Caregivers’ Perspectives on the Impact of Cannabidiol (CBD) Treatment for Dravet and Lennox-Gastaut Syndromes: A Multinational Qualitative Study

Abstract

Objective

To increase understanding of the impact of cannabidiol (CBD) on outcomes beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome.

Methods

Qualitative interviews were conducted with caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived, highly purified CBD medicine (Epidiolex in the USA; Epidyolex in Europe; 100 mg/mL oral solution). Symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome on individuals were explored, as were the effects of CBD. Data were analyzed using thematic analysis.

Results

Twenty-one caregivers of individuals with Dravet syndrome (n = 14) and Lennox-Gastaut syndrome (n = 7) aged 4-22 years participated. Health-related quality of life improvements associated with CBD included cognitive function, communication, behavior, mobility, and participation in daily activities. Seizure frequency reduction was commonly reported (n = 12), resulting in caregivers having greater freedom and family life being less disrupted. Adverse events were reported by 10 caregivers.

Conclusion

In addition to reduced seizure frequency, CBD may have a wide range of beneficial effects beyond seizure control that warrant further investigation.

Introduction

Dravet syndrome and Lennox-Gastaut syndrome are rare, severe developmental and epileptic encephalopathies.^1–4 Both syndromes have early childhood onset and impact mortality.^1–3,5–8 Dravet syndrome and Lennox-Gastaut syndrome also exhibit multiple seizure types and a high degree of treatment resistance.^3,4,9

Health-related quality of life is considerably impacted in patients with Dravet syndrome and with Lennox-Gastaut syndrome,^10–12 and their caregivers.^12,13 In addition to epileptic seizures, factors that may contribute to lowered patient health-related quality of life include affected mobility,^1,11–14 cognitive impairment,^1,11,15 and eating difficulties or reduced appetite.^15,16

Highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in the United Kingdom and European Union [GW Pharma (International) BV, now part of Jazz Pharmaceuticals, Inc]) has demonstrated efficacy for seizure control with an acceptable safety profile in patients with Dravet syndrome and Lennox-Gastaut syndrome in 4 randomized controlled trials.^17–20 However, there is limited evidence of CBD effects beyond seizure control for patients with Dravet syndrome and Lennox-Gastaut syndrome, and their caregivers.

Evidence from open-label studies of CBD in patient populations with treatment-resistant epilepsy suggests that CBD has positive impacts on health-related quality of life independent of reduced seizure frequency effects.^21,22 Retrospective studies have also found that caregivers and patients with treatment-resistant epilepsy report improved sleep, mood, communication, language use, and behavior/alertness after patient treatment with CBD-enriched cannabis or oral cannabis extracts.^23–25 Similarly, a recent observational clinical audit at 2 UK neurology centers found positive effects of CBD on cognition, particularly regarding language, in adults with Dravet syndrome, even without significant reduction in seizures. ²⁶

Quality of life, adaptive behavior, and cognition measures were included as secondary endpoint variables in the CBD clinical trials.^17–20 However, in the largest pivotal trials of CBD in Dravet syndrome and Lennox-Gastaut syndrome, the numbers of patients who completed quality of life and adaptive behaviors scores, eg, Quality of Life in Childhood Epilepsy (QOLCE) and composite Vineland-II scores, were low, limiting the interpretability of results.^18,20 A recent review highlighted that the Vineland Adaptive Behavior Scales may be insensitive to functional changes among children with Lennox-Gastaut syndrome due to the high degree of impairment among most children. ²⁷ The QOLCE was developed for use in patients with epilepsy and includes items that are not applicable to patients with severe epilepsy and associated learning difficulties, such as those seen in Dravet syndrome and Lennox-Gastaut syndrome. The absence of appropriate instruments limits the ability to generate quantitative evidence of health-related quality of life outcomes in a clinical trial setting.

Qualitative research is an established field that enables in-depth exploration of the impact of a condition and its treatment on patients or caregivers by allowing them to speak freely about their experiences outside the constraints of closed question surveys or questionnaires.^28,29 This allows caregivers and patients to identify and prioritize aspects of the patient's condition that are important to them and generates rich contextual data on the meaning and experience of health, illness, and treatment for patients or caregivers, as well as the wider impact on their lives. ²⁸ This is particularly useful for rare diseases where quantitative research is lacking. To date, no qualitative studies have examined the impact of CBD on individuals with Dravet syndrome or Lennox-Gastaut syndrome, or specifically explored the impact of CBD on outcomes beyond seizure control.

The study aim was to understand the impact of ≥6 months of treatment with CBD on outcomes beyond seizure control (eg, cognition, behavior, and health-related quality of life) among individuals with Dravet syndrome or Lennox-Gastaut syndrome, their caregivers, and their wider family.

Methods

Study Design and Recruitment

A qualitative interview study with caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived highly purified CBD medicine (Epidiolex [USA], Epidyolex [UK and Germany]; 100 mg/mL oral solution) in the United States, the United Kingdom, and Germany was conducted. Recruitment occurred between February and June 2021 via local patient advocacy groups and a market research agency (US participants only). Interested caregivers were provided with a study information sheet and were asked to complete a screening form.

The study aimed to recruit 20 caregivers per syndrome (n = 40 in total), based on qualitative research guidelines, which recommend sample sizes of between 20 and 30 per cohort to achieve data saturation (ie, a point where no new themes or topics emerge). ³⁰ A purposive sampling framework was used, whereby a broad patient age range and variation in patient intellectual ability were targeted to enable subgroup comparisons and a wide range of caregiver perceptions and experiences to be captured.

To minimize bias, it was planned for participants to be blinded to the study's focus on CBD during screening prior to interview. The screening process comprised a 5-minute questionnaire that included 9 questions on participant and patient characteristics (eg, age, residence, patient diagnosis, relationship to the patient, etc) and previous patient treatment. During the initial blinded screening process, a large proportion of participants were found to be ineligible because the patient had not received CBD for at least 6 months. At this time, CBD had been relatively recently approved in the United Kingdom, so only a small proportion of patients were taking CBD. Ineligible caregivers and patient advocacy groups reported frustration over the substantial time that caregivers had wasted in completing the screening process and perceived this as avoidable. Taking into account the substantial burden of caring for someone with complex needs, as well as respecting the impact that their caring responsibilities have on their time, it was decided to inform potential participants of the study's focus on CBD before screening to lower the number of caregivers spending time completing the screening form unnecessarily.

Participants

Inclusion criteria for caregiver participants were as follows: aged ≥18 years; the main, unpaid caregiver of an individual with Dravet syndrome or Lennox-Gastaut syndrome aged ≥2 years who had received CBD medicine for a minimum of 6 months; a resident in the United States, the United Kingdom, or Germany; and willing to participate in an audio-recorded interview. Participants were excluded from the study if they did not meet the inclusion criteria.

All participants were required to provide written informed consent prior to study participation.

Procedures

Consenting participants completed a background questionnaire on sociodemographic characteristics, time spent caring, and the patient's clinical characteristics. Responses were used to ensure interview questions were appropriate for the patient's condition and treatment characteristics.

All semistructured interviews were conducted using an interview guide, developed based on a targeted literature review of the symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome (see Supplemental information). The guide was designed to initially encourage spontaneous reporting of symptoms of Dravet syndrome/Lennox-Gastaut syndrome and the impacts on the patient and caregivers’ health-related quality of life. Caregivers’ views about the symptoms of Dravet syndrome and Lennox-Gastaut syndrome currently experienced, as well as the broader health-related quality of life impacts on patients, caregivers, and other family members (eg, on daily or social activities), were then explored. Caregivers were subsequently asked whether symptoms or broader impacts had changed over time and whether this occurred following initiation of treatment with CBD. This structure allowed participants to speak freely about any seizure- or beyond-seizure-related impacts of CBD before they were prompted to speak about this topic, with the aim to minimize potential bias such as recall and social desirability bias. The interview concluded with general questions on the caregivers’ experiences of CBD.

Interviews were conducted by 3 experienced interviewers using online video conferencing. All interviews were audio recorded to permit transcription. German language transcripts were translated into English prior to analysis. The interviews and transcripts were deidentified and assigned participant identification numbers. All researchers involved in the analysis had postgraduate degrees in relevant fields and more than 19 years’ combined qualitative research experience. The researchers had no personal experience with epilepsy or seizures, or familiarity with the study participants.

Analysis

Data from the background questionnaires were summarized descriptively. Interview data were analyzed using thematic analysis in MAXQDA 2020 (generation 20.3.0), a method for identifying, analyzing, and reporting themes in qualitative data. ³¹ The analysis followed the 6 stages outlined by Braun and Clarke: familiarization, generation of codes, searching for themes, reviewing themes, defining the themes, and reporting.

A coding framework was developed based on the topics covered in the interview guide. A sample of transcripts were independently coded by 2 researchers who conducted the interviews; findings were compared and discrepancies discussed. The coding framework was revised following this discussion, and the remaining transcripts were coded by 3 researchers. Additional data-driven amendments were made to the coding framework throughout the coding process.

The codes were then grouped into themes relating to the symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome and experience with CBD. A conceptual model was developed to illustrate the symptoms and impacts experienced by individuals with Dravet syndrome/Lennox-Gastaut syndrome, and the moderating impact of CBD on these symptoms and impacts.

Data saturation was monitored during the analysis using saturation matrices to ensure all relevant concepts were fully represented, following the methodology suggested by Leidy and Vernon. ³²

Results

Sample Characteristics

A sample of 21 caregivers (Dravet syndrome = 14; Lennox-Gastaut syndrome = 7) was achieved. Three caregivers were recruited through blind screening and 18 through unblinded screening. All, except 1 caregiver, cared for an individual currently being treated with CBD (n = 20). Caregiver and patient characteristics are detailed in Tables 1 and 2. Despite difficulties with recruitment, data saturation matrices provided some evidence that saturation had been reached, with all but 2 concepts emerging in the first 5 interviews.

Table 1.

Caregiver Characteristics (n = 21).^a

	DS (n = 14; 67%)	LGS (n = 7; 33%)
Mean (SD; range) age (y)	42.29 (7.75; 29-55)	44.86 (11.04; 25-57)
Mean (SD; range) hours spent providing practical and emotional care per week	96.79 (50; 25-168)	120.29 (45.14; 50-168)
Occupation, n (%)
Employed full time	3 (21)	1 (14)
Employed part time	4 (29)	2 (29)
Self-employed	2 (14)	1 (14)
Full-time homemaker/caregiver	7 (50)	3 (43)
Country of residence, n (%)
United States	12 (86)	6 (86)
Germany	1 (7)	1 (14)
United Kingdom	1 (7)	0 (0)
Relationship to individual, n (%)
Mother	13 (93)	7 (100)
Father	1 (7)	0 (0)
Current living situation, n (%)
Living with partner	13 (93)	4 (57)
Living alone	0 (0)	2 (29)
Other	1 (7)	1 (14)
Impact of caring responsibility on work, n (%)
Stopped working	11 (79)	5 (71)
Reduced working hours	9 (64)	3 (43)
Changed job	6 (43)	4 (57)

Abbreviations: DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome; SD, standard deviation.

^a Sum of percentages does not equal 100 in every instance, as some caregivers selected more than one option for certain questions.

Table 2.

Characteristics of Individuals With DS or LGS (n = 21).

Characteristic	DS (n = 14; 67%)	LGS (n = 7; 33%)
Mean (SD; range) age (y)
At diagnosis	1.23 (1.03; 0.50-3)	6.20 (5.89; 1-16)
Current	9.29 (4.66; 4-20)	14.86 (6.18; 6-22)
Mean (SD; range) duration of CBD treatment (n = 17; y)	3.03 (1.98; 0.67-7.33)	1.5 (0.88; 0.58-2.33)
Current antiseizure medication, n (%)
CBD	14 (100)	6 (86)
Cenobamate	1 (7)	2 (29)
Clobazam	11 (79)	5 (71)
Clonazepam	0 (0)	2 (29)
Felbamate	1 (7)	2 (29)
Fenfluramine	2 (14)	0 (0)
Lamotrigine	0 (0)	1 (14)
Levetiracetam	2 (14)	3 (43)
Rufinamide	0 (0)	2 (29)
Sodium valproate	4 (29)	1 (14)
Stiripentol	3 (21)	1 (14)
Topiramate	3 (21)	0 (0)
Zonisamide	2 (14)	2 (29)

Abbreviations: CBD, cannabidiol; DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome; SD, standard deviation.

Frequencies of spontaneous and prompted reporting of concepts relating to symptoms and functions, and impacts on individuals with Dravet syndrome or Lennox-Gastaut syndrome, caregivers, and families are shown in Figures 1 and 2.

Figure 1.

Frequency of spontaneous and prompted reporting of concepts relating to current symptoms and functions, and impacts on individuals with DS or LGS, caregivers, and families. Abbreviations: DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome.

Figure 2.

Frequency of spontaneous and prompted reporting of concepts relating to changes to symptoms and functions, and impacts on individuals with DS or LGS, caregivers, and families, since treatment with CBD commenced. Abbreviations: CBD, cannabidiol; DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome.

Current Symptoms and Functions of Dravet Syndrome and Lennox-Gastaut Syndrome

Figure 3 shows the conceptual model, illustrating current symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome among individuals living with these conditions.

Figure 3.

Conceptual model illustrating the relationships between symptoms and impacts of DS and LGS, and those mediated by CBD. ^aSymptom/impact not caused by DS or LGS. Symptoms/impacts that are italicized represent mediated changes that were mentioned by ≥5 caregivers. The symptoms/impacts that were positively mediated by CBD are shown in green, those that were negatively mediated are shown in red, and those that were both positively and negatively mediated are shown in orange. Abbreviations: ADHD, attention-deficit hyperactivity disorder; DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome.

Seizures. All individuals experienced epileptic seizures. Seizures were commonly reported to be unpredictable, and seizure type, length, and frequency varied on a monthly, weekly, or daily basis:

There is no rhyme or reason to his [seizures]… they will just happen… he's very unpredictable and everything, so we have to make sure that we are always on guard.—Caregiver of patient with Dravet syndrome aged 6 years

Seizure types included tonic-clonic (Dravet syndrome = 11; Lennox-Gastaut syndrome = 6), clonic (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1), tonic (Dravet syndrome = 1; Lennox-Gastaut syndrome = 2), atonic (Dravet syndrome = 5; Lennox-Gastaut syndrome = 4), absence (Dravet syndrome = 6; Lennox-Gastaut syndrome = 4), focal with impaired awareness (Dravet syndrome = 5; Lennox-Gastaut syndrome = 1), and myoclonic (Dravet syndrome = 7; Lennox-Gastaut syndrome = 2). Seizure frequency ranged between 0 and 50 per day. Tonic-clonic seizures were typically reported to occur 2 to 4 times a week.

Cognitive function and communication. All caregivers stated that their child had limited cognitive function and delayed development. Some also reported impaired short-term memory (Dravet syndrome = 4; Lennox-Gastaut syndrome = 1):

If you ask her something on a typical day “What did you do at school?” her automatic response is “Lunch.” And she likes her lunch, but if you try to ask her about an art project that she brought home, or an activity that you know went on, maybe one out of three times she’ll be able to recall that even with a specific question being asked.—Caregiver of patient with Dravet syndrome aged 14 years

Conversely, 3 caregivers noted their child had comparatively functional long-term memory (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1).

Some caregivers reported their child struggled with planning, problem solving, and understanding abstract concepts, such as time, safety, and danger (Dravet syndrome = 3; Lennox-Gastaut syndrome = 2):

There's a lot of concepts that are still very difficult to him, especially with safety, that's a huge problem. It's difficult. He doesn’t understand his actions a lot of the time.—Caregiver of patient with Dravet syndrome aged 11 years

All caregivers described their child having difficulty in communicating verbally. This ranged from ability to use full sentences (albeit at a lower communication level to their peers, Dravet syndrome = 3; Lennox-Gastaut syndrome = 1), to using short phrases or words (Dravet syndrome = 6), to having no speech (Dravet syndrome = 4; Lennox-Gastaut syndrome = 6).

Mobility. The mobility of children was varied. Children were described as completely mobile (Dravet syndrome = 4; Lennox-Gastaut syndrome = 1), needing support to walk (Dravet syndrome = 4; Lennox-Gastaut syndrome = 3) and/or requiring a wheelchair for long distances (Dravet syndrome = 5; Lennox-Gastaut syndrome = 2), or unable to walk (Dravet syndrome = 1; Lennox-Gastaut syndrome = 3). Of those unable to walk, 2 children could not make any purposeful movements (Lennox-Gastaut syndrome = 2), but 2 were able to crawl and move on the floor (Dravet syndrome = 1; Lennox-Gastaut syndrome = 1).

Regardless of ability to walk, many individuals had difficulty balancing (Dravet syndrome = 7; Lennox-Gastaut syndrome = 2), with patients at risk of falling, or difficulty with hand-eye coordination (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1). Children were reported to experience muscle weakness and low muscle tone (Dravet syndrome = 5; Lennox-Gastaut syndrome = 2). In some cases, muscle weakness caused tiredness or fatigue (Dravet syndrome = 5).

Behavior. Several caregivers reported their child experienced behavioral difficulties (Dravet syndrome = 14; Lennox-Gastaut syndrome = 4), some of which were described as related to a diagnosis of autism spectrum disorder (Dravet syndrome = 4; Lennox-Gastaut syndrome = 1) or attention-deficit hyperactivity disorder (Lennox-Gastaut syndrome = 1). These included episodes of tantrums, crying, and aggressive behaviors, such as self-injury and hitting/pushing others. Some caregivers of individuals with Dravet syndrome mentioned their child had periods of hyperactivity, repetitive behavior, and limited attention span (Dravet syndrome = 4). Conversely, other caregivers reported no behavioral issues or their child being normally “calm” or “chilled” (Dravet syndrome = 3; Lennox-Gastaut syndrome = 3).

Pain and discomfort. Some caregivers thought their child experienced pain and discomfort (Dravet syndrome = 5; Lennox-Gastaut syndrome = 4); headaches and pain before, during, or after seizures were most often reported (Dravet syndrome = 2; Lennox-Gastaut syndrome = 3). Some caregivers believed their child had a high pain threshold (Dravet syndrome = 6), which they perceived as common for individuals with Dravet syndrome and could result in injury.

Sleep disturbance. Several caregivers reported their child's sleep was disrupted. Insomnia (Dravet syndrome = 4; Lennox-Gastaut syndrome = 2) and night-time seizures (Dravet syndrome = 3; Lennox-Gastaut syndrome = 1) were both stated as causes.

Appetite and feeding. Feeding independence varied among the cohort. Some children could feed themselves (Dravet syndrome = 3), and 1 was spoon-fed (Lennox-Gastaut syndrome = 1). Several caregivers reported their child was fed through a feeding tube (Dravet syndrome = 3; Lennox-Gastaut syndrome = 4) for reasons including poor appetite (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1) or limited motor function (Lennox-Gastaut syndrome = 1). Three children received all their food this way (Dravet syndrome = 1; Lennox-Gastaut syndrome = 2).

Other symptoms. Other symptoms reported by caregivers included gastrointestinal symptoms, for example, vomiting (Lennox-Gastaut syndrome = 1) and constipation (Lennox-Gastaut syndrome = 2); and susceptibility to infections (Dravet syndrome = 2; Lennox-Gastaut syndrome = 3), for example, viral gastrointestinal infections (Lennox-Gastaut syndrome = 2), ear infections (Dravet syndrome = 1, Lennox-Gastaut syndrome = 1), pneumonia (Lennox-Gastaut syndrome = 1), glandular fever (Lennox-Gastaut syndrome = 1), and other unspecified infections (Dravet syndrome = 1).

Current Impacts of Condition on Individuals With Dravet Syndrome or Lennox-Gastaut Syndrome

Self-care. Some individuals with Lennox-Gastaut syndrome were fully dependent on caregivers for their self-care, including washing, dressing, and mobility because of limited motor function (Lennox-Gastaut syndrome = 3 [age range 6-22 years]) or cognitive function (Lennox-Gastaut syndrome = 1 [aged 21 years]). However, most caregivers reported their child could conduct certain self-care tasks with supervision (Dravet syndrome = 12 [age range 4–20 years]; Lennox-Gastaut syndrome = 3 [age range 16-21 years]). For example, a 16-year-old individual with Lennox-Gastaut syndrome had general basic life skills and was able to shower and prepare simple meals, with supervision.

Leisure activities. All caregivers stated that their child's participation in leisure activities was affected by seizures, with most individuals requiring caregiver supervision in case a seizure occurred (Dravet syndrome = 8; Lennox-Gastaut syndrome = 3). Some individuals were also limited by their seizure triggers.

Leisure activities were affected by motor and cognitive function. Children with milder physical and cognitive limitation were less restricted in their activities (Dravet syndrome = 7; Lennox-Gastaut syndrome = 1); some were able to play basketball, ride a bicycle, or go swimming. Those with more severe physical or cognitive limitations could only carry out seated activities (Dravet syndrome = 2; Lennox-Gastaut syndrome = 3) or activities not requiring active participation, such as watching others and being read to (Lennox-Gastaut syndrome = 2).

School. Over half of school-aged children attended school or nursery, including specialist schools and mainstream schools with specialist support (Dravet syndrome = 11; Lennox-Gastaut syndrome = 3). Because of limited motor function, learning difficulties, and concentration problems, many individuals struggled with schoolwork and required one-to-one classroom support (Dravet syndrome = 5; Lennox-Gastaut syndrome = 3).

Some caregivers reported their child's behavior at school could be disruptive and difficult to manage (Dravet syndrome = 4; Lennox-Gastaut syndrome = 1). Many individuals regularly missed school or attended shorter hours because of seizure recovery or tiredness (Dravet syndrome = 4; Lennox-Gastaut syndrome = 2).

Social activities and relationships. Although some individuals were able to form relationships and enjoyed company (Dravet syndrome = 6; Lennox-Gastaut syndrome = 2), several caregivers reported their child had difficulty interacting with peers and making friends. Reasons cited included the individual's limited motor function or inability to speak (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1), or difficulty understanding boundaries or how to interact with their peers (Dravet syndrome = 4).

Concerns about aggressive behavior toward other children resulted in caregivers avoiding taking their child to parks or playgrounds when other children were around (Dravet syndrome = 2) or other children avoiding interacting with the individual (Dravet syndrome = 4).

Emotional well-being. Many caregivers reported their child's emotional well-being was impacted because of their condition. The most reported emotion was frustration, which was sometimes linked to emotional outbursts (Dravet syndrome = 4; Lennox-Gastaut syndrome = 1) and was mostly attributed to age or learning difficulties. However, several individuals were described as typically happy and rarely exhibiting negative emotions (Dravet syndrome = 9; Lennox-Gastaut syndrome = 3).

Caregiver impacts and responsibilities. Caregivers commonly reported their day was focused on providing constant care for their child, including washing, dressing, and feeding (Dravet syndrome = 6; Lennox-Gastaut syndrome = 5). In addition to direct care, many caregivers conducted administrative tasks, for example, managing and administering medication (Dravet syndrome = 8; Lennox-Gastaut syndrome = 4).

Several caregivers described the importance of being alert and continuously monitoring the individual, because of their inability to recognize danger and/or the unpredictability of seizures (Dravet syndrome = 7; Lennox-Gastaut syndrome = 4). Some caregivers said they never left their child alone, and always needed another caregiver present when carrying out daily activities (Dravet syndrome = 2; Lennox-Gastaut syndrome = 2):

You couldn’t leave him just to nip to the toilet… somebody would have to be with him, or you’d have to take him with you. He can never be left alone.—Caregiver of patient with Dravet syndrome aged 6 years

Additionally, 2 caregivers described their need to manage their child's behavioral difficulties, especially when outside of the house (Dravet syndrome = 1; Lennox-Gastaut syndrome = 1).

Daily, leisure, and social activities. Daily, leisure, and social activities were limited because of caring responsibilities (Dravet syndrome = 7; Lennox-Gastaut syndrome = 5), including lack of time to exercise (Dravet syndrome = 3; Lennox-Gastaut syndrome = 2), travel or go out (Dravet syndrome = 3; Lennox-Gastaut syndrome = 1), socialize (Dravet syndrome = 4; Lennox-Gastaut syndrome = 2), and engage with hobbies (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1). This was often attributed to the continuous supervision of their child, lack of trust in other caregivers due to complex needs, and the requirement to constantly change plans.

Work and professional life. Almost all caregivers had to adjust working hours (Dravet syndrome = 5; Lennox-Gastaut syndrome = 2) or quit their job (Dravet syndrome = 7; Lennox-Gastaut syndrome = 3) to focus on their caring responsibilities. This was commonly due to the urgent intervention required during seizures and the frequent hospitalizations. Four caregivers mentioned being financially impacted due to loss of income (Dravet syndrome = 3; Lennox-Gastaut syndrome = 1).

Impact on relationships. Caregivers commonly described how friendships had been impacted by their caring responsibilities; many had a small social circle, consisting only of close family and friends (Dravet syndrome = 5; Lennox-Gastaut syndrome = 3).

Family. Most caregivers described how living with Dravet syndrome or Lennox-Gastaut syndrome impacted the whole family and how their daily lives were centered around the individual with the condition. Difficulty with day trips or holidays as a family was reported (Dravet syndrome = 5; Lennox-Gastaut syndrome = 3).

Many caregivers reported that their other children were impacted by their sibling's condition (Dravet syndrome = 7; Lennox-Gastaut syndrome = 3). This included restrictions to leisure activities and receiving less attention because of the focus on the child with Dravet syndrome/Lennox-Gastaut syndrome.

Caregivers described how their other children were often at the receiving end of their sibling's aggressive behavior (Dravet syndrome = 3). Nonetheless, several caregivers still tried to allow their family to live normal lives and make plans despite difficulties in caring for their child (Dravet syndrome = 5; Lennox-Gastaut syndrome = 3).

Changes to Symptoms and Functions Since Taking CBD

In the conceptual model (Figure 3), it is outlined where CBD was reported as having a mediating influence on seizure and beyond-seizure-related impacts, based on the qualitative data obtained. Changes in symptoms were noted for both patients with Dravet syndrome and Lennox-Gastaut syndrome. Changes in caregiver and family impacts were mostly reported for individuals with Dravet syndrome, who represented most of the patient cohort.

Seizures. Several caregivers believed their child's seizures had improved since taking CBD (Dravet syndrome = 12; Lennox-Gastaut syndrome = 4); however, 3 reported that this improvement lasted for only 2-6 months (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1). The majority reported a reduced seizure frequency (Dravet syndrome = 9; Lennox-Gastaut syndrome = 3), although reduced seizure severity (Dravet syndrome = 1) and length (Dravet syndrome = 5; Lennox-Gastaut syndrome = 1) were also noted; others witnessed fewer occasions of seizure clustering (Dravet syndrome = 3). These impacts improved the caregiver's ability to manage seizures at home as status epilepticus and the need for emergency medication or hospitalization were less likely.

CBD was also reported by caregivers to affect their child's seizure triggers (Dravet syndrome = 2), including reduced likelihood of triggering by temperature changes.

The remaining caregivers reported that CBD had no effect on their child's seizures (Dravet syndrome = 1; Lennox-Gastaut syndrome = 2).

Cognitive function and communication. Most caregivers reported improvements in their child's cognitive function since they started taking CBD (Dravet syndrome = 10; Lennox-Gastaut syndrome = 2), including 2 caregivers who reported no effect of CBD on their child's seizures (Dravet syndrome = 1; Lennox-Gastaut syndrome = 1). Cognitive improvements included increased attention span (Dravet syndrome = 4), awareness, and ability to focus and concentrate (Dravet syndrome = 5; Lennox-Gastaut syndrome = 2):

In the past, if he was going to do a puzzle, he may only do two or three pieces; now, he will complete the whole thing, so he definitely can focus on a task for more of an extended period of time.—Caregiver of patient with Dravet syndrome aged 9 years

Some caregivers mentioned their child's memory (Dravet syndrome = 2) and ability to learn new skills and retain information (Dravet syndrome = 3; Lennox-Gastaut syndrome = 1) had improved since taking CBD. Some individuals were reported to participate in longer conversations because of having greater ability to focus or having a wider vocabulary.

Many caregivers reported improvements in their child's ability to interact (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1) and communicate (Dravet syndrome = 8; Lennox-Gastaut syndrome = 1):

I think a year after taking [CBD], we were fishing one day, and I turned around and I said, “Buddy, I love you,” he goes, “I love you.” Hadn’t heard that in 3 years. So amazing.—Caregiver of patient with Dravet syndrome aged 9 years

Motor function. Three caregivers stated their child's motor function had improved since taking CBD (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1 [all aged 11 or under]). This included 2 individuals with Dravet syndrome reported to have improved coordination, ability to balance, or strength/stability. One individual with Lennox-Gastaut syndrome was reported to have greater upper limb function and ability to crawl and roll on the floor, perceived to be related to improved awareness of their surroundings:

He's just stronger and more stable. The fact that again he learnt how to swim, that was so huge, that was such a big deal. His coordination just got a little better.—Caregiver of patient with Dravet syndrome aged 11 years

She just seems to be aware of what's going on around her a lot more, and is able to reach for things, and lift her arms up to ask to be picked up and is just more cognitively aware of what she wants.—Caregiver of patient with Lennox-Gastaut syndrome aged 8 years

In addition, the 3 caregivers who described a reduction in seizures for a limited period also reported that motor function had improved for this period (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1). This included 1 Lennox-Gastaut syndrome caregiver who mentioned their child had “more drive” and improved fine motor skills, which enabled them to play with toys more easily.

Behavioral difficulties. A change in behavior since taking CBD was reported for some individuals (Dravet syndrome = 5; Lennox-Gastaut syndrome = 2); most commonly they became more calm or relaxed (Dravet syndrome = 3; Lennox-Gastaut syndrome = 2). Two caregivers described how CBD may have negatively impacted their child's behavior (Dravet syndrome = 2), reporting an increased number of “meltdowns” or difficulty with calming down; it was not clear in either case whether this was solely due to CBD.

Other symptoms. Some caregivers mentioned changes to their child's appetite since taking CBD, with 2 individuals reported to have greater interest in a wider range of food types (Dravet syndrome = 1; Lennox-Gastaut syndrome = 1) and 2 individuals reported to have a reduced appetite (Dravet syndrome = 1; Lennox-Gastaut syndrome = 1).

Two caregivers of patients with Dravet syndrome stated that their child had more regular sleep since taking CBD. A further individual with Dravet syndrome was reported to have experienced less drowsiness and brain “fog.” Conversely, 1 individual with Dravet syndrome had a higher level of drowsiness since taking CBD.

One of the most commonly reported negative changes following CBD initiation was worsening gastrointestinal symptoms, such as loose stools (Dravet syndrome = 2), diarrhea (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1), and constipation (Dravet syndrome = 1).

Changes to Impacts on Individuals With Dravet Syndrome or Lennox-Gastaut Syndrome Since Taking CBD

Daily activities. Reported impacts on children's daily activities since taking CBD included changes to their ability to take care of themselves (Dravet syndrome = 1; Lennox-Gastaut syndrome = 1), with 1 individual reported to now be “potty trained” (Dravet syndrome = 1) and another now able to lift a cup to drink independently (Lennox-Gastaut syndrome = 1). Greater freedom to go outside and increased activeness was also reported; this related to reduced seizure frequency and seizure triggers, and reduced time recovering from seizures (Dravet syndrome = 4).

Additionally, 1 individual with Lennox-Gastaut syndrome was reported to have shown more interest in participating in outdoor activities, attributed to their improved awareness and cognitive function:

The fact that she is more cognitively aware definitely has impacted… the fact that she wants to be picked up, or go outside, or do things.—Caregiver of patient with Lennox-Gastaut syndrome aged 8 years

Some caregivers reported improvements in their child's ability to actively participate in school since they started taking CBD (Dravet syndrome = 2; Lennox-Gastaut syndrome = 2), including 1 Lennox-Gastaut syndrome caregiver who had described their child's seizure reduction as lasting for a limited period:

She was starting to act more herself. She was getting more active, she was more interested in like playing with things, and watching her tablet. She was really enjoying school.—Caregiver of patient with Lennox-Gastaut syndrome aged 6 years

Emotional well-being. Some caregivers of individuals with Dravet syndrome reported improvements in their child's emotional well-being since starting CBD. This included 3 caregivers who felt the impact of CBD on their child's seizures and cognitive function in turn influenced their overall quality of life:

Because we’re seeing improvements, so many improvements, […] I would definitely say it's improved his quality of life, definitely… it's allowing him to develop and grow.—Caregiver of patient with Dravet syndrome aged 6 years

In addition, 1 individual was reported to have increased affection since taking CBD (Dravet syndrome = 1) and another to have increased confidence (Dravet syndrome = 1):

I think he just was able to become more coordinated. […] you could see things just connecting that we didn’t have before. Then also just having more seizure stability we were able to try more things. It opened a whole world of not being afraid to try something. I think he also felt more confident in himself.—Caregiver of patient with Dravet syndrome aged 11 years

Social activities and relationships. Some caregivers spoke about how their child's social activities had changed since starting CBD (Dravet syndrome = 3; Lennox-Gastaut syndrome = 1), including a greater interest in friendships and social interaction, which was attributed to their improved awareness and cognitive function (Dravet syndrome = 2; Lennox-Gastaut syndrome = 1):

She's becoming for the first time a little bit interested in friends. Where there was a lot of parallel play that never went anywhere, it was nice to have other bodies around but there wasn’t reaching out or asking about the other[s]. She's starting now to ask about other people and wanting to be with other people.—Caregiver of patient with Dravet syndrome aged 14 years

Additionally, 1 caregiver described that their child could now communicate with, and relate to, others more easily (Dravet syndrome = 1). This caregiver also described a stronger sibling relationship due to improvements in cognitive function and verbal communication:

I mean they have a really strong relationship with his brothers and sisters. I do think it helps. The cognitive and speech effects along with the reduction in seizure length all are very helpful for the family.—Caregiver of patient with Dravet syndrome aged 8 years

Changes to caregiver and family impacts since taking CBD. Caregivers noted that reduced seizure frequency allowed more time to focus on other aspects of the individual's care (Dravet syndrome = 1), and family life was less disrupted due to reduced hospital visits (Dravet syndrome = 1).

Some caregivers reported a greater ability to have family life experiences (Dravet syndrome = 3; Lennox-Gastaut syndrome = 2) due to reduced anxiety outside of the home owing to reduced seizure frequency and behavioral improvements:

Being able to travel some, know that she's enjoying stuff, gives us those experiences, also allows us to get out and have those experiences. And with her being somewhat stable, it gives us the confidence to be able to branch out a little bit more.—Caregiver of patient with Lennox-Gastaut syndrome aged 8 years

Caregivers also reported improved emotional well-being, particularly in relation to stress/anxiety about their child's seizures (Dravet syndrome = 4; Lennox-Gastaut syndrome = 1). Many caregivers also mentioned how their child's improvement in motor and cognitive function increased their happiness and hopes for the future (Dravet syndrome = 7; Lennox-Gastaut syndrome = 1):

Just watching him every day say a new word, or every couple of days say a new word. I think it's helped us a lot, from what he was a couple of years ago.—Caregiver of patient with Dravet syndrome aged 9 years

One caregiver described less disruption to their family's sleep as the individual had fewer nocturnal seizures since taking CBD:

We’re sleeping better as a family, because we put her down, we know that if we stay up another hour then our sleep cycle isn’t interrupted by an evening seizure.—Caregiver of patient with Dravet syndrome aged 14 years

Discussion

This was the first qualitative study to explore the effects of CBD beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome, their caregivers, and wider family members, as reported by the caregiver.

Caregivers reported a wide range of symptoms and functions of Dravet syndrome and Lennox-Gastaut syndrome in addition to frequent seizures. These included cognitive impairment, communication, mobility and behavioral difficulties, sleep disruption, reduced appetite, pain and discomfort, and gastrointestinal issues. A combination of these symptoms and functions, particularly the risk of seizures, cognitive impairment, mobility, and behavioral difficulties, meant all individuals with Dravet syndrome or Lennox-Gastaut syndrome needed round-the-clock supervision, and many required assistance with self-care. The ability of some individuals to carry out leisure and social activities and attend and participate in school was also affected. The symptoms and impacts of Dravet syndrome or Lennox-Gastaut syndrome on the individuals discussed in this study largely correspond with those reported previously.^1,9,14,33

The impacts of Dravet syndrome and Lennox-Gastaut syndrome on caregivers and their wider family found in this study also largely align with those reported previously.^1,12,14,34 Caregivers described how their overall health-related quality of life was affected, with most reporting lack of personal time and difficulty making spontaneous or future plans. This affected the ability of some to sustain a job, maintain friendships, and find time to exercise, travel, or engage with hobbies.

Many caregivers reported positive changes to the individual's cognitive function following treatment with CBD, including improvements in their awareness of surroundings, attention span, and ability to learn new skills and retain information. These improvements were also reported for 1 individual with Dravet syndrome and another with Lennox-Gastaut syndrome who did not experience a reduction in severity and frequency of seizures. This builds on previous findings from open-label studies of CBD in individuals with treatment-resistant epilepsy, where improvements in health-related quality of life, considered independent from reduction in seizure frequency, were seen after up to 12 months of CBD.^21,22

Individuals’ improvements in cognitive function were reported to have a positive impact on communication. For instance, some caregivers reported that their child showed greater interest in and ability to interact with others because of improved awareness, attention span, and ability to learn words. This supports previous findings of improvements in cognitive abilities, particularly regarding language, up to 6 months following CBD initiation. ²⁶

Negative changes were also reported by 10 caregivers following their child's CBD treatment, including loose stools, diarrhea, somnolence, worsening behavioral difficulties, and reduced appetite. These are broadly similar to the common adverse events reported in the largest pivotal trials of CBD in Dravet syndrome and Lennox-Gastaut syndrome.^17–20

Importantly, this study additionally provided novel in-depth understanding of caregivers’ views about the effects of CBD on seizure control and other aspects of health-related quality of life. Following treatment with CBD, some caregivers mentioned a greater ability to have family life experiences and travel because of reduced anxiety about seizures or behavioral difficulties when away from home. Caregivers also reported lower levels of anxiety/stress and increased hope for the future after witnessing cognitive and motor function improvements in their child.

Qualitative research is a valuable tool for providing insights into the experience of patients and their families with rare conditions, which can be used as a basis for future research. This has been demonstrated for treatments in other rare diseases, such as the medical management of seizures in tuberous sclerosis complex ³⁵ and ataluren in Duchenne muscular dystrophy. ³⁶ The benefits of qualitative research were also highlighted in the US Food and Drug Administration’s (FDA's) patient-focused drug development guidance. ³⁷ This suggests the inclusion of patient exit interviews in clinical trials for rare diseases as a way of better understanding patient experience, adding greater depth to data and obtaining input on meaningful outcomes or changes for patients.

In this study, a patient-centered conceptual model was developed that was directly based on the important concepts reported by caregivers. As well as highlighting the symptoms and impacts of Dravet syndrome/Lennox-Gastaut syndrome and potential impacts of treatment, the conceptual model can provide a useful tool for informing a patient-centered measurement strategy for clinical trials of new treatments. In fact, the researchers are currently using findings from this study to inform the selection of appropriate patient-reported outcome (PRO) measures for use in future observational studies for CBD. This will involve mapping variables assessed by PRO measures deemed relevant to the Dravet syndrome/Lennox-Gastaut syndrome patient population with the concept identified by this study and assessing likely sensitivity to treatment effects.

Although this study provides novel insights, it also had some limitations. Participants were recruited from the United States, the United Kingdom, and Germany, but a large majority were from the USA. There was also a larger number of caregivers of individuals with Dravet syndrome compared with individuals with Lennox-Gastaut syndrome; all participants cared for individuals aged ≥4 years. This meant that it was difficult to establish the impact of CBD across the different countries and conditions examined and among younger infants. The recruitment target of 40 caregivers was not reached, with 21 caregivers recruited in total. Several factors likely contributed to the difficulty with caregiver recruitment, including the rarity of Dravet syndrome and Lennox-Gastaut syndrome, the limited number of patient groups in some countries, and caregiver unavailability because of the need to care for their child. Difficulty in recruitment during the COVID-19 pandemic and the requirement for prior CBD treatment of at least 6 months are also believed to explain the low number of participants; there were 20 potential participants excluded at screening because of their child not taking CBD. Lastly, CBD gained marketing authorization for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in 2018 in the USA ³⁸ and 2019 in the EU, in conjunction with clobazam, ³⁹ so there was limited time between marketing authorization and study recruitment. Nevertheless, in qualitative research, the sample size is not necessarily a key indicator of high-quality research; rather, the depth, richness, and appropriateness of data and the extent to which sufficient evidence is generated to address the research question are more critical. ⁴⁰ It is important to note that while there was some evidence of data saturation being reached in this study, the heterogeneous nature of the caregiver and patient experience in our study mean that a larger sample size may have highlighted additional themes or topics.

It is also possible that the sample may have been biased towards those with more favorable opinions and experiences of CBD, as participants were aware that their child had to have taken the treatment for at least 6 months to be eligible for the study. Although we were not able to remove this potential bias, the intention of the study was to review all potential impacts of ≥6 months of treatment with CBD on patients and caregivers and summarize these qualitatively. Including patients with a shorter duration of CBD use may not have yielded the longer-term or beyond-seizure impacts of CBD that were highlighted by some caregivers; however, it may have captured a greater proportion reporting negative impacts resulting from treatment-related adverse events. Nevertheless, the positive and negative impacts of CBD reported suggest that representative views of all aspects of CBD treatment were not excluded in this qualitative study.

Conclusion

This is the first qualitative study to provide an in-depth exploration of the effects of CBD beyond seizure control among children and young adults with Dravet syndrome or Lennox-Gastaut syndrome, and their caregivers and wider family members. The results suggest that, in addition to reduced seizure frequency and/or severity, CBD may have a wide range of beneficial effects beyond seizure control, which warrants further investigation. Quantitative studies with larger sample sizes are required to determine the generalizability of findings, as well as to explore potential differences by condition and age.