FULL-LENGTH ORIGINAL RESEARCH
Psychosocial long-term outcome in juvenile myoclonic epilepsy *Martin Holtkamp, †Philine Senf, *Andrea Kirschbaum, and *Dieter Janz Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
SUMMARY
Martin Holtkamp is Medical Director of the Epilepsy-Center Berlin-Brandenburg, Germany.
Philine Senf is Assistant Physician at the Clinic for Psychosomatic, Berlin, Charite Germany.
Purpose: Juvenile myoclonic epilepsy (JME) is a well-defined subsyndrome of idiopathic generalized/genetic epilepsy. It is allegedly related to specific personality characteristics and has been associated with unfavorable social outcome. We aimed to analyze psychosocial outcome in patients with JME. To delineate consequences of the chronic seizure disorder from possible neurobiologic contributions being inherent to the condition itself, we compared social outcome in JME subjects with that of age- and sexmatched control patients with absence epilepsy (AE). Methods: Patients with an epilepsy course of at least 20 years were included. All JME and AE patients (n = 41 in each group) answered a structured questionnaire asking about seizures, treatment, and psychosocial variables. In addition, patients with JME were assessed with the Quality of Life in Epilepsy Inventory 31 (QOLIE-31). Results: In JME, 46.3 years (20–69) after onset of epilepsy, the overall psychosocial long-term outcome was favorable (80.5% of patients had never been unemployed for more than 1 year, 90.2% were well integrated into social context). Quality of life in all inquired subdomains revealed high scores. Compared with AE controls, JME patients did not perform worse regarding psychosocial outcome; rate of university access and degrees in JME patients was even higher (70% vs. 34%, p = 0.001). JME patients showed a high level of quality of life, and current or previous psychiatric comorbidity was associated significantly with lower overall quality of life scores (p = 0.02). Significance: Our long-term study on JME patients demonstrated favorable psychosocial outcome that contrasted previous findings. This is the first study to compare social outcome in JME with another genetically determined form of epilepsy. Similar outcomes in JME and AE patients argue against specific neurobiologic alterations in JME that may predispose to social deficits. In JME, reduced quality of life seems to be associated with psychiatric comorbidity. KEY WORDS: Idiopathic generalized epilepsy, Genetic epilepsy, Absence epilepsy, Neurobiological alterations.
Accepted July 16, 2014. *Epilepsy-Center Berlin-Brandenburg, Department of Neurology, Charite – Universit€atsmedizin Berlin, Berlin, Germany; and †Department of Psychosomatics, Charite – Universit€atsmedizin Berlin, Berlin, Germany M. Holtkamp and P. Senf contributed equally to this work. Address correspondence to Martin Holtkamp, Department of Neurology, Epilepsy-Center Berlin-Brandenburg, Charite – Universit€atsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
1
2 M. Holtkamp et al. Juvenile myoclonic epilepsy (JME) is a well-defined subsyndrome of idiopathic generalized/genetic epilepsy that usually manifests during adolescence or late childhood. It is characterized by bilateral myoclonic jerks, which are often followed by generalized tonic–clonic seizures. The neurologic and intellectual capabilities of patients are generally normal. Sleep deprivation, excessive alcohol consumption, fatigue, and stress can elicit seizures. JME can be controlled with valproate or other appropriate drugs in 76–88% of cases.1,2 Janz and Christian have maintained that people with JME tend to be immature and irresponsible.3,4 Further studies have reported that JME may be related to specific personality characteristics such as impressionability, unreliability, and emotional instability, which are similar to those observed in patients with frontal lobe lesions.4–10 As stated by Janz and Christian in the first description of JME, the treatment of such patients seems to be difficult due to their specific personality profile.3 Due to their irregular lifestyle, it may be challenging for JME patients to follow a structured daily routine with avoidance of the above-named seizure triggers. JME patients exhibit problems in adherence to antiepileptic drugs (AEDs) as well as a tendency to negotiate the severity of their disease.3 This may result in problems in terms of seizure control and psychosocial integration. Keeping this in mind, only two studies so far specifically have addressed the psychosocial long-term outcome of patients with JME.11,12 The aim of our study was to assess psychosocial longterm outcome in 41 patients with JME. We compared JME data to 41 sex- and age-matched controls with absence epilepsy (AE). The use of this control group that had another generalized epilepsy subsyndrome allowed control for psychosocial long-term outcome data in JME for the impact of epilepsy and seizures itself, for associated and still prevalent stigma, and for possible side effects of chronic AED treatment, and thus possible delineation of specific neurobiologic features of JME.
Methods Patient data The Janz Archive at the Department of Neurology at the Charite University Hospital Berlin (Germany) has at its disposal all case records of outpatients who had epilepsy and had consulted D. Janz both during and after his academic career (first patient contact between 1955 and 2000). Of the 870 records of the Janz Archive, 343 patients had idiopathic generalized epilepsy (IGE). Eighty-two patients were diagnosed with JME, 190 with absence epilepsy, 52 with epilepsy with grand mal on awakening, and 19 had unclassifiable generalized epilepsy characterized by random grand mal. We included patients with a diagnosis of JME and AE according to the Classification of the International Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
League Against Epilepsy (ILAE).13 At small variance to the ILAE classification, all patients with myoclonic jerks were categorized to the JME group even if they had a prior history of absence seizures.14 Further inclusion criteria were a follow-up period after epilepsy onset of at least 20 years and the possibility of contacting patients to send them a questionnaire. Of 82 patients with JME, 41 met the inclusion criteria (33 patients could not be included because of loss to follow-up and another 8 patients because of insufficient documentation in the charts). The 41 JME patients were matched with AE patients for sex and age as accurate as possible. Following the ILAE classification,13 at investigation 18 AE patients were categorized as childhood absence epilepsy and 23 patients as juvenile absence epilepsy. AE patients did not differ statistically from JME patients in terms of follow-up time, duration of active epilepsy, and duration of treatment (Table 1). Follow-up time was defined as the period between onset of epilepsy and completion of the questionnaire, duration of active epilepsy as the period between first and last seizure, and treatment duration as the period between the first and the last intake of AEDs. The study was approved by the Institutional Review Board of Charite – Universit€atsmedizin Berlin. Written informed consent was obtained from all participants. Indicator evaluation All patients were given a structured questionnaire asking for seizures, treatment, and psychosocial parameters. Seizure outcome data of JME patients comprising a larger group than analyzed in the current study have been published previously.14 The current questionnaire included direct yes/ no questions on education, professional situation, family, and social situation, as well as on psychiatric comorbidities and application of psychiatric medication. In this study, patients were not clinically examined regarding psychiatric disorders. Qualitative questions had to be answered with a Likert scheme, as used previously in other studies.11,12 Quality of life evaluation All JME patients were additionally tested with Quality of Life in Epilepsy Inventory 31 (QOLIE-31; German version), which has shown good reliability and construct validity.15 The QOLIE-31 is a widely adopted epilepsy-specific instrument for assessment of quality of life (QoL).16 It comprises 30 items divided into seven subscale domains: seizure worry (five items), emotional well-being (five items), energy/ fatigue (four items), cognitive functioning (six items), medication effects (three items), overall QoL (two items), and social functioning (five items). Each domain was scored by calculating the mean score of responses within that domain. The raw scores were converted to “0–100,” with higher scores reflecting better QOL. Total and subscale scores were calculated according to the QOLIE-31 scoring manual.17,18
3 Psychosocial Long-Term Outcome in JME Table 1. Clinical variables
Variable Sex Male, n (%) Female, n (%) Age (mean SD); years Follow-up time (mean SD); years Duration of active epilepsy 20 years; n (%) Treatment duration 30 years; n (%) 5-year-terminal remission Yes; n (%) No; n (%) AED Yes; n (%) No; n (%) Monotherapy/polytherapy Mono; n (%) Poly; n (%)
JME n = 41
Absence n = 41 n = 18 CAE, n = 23 JAE
18 (43.9) 23 (56.1) 60.7 13.1 46.3 12.9
18 (43.9) 23 (56.1) 61.0 12.9 50.0 13.3
1.000
7 (17.1) 8 (19.5) 26 (63.4)
3 (7.3) 6 (14.6) 32 (78.1)
0.290
1 (2.4) 12 (29.3) 28 (68.3)
3 (7.3) 10 (24.4) 28 (68.3)
0.55
28 (68.3) 13 (31.7)
31 (75.6) 10 (24.4)
0.46
30 (73.2) 11 (26.8)
31 (75.6) 10 (24.4)
0.8
25 (83.3) 5 (16.7)
15 (48.4) 16 (51.6)
0.004
p-Value
0.919 0.201
JME, juvenile myoclonic epilepsy; AE, absence epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy. Bold indicates significant differences.
Statistical analyses Data were analyzed using SPSS (version 18.0; IBM, Armonk, NY, U.S.A.). For comparison of psychosocial long-term outcome parameters in JME and AE patients, chisquare test was used for categorical dependent variables and univariate analysis of variance (ANOVA) for metric variables. To test the strength and direction of influence of the indicators on the dependent variable QOLIE-31 scores, we also used univariate ANOVA.
Results The 41 JME patients included in the study had a mean age at follow-up of 60.7 (standard deviation) 13.1 years (min 30; max 85) and a mean follow-up of 46.3 12.9 years (min 20; max 69). This did not differ from the 41 matched AE patients with a mean age of 61 12.9 years (min 32; max 87) (p = 0.919) and with a mean follow-up of 50 13.3 years (min 25; max 77) (p = 0.201). At the time of interview, JME patients were significantly more often treated with AED monotherapy (83.3%) versus polytherapy than AE patients (48.4%) (p = 0.004). Further clinical variables on JME and AE patients are given in Table 1. Psychosocial outcome All psychosocial parameters as surveyed by the structured questionnaire are given in detail in Tables 2 and 3. At the end of follow-up, we found only one variable to be
significantly different comparing psychosocial long-term outcome in JME and AE patients: 70.7% of JME patients had achieved a qualification for university access or even had graduated from university, whereas only 34.1% of AE patients had done so (p = 0.001). A total of 80.5% of JME patients stated that they had never been unemployed for more than 1 year compared with 73.2% of AE patients, and 80.5% of JME patients described their financial situation as wealthy or sufficient compared with 75.6% of AE patients. The social situation was reported as satisfying by 90.2% of JME and 78.1% of AE patients. Integration into social context was described as good by 90.3% of JME and AE patients, respectively. Of patients with JME, 24.4% reported current or previous psychiatric comorbidity (19.5% depression, 4.9% anxiety disorder) compared with 22% of AE patients (9.8% depression, 9.8% anxiety disorder, 2.4% psychosis). Terminal seizure remission for at least 5 years was not associated with the outcome of any of the psychosocial parameters, neither in the JME nor in the AE group (data not shown). QOLIE-31 and indicators for quality of life For JME patients, detailed results of the QOLIE-31 are shown in Table 4. Current or previous psychiatric comorbidity (n = 10 patients) was significantly associated with and thus an indicator for lower total scores in QoL Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
4 M. Holtkamp et al. Table 2. Social outcome
Variable Profession Employed Freelanced Unemployed Unable to work Retired Household Qualification for university access or graduation from university Family status Married Single Divorced Living in relationship Living apart Widowed Financial situation Wealthy Sufficient Not sufficient Totally insufficient >12 month unemployed Never Once Several times Most of the time Satisfied with social situation Satisfied Not very satisfied Unsatisfied Integration in social context Good Not so good Bad Satisfying friendships Very satisfying Not so satisfying Not at all satisfying Lifelong friendships Yes, several Yes, one None To feel socially confident Very much Not very much Not at all Children Yes No None because of epilepsy Alcohol past 12 months Not at all At least once At least once a month Every week Every day
JME n = 41 n (%)
Absence n = 41 n = 23 JAE, n = 18 CAE n (%)
19 (46.3) 6 (14.6) 1 (2.4) 0 13 (31.7) 2 (5.0 ) 29 (70.7)
21 (51.2) 7 (17.1) 2 (4.9) 3 (7.3) 6 (14.6) 2 (4.9) 14 (34.1)
28 (68.3) 6 (14.6) 3 (7.3) 1 (2.4) 1 (2.4) 1 (2.4)
22 (53.7) 8 (19.5) 9 (22.0) 1 (2.4) 0 1 (2.4)
0.417
10 (24.4) 23 (56.1) 3 (7.3) 5 (12.2)
8 (19.5) 23 (56.1) 4 (9.8) 6 (14.6)
0.830
33 (80.5) 4 (9.8) 2 (4.9) 2 (4.9)
30 (73.2) 5 (9.8) 3 (7.3) 3 (7.3)
0.819
37 (90.2) 3 (7.3) 1 (2.4)
32 (78.1) 6 (14.6) 3 (7.3)
0.307
37 (90.3) 4 (9.7) 0
37 (90.3) 4 (9.7) 0
36 (87.8) 5 (12.2) 0
34 (83.0) 5 (12.2) 2 (4.9)
0.358
18 (43.9) 14 (34.1) 9 (22.0)
14 (34.1) 17 (41.5) 10 (24.4)
0.145
36 (87.8) 5 (12.2) 0
36 (87.8) 2 (4.9) 3 (7.3)
0.117
27 (65.9) 9 (22.0) 5 (12.2)
25 (61.0) 13 (31.7) 3 (7.3)
0.521
15 (36.6) 7 (17.1) 5 (12.2) 8 (19.5) 6 (14.6)
16 (39.0) 9 (22.0) 7 (17.1) 4 (9.8) 5 (12.2)
0.73
p-Value 0.298
0.001
0.344 1.000
Continued
Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
5 Psychosocial Long-Term Outcome in JME Table 2. Continued.
Variable CAGE questionnaire None One answer Two answers >Two answers Nicotine Never Stopped >1 year ago Yes, not daily Yes, daily
JME n = 41 n (%)
Absence n = 41 n = 23 JAE, n = 18 CAE n (%)
33 (80.5) 6 (14.6) 1 (2.4) 1 (2.4)
35 (85.4) 4 (9.8) 2 (4.9) 0
0.617
21 (51.2) 12 (29.3) 1 (2.4) 7 (17.1)
27 (65.9) 8 (19.5) 1 (2.4) 5 (12.2)
0.597
p-Value
JME, juvenile myoclonic epilepsy; AE, absence epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy; CAGE, questionnaire screening for alcohol abuse, the acronym refers to the four items focusing on Cutting down, Annoyance by criticism, Guilty feeling, and Eye-openers. Bold indicates significant differences.
(65.6 3.2 total score QOLIE vs. 79.6 2.4 total score QOLIE in 31 patients without psychiatric comorbidity; p = 0.02). Total QOLIE-31 scores did not differ significantly in all other variables assessed, comprising male/ female, AED yes/no, employed/unemployed, university degree/no university degree, married/not married, children/ no children, satisfied with social situation/not satisfied with social situation, and satisfied with friendships/not satisfied with friendships. Terminal seizure remission for at least 5 years was also not associated with QoL (p-values from univariate ANOVA correlating terminal remission and QoL parameters: p = 0.291 total score, p = 0.510 overall QoL, p = 0.610 well-being, p = 0.147 energy/fatigue, p = 0.548 cognitive functioning, p = 0.955 medication effects, p = 0.217 social functioning).
Discussion The current study demonstrates a favorable psychosocial long-term outcome in a cohort of 41 patients with JME more than four decades after epilepsy onset. Patients with JME did not perform worse than a matched control group with AE. On the contrary, the fraction of patients with university access or graduation was higher in JME compared with AE patients. So far, two previous studies have assessed psychosocial long-term outcome in JME patients.11,12 The current study is the first ever that included a control group comprising patients with another generalized epilepsy syndrome. By comparing JME with AE patients, we were able to demonstrate equitable social outcome. This finding does not support the previous doctrine of unfavorable psychosocial long-term outcome specifically in JME, which had been attributed to neurobiologic alterations inherent to the condition itself.
Table 3. Psychiatric comorbidity
Variable Psychiatric comorbidity Depression Anxiety Psychosis None Psychotherapy Yes No Antidepressant medication Yes, earlier Yes, still ongoing Never Anxiolytic medication Yes, earlier Yes, still ongoing Never
JME n = 41 n (%)
Absence n = 41 n = 18 CAE, n = 23 JAE n (%)
8 (19.5) 2 (4.9) 0 31 (75.6)
4 (9.8) 4 (9.8) 1 (2.4) 32 (78.0)
0.794
8 (19.5) 33 (80.5)
7 (17.1) 34 (82.9)
0.646
3 (7.3) 4 (9.8) 34 (82.9)
3 (7.3) 2 (4.9) 36 (87.8)
0.696
3 (7.3) 2 (4.9) 36 (87.8)
0 0 41 (100)
0.070
p-Value
JME, juvenile myoclonic epilepsy; AE, absence epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy.
Table 4. Results of QOLIE-31 in JME patients QOLIE-31 subscale domains Seizure worry Overall QOL Well-being Energy fatigue Cognitive functioning Medication effects Social functioning Overall score
Mean score of all JME patients (n = 41)a 89 71.1 70.6 57.9 73.7 83 86.8 74.4
2.8 3 2.6 2.8 3.4 3.9 3 2.6
QOLIE, quality of life in epilepsy; JME, juvenile myoclonic epilepsy. a Values are standard deviation.
Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
6 M. Holtkamp et al. The first comparable previous study demonstrated a high rate of what had been called major unfavorable social outcomes.11 Those were defined as failure to complete high school, unplanned pregnancy, depression, unemployment, living alone, and failure to maintain a relationship longer than 3 months. After follow-up of approximately 26 years, the authors noted the presence of at least one unfavorable social event in 76% of their patients. This finding was largely confirmed by another German study that reported at least one major unfavorable social outcome in 88% of patients with JME.12 A recent cross-sectional study demonstrated unfavorable psychosocial variables in patients with JME compared with matched healthy controls, in particular regarding the factors work and family relationship.19 In contrast to previous findings on social outcome in JME, we demonstrated that the overall psychosocial outcome in the current JME patients was generally satisfying and—likewise important—did not differ from patients with absence epilepsy. Both JME and AE patients showed stable familiar relationships, a favorable social network, and a high socioeconomic status. JME and AE patients originate from the same patient collective; all patients were diagnosed and treated by D. Janz. Therefore, there was no social privilege of the JME group compared with the AE group. JME patients compared with AE patients were significantly more often treated with AED monotherapy, which may suggest a more benign course of epilepsy. We cannot completely exclude that the social outcome in JME would be less favorable if more patients were on AED polytherapy, indicating a more difficult-to-treat condition. Aside from the above-mentioned studies on social long-term outcome in JME, it seems to be common opinion that neurobiologic alterations in terms of impaired executive functions have important implications for the educational, occupational, and psychosocial prognosis of patients.20,21 This would explain a less favorable social outcome compared with the general population or patients with other epilepsy syndromes. Regarding our patient collective in total (JME and AE patients), one may speculate that our positive findings are due to the fact that all JME and AE patients were treated for years and decades by one of the authors (D. Janz). The long and stable relationship with the treating physician compared with other patients with epilepsy may represent a bias. This assumption is emphasized by comparing the current QOLIE results with our data on a more general population of patients with epilepsy (data unpublished). In these patients (n = 302) with a mean follow-up time of 24.2 (standard deviation) 17.9 years, all mean values of the QOLIE items were about 20 points lower than those of the current JME patients. These differences suggest that repetitive visits and a stable physician–patient relationship may have a protective factor on QoL and possibly on social long-term outcome. An additional explanation for the generally positive social outcome in our JME patients may be the extraordiEpilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
narily long mean follow-up time of >45 years, with a mean age of 60.7 years in our cohort. The mean age of patients in comparable studies was 52.3 years12 and 36.5 years.11 Taking this difference in patients’ age and thus follow-up time into consideration, one may speculate that the higher age of our patients naturally leads to an increasingly calm, steady, and satisfying lifestyle. Severity of epilepsy and lack of seizure freedom may impact psychosocial outcome in JME. Schneider et al.12 found that ongoing seizures correlate highly with irregularities in major aspects of the social, educational, and occupational life in patients with JME. The cross-sectional study from Moschetta et al.19 also supported the correlation between high seizure frequency and poor social adjustment. These findings were in contrast to the data from Camfield and Camfield,11 who did not identify a correlation between remission and social outcome. The data of our study support these latter findings, as we could not show a correlation between seizure freedom, at least in the 5 years before investigation, and long-term social outcome. In addition to the overall social outcome, we assessed a QoL inventory and analyzed possible predictors influencing long-term QoL for the JME group, which generally showed a high score of quality of life aspects. Furthermore, in our analysis psychiatric comorbidity was identified as a potential indicator for QoL in JME patients. Several studies have emphasized the negative influence of psychiatric comorbidities on QoL of patients with JME.22–24 Some authors have hypothesized that JME with psychiatric comorbidity constitutes a more severe subgroup of this condition.24 Finally, Schneider et al.12 demonstrated that higher scores on Becks Depression Inventory – II were correlated with a lower QoL level. This can be a hint that JME with psychiatric comorbidity might represent a severe subtype of JME with a higher risk of a decreased overall QoL, but more data are needed to fuel this hypothesis. The strengths of our study were as follows: (1) extraordinarily long follow-up time compared with previous studies; (2) implementation of a standardized QoL inventory and of a control group with another genetically determined generalized epilepsy syndrome; and (3) analysis of possible indicators for a negative psychosocial outcome. The study has the following limitations: (1) the fact that the sample was not population-based might include a bias; and (2) low case number, resulting in a limited statistical power. In summary, psychosocial outcome in 41 JME patients approximately 45 years after epilepsy onset was overall satisfying and comparable to that of control subjects with absence epilepsy. This finding suggests that specific neurobiologic alterations in JME, if they exist at all, do not contribute in a primary fashion to psychosocial outcome. We identified psychiatric comorbidity as a negative significant predictor for long-term QoL in these patients. In patients
7 Psychosocial Long-Term Outcome in JME with JME, further population-based studies focusing in particular on psychosocial aspects and psychiatric comorbidities are warranted.
Acknowledgments MH holds the “Friedrich-v.-Bodelschwingh Endowed Professorship for Clinical and Experimental Epileptology” at the Department of Neurology at the Charite – Universit€atsmedizin Berlin funded by v. Bodelschwingh Foundation.
Disclosure MH has served on scientific advisory boards for Eisai Inc., Janssen, UCB, and ViroPharma. He has received reimbursement for traveling expenses and/or speaker honoraria from Desitin, Eisai Inc., GlaxoSmithKline, Janssen, UCB, and ViroPharma. PS, AK, and DJ have no disclosures. We confirm that we have read the Journal’s position on issues involved in ethical publication and confirm that this report is consistent with the guidelines.
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9. Karachristianou S, Katsarou Z, Postantjopoulou S, et al. Personality profile in patients with juvenile myoclonic epilepsy. Epilepsy Behav 2008;13:654–657. 10. Piazinni A, Turner K, Vignoli A, et al. Frontal cognitive dysfunction in juvenile myoclonic epilepsy. Epilepsia 2008;49:657–662. 11. Camfield CS, Camfield PR. Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. Neurology 2009;73:1041–1045. 12. Schneider-von Podewils S, Gasse C, Geithner J, et al. Clinical predictors of the long-term social outcome and quality of life in juvenile myoclonic epilepsy: 20–65 years of follow-up. Epilepsia 2014;55:322–330. 13. Commission on classification and terminology of the International League Against Epilepsy (ILAE). Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–399. 14. Senf P, Schmitz B, Holtkamp M, et al. Juvenile myoclonic epilepsy 45 years after onset: seizure outcome and predictors. Neurology 2013;81:2128–2133. 15. Cramer JA, Perrine K, Devinsky O, et al. Development and crosscultural translation of a 31-item quality of life questionnaire (QOLIE31). Epilepsia 1998;39:81–88. 16. Devinsky O, Vickrey BG, Cramer J, et al. Development of the quality of life in epilepsy inventory. Epilepsia 1995;36:1089–1104. 17. Vickrey BG. A procedure for developing a quality-of-life measure for epilepsy surgery patients. Epilepsia 1993;34(Suppl. 4): S22–S27. 18. Pauli C, de Oliveira Thais ME, Claudino LS, et al. Predictors of quality of life in patients with refractoral mesial temporal lobe epilepsy. Epilepsy Behav 2012;25:208–213. 19. Moschetta S, Valtente KF. Impulsivity and seizure frequency, but not cognitive deficits, impact social adjustment in patients with juvenile myoclonic epilepsy. Epilepsia 2013;54:866–870. 20. Wandschneider B, Thompson PJ, Vollmar C, et al. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia 2012;53:2091–2098. 21. Loughman A, Bowden SC, D`Souza C. Cognitive functioning in idiopathic generalized epilepsies: a systematic review and metaanalysis. Neurosci Biobehav Rev 2014;14:20–34. 22. Trinka E, Kienpointner G, Unterberger I, et al. Psychiatric comorbidity in juvenile myoclonic epilepsy. Epilepsia 2006;47:2086– 2091. 23. Gelisse P, Thomas P, Samuelian JC, et al. Psychiatric disorders in juvenile myoclonic epilepsy. Epilepsia 2007;48:1032–1033. 24. Filho GM, Mazetto L, da Silva JM, et al. Psychiatric comorbidity in patients with two prototypes of focal versus generalized epilepsy syndromes. Seizure 2011;20:383–386.
Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
Psychosocial long-term outcome in juvenile myoclonic epilepsy *Martin Holtkamp, †Philine Senf, *Andrea Kirschbaum, and *Dieter Janz Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
SUMMARY
Martin Holtkamp is Medical Director of the Epilepsy-Center Berlin-Brandenburg, Germany.
Philine Senf is Assistant Physician at the Clinic for Psychosomatic, Berlin, Charite Germany.
Purpose: Juvenile myoclonic epilepsy (JME) is a well-defined subsyndrome of idiopathic generalized/genetic epilepsy. It is allegedly related to specific personality characteristics and has been associated with unfavorable social outcome. We aimed to analyze psychosocial outcome in patients with JME. To delineate consequences of the chronic seizure disorder from possible neurobiologic contributions being inherent to the condition itself, we compared social outcome in JME subjects with that of age- and sexmatched control patients with absence epilepsy (AE). Methods: Patients with an epilepsy course of at least 20 years were included. All JME and AE patients (n = 41 in each group) answered a structured questionnaire asking about seizures, treatment, and psychosocial variables. In addition, patients with JME were assessed with the Quality of Life in Epilepsy Inventory 31 (QOLIE-31). Results: In JME, 46.3 years (20–69) after onset of epilepsy, the overall psychosocial long-term outcome was favorable (80.5% of patients had never been unemployed for more than 1 year, 90.2% were well integrated into social context). Quality of life in all inquired subdomains revealed high scores. Compared with AE controls, JME patients did not perform worse regarding psychosocial outcome; rate of university access and degrees in JME patients was even higher (70% vs. 34%, p = 0.001). JME patients showed a high level of quality of life, and current or previous psychiatric comorbidity was associated significantly with lower overall quality of life scores (p = 0.02). Significance: Our long-term study on JME patients demonstrated favorable psychosocial outcome that contrasted previous findings. This is the first study to compare social outcome in JME with another genetically determined form of epilepsy. Similar outcomes in JME and AE patients argue against specific neurobiologic alterations in JME that may predispose to social deficits. In JME, reduced quality of life seems to be associated with psychiatric comorbidity. KEY WORDS: Idiopathic generalized epilepsy, Genetic epilepsy, Absence epilepsy, Neurobiological alterations.
Accepted July 16, 2014. *Epilepsy-Center Berlin-Brandenburg, Department of Neurology, Charite – Universit€atsmedizin Berlin, Berlin, Germany; and †Department of Psychosomatics, Charite – Universit€atsmedizin Berlin, Berlin, Germany M. Holtkamp and P. Senf contributed equally to this work. Address correspondence to Martin Holtkamp, Department of Neurology, Epilepsy-Center Berlin-Brandenburg, Charite – Universit€atsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
1
2 M. Holtkamp et al. Juvenile myoclonic epilepsy (JME) is a well-defined subsyndrome of idiopathic generalized/genetic epilepsy that usually manifests during adolescence or late childhood. It is characterized by bilateral myoclonic jerks, which are often followed by generalized tonic–clonic seizures. The neurologic and intellectual capabilities of patients are generally normal. Sleep deprivation, excessive alcohol consumption, fatigue, and stress can elicit seizures. JME can be controlled with valproate or other appropriate drugs in 76–88% of cases.1,2 Janz and Christian have maintained that people with JME tend to be immature and irresponsible.3,4 Further studies have reported that JME may be related to specific personality characteristics such as impressionability, unreliability, and emotional instability, which are similar to those observed in patients with frontal lobe lesions.4–10 As stated by Janz and Christian in the first description of JME, the treatment of such patients seems to be difficult due to their specific personality profile.3 Due to their irregular lifestyle, it may be challenging for JME patients to follow a structured daily routine with avoidance of the above-named seizure triggers. JME patients exhibit problems in adherence to antiepileptic drugs (AEDs) as well as a tendency to negotiate the severity of their disease.3 This may result in problems in terms of seizure control and psychosocial integration. Keeping this in mind, only two studies so far specifically have addressed the psychosocial long-term outcome of patients with JME.11,12 The aim of our study was to assess psychosocial longterm outcome in 41 patients with JME. We compared JME data to 41 sex- and age-matched controls with absence epilepsy (AE). The use of this control group that had another generalized epilepsy subsyndrome allowed control for psychosocial long-term outcome data in JME for the impact of epilepsy and seizures itself, for associated and still prevalent stigma, and for possible side effects of chronic AED treatment, and thus possible delineation of specific neurobiologic features of JME.
Methods Patient data The Janz Archive at the Department of Neurology at the Charite University Hospital Berlin (Germany) has at its disposal all case records of outpatients who had epilepsy and had consulted D. Janz both during and after his academic career (first patient contact between 1955 and 2000). Of the 870 records of the Janz Archive, 343 patients had idiopathic generalized epilepsy (IGE). Eighty-two patients were diagnosed with JME, 190 with absence epilepsy, 52 with epilepsy with grand mal on awakening, and 19 had unclassifiable generalized epilepsy characterized by random grand mal. We included patients with a diagnosis of JME and AE according to the Classification of the International Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
League Against Epilepsy (ILAE).13 At small variance to the ILAE classification, all patients with myoclonic jerks were categorized to the JME group even if they had a prior history of absence seizures.14 Further inclusion criteria were a follow-up period after epilepsy onset of at least 20 years and the possibility of contacting patients to send them a questionnaire. Of 82 patients with JME, 41 met the inclusion criteria (33 patients could not be included because of loss to follow-up and another 8 patients because of insufficient documentation in the charts). The 41 JME patients were matched with AE patients for sex and age as accurate as possible. Following the ILAE classification,13 at investigation 18 AE patients were categorized as childhood absence epilepsy and 23 patients as juvenile absence epilepsy. AE patients did not differ statistically from JME patients in terms of follow-up time, duration of active epilepsy, and duration of treatment (Table 1). Follow-up time was defined as the period between onset of epilepsy and completion of the questionnaire, duration of active epilepsy as the period between first and last seizure, and treatment duration as the period between the first and the last intake of AEDs. The study was approved by the Institutional Review Board of Charite – Universit€atsmedizin Berlin. Written informed consent was obtained from all participants. Indicator evaluation All patients were given a structured questionnaire asking for seizures, treatment, and psychosocial parameters. Seizure outcome data of JME patients comprising a larger group than analyzed in the current study have been published previously.14 The current questionnaire included direct yes/ no questions on education, professional situation, family, and social situation, as well as on psychiatric comorbidities and application of psychiatric medication. In this study, patients were not clinically examined regarding psychiatric disorders. Qualitative questions had to be answered with a Likert scheme, as used previously in other studies.11,12 Quality of life evaluation All JME patients were additionally tested with Quality of Life in Epilepsy Inventory 31 (QOLIE-31; German version), which has shown good reliability and construct validity.15 The QOLIE-31 is a widely adopted epilepsy-specific instrument for assessment of quality of life (QoL).16 It comprises 30 items divided into seven subscale domains: seizure worry (five items), emotional well-being (five items), energy/ fatigue (four items), cognitive functioning (six items), medication effects (three items), overall QoL (two items), and social functioning (five items). Each domain was scored by calculating the mean score of responses within that domain. The raw scores were converted to “0–100,” with higher scores reflecting better QOL. Total and subscale scores were calculated according to the QOLIE-31 scoring manual.17,18
3 Psychosocial Long-Term Outcome in JME Table 1. Clinical variables
Variable Sex Male, n (%) Female, n (%) Age (mean SD); years Follow-up time (mean SD); years Duration of active epilepsy 20 years; n (%) Treatment duration 30 years; n (%) 5-year-terminal remission Yes; n (%) No; n (%) AED Yes; n (%) No; n (%) Monotherapy/polytherapy Mono; n (%) Poly; n (%)
JME n = 41
Absence n = 41 n = 18 CAE, n = 23 JAE
18 (43.9) 23 (56.1) 60.7 13.1 46.3 12.9
18 (43.9) 23 (56.1) 61.0 12.9 50.0 13.3
1.000
7 (17.1) 8 (19.5) 26 (63.4)
3 (7.3) 6 (14.6) 32 (78.1)
0.290
1 (2.4) 12 (29.3) 28 (68.3)
3 (7.3) 10 (24.4) 28 (68.3)
0.55
28 (68.3) 13 (31.7)
31 (75.6) 10 (24.4)
0.46
30 (73.2) 11 (26.8)
31 (75.6) 10 (24.4)
0.8
25 (83.3) 5 (16.7)
15 (48.4) 16 (51.6)
0.004
p-Value
0.919 0.201
JME, juvenile myoclonic epilepsy; AE, absence epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy. Bold indicates significant differences.
Statistical analyses Data were analyzed using SPSS (version 18.0; IBM, Armonk, NY, U.S.A.). For comparison of psychosocial long-term outcome parameters in JME and AE patients, chisquare test was used for categorical dependent variables and univariate analysis of variance (ANOVA) for metric variables. To test the strength and direction of influence of the indicators on the dependent variable QOLIE-31 scores, we also used univariate ANOVA.
Results The 41 JME patients included in the study had a mean age at follow-up of 60.7 (standard deviation) 13.1 years (min 30; max 85) and a mean follow-up of 46.3 12.9 years (min 20; max 69). This did not differ from the 41 matched AE patients with a mean age of 61 12.9 years (min 32; max 87) (p = 0.919) and with a mean follow-up of 50 13.3 years (min 25; max 77) (p = 0.201). At the time of interview, JME patients were significantly more often treated with AED monotherapy (83.3%) versus polytherapy than AE patients (48.4%) (p = 0.004). Further clinical variables on JME and AE patients are given in Table 1. Psychosocial outcome All psychosocial parameters as surveyed by the structured questionnaire are given in detail in Tables 2 and 3. At the end of follow-up, we found only one variable to be
significantly different comparing psychosocial long-term outcome in JME and AE patients: 70.7% of JME patients had achieved a qualification for university access or even had graduated from university, whereas only 34.1% of AE patients had done so (p = 0.001). A total of 80.5% of JME patients stated that they had never been unemployed for more than 1 year compared with 73.2% of AE patients, and 80.5% of JME patients described their financial situation as wealthy or sufficient compared with 75.6% of AE patients. The social situation was reported as satisfying by 90.2% of JME and 78.1% of AE patients. Integration into social context was described as good by 90.3% of JME and AE patients, respectively. Of patients with JME, 24.4% reported current or previous psychiatric comorbidity (19.5% depression, 4.9% anxiety disorder) compared with 22% of AE patients (9.8% depression, 9.8% anxiety disorder, 2.4% psychosis). Terminal seizure remission for at least 5 years was not associated with the outcome of any of the psychosocial parameters, neither in the JME nor in the AE group (data not shown). QOLIE-31 and indicators for quality of life For JME patients, detailed results of the QOLIE-31 are shown in Table 4. Current or previous psychiatric comorbidity (n = 10 patients) was significantly associated with and thus an indicator for lower total scores in QoL Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
4 M. Holtkamp et al. Table 2. Social outcome
Variable Profession Employed Freelanced Unemployed Unable to work Retired Household Qualification for university access or graduation from university Family status Married Single Divorced Living in relationship Living apart Widowed Financial situation Wealthy Sufficient Not sufficient Totally insufficient >12 month unemployed Never Once Several times Most of the time Satisfied with social situation Satisfied Not very satisfied Unsatisfied Integration in social context Good Not so good Bad Satisfying friendships Very satisfying Not so satisfying Not at all satisfying Lifelong friendships Yes, several Yes, one None To feel socially confident Very much Not very much Not at all Children Yes No None because of epilepsy Alcohol past 12 months Not at all At least once At least once a month Every week Every day
JME n = 41 n (%)
Absence n = 41 n = 23 JAE, n = 18 CAE n (%)
19 (46.3) 6 (14.6) 1 (2.4) 0 13 (31.7) 2 (5.0 ) 29 (70.7)
21 (51.2) 7 (17.1) 2 (4.9) 3 (7.3) 6 (14.6) 2 (4.9) 14 (34.1)
28 (68.3) 6 (14.6) 3 (7.3) 1 (2.4) 1 (2.4) 1 (2.4)
22 (53.7) 8 (19.5) 9 (22.0) 1 (2.4) 0 1 (2.4)
0.417
10 (24.4) 23 (56.1) 3 (7.3) 5 (12.2)
8 (19.5) 23 (56.1) 4 (9.8) 6 (14.6)
0.830
33 (80.5) 4 (9.8) 2 (4.9) 2 (4.9)
30 (73.2) 5 (9.8) 3 (7.3) 3 (7.3)
0.819
37 (90.2) 3 (7.3) 1 (2.4)
32 (78.1) 6 (14.6) 3 (7.3)
0.307
37 (90.3) 4 (9.7) 0
37 (90.3) 4 (9.7) 0
36 (87.8) 5 (12.2) 0
34 (83.0) 5 (12.2) 2 (4.9)
0.358
18 (43.9) 14 (34.1) 9 (22.0)
14 (34.1) 17 (41.5) 10 (24.4)
0.145
36 (87.8) 5 (12.2) 0
36 (87.8) 2 (4.9) 3 (7.3)
0.117
27 (65.9) 9 (22.0) 5 (12.2)
25 (61.0) 13 (31.7) 3 (7.3)
0.521
15 (36.6) 7 (17.1) 5 (12.2) 8 (19.5) 6 (14.6)
16 (39.0) 9 (22.0) 7 (17.1) 4 (9.8) 5 (12.2)
0.73
p-Value 0.298
0.001
0.344 1.000
Continued
Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
5 Psychosocial Long-Term Outcome in JME Table 2. Continued.
Variable CAGE questionnaire None One answer Two answers >Two answers Nicotine Never Stopped >1 year ago Yes, not daily Yes, daily
JME n = 41 n (%)
Absence n = 41 n = 23 JAE, n = 18 CAE n (%)
33 (80.5) 6 (14.6) 1 (2.4) 1 (2.4)
35 (85.4) 4 (9.8) 2 (4.9) 0
0.617
21 (51.2) 12 (29.3) 1 (2.4) 7 (17.1)
27 (65.9) 8 (19.5) 1 (2.4) 5 (12.2)
0.597
p-Value
JME, juvenile myoclonic epilepsy; AE, absence epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy; CAGE, questionnaire screening for alcohol abuse, the acronym refers to the four items focusing on Cutting down, Annoyance by criticism, Guilty feeling, and Eye-openers. Bold indicates significant differences.
(65.6 3.2 total score QOLIE vs. 79.6 2.4 total score QOLIE in 31 patients without psychiatric comorbidity; p = 0.02). Total QOLIE-31 scores did not differ significantly in all other variables assessed, comprising male/ female, AED yes/no, employed/unemployed, university degree/no university degree, married/not married, children/ no children, satisfied with social situation/not satisfied with social situation, and satisfied with friendships/not satisfied with friendships. Terminal seizure remission for at least 5 years was also not associated with QoL (p-values from univariate ANOVA correlating terminal remission and QoL parameters: p = 0.291 total score, p = 0.510 overall QoL, p = 0.610 well-being, p = 0.147 energy/fatigue, p = 0.548 cognitive functioning, p = 0.955 medication effects, p = 0.217 social functioning).
Discussion The current study demonstrates a favorable psychosocial long-term outcome in a cohort of 41 patients with JME more than four decades after epilepsy onset. Patients with JME did not perform worse than a matched control group with AE. On the contrary, the fraction of patients with university access or graduation was higher in JME compared with AE patients. So far, two previous studies have assessed psychosocial long-term outcome in JME patients.11,12 The current study is the first ever that included a control group comprising patients with another generalized epilepsy syndrome. By comparing JME with AE patients, we were able to demonstrate equitable social outcome. This finding does not support the previous doctrine of unfavorable psychosocial long-term outcome specifically in JME, which had been attributed to neurobiologic alterations inherent to the condition itself.
Table 3. Psychiatric comorbidity
Variable Psychiatric comorbidity Depression Anxiety Psychosis None Psychotherapy Yes No Antidepressant medication Yes, earlier Yes, still ongoing Never Anxiolytic medication Yes, earlier Yes, still ongoing Never
JME n = 41 n (%)
Absence n = 41 n = 18 CAE, n = 23 JAE n (%)
8 (19.5) 2 (4.9) 0 31 (75.6)
4 (9.8) 4 (9.8) 1 (2.4) 32 (78.0)
0.794
8 (19.5) 33 (80.5)
7 (17.1) 34 (82.9)
0.646
3 (7.3) 4 (9.8) 34 (82.9)
3 (7.3) 2 (4.9) 36 (87.8)
0.696
3 (7.3) 2 (4.9) 36 (87.8)
0 0 41 (100)
0.070
p-Value
JME, juvenile myoclonic epilepsy; AE, absence epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy.
Table 4. Results of QOLIE-31 in JME patients QOLIE-31 subscale domains Seizure worry Overall QOL Well-being Energy fatigue Cognitive functioning Medication effects Social functioning Overall score
Mean score of all JME patients (n = 41)a 89 71.1 70.6 57.9 73.7 83 86.8 74.4
2.8 3 2.6 2.8 3.4 3.9 3 2.6
QOLIE, quality of life in epilepsy; JME, juvenile myoclonic epilepsy. a Values are standard deviation.
Epilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
6 M. Holtkamp et al. The first comparable previous study demonstrated a high rate of what had been called major unfavorable social outcomes.11 Those were defined as failure to complete high school, unplanned pregnancy, depression, unemployment, living alone, and failure to maintain a relationship longer than 3 months. After follow-up of approximately 26 years, the authors noted the presence of at least one unfavorable social event in 76% of their patients. This finding was largely confirmed by another German study that reported at least one major unfavorable social outcome in 88% of patients with JME.12 A recent cross-sectional study demonstrated unfavorable psychosocial variables in patients with JME compared with matched healthy controls, in particular regarding the factors work and family relationship.19 In contrast to previous findings on social outcome in JME, we demonstrated that the overall psychosocial outcome in the current JME patients was generally satisfying and—likewise important—did not differ from patients with absence epilepsy. Both JME and AE patients showed stable familiar relationships, a favorable social network, and a high socioeconomic status. JME and AE patients originate from the same patient collective; all patients were diagnosed and treated by D. Janz. Therefore, there was no social privilege of the JME group compared with the AE group. JME patients compared with AE patients were significantly more often treated with AED monotherapy, which may suggest a more benign course of epilepsy. We cannot completely exclude that the social outcome in JME would be less favorable if more patients were on AED polytherapy, indicating a more difficult-to-treat condition. Aside from the above-mentioned studies on social long-term outcome in JME, it seems to be common opinion that neurobiologic alterations in terms of impaired executive functions have important implications for the educational, occupational, and psychosocial prognosis of patients.20,21 This would explain a less favorable social outcome compared with the general population or patients with other epilepsy syndromes. Regarding our patient collective in total (JME and AE patients), one may speculate that our positive findings are due to the fact that all JME and AE patients were treated for years and decades by one of the authors (D. Janz). The long and stable relationship with the treating physician compared with other patients with epilepsy may represent a bias. This assumption is emphasized by comparing the current QOLIE results with our data on a more general population of patients with epilepsy (data unpublished). In these patients (n = 302) with a mean follow-up time of 24.2 (standard deviation) 17.9 years, all mean values of the QOLIE items were about 20 points lower than those of the current JME patients. These differences suggest that repetitive visits and a stable physician–patient relationship may have a protective factor on QoL and possibly on social long-term outcome. An additional explanation for the generally positive social outcome in our JME patients may be the extraordiEpilepsia, **(*):1–7, 2014 doi: 10.1111/epi.12751
narily long mean follow-up time of >45 years, with a mean age of 60.7 years in our cohort. The mean age of patients in comparable studies was 52.3 years12 and 36.5 years.11 Taking this difference in patients’ age and thus follow-up time into consideration, one may speculate that the higher age of our patients naturally leads to an increasingly calm, steady, and satisfying lifestyle. Severity of epilepsy and lack of seizure freedom may impact psychosocial outcome in JME. Schneider et al.12 found that ongoing seizures correlate highly with irregularities in major aspects of the social, educational, and occupational life in patients with JME. The cross-sectional study from Moschetta et al.19 also supported the correlation between high seizure frequency and poor social adjustment. These findings were in contrast to the data from Camfield and Camfield,11 who did not identify a correlation between remission and social outcome. The data of our study support these latter findings, as we could not show a correlation between seizure freedom, at least in the 5 years before investigation, and long-term social outcome. In addition to the overall social outcome, we assessed a QoL inventory and analyzed possible predictors influencing long-term QoL for the JME group, which generally showed a high score of quality of life aspects. Furthermore, in our analysis psychiatric comorbidity was identified as a potential indicator for QoL in JME patients. Several studies have emphasized the negative influence of psychiatric comorbidities on QoL of patients with JME.22–24 Some authors have hypothesized that JME with psychiatric comorbidity constitutes a more severe subgroup of this condition.24 Finally, Schneider et al.12 demonstrated that higher scores on Becks Depression Inventory – II were correlated with a lower QoL level. This can be a hint that JME with psychiatric comorbidity might represent a severe subtype of JME with a higher risk of a decreased overall QoL, but more data are needed to fuel this hypothesis. The strengths of our study were as follows: (1) extraordinarily long follow-up time compared with previous studies; (2) implementation of a standardized QoL inventory and of a control group with another genetically determined generalized epilepsy syndrome; and (3) analysis of possible indicators for a negative psychosocial outcome. The study has the following limitations: (1) the fact that the sample was not population-based might include a bias; and (2) low case number, resulting in a limited statistical power. In summary, psychosocial outcome in 41 JME patients approximately 45 years after epilepsy onset was overall satisfying and comparable to that of control subjects with absence epilepsy. This finding suggests that specific neurobiologic alterations in JME, if they exist at all, do not contribute in a primary fashion to psychosocial outcome. We identified psychiatric comorbidity as a negative significant predictor for long-term QoL in these patients. In patients
7 Psychosocial Long-Term Outcome in JME with JME, further population-based studies focusing in particular on psychosocial aspects and psychiatric comorbidities are warranted.
Acknowledgments MH holds the “Friedrich-v.-Bodelschwingh Endowed Professorship for Clinical and Experimental Epileptology” at the Department of Neurology at the Charite – Universit€atsmedizin Berlin funded by v. Bodelschwingh Foundation.
Disclosure MH has served on scientific advisory boards for Eisai Inc., Janssen, UCB, and ViroPharma. He has received reimbursement for traveling expenses and/or speaker honoraria from Desitin, Eisai Inc., GlaxoSmithKline, Janssen, UCB, and ViroPharma. PS, AK, and DJ have no disclosures. We confirm that we have read the Journal’s position on issues involved in ethical publication and confirm that this report is consistent with the guidelines.
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