0</td><td></td></tr><tr><td>Drug resistant</td><td></td><td>78 (72.9)</td></tr><tr><td>Drug sensitive</td><td></td><td>28 (26.2)</td></tr><tr><td>insufficient hindsight (&lt; 1 year)</td><td></td><td>1 (0.9)</td></tr><tr><td>Medication adherence</td><td>0</td><td></td></tr><tr><td>Excellent</td><td></td><td>93 (86.9)</td></tr><tr><td>Average</td><td></td><td>13 (12.2)</td></tr><tr><td>Poor</td><td></td><td>1 (0.9)</td></tr></tbody></table>

[11] (www.grenat.org), and from databases of French epilepsy exploration centers. Once identified, the referring neurologist was contacted. He sent a standardized letter to the eligible patient. Inclusion in the study was then done by the referring neurologist. In this ancillary

analysis, patients were included only if they underwent the interview with a psychologist, as well as their proxy respondent. Participants were recruited between 01/01/2011 and 03/31/2019.

Socio-demographic and lifestyle data, as well as personal and family history, were collected via a standardized questionnaire. Epilepsy characteristics were collected from the referring neurologist and completed using the medical records of the epilepsy centers that performed the patient's diagnostic work-up. Medical records were also used to evaluate past and present comorbidities.

An interview of about 1.5 h in person or by telephone was conducted by the same trained psychologist independently for the patient and the proxy (family member, spouse or friend). Patient or proxy were randomly contacted first, depending of schedule availability and both interview were usually made at different day, close to each other (less than 1 week for the most part). Interviews included the exploration of psychiatric comorbidities, sleep apnea and daytime sleepiness, and medication adherence.

Psychiatric comorbidities were recorded using a French validated semi-structured interview, the Mini International Neuropsychiatric Interview (MINI) and two French validated scales (STAI-Y₂ and NDDI-E). For the MINI [12], only the modules "Major depressive disorder", "Dysthymic disorder" and "Suicidality" were used. For the six-item Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) [13], a score above 15 was considered to indicate the presence of a current episode of major depression. Anxiety was explored using the State Trait Inventory Anxiety form (STAI-Y₂) [14]. Composed of 20 graded questions, 5 levels of anxiety were defined according to the final score: above 65 (very high), 56–65 (high), 46–55 (medium), 36–45 (low), below 35 (very low). Sleep disorders were explored via the French version of SDQ-SA and Epworth questionnaires. For sleep apnea, the Sleep Apnea Scale of the Sleep Disorders Questionnaire (SDQ-SA) [15] was administered. Consisting of 12 items, a cut-off of 25 was used to define suspected sleep apnea, as recommended in the epilepsy patient population [16]. The Epworth scale [17] is simpler with only six questions; a score above 10 was indicative of excessive daytime sleepiness, potentially indicative of sleep apnea. Finally, medication adherence was estimated through four simple “yes or no” questions, focusing on:

1. The overall careless attitude towards taking medication

2. The occurrence of forgetting to take their medication

3. Voluntary reduction of dosage without medical advice when feeling better

4. Voluntary increase of dosage without medical advice when feeling worse

Compliance was considered excellent if all four questions were answered negatively; average if one or two questions were answered positively; and poor if three or all four questions were answered positively.

## 2.1. Statistical analysis

Characteristics of patients are presented by their frequency and associated percentage for categorical variables and by the mean and standard deviation or median with inter-quartile range for quantitative variables. To explore if epilepsy type affected the perception from the proxy respondent, patients with generalized epilepsy or combined focal & generalized epilepsy, such as in Lennox Gastaut were pooled together as generalized while the others were pooled as focal. The agreement between patient and proxy was estimated by Gwet's AC1 for nominal variables and by Gwet's AC2 for ordinal variables, with 95% confidence intervals. These estimates are interpreted in the same way as the Cohen's kappa and reflect the degree of agreement between respondent (is the information gathered from both similar or not). Although less common then kappa, Gwet's agreement coefficients, are much less affected by marginal probabilities and present a compelling alternative in

<footnote>* 3 friends, 1 healthcare professional in an institution.</footnote>

<footnote># 2 Strokes, 1 hippocampic sclerosis.</footnote>

<footnote>° As recorded in the medical file.</footnote>
<figure><img src="image_6.png" /><figcaption>Fig. 2. Level of agreement according to Gwet's AC.</figcaption></figure>

agreement study based on real life conditions [18]. Estimations could vary between 0 and 1, and an estimate below 0.4 was considered to show poor agreement, between 0.4 and 0.6 moderate agreement, between 0.6 and 0.8 good agreement and above 0.8 it was considered excellent [18].

The agreement analysis was conducted on the whole population and in the following subgroups: in men and in women; according to the type of epilepsy; and according to the proximity of the respondent to the patient. The proxy respondent was considered close in two cases: (i) family member living with the patient, or (ii) spouse living at home with the patient. All statistical analyses were performed using SAS® 9.4 software.

Results are reported according to the GRRAS recommendations [10].

## 2.2. Standard protocol approvals, registrations and patient consents

This study was approved by the national committee authorizing data collection (CNIL n° DR-2010-3030) and an French ethics committee: the “Sud Est II” committee for the protection of persons (CPP Sud Est II n° 2010-006-AM6).

## 3. Results

In this study, 331 patient-proxy dyads were screened, of whom 70 were excluded for a lack of psychologist interview and a further 154 due to lack of data from the proxy. Finally, 107 patient-proxy dyads were analyzed (Fig. 1).

The characteristics of the population are described in Table 1. Briefly, the epilepsy patient population consisted of 49.5% women, with an average age of 31.7 ± 11.6 years. The majority of the proxy respondents were family members (65.4%) or spouses (30.8%). Only five patients with moderate intellectual disability were included, due to interview difficulties. For epilepsy characteristics, 73.8% of patients had focal epilepsy compared to 26.1% with generalized epilepsy. Nine patients had undergone epilepsy surgery and 72.9% of the patients were drug resistant, compared to 26.1% who were drug sensitive.

Agreement estimates between patient and proxy are shown in Fig. 2 and showed excellent agreement for current major depression by the MINI (0.81 [0.65; 0.97]), and only good agreement by the NDDI-E (0.67 [0.5; 0.84]). In contrast, exploration of past major depression by the MINI showed very poor agreement with a Gwet's AC1 of 0.3 [0.12; 0.49]. Exploration of melancholia or dysthymia by the MINI also showed excellent agreement with respectively a Gwet's AC1 of 0.91 [0.74; 1] and 0.96 [0.61; 1]. Suicide risk evaluation had a slightly poorer agreement with a Gwet's AC1 of 0.77 [0.60; 0.94]. The STAI-Y₂ questionnaire showed a moderate agreement on the level of anxiety (0.5 [0.38; 0.62]).

For the exploration of sleep disorder, SDQ-SA seemed to have a better inter-rater agreement than the Epworth questionnaire with a Gwet's AC2 of respectively 0.73 [0.51; 0.95] and 0.45 [0.26; 0.63]. Finally, the overall agreement rate for medication adherence was excellent (0.90 [0.78; 1]), except for the question on the overall careless attitude towards taking medication (0.42 [0.24; 0.6]) (Table 2).

These agreement estimates did not vary greatly in subgroup analysis (Table 3). Of note, agreement appeared slightly better in men compared to women when assessing the suicidal risk using the MINI, but with an inverse effect when exploring current depression, with either the MINI or NDDI-E. As expected, agreement was consistently better when the proxy respondent lived with the patient, either being the spouse or a family member. This effect was most evident when exploring sleep apnea using the SDQ-SA with an agreement estimate of 0.83 [0.60; 1] for dyads living together, compared with 0.56 [0.18; 0.93] for others.

## 4. Discussion

In this study, we found good-to-excellent agreement between patients and their proxy respondents when exploring current psychiatric pathologies using the MINI. However, the NDDI-E revealed much weaker agreement, and agreement was only moderate when exploring anxiety with the STAI-Y₂ questionnaire. When exploring a more functional pathology such as sleep apnea, agreement was good with the SDQ-SA but moderate with the Epworth. Regarding compliance with
<table><caption>**Table 2**
Agreement for each explored elements between patient and their proxy.</caption><thead><tr><th></th><th>According to<br>Patient n (%)</th><th>According to<br>Proxy n (%)</th><th>Gwet's AC<br>[95% CI]</th></tr></thead><tbody><tr><td><strong>Agreement on:</strong></td><td></td><td></td><td></td></tr><tr><td><strong>Psychiatric comorbidities<br>exploration:</strong></td><td></td><td></td><td></td></tr><tr><td>Present depression (MINI)</td><td>15 (15.2)</td><td>7 (7.1)</td><td>0.81 [0.65;<br>0.97]</td></tr><tr><td>Present depression<br>(NDDI-E)</td><td>22 (21.8)</td><td>17 (16.8)</td><td>0.67 [0.5;<br>0.84]</td></tr><tr><td>Past depression (MINI)</td><td>38 (38.4)</td><td>41 (41.4)</td><td>0.3 [0.12;<br>0.49]</td></tr><tr><td>Present Melancholia<br>(MINI)</td><td>7 (7.4)</td><td>2 (2.1)</td><td>0.91 [0.74;<br>1]</td></tr><tr><td>Present dysthymia (MINI)</td><td>0 (0)</td><td>2 (7.7)</td><td>0.96 [0.61;<br>1]</td></tr><tr><td>Present suicidal risk<br>(MINI)</td><td>23 (23.7)</td><td>9 (9.3)</td><td>0.77 [0.6;<br>0.94]</td></tr><tr><td>Present anxiety level</td><td></td><td></td><td>0.5 [0.38;<br>0.62]</td></tr><tr><td>STAI- Y<sub>2</sub><sup>*</sup></td><td></td><td></td><td></td></tr><tr><td>Very Low</td><td>21 (20.4)</td><td>17 (16.5)</td><td></td></tr><tr><td>Moderate</td><td>28 (27.2)</td><td>35 (34)</td><td></td></tr><tr><td>moderately high</td><td>34 (33)</td><td>28 (27.2)</td><td></td></tr><tr><td>High</td><td>14 (13.6)</td><td>21 (20.4)</td><td></td></tr><tr><td>Very High</td><td>6 (5.8)</td><td>2 (1.9)</td><td></td></tr><tr><td><strong>Sleep apnea & daytime<br>sleepiness exploration:</strong></td><td></td><td></td><td></td></tr><tr><td>With the SDQ-SA <sup>**</sup></td><td>32 (50)</td><td>17 (26.6)</td><td>0.73 [0.51;<br>0.95]</td></tr><tr><td>With the Epworth <sup>†</sup></td><td>42 (41.2)</td><td>26 (25.5)</td><td>0.45 [0.26;<br>0.63]</td></tr><tr><td><strong>Medication adherence<br>explorations:</strong></td><td></td><td></td><td></td></tr><tr><td>Overall adherence</td><td></td><td></td><td>0.90 [0.78;<br>1]</td></tr><tr><td>Poor</td><td>0 (0)</td><td>1 (0.9)</td><td></td></tr><tr><td>Moderate</td><td>18 (17)</td><td>14 (13.2)</td><td></td></tr><tr><td>High</td><td>88 (83)</td><td>91 (85.8)</td><td></td></tr><tr><td>1 Careless attitude towards<br>taking medication</td><td>90 (84.9)</td><td>71 (67)</td><td>0.42 [0.24;<br>0.6]</td></tr><tr><td>1 Sometimes forget to take<br>medication</td><td>17 (16)</td><td>14 (13.2)</td><td>0.83 [0.68;<br>0.99]</td></tr><tr><td>1 Less compliance when<br>feeling better</td><td>2 (1.9)</td><td>3 (2.8)</td><td>0.95 [0.79;<br>1]</td></tr><tr><td>1 Less compliance when<br>feeling worse</td><td>0 (0)</td><td>4 (3.8)</td><td>0.96 [0.8;<br>1]</td></tr></tbody></table>

* Explored by the NDDI-E, a patient was considered depressed when the total score was over 15.

* Explored by the STAI- Y₂, there was 5 anxiety levels (0–35= very low, 35–45= moderate, 45–55=moderately high, 55–65=high, >65= very high).

† For the SDQ-SA, sleep apnea was considered probable when score was over 25.

§ For the Epworth, sleep disorder was considered probable when the score was over 10.

medication, the agreement was excellent overall, but with weaker agreement when asked about the careless attitude toward taking medication.

Unsurprisingly, agreement was generally better when the patient and proxy lived together (either spouse or family) for all indicators. Exploring agreement by sex or epilepsy type did not substantially alter estimates, in line with previous findings [19].

The agreement between the answers given by a proxy and those given by the patient has previously been explored in specific contexts such as the agreement on subjective measures between children and their parents [19–22] or between a care taker and a patient with diminished cognitive functions [23]. In these cases, the aim was to evaluate whether the assessment of a caretaker or relative could be used to evaluate a health condition and, subsequently, adapt care. The results of these studies are contradictory, with good agreement often found when measuring objective criteria or presenting a clearly externalized symptomatology or with greater severity [1,23–27], yet poor agreement

for more subjective information such as the quality of life [23,28–30]. There is also a more varying agreement for patient with intellectual disabilities [31]. This should be kept in mind when proxy information is reported. In epilepsy, the cognitive state is generally not impaired, with the exception of developmental and epileptic encephalopathies associated with intellectual disability.

In the context of research on SUDEPs, we are interested in patients for whom self-reported information is no longer measurable. This has already been explored in the slightly different case of suicide risk factors [32]. The psychological autopsy performed in these cases allows the clinician to gather valuable and otherwise unavailable information on the mental state of the suicide completor [32]. This information, even if incomplete, can improve prevention by identifying potentially precipitating factors. This type of interview allows information to be cross referenced between several relatives and the medical file. This also allows for more complete information on all patients, as it avoids the bias linked to unequal patient follow-up, as some patients limit their follow-up with a health professional through choice or economic or logistical difficulty [6]. However, to make the most of this source of information, it is necessary to have the cooperation of a good proxy, sufficiently close to the patient, as seen here in the subgroup analyses (Table 3). This kind of interview must be undertaken carefully, given the delicate period of mourning after a sudden event such as SUDEP, as laid out in the recommendations [9,33]. Interestingly, these interviews can allow the healthcare teams to follow-up on the family and had a therapeutic effect [34], helping the family in their mourning.

In epilepsy, the agreement between patient and family has only been explored in very particular cases of agreement between children with epilepsy and their parents [22,29,35]. It first showed limited agreement, especially when a subjective criterion is being evaluated. However, Stevanovic et al. showed encouraging results with an acceptable agreement between child self-report and parent proxy-report when evaluating depression and anxiety with specific questionnaires in pediatric epilepsy [35].

Agreement between adults is also linked to the level of proximity of the respondents. In particular, the results are better for family members than for friends [36]. This supports our results regarding proximity, measured by the relationship to the patient but also if the person shared the patient's living space.

In the field of epilepsy, few studies have looked at the quality of the information collected when direct assessment was impossible, as in SUDEP. In order to explore the potential precipitating factor of SUDEP, it is necessary to access as much information as possible in a time frame as close as possible to the event. The assessment of the agreement of information provided by a relative is therefore essential

## 4.1. Strengths and weaknesses

This study has a number of weaknesses. Firstly, these results are limited to a specific subgroup of patients with epilepsy, whose profile differs from the national average. Indeed, the rate of patients with drug resistant epilepsy was twice as high as that described in the literature [37]. This result is expected given that our patients were matched to SUDEP cases, who have less controlled epilepsy, partly because of drug-resistance.

The sample size was also limited, leading to some estimates with wide confidence intervals. The number of questionnaires explored in this study was also restricted on specific domains considered most relevant in the search for risk factors of SUDEP and to avoid overwhelming respondents to maximize response rate. Questions about adherence were also subjective and limited to binary response and therefore we were not able to finely judge the degree of adherence. The interviewing psychologist was also not blind to the proxy or patient, which could have increased the level of agreement, even if use of standardized questionnaires should have limited this potential bias.

One of the strengths of this study is that the interviews were
<table><caption>**Table 3**
Subgroup agreement analysis</caption><thead><tr><th></th><th>Male patient<br>n=54</th><th>Female<br>Patient n=53</th><th>Focal epilepsy<br>n=79</th><th>Generalized & Combined<br>epilepsy n=28</th><th>Respondent living with the<br>patient n=64</th><th>Respondent not living with<br>the patient n=43</th></tr></thead><tbody><tr><td><strong>Agreement on:</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Psychiatric comorbidities<br>exploration:</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Present depression (MINI)</td><td>0.76 [0.54;<br>0.99]</td><td>0.85 [0.63; 1]</td><td>0.82 [0.64;<br>0.99]</td><td>0.78 [0.43; 1]</td><td>0.91 [0.74; 1]</td><td>0.63 [0.39; 0.87]</td></tr><tr><td>Present depression (NDDI-E)</td><td>0.55 [0.3;<br>0.79]</td><td>0.79 [0.55; 1]</td><td>0.66 [0.47;<br>0.86]</td><td>0.69 [0.35; 1]</td><td>0.72 [0.53; 0.91]</td><td>0.57 [0.29; 0.85]</td></tr><tr><td>Past depression (MINI)</td><td>0.37 [0.11;<br>0.64]</td><td>0.24 [0; 0.5]</td><td>0.25 [0.03;<br>0.47]</td><td>0.5 [0.11; 0.9]</td><td>0.34 [0.09; 0.59]</td><td>0.22 [-0.09; 0.53]</td></tr><tr><td>Present Melancholia (MINI)</td><td>0.91 [0.68;<br>1]</td><td>0.9 [0.67; 1]</td><td>0.91 [0.73; 1]</td><td>0.9 [0.54; 1]</td><td>0.98 [0.82; 1]</td><td>0.78 [0.54; 1]</td></tr><tr><td>Present dysthymia (MINI)</td><td>0.93 [0.45;<br>1]</td><td>-</td><td>0.94 [0.52; 1]</td><td>-</td><td>0.95 [0.59; 1]</td><td>-</td></tr><tr><td>Present suicidal risk (MINI)</td><td>0.89 [0.65;<br>1]</td><td>0.64 [0.4;<br>0.88]</td><td>0.78 [0.59;<br>0.97]</td><td>0.73 [0.39; 1]</td><td>0.75 [0.56; 0.94]</td><td>0.82 [0.58; 1]</td></tr><tr><td>Present anxiety level STAI-Y<sub>2</sub><sup>*</sup></td><td>0.51 [0.34;<br>0.68]</td><td>0.5 [0.33;<br>0.66]</td><td>0.53 [0.39;<br>0.66]</td><td>0.43 [0.21; 0.65]</td><td>0.52 [0.39; 0.65]</td><td>0.47 [0.3; 0.64]</td></tr><tr><td><strong>Sleep apnoea exploration &<br>daytime sleepiness</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>SDQ-SA <sup>**</sup></td><td>0.62 [0.28;<br>0.95]</td><td>0.82 [0.53; 1]</td><td>0.75 [0.49; 1]</td><td>0.69 [0.26; 1]</td><td>0.83 [0.6; 1]</td><td>0.56 [0.18; 0.93]</td></tr><tr><td>Epworth <sup>§</sup></td><td>0.56 [0.31;<br>0.81]</td><td>0.33 [0.06;<br>0.59]</td><td>0.47 [0.26;<br>0.69]</td><td>0.37 [0.02; 0.73]</td><td>0.55 [0.34; 0.77]</td><td>0.26 [0; 0.58]</td></tr><tr><td><strong>Medication adherence<br>questions</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall adherence</td><td>0.89 [0.71;<br>1]</td><td>0.91 [0.77; 1]</td><td>0.91 [0.80; 1]</td><td>0.86 [0.59; 1]</td><td>0.90 [0.76; 1]</td><td>0.79 [0.58; 1]</td></tr><tr><td>Careless attitude towards<br>taking medication</td><td>0.43 [0.17;<br>0.69]</td><td>0.42 [0.17;<br>0.67]</td><td>0.49 [0.29;<br>0.7]</td><td>0.22 [0; 0.59]</td><td>0.58 [0.35; 0.8]</td><td>0.11 [0; 0.43]</td></tr><tr><td>Sometimes forget to take<br>medication</td><td>0.79 [0.57;<br>1]</td><td>0.88 [0.66; 1]</td><td>0.86 [0.69; 1]</td><td>0.75 [0.44; 1]</td><td>0.83 [0.66; 1]</td><td>0.83 [0.62; 1]</td></tr><tr><td>Less compliance when feeling<br>better</td><td>0.96 [0.74;<br>1]</td><td>0.94 [0.72; 1]</td><td>0.97 [0.8; 1]</td><td>0.88 [0.57; 1]</td><td>0.91 [0.76; 1]</td><td>-</td></tr><tr><td>Less compliance when feeling<br>worse</td><td>0.94 [0.72;<br>1]</td><td>0.98 [0.76; 1]</td><td>0.94 [0.77; 1]</td><td>0.88 [0.57; 1]</td><td>0.95 [0.8; 1]</td><td>0.98 [0.77; 1]</td></tr></tbody></table>

conducted under medical conditions, as described in psychological topsy, by an experienced psychologist. This allows for better agreement than if the interviews were collected by different untrained practitioners. The results also show that the relative can be relied upon relatively well for the assessment of depression or medication adherence, provided the person is close enough, defined here by the living condition between patient and proxy. For information on depression, the MINI seemed preferable to the NDDI-E and provided more consistent information, whereas for sleep disorder, the SDQ-SA seemed to be more appropriate than the Epworth.

## 5. Conclusion

In the context of interviews with bereaved families following a SUDEP, comorbidities present at the time of death could be explored with standardized questionnaires, making it possible to gather valuable information of relatively good quality for research. Caution should be applied to corroborate the medical information with the patient's medical record and the neurologists, if possible.

## Contributors

M-C P proposed the objective, conception and design of the study.
M-C P, MF ensured the coordination of the RSME network centres,
including the completion and accuracy of the clinical data.

M-C P, AJ and CS contributed to conception, data management and

analysis of data.

CS was responsible for the statistical analysis.

CS, M-C P, drafted the manuscript.

MCP and CS were responsible for the overall content as guarantors.

All authors contributed to the critical revision of the manuscript for important intellectual content, and gave their final approval of the version to be published. The corresponding author certifies that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

## Declaration of Competing Interest

None.

## Data availability

The raw data after de-identification can be shared upon individual request to Marie-Christine Picot: mc-picot@chu-montpellier.fr.

## Acknowledgments

We specially thank Bernadette Larquier, head of the Bereaved Families Network of the RSME, Myriam Boulhais, psychologist of the RSME, Sarah Kabani for editing the manuscript, and Dr Anna Kaminska from the GRENAT registry. We also thank the investigators of the

<footnote>* Explored through the NDDI-E, a patient was considered depressed when the total score was over 15</footnote>

<footnote>* Explored through the STAI-Y<sub>2</sub>, there was 5 anxiety levels (0-35= very low, 35-45= moderate, 45-55=moderately high, 55-65=high, >65= very high)</footnote>

<footnote>§ For the SDQ-SA, sleep apnea was considered probable when score was over 25</footnote>

<footnote>For the Epworth, sleep disorder was considered probable when the score was over 10</footnote>

<footnote>could not be computed because of a low number of response</footnote>
PRERIES Study that included patients but were not among the authors: Isnard J., Valton L., Gelisse P., Aubert S., Cances C., Michel V., Vignal J., Chochoi M., Petit J., Biraben A., Bonini F., Guye M., Hamelin S., Kahane P., Maillard L., Mercedes Alvarez B., Monpeurt C., Tourniaire D.

## Funding

Financial support was provided by the FFRE - French Research Foundation for Epilepsy (Grant 2009) and the annual subvention from the LFCE - French League Against Epilepsy.

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