Content or context? A study protocol for a three-arm parallel randomised controlled trial of Re-PROGRAM, a brief internet-based intervention for patients with functional seizures

Abstract

Introduction

Functional seizures (FS) mimic epilepsy but are not caused by epileptic electrical activity in the brain and are believed to have a psychological origin. There is a well-documented gap between the needs of patients with FS and available therapeutic resources. While there is potential for reducing seizure burden in patients via psychosocial intervention, there is no evidence-based care pathway or consistent availability of treatment and no effective pharmacological treatment. The objective of this study is to investigate the clinical efficacy and tolerability of a novel internet-based intervention in reducing seizure frequency.

Methods and analysis

A 3-arm parallel randomised controlled trial will compare the efficacy of brief guided internet-based therapy to unguided internet-based therapy and to standard care. Approximately 100 participants with FS will be recruited, with diagnostic criteria based on gold standard video-electroencephalogram (v-EEG) monitoring; patients will be randomly assigned to one of the three study arms. The primary study outcome will be FS frequency at 6 weeks and at follow-up (6 and 12 months) compared with baseline. Seizure frequency will be modelled using Poisson regression. Secondary outcomes include psychosocial functioning, healthcare resource usage, anxiety, depression, somatisation and life impact. Between-group differences will be evaluated using analysis of variance. Analysis of covariance will estimate within-group changes on secondary outcomes. Cognitive and psychological factors will be used as predictors of seizure reduction in exploratory analyses. A qualitative survey using a semi-structured interview will use thematic analyses to explore participants’ treatment experiences, their impressions of FS management and perceived mechanisms for change.

Ethics and dissemination

The study was approved by the Human Research and Ethics Committee of the Alfred Hospital Human Research Ethics Committee as part of the Australian Multisite Ethics approval system. Results of the study will be presented at national and international conferences and published in peer-reviewed journals.

Trial registration number

ACTRN12622000262707.

Strengths and limitations of this study.

• To our knowledge, this is the first major study of a self-guided internet therapy programme for functional seizures.

• The study will collect rich quantitative and qualitative data to highlight strengths and limitations of internet therapy for functional seizures in different settings.

• Using the internet as a delivery mode for the intervention may exclude some primary care patients who do not have access to the internet.

• It is not designed to generate a cost-effectiveness analysis.

Background

Functional seizures (FS) are debilitating, paroxysmal events that often resemble epileptic seizures but are not associated with epileptic brain discharges.¹ These types of seizures have long believed to be primarily psychological in origin, however, their aetiology is still not clear.^2–5 FS commonly present in epilepsy practice, representing approximately 30% of patients admitted to video-electroencephalogram (v-EEG) monitoring units, and carry similar or greater morbidity, mortality and healthcare resource usage to epilepsy.^{6 7} They account for more than a quarter of all seizure presentations to emergency departments, where they are often subject to iatrogenic harm and a sixth of patients are admitted to intensive care units unnecessarily.^{8 9} The gap between the needs of patients with newly diagnosed FS and available therapeutic resources is well documented.^{2 10} While there is potential for reducing seizure burden in patients,^{11 12} there is no evidence-based care pathway or consistent availability of treatment for adults with FS.^{13 14} Few patients receive treatment, and those who do experience significant delays between receiving the diagnosis and commencing an appropriate psychological therapeutic intervention.¹⁵ In addition, for those patients receiving treatment there have been few studies evaluating response predictors to psychotherapeutic interventions for patients with newly diagnosed FS within a randomised controlled trial (RCT) framework.^{12 16} Identifying prognostic factors would provide specific targets for more individualised interventions and more successful treatment outcomes.

Internet therapy for functional seizures

Internet-based therapies have the potential to reach many patients quickly, overcoming barriers of resource and geographical constraints. Internet therapies using a Cognitive Behavioural Framework (CBT) have been demonstrated to be effective in treating mental health conditions including anxiety and depression¹⁷ with greater improvements for guided versus unguided therapies.¹⁸ There is also a growing body of evidence supporting the use of internet-based CBT for various functional and somatic disorders characterised by disabling symptoms (eg, fibromyalgia, irritable bowel syndrome, atrial fibrillation),^{19 20} highlighting the potential benefits of using online psychological interventions for FS. Internet-based therapy courses have not yet been developed or systematically evaluated in FS. Evaluation of a self-guided psychoeducation website for patients with motor functional neurological disorder (FND) in the Netherlands concluded that the website was well-received despite not leading to improvements.²¹ A structured internet-based therapy intervention would build on the feasibility of website resources available to patients with FND to evaluate targeted, guided and minimally-guided FS programmes. In Australia, individuals with FS struggle to access specialised treatment.²² Barriers to treatment include a lack of knowledge of functional disorders among health professionals, referral patterns, circular healthcare pathways, with patients often falling between the cracks of different medical specialties in public versus private healthcare and between physical and mental healthcare.^{15 23 24} Limited access to specialised treatment services for FS catalysed our research team to develop Re-PROGRAM, an internet-based therapy for FS.

Re-PROGRAM structure

Re-PROGRAM is a 5-week structured skills-based programme designed to enhance participants’ knowledge of FS and to teach them seizure-management strategies. It is designed to be delivered with or without assistance from a therapist. The programme consists of 43 brief modules spanning five sessions (8–13 modules per session). Examples of modules include psychoeducation on seizure-related mechanisms, rationale for seizure-management strategies, learning activities, practical techniques, reflection tasks or homework recommendations. Each session takes approximately 60–90 min. Participants are encouraged to complete one session per week. The self-guided version of Re-PROGRAM is suitable for use on mobile phone, tablet or computer, and contains videos, theory, interactive quizzes, recommended activities, frequently asked questions, downloadable resources and weekly homework to consolidate learning and to practice new skills. The e-version also includes a learning journal, which allows participants to enter text responses to journal prompts throughout the modules. At the end of each session, participants can email the learning journal to the therapist and print the journal, which includes all of their responses. Their responses are saved to the browser so they persist on future visits to the course. Completed modules remain available throughout the intervention.

Re-PROGRAM content

The Re-PROGRAM protocol was developed through a comprehensive literature review on the mechanisms, risk factors, and vulnerabilities associated with FS and established psychological treatment models.^{25 26} Specific empirically validated psychological and behavioural techniques that mapped onto these documented risk factors and outcomes were then extracted and combined.^27–30

Re-PROGRAM incorporates treatment components to address the potential neurobiological mechanisms of FS.^31–34 Psychoeducation regarding altered brain connectivity patterns, and targeted strategies to manage autonomic nervous system dysregulation and improve interoceptive awareness, in conjunction with cognitive behavioural therapy techniques, facilitates patients’ understanding of the psychophysiological processes involved in FS to facilitate self-management of symptoms. The sequencing of content strategically transitions from a behavioural and physiological focus at the outset to a more psychological focus over the course of treatment. A therapist manual aids treatment consistency and fidelity to the treatment model. The programme was retrospectively evaluated in an outpatient clinical setting for feasibility and acceptability. An overview of the intervention is provided in figure 1.

Figure 1.

Re-PROGRAM content.

Aims/outcomes

The aims of the study are to test the feasibility and efficacy of an internet-based intervention programme for individuals with FS, to compare the guided and unguided versions of the internet-based intervention and to identify response predictors to successful treatment outcome. The rationale for the choice of comparators is to evaluate two modalities of a brief add-on therapy to each other and to standard care, where all participants in the trial receive consistent standard care that would normally be delivered.

The primary outcome variable is monthly seizure frequency, as measured by self-report. Data will be collected at baseline, and 6 weeks, and 3, 6 and 12 months from baseline.

The secondary outcome variables are life impact as measured by the SF-12 V.2 Short Form Health Survey,³⁵ psychosocial functioning as measured by the Work and Social Adjustment Scale,³⁶ health resource usage as measured via the adapted self-report Client Service Receipt Inventory,³⁷ psychological distress/severity of somatic symptoms (physical symptoms) as measured by the Patient Health Questionnaire,³⁸ anxiety as measured by the General Anxiety Disorder questionnaire³⁹ and depression as measured by the Neurological Disorders Depression Inventory for Epilepsy.⁴⁰ All secondary outcomes will be collected at baseline, 6 weeks from baseline, and 3, 6 and 12 months from baseline (see table 1).

Table 1.

Study assessments administered per measurement occasion

	Enrolment	Monitoring (4 weeks)	Baseline	Allocation	Post allocation
					6 weeks	3 months	6 months	12 months
Enrolment
Eligibility screen	X
Informed consent	X
Psychiatric screen	X
Randomisation				X
Study arms
Guided Re-PROGRAM
Unguided Re-PROGRAM
Standard care
Assessments
Demographics			X
Primary outcome
Seizure frequency			X		X	X	X	X
Secondary outcomes
SF-12 V.2			X		X	X	X	X
CSRI			X			X	X	X
NDDI-E			X		X	X	X	X
GAD-7			X		X	X	X	X
PHQ-15			X		X	X	X	X
WSAS			X		X	X	X	X
Exploratory variables
PAQ			X
Brief IPQ			X
LEAS			X		X
PTQ			X
Brief COPE			X
RFQ-8			X
DES			X
BEAQ			X
PID-5-BF			X
MAIA-2			X
IEUQ					X
CSQ-8					X
FSPICS					X
RG			X		X

BEAQ, Brief Experiential Avoidance Questionnaire; COPE, Coping Orientation to Problems Experienced; COWAT, Controlled Oral Word Association Test; CSQ-8, Client Satisfaction Questionnaire; CSRI, Client Service Receipt Inventory; DES, Dissociative Experiences Scale; DS, Digit Span; FSPICS, Functional Seizures Pre-post Intervention Comparison Survey; GAD-7, General Anxiety Disorder; IEUQ, Internet Evaluation and Utility Questionnaire; IPQ, The Illness Perception Questionnaire; LEAS, Levels of Emotional Awareness Scales; MAIA-2, The Multidimensional Assessment of Interoceptive Awareness; MC, Mental Control; NDDI-E, Neurological Disorders Depression Inventory for Epilepsy; PAQ, Perth Alexithymia Questionnaire; PHQ-15, Patient Health Questionnaire; PID-5, The Personality Inventory for DSM-5-BF; PTQ, Perseverative Thinking Questionnaire; RFQ-8, The Reflective Functioning Questionnaire; RG, Repertory Grid; SF-12, Short Form Health Survey; TOPF, Test of Premorbid Functioning; VST, Victoria Stroop Test; WSAS, Work and Social Adjustment Scale.

Additional outcomes will be explored as predictors and mediators of treatment response including measures of dissociation, experiential avoidance, personality, interoceptive awareness, alexithymia, illness, emotional awareness, perseverative thinking, coping, reflective functioning, personal constructs, measures of cognition (attention, processing speed, mental control, executive function) and evaluation of the intervention (table 1). The study will use advanced statistical modelling to identify predictors of treatment response and non-response, and correlations between FS frequency and behaviour and cognitive function.

Methods/design

The study is a single site single blinded three-parallel arm RCT of a brief intervention programme in patients with FS. Participants will participate in 5 weeks of psychological therapy using Re-PROGRAM unguided, Re-PROGRAM with synchronous psychologist support, or standard care. One hundred and eleven participants will be recruited into the study between February 2022 and February 2024, which will be conducted at the Alfred Hospital in Melbourne, Australia. Ethics approval was granted by the Alfred Health Human Research Ethics Committee, Melbourne (462/21).

Eligibility criteria

Inclusion criteria: participants will have a documented diagnosis of FS following admission to the video EEG monitoring (VEM) unit; be aged 18 years or over; have access to a computer or tablet with reliable internet connection; a valid email address; basic computer literacy/competency; English proficiency at a level that allows provision of written informed consent, completion of cognitive tests, questionnaire engagement and undertaking the intervention consent; be eligible for Medicare; and exceed the cut-off score of at least four typical FS per month.

Exclusion criteria: participants will be excluded if they have a diagnosis of active comorbid epilepsy (≥1 epileptic seizure in past 12 months); a severe neurocognitive disorder that precludes the ability to give informed consent and impacts cognition (eg, dementia, moderate–severe intellectual disability); impaired vision or audition that would prevent them from perceiving test materials necessary for cognitive assessment; insufficient English that would confound the cognitive assessment; severe comorbid psychiatric disorders (ie, bipolar disorder, psychotic disorders); comorbid substance use disorder other than nicotine; active elevated risk of self-harm or suicide requiring urgent clinical management; or a medical condition that would interfere with therapy participation.

Intervention, randomisation and blinding

Following consent by one of the Alfred FS psychiatrists or neurologists, participants will be enrolled in the study by a neuropsychologist, who will assign a unique study number, and conduct a baseline assessment, before being randomised into the study arms by an independent researcher using block randomisation generated within Research Electronic Data Capture’s (REDCap) electronic case report form (eCRF; subject to entry of key data into the eCRF). Outcome assessors will be blinded throughout the course of the study. Study participants, treating clinicians and the researcher delivering the therapy are not able to be blinded.

Confidentiality and security

Once recruited, participants will be assigned a unique study ID. Only participant initials, date of birth and hospital identification number will be stored alongside their unique ID. This information will be securely stored on a password protected spreadsheet, separate from any cognitive or medical data. A separate spreadsheet will then contain the participants ID along with all cognitive data and clinical characteristics (the participants initials and date of birth will not be recorded on this spreadsheet). It is unlikely that any individual will be able to be re-identified based on cognitive data alone, however, it is plausible some individuals within the clinical group may have uniquely identifiable clinical characteristics. The final trial clinical data set will be represented within the spreadsheet in a coded manner, with the interpretation of each code securely stored in a separate document, meaning only researchers involved in the project will be able to interpret the spreadsheet. Only re-identifiable data will be published in the scientific literature.

Patient and public involvement

No patient involved.

Procedures and assessments

A recruitment flyer will be disseminated to relevant clinical colleagues and FND-affiliated networks. Patients with a documented diagnosis of FS made via inpatient video-EEG monitoring who meet study criteria and consent to study participation will undergo a comprehensive neuropsychiatry assessment and a general health assessment. The neuropsychiatric assessment will be conducted using the Diagnostic and Statistical Manual of Mental Disorders (fifth edition; DSM-5); American Psychiatric Association, 2013; criteria.⁴¹ Psychiatric diagnoses and formulation, including personality disorders, will be established according to the DSM-5 criteria applied during the comprehensive evaluation and established via expert consensus discussion. Patients determined to have a severe comorbid psychiatric disorder that would interfere with the ability to attend or participate in therapy will be excluded from the trial. This includes patients with current psychotic illness, severe affective illness, active self-harm or suicide risk, poor insight or significant cognitive dysfunction.

Patients who meet inclusion criteria will record their seizure activity for a 4-week period prior to beginning the study to provide an objective baseline measurement of seizure frequency. Participants will subsequently attend a baseline assessment via Telehealth, where a neuropsychology registrar will administer questionnaires, a semi-structured interview and a brief cognitive assessment. The semi-structured interview will collect qualitative data, including participants’ experiences of FS; acceptance and understanding of the condition; perception surrounding delivery of the diagnosis; impressions of the condition; family attitudes and responses to FS; and pragmatic and psychological effects of FS on their lives.

Participants will complete follow-up questionnaires at the conclusion of therapy, and at 3, 6 and 12 months post-baseline when attending follow-up appointments with neuropsychiatry. Participants in the active study arms will complete additional questionnaires with a qualitative component to gain insight into their perceptions of the intervention and perceived mechanisms for change. A combination of patients’ self-report and data from the website will be used to record use of the internet intervention. Participants who stop using the programme they are assigned to will still be sent all follow-up questionnaires to complete (unless they have requested to be withdrawn from the study) and continue to be seen for standard medical care by clinicians (neurologists, psychiatrists and psychiatry registrars) in the FS outpatient clinic every 6 weeks.

In the Re-PROGRAM synchronous therapy arm, a psychologist will interact with the participant via videoconferencing in a weekly individual 60–90 min session across five consecutive weeks. The psychologist will use a standardised therapy manual, conceptualised and piloted for safety, feasibility and acceptability. Following intervention completion, participants will revert to clinical follow-up as usual, which consists of a review appointment with a clinician (neurologists, psychiatrists or psychiatry registrar) in the FS clinical approximately every 6 weeks. Participants in the synchronous therapy arm are allowed concomitant care to treat physical and mental comorbidities but no targeted cognitive behavioural therapy for FS is permitted for the duration of the intervention.

Participants in the unguided Re-PROGRAM arm will be encouraged to complete the internet intervention across five consecutive weeks, with the programme available for 3 months maximum. Asynchronous psychologist support will take part individually. Participants will be provided with a recommended timetable of weekly module completion and instructions detailing how to contact a psychologist within the platform regarding technical difficulties. They will receive 10 min per week of psychologist-client contact in the form of email or phone correspondence. In general, the role of the psychologist in this arm is to ensure participants progress through the e-intervention and complete activities and homework on time. The psychologist will be permitted to give feedback on homework, answer questions (providing reference to the programme when necessary), encourage progress, provide support and validation and handle scheduling issues. The psychologist will answer questions via email within 24 hours. Following intervention completion, participants will revert to standard medical care, which consists of a review appointment with a clinician (neurologist, psychiatrist or psychiatry registrar) in the FS clinical approximately every 6 weeks. If participants do not complete the intervention within 3 months, the number of sessions completed will be recorded and documented as not completed. Participants in the unguided arm are allowed concomitant care to treat physical and mental comorbidities but no targeted cognitive behavioural therapy for FS is permitted for the duration of the intervention.

Participants in the standard care arm (control group) will attend a review appointment every 6 weeks for standard medical care with a clinician (neurologist, psychiatrist or psychiatry registrar) in the FS outpatient clinic. Standard medical care will include supportive counselling, consideration and treatment of psychiatric comorbidities and any associated drug treatment and general review, but CBT techniques for FS will not be discussed. Study testing and procedures are outlined in table 1.

Measures

Cognitive battery

All cognitive test performances are scaled according to age-stratified and sex-stratified normative data. An assessment at baseline will examine aspects of cognition comprising the following:

Premorbid intellectual function

The Test of Premorbid Functioning (TOPF) will be used to estimate premorbid intellectual capability.⁴² The TOPF requires participants to read and pronounce words that have irregular grapheme-to-phoneme translation and does not require comprehension or knowledge of word meaning.

Attention

Digit Span, a subset of the Working Memory Index of the Wechsler Adult Intelligence Scale, third edition⁴³ will be used to assess attention. Participants are required to verbally recall increasingly longer digit sequences read to them. The task consists of three conditions: forward, backward and sequencing.

Mental control

Measured using mental control subtest from the Wechsler Memory Scale—third edition.⁴⁴ The mental control task assesses speeded performance for reciting the alphabet, counting forward and backward, days of the week forward and backward, months of the year forward and backward and counting by 6 s while stating days of the week in order.

Information processing

The Oral Symbol Digit Modalities Test will be used to measure information processing speed.^{45 46} Using a reference key, individuals have 90 s to substitute numerical digits with corresponding abstract symbols using oral responses.

Executive function

Measured by The Controlled Oral Word Association Test (COWAT)⁴⁷ and the Stroop Color-Word Test-Victoria version (VST).⁴⁸ In the COWAT, individuals are given 1 min to name as many words as possible beginning with a particular letter. There are three trials, each using a different letter. Verbal fluency is a cognitive function that facilitates information retrieval from memory, which requires executive control over cognitive processes such as selective attention, mental set shifting, internal response generation and self-monitoring. The VST uses three conditions that consist of naming the colour of dots, neutral words and colour words printed in incongruent colours and requires the ability to inhibit an automatic response.

Safety assessments

All participants will receive psychiatric risk assessments at initial screening, at baseline, and following completion of the intervention for the therapy arms and at approximately 6 weeks intervals post baseline as part of standard medical care. This will incorporate general mental and physical health assessment at baseline to screen for medical issues which would place a participant at risk from undertaking intervention activities.

In the event that risk of harm to self or others is assessed as significant by the psychologist administering the assessment or the intervention, the assessment or intervention will be stopped immediately and the participant will be offered supportive counselling or referred to acute mental health services where necessary. Major risks, including that of increased distress, clinical deterioration and or risk of harm to self or others will be closely monitored by the clinical FS service, integrated locally with the acute mental health services. Crisis contacts will be reinforced at the beginning of the intervention.

Power and sample size

A power analysis was performed for sample size estimation, based on data from the CODES (Cognitive Behavioural Therapy for Dissociative (Non-Epileptic) Seizures) trial,¹⁶ which used a comparable study design (N=368), comparing treatment outcome between two study arms. The effect size in this study was 0.36, considered to be medium using Cohen’s criteria.⁴⁹ For a more conservative estimate of sample size using a Cohen’s f of 0.20, an alpha=0.05 and power=0.80, the projected sample size needed with this effect size (G*Power V.3.1) is approximately N=78 for this simplest between group comparison of three study arms. Due to the well-documented high attrition rate of up to 25% in this patient population,⁵⁰ our proposed sample size of 98+ (33+ per group) will be more than adequate for the main objective of this study. To allow for additional objectives of conducting subgroup analysis, a power analysis using a Cohen’s f of 0.30, alpha=0.05 and power 0.80, the projected sample size is approximately N=111 to detect a moderate effect (37+ per group).

Outcomes and overview

Primary outcome

The primary outcome measure will be seizure frequency at 6 weeks compared with baseline and at follow-up (months 6 and 12 compared with baseline). Monthly seizure frequency is a continuous variable that comprises a count of seizures over a 4-week period. Statistical analyses will be dependent on the final sample size and determined in consultation with an independent statistician. Seizure counts will be modelled using Poisson regression.

Secondary outcomes

The secondary outcome measures are psychosocial functioning, healthcare resource usage, psychological symptoms, physical symptoms and life impact (see table 1) at 6 weeks compared with baseline and at follow-up (months 6 and 12 compared with baseline). Continuity-adjusted χ² will be used to compare treatment groups on baseline categorical variables. Between-group differences in continuous variables will be evaluated using analysis of variance. Analysis of covariance will be used to estimate within-group changes on continuous secondary outcomes.

Subgroup analysis

If the data reported allows, we will explore subgroup and adjusted analyses based on the following patient subtypes to understand which interventions most effectively reduce FS for different conditions: post-traumatic stress disorder, autism spectrum disorder, semiology subtype (ie, dissociation, convulsions, drop attacks); and adjustments for length of illness, and comorbid functional motor symptoms.

Qualitative data

Thematic analysis of qualitative data using NVivo⁵¹ will identify themes associated with patient perspectives on FS, and the potential positive changes brought about by Re­-PROGRAM.

Retention

All randomised participants completing the 12-month evaluation schedule will have fulfilled the requirements of the study. Randomised participants who prematurely discontinue or fail to complete either the self-guided or guided intervention within 3 months will follow the same schedule of events as those in the standard care arm and will be followed through 12 months as scheduled. Once a participant is enrolled or randomised, every reasonable effort to follow the participant for the entire study period will be taken.

Participant withdrawal

Participants may withdraw from the study for any reason at any time. The investigator also may withdraw participants from the study in order to protect their safety and/or if they are unwilling or unable to comply with required study procedures. When the participant withdraws, no further data will be collected, however, data collected up to the time of withdrawal will still form part of the research study results. Reasons for treatment non-adherence and study non-retention will be recorded to inform the handling of missing data and interpretation of results. Participants who withdraw and who consent for continued follow-up will be included in the analysis by modern imputation methods for missing data. Ongoing standard care in the FS clinic will be provided to participants who discontinue or fail to complete Re-PROGRAM. Re-PROGRAM may be offered to standard care participants following trial participation.

Safety and feasibility

Safety will be determined by frequency of adverse and serious adverse events.

Monitoring and data quality

In accordance with International Council for Harmonisation Good Clinical Practice guidelines, the project manager will carry out source document verification at regular intervals to ensure that the data collected in the eCRF are accurate and reliable. The frequency of monitoring visits will be determined by the rate of subject recruitment.

Ethics and dissemination

This study has been approved by the Alfred Hospital Human Research Ethics Committee (HREC, 462/21). Results of the study will be disseminated through presentations at national and international conferences and published in peer-reviewed journals. Any amendments to the protocol will be approved by the HREC prior to implementation and subsequently updated on ANZCTR.

Ethics statements

Patient consent for publication

Not applicable.