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Caregivers' top concerns are speech/communication, sibling impacts, and cognitive impairment.
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SCN1A mutation status may be correlated with bradycardia, heart abnormalities, and delayed puberty.
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Frequency of osteopenia, broken bones, and gait disturbances increased with age.
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Photosensitivity, hypotonia, and ataxia appear early in DS.
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Seizures are not the only measureable outcome appropriate for research in Dravet syndrome.
Abstract
The Dravet Syndrome Foundation (DSF) conducted the largest in-depth survey of parents and caregivers of patients with Dravet syndrome (DS) to date, in order to (1) identify top concerns among caregivers, (2) establish an approximate frequency of characteristics and comorbidities of DS beyond seizures, and (3) provide direction for clinicians and researchers looking to study the effects of DS on the patient and family unit. Two hundred fifty-six responses were received representing a patient age range of 9 months to 32 years with a median age group of 7–10 years (IQR = 8). In an open response, caregivers ranked speech/communication, impacts on siblings, and cognitive impairment as their top concerns after seizure control, and nearly two-thirds of caregivers reported having suffered from depression. Some characteristics of DS such as gait issues increased with patient age, while others, including photosensitivity, hypotonia, and ataxia, were present from a young age. Comorbidities such as sleep disturbances and cardiac abnormalities were more frequently reported than in previous studies and some (including bradycardia) were correlated with SCN1A mutation status. This survey supports the concept of Dravet syndrome as a disease of the central nervous system with far-reaching effects and highlights the importance of the patient voice in determining appropriate research objectives. While seizure frequency is a relatively well-understood objective, seizures represent only a portion of parent and caregiver concerns. Studying the characteristics of DS described herein may identify additional outcomes significant for research.
]. Associated with mutations of the SCN1A gene in 75% of cases, DS is characterized by frequent prolonged seizures, developmental delays, speech impairment, and motor/orthopedic issues [
]. Previously described characteristics and comorbidities of the syndrome include dysautonomia, nutrition issues, characteristics of autism, and a high rate of sudden unexpected death in epilepsy (SUDEP) [
]. Dravet syndrome may be better viewed as a disease of the central nervous system with non-epileptic manifestations rather than merely an epilepsy syndrome [
]. While research and treatment often focus on managing refractory seizures with antiepileptic drugs (AEDs), other issues are common and may not be adequately addressed by the medical community [
The European patient with Dravet syndrome: results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome.
]. Health-related quality of life (HRQOL) is typically lower in patients with DS than in both the general population and in patients with epilepsy not classified as DS [
Despite the wealth of knowledge about DS, there is little understanding of how the characteristics of the disease impact the patient, caregiver, and family unit. As the research paradigm expands to include patient-centered outcomes research, the effects of the characteristic issues demand increased attention and elucidation. Previous interviews with a small set of caregivers showed that DS impacts the patient and family differently in each of three stages from infancy to adulthood [
The European patient with Dravet syndrome: results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome.
Historically, some clinicians have been hesitant to diagnose patients who did not exhibit severe developmental delay or mobility problems with Dravet syndrome, especially in the first years of life [
Our objective, using the largest survey to date of DS characteristics and caregivers' concerns, was to clearly define challenges the patients and caregivers face and establish a baseline frequency of current characteristics of the disease using a cross-sectional survey. We were uniquely able to access the caregiver perspective through the Dravet Syndrome Foundation Support Group, the largest community of parents and caregivers of patients with DS in the world. The support group is a fairly representative sample of families living with DS despite a large percentage of members living in the United States. The data may be used to guide researchers and clinicians in future studies as it is imperative that upcoming research address refractory seizures as well as the issues most important to patients and their families.
2. Material and methods
2.1 Survey design
The Dravet Syndrome Foundation (DSF) distributed an online survey between March 2016 and May 2016 to parents and caregivers of patients with Dravet syndrome designed using results from previous parent-reported surveys and recent topics of discussion in DSF's online support group. After piloting the survey to three caregivers, it was divided into two separate surveys, Survey 1 and Survey 2, to prevent participant fatigue (Table S1, Table S2). No identifiers were obtained to link Survey 1 and Survey 2. The Dravet Syndrome Foundation posted the survey link in the Dravet Parent & Caregiver Support Group on Facebook, consisting of 1610 members, which represented an estimated 800–1000 patients, and distributed the survey to their 4503-member e-mail subscriber list representing an estimated additional 100 caregivers. Participation in the survey was voluntary, data were collected anonymously, and IRB approval was not required because DSF is not a covered entity.
Permission to use deidentified data was obtained prior to participation, and each survey included a demographic session as well as content-related sections about characteristics, possible comorbidities, medications and efficacy, and caregiver/family dynamics (Table S1, Table S2). Responses included six-point Likert scales, lists, closed-question multiple choice, and open response. Participants were not required to answer any content-related question.
2.2 Statistical analysis
Correlations were measured using a chi-square calculation with an alpha level of 0.05. Two-tailed Fisher exact tests were performed when the expected frequencies for chi-square fell below 2. Post hoc analysis was performed where indicated.
3. Results
3.1 Demographics
As expected, more respondents completed Survey 1 than Survey 2 (Table 1). Patient age ranged from 9 months to 32 years (Table 1). The country of residence accurately reflects the DSF Parent & Caregiver Support Group membership distribution. The frequency of reported SCN1A mutations was slightly higher than the estimated mutation rate of 75–80% in DS [
More than two-thirds of caregivers reported at least one issue in each of the 13 areas surveyed, with many areas achieving a reported frequency higher than 90% (Table S3).
3.2 Medical specialists
Caregivers reported seeing several medical specialists throughout the patient's life (Table S4). Some specialty care, such as speech, occupational, and physical therapy, was sought early in the course of the disease, while other specialists such as neuropsychologists were not required until later in the patient's life, highlighting the characteristic progression of the disease (Fig. 1).
Fig. 1Specialists consulted and issues experienced by age of patient.
Concerns about sleep issues were reported by 97% of caregivers (Table S3). With the exception of nocturnal seizures, which appeared to peak very slightly in the 16- to 25-year age group, there was little variation in sleep issues among patient age groups (Fig. 1; Table 2).
Table 2Frequencies of the most commonly reported issues.
Data include all age groups unless otherwise indicated. In some areas, such as psychiatric issues, excluding the young age groups would increase the frequency of issues reported. For complete list of issues surveyed, see Table S6.
Category
Issue
n/N (%)
Category
Issue
n/N (%)
Sleep
Sleep disturbances
205/240 (85%)
Orthopedic/movement
Gait disturbances
170/226 (75%)
Nocturnal seizures
181/235 (77%)
Hypotonia
162/225 (72%)
Insomnia
168/236 (71%)
Ataxia
146/225 (65%)
Premature awakening
146/235 (62%)
Tremor
121/224 (54%)
Hearing/vision/neuro
Photosensitivity
98/232 (42%)
Autistic traits
Perseveration
150/220 (68%)
Hyperacusis
80/231 (35%)
Autistic-like traits
145/216 (67%)
Frequent blinking
76/232 (33%)
Obsessions
137/215 (64%)
Pattern sensitivity
61/232 (26%)
Difficulty with transitions
134/218 (61%)
Growth, endocrine, and metabolism
Dysregulation of body temperature
198/224 (88%)
Lack of social reserve/overly familiar to strangers
124/219 (57%)
Lack of sweating
149/221 (67%)
Prefers interaction with adults vs. peers
115/219 (53%)
Failure to thrive, slow growth, underweight, small stature
Psychiatric issues (reported as “often” or “sometimes”)
Difficulty with impulse control
116/220 (53%)
Vitamin D deficiency
59/154 (38%)
ADD or ADHD
111/222 (50%)
Iron deficiency
58/155 (37%)
Irritability
108/219 (49%)
Infection & immunity
Frequent/chronic otitis
90/224 (40%)
Aggression
96/221 (43%)
Diagnosed with allergies
65/223 (29%)
Frequent/chronic bronchitis and/or pneumonia
63/224 (28%)
a Data include all age groups unless otherwise indicated. In some areas, such as psychiatric issues, excluding the young age groups would increase the frequency of issues reported. For complete list of issues surveyed, see Table S6.
b Data include only patients age 4 years and older.
Use of audio or video baby monitors was reported by 85% of caregivers, and 82% sleep with the patient. Nearly half (46%) use a pulse oximeter, 25% use an Emfit movement monitor, and 14% use a SAMi sleep activity monitor. In terms of safety, 45% have locks or alarms on doors and windows. A small percentage of the population (3–5%) currently use a Smart Monitor Watch or Embrace Watch (Table S5).
3.4 Cardiac issues
Over two-thirds of patients in this survey had EKG testing, and nearly one-third had worn a 24-h Holter monitor (Table S6). Approximately one-third of patients had consulted with a cardiologist (Table S4). Long Q-T intervals, which have been questioned in suspected cardiorespiratory arrest associated with SUDEP, appeared in four patients, all of whom had SCN1A mutations. Similarly, five of 232 patients reported abnormalities or changes in the heart structure, all of whom were SCN1A-positive (Table S7).
Both bradycardia and tachycardia were reported (13% and 30%, respectively). However, patients without an SCN1A mutation were more likely to experience bradycardia than those with an SCN1A mutation (p = 0.03) (Table S7).
3.5 Hearing, vision, and neurological issues
The presence of photosensitivity and pattern sensitivity showed a fairly steady response rate across patient age groups, suggesting they are not symptoms that appear as children grow but rather are present from a very young age (Table 2; Table S8). Females were nearly twice as likely as males to experience pattern sensitivity (p = 0.02) or frequent blinking (p = 0.005) (Table S9). There were no significant differences between patients with SCN1A mutations and patients without SCN1A mutations in terms of hearing, vision, and neurological issues.
3.6 Dental, orthopedic and movement issues
Gait disturbances, hypotonia, and ataxia were relatively common in the 1- to 3-year age group (Fig. 1; Table 2; Table S8). While the frequency of ataxia and hypotonia appeared to plateau over the age of 4 years (near 60% and 76%, respectively), the frequency of gait disturbances increased steadily through the age groups, reaching nearly 90% in the 16- to 25-year age group and 100% in the 26+-year group (Table S8).
Osteopenia increased with patient age (Fig. 1; Table S8). Broken bones followed the same pattern, increasing with age and proving to be more prevalent in the adolescent and adult population than the infant and toddler groups (Fig. 1; Table S8). It is unclear whether this is a cumulative effect. Because growth/metabolism was in Survey 1 and medication use was in Survey 2, a statistical correlation between medications and symptoms such as osteopenia, broken bones, and vitamin D deficiency could not be assessed.
While 70% of respondents use a wheelchair or adaptive stroller at least part of the time, 13% of those over the age of 3 years use this as their primary means of mobility (Table S8).
No significant differences were seen in orthopedic and mobility issues between patients with SCN1A mutations and patients without SCN1A mutations.
3.7 Urinary tract, bowel, digestive, and infection/immunity issues
Appetite disturbances were common (Table 2). Nephrocalcinosis was more often reported in patients without SCN1A mutations than in patients with SCN1A mutations, although the low sample size did not result in statistical significance (p = 0.06) (Table S7). This information was collected in Survey 1, while medication information was collected in Survey 2, preventing correlation between the two.
Roughly one-third of caregivers reported frequent/chronic infections and immunity issues such as otitis media, bronchitis/pneumonia, or allergies (Table 2). Males were 1.7 times more likely to be diagnosed with allergies than females (p = 0.009) (Table S9).
3.8 Dysautonomia, growth, endocrine function, and metabolism issues
Difficulty with temperature regulation was present in roughly 80% of the 1- to 3-year old age group and remained steady throughout the older age groups (Table S8). Further study is needed to determine whether the common issue of lack of sweating is due to Dravet syndrome itself, medications patients may be taking, or a combination of the two.
Roughly 9% of caregivers reported delayed puberty, and 9% reported precocious puberty. Interestingly, none of the patients without SCN1A mutations experienced precocious puberty, but 33% of the patients with SCN1A mutations experienced delayed puberty. While the number of positive precocious puberty responses was not large enough to determine statistical significance, those who were SCN1A-negative were more likely to experience delayed puberty (p = 0.02) (Table S7).
3.9 Development, autistic characteristics, and communication issues
Caregivers reported changes in development such as slowing, stagnation, and regression. These changes were reported in relation to prolonged seizures or periods of increased seizure frequency more often than unrelated to seizures (Table S10).
Seventy-three percent of caregivers reported mild developmental delay, 72% reported moderate developmental delay, and 57% reported severe developmental delay (Table S11). The survey allowed more than one answer to this question, and caregivers may have chosen more than one level of delay due to scattered developmental areas or varying delay throughout the patient's history.
The commonly reported lack of social reserve may play a role in the seemingly low rate of autism spectrum disorder (ASD) diagnosis compared with autistic traits (Table 2; Table S6). Although there was no difference in frequency of ASD diagnosis between genders, males were 1.4 times more likely to exhibit a lack of social reserve than females (p = 0.02) (Table S9). Consistent with the clinical symptoms of Dravet syndrome, communication issues were reported in more than two-thirds of patients (Table 2). More than one-third of patients over the age of 4 years were able to read and/or write, although the level of literacy was not specified on the survey (Table S6).
There were no significant differences between patients with SCN1A mutations and patients without SCN1A mutations with regard to the frequency of most autistic traits, developmental delays, or communication issues, with the exception of a slight correlation between patients with SCN1A mutations and the preference for interaction with adults vs. peers (p = 0.04) (Table S7). There is a possible correlation between reduced sensitivity to pain and the presence of an SCN1A mutation that approached statistical significance (p > 0.05) in this small sample and should be studied on a larger scale (Table S7).
3.10 Patient psychiatric issues
Behavioral and psychiatric issues were commonly reported in the survey and often appeared in the open response portion addressing caregiver concerns (Table 2; Table 4). Measuring other symptoms such as anxiety, self-esteem, and depression can be difficult in patients with low communication abilities.
Caregivers reported difficulty with impulse control and ADD/ADHD most often in the 7- to 10-year age group (38% and 39%, respectively), with an average frequency of 29% in patients over the age of 3 years in both categories (Table S12). Other psychiatric symptoms, while not as frequent, appeared mainly in patients over age 3 years (Table S12). Interestingly, only 186 people responded to the question about depression, compared to 220 responses for most other questions. There were no statistically significant correlations between SCN1A status or gender and psychiatric issues.
3.11 Medications and treatment
Medications and treatments were addressed in Survey 2. The four most common daily medications tried at any time by patients (all greater than 79% affirmative) were valproic acid, levetiracetam, clobazam, and topiramate (Table S13). Use of contraindicated medications was reported frequently (lamotrigine in 49% of patients, carbamazepine in 39%, and oxcarbazepine in 36%) (Table S13). The survey did not distinguish between medications used prediagnosis and those used postdiagnosis, but 32% (6/19) of responders with children aged 3 years or younger reported having used oxcarbazepine, 21% reported having used lamotrigine, and 16% reported having used carbamazepine.
Caregivers were asked to rate the effectiveness of current and previous daily medications and treatments on a six-point Likert scale (Table 3; Table S14). These are subjective caregiver reports of treatments and do not represent quantifiable seizure or side effect data. Average ratings for each medication were obtained by dividing the summative scores by the number of respondents who had tried each medication. The scores for treatments with more respondents who had tried them thus carry more power than the less frequently tried treatments (Table 3; Table S14).
Table 3Caregiver ranking of daily medications (efficacy).
A similar scale was used to assess emergency treatments. Not surprisingly, 94% of respondents had used diazepam as an emergency treatment, followed by 70% having used lorazepam, and 68% having used midazolam (Table S15). One surprising finding was that 40% of patients had used valproic acid and 34% had used levetiracetam as emergency treatments despite their general acceptance as daily medications. Also of note were 14% of responders whose patients had used cannabidiol (CBD) or medical marijuana (not Epidiolex) as an emergency treatment (Table S15). Respondents rated the three emergency benzodiazepines as most effective, and phenytoin and fosphenytoin as least effective (Table S16). There were not enough SCN1A-negative respondents to correlate medication efficacy with mutation status, though it should be noted that none of the patients for whom lamotrigine was effective had an SCN1A mutation.
3.12 Caregiver issues and family dynamics
Nearly two-thirds of caregivers (66%) reported having suffered from depression, but only 26% have received some form of family therapy (Table S17).
Seventy-four percent (114/154) of caregivers reported having concerns about the emotional impact on siblings, which also appeared as a common concern in the open response portion of the survey (Table S17; Table 4). When asked to rank their top three concerns in an open response, aside from seizure control, caregivers highlighted the behavioral and communication challenges and family effects of caring for a patient with Dravet syndrome (Table 4).
Table 4Most common caregiver concerns in open response sections.
Caregivers were asked to “List the top 3 concerns for the patient or family” after seizure control in open response. Responses were categorized post hoc.
(n)
Speech/communication (cannot vocalize pain)
43
Sibling impacts
42
Cognitive/developmental delay/regression
39
Behavioral issues including violence and autistic traits
34
Long-term care when parents are gone
27
SUDEP or death
21
Lack of independence/constant care
19
Anxiety/depression/isolation (parent)
19
Mobility
17
Finances (parent)
15
Quality of life (family)
15
Medication side effects
8
a Caregivers were asked to “List the top 3 concerns for the patient or family” after seizure control in open response. Responses were categorized post hoc.
Our findings support the concept of Dravet syndrome as a disease of the central nervous system with far-reaching effects and characteristic symptoms including gait disturbance, ataxia, hypotonia, cognitive impairment, speech delay, temperature dysregulation, nocturnal seizures, and autistic traits as well as comorbidities including sleep issues, frequent infections, blood abnormalities, and some psychiatric issues [
]. As such, DS requires comprehensive care management that may necessitate a multidisciplinary clinic.
This study found that the frequency of most issues increased compared to previous studies, and the frequency of issues the patient experiences changes during the course of the disease. Caregiver reports of nocturnal seizures were 27% higher in this study than in the study completed in 2009, though the two studies may not have drawn from the same population [
]. Increased awareness and testing encouraged by recent studies on cardiac SCN1A expression as a possible mechanism for SUDEP has undoubtedly contributed to the two-thirds of patients undergoing in-depth cardiac testing, reflecting a more proactive approach to cardiac monitoring [
]. The possible correlations between Dravet syndrome, SCN1A mutations, and heart rate/rhythm abnormalities warrant further investigation on a larger scale [
]. Issues that increase in frequency as the patient grows older include nocturnal seizures, severe developmental delay, and gait disturbances. Consultation with a dietician increased after age 4–6 years, which could reflect anorexia from medication side effects, appetite disturbances due to the syndrome itself, or interest in the ketogenic diet due to refractory seizures that do not respond to traditional medication.
4.2 Caregiver concerns
This survey supports previous small-scale parent interviews that divided DS into three stages of disease and quantifies the described effects on the family [
]. Caregivers of young patients under age 4 years, who present with frequent status epilepticus, were more likely to list “seizure control” or “status protocol” as their top concern, while caregivers of children over age 6 years reported struggling with behavior, gait issues, effects on siblings, and cognitive impairment. Caregivers of young adults and adults reported difficulty with transition of care to the adult medical system. The alarmingly high percentage of caregivers sleeping with the patient for safety (80%) and half using a pulse oximeter likely reflects the general fear of SUDEP which contributes to stress, depression, and family fragility. Several caregivers noted in the open comments section that a pulse oximeter provides the most peace of mind, and others noted they wake up frequently to check on the child. Still, some physicians are hesitant to recommend pulse oximeters due to false alarms and disrupted sleep [
]. Photosensitivity, temperature dysregulation, and behavioral issues can severely impact the family's ability to participate in typical outings and activities, directly extending DS's reach to siblings. It is clear that the stress Dravet syndrome places on parents and caregivers is real, pervasive, and not limited to seizures.
4.3 Dravet syndrome vs. epilepsy in general
It can be difficult to identify which issues are unique to Dravet syndrome and which issues or comorbidities may be consequences of epilepsy or the medication used to control it. Long-term AED use and the seizures themselves are often blamed for the negative issues that patients experience. This study, which found 75% of patients experience gait disturbances, supports the recent finding that gait issues are a unique characteristic of DS, even when compared with Lennox–Gastaut syndrome, whose patients share a long history of multiple AED use and frequent seizures [
]. Certain conditions that appear age-related in this survey such as osteopenia and broken bones may indeed be the result of long-term medication use and are common in the general population with epilepsy [
]. Other potentially characteristic (as opposed to comorbid) issues include the speech issues and autistic traits children with DS experience. While this survey showed that more than half of patients were overly familiar with strangers, preferred interaction with adults vs. peers, and had significantly delayed language, the rate of having an autism spectrum disorder (ASD) diagnosis (31%) is well in line with the rate of ASD in the general population with epilepsy [
]. This supports previous studies that showed socialization skills are higher than communication and autonomy skills in DS, excluding ASD in many cases [
While this study was neither controlled nor comparative, the reported rates of frequent infection were elevated. For example, the presence of frequent otitis media in the population with DS was in line with the presence of otitis media in the general population (40%), though the frequency of recurrence may indeed be higher in patients with DS [
]. Clearly, further study of the natural history of DS and comparative controlled studies in this area is needed.
4.4 Caregiver perspective on treatment
This study highlights the different views held by physicians and caregivers. Traditional first-line treatments for DS include sodium valproate and clobazam, while second-line treatments may include stiripentol, topiramate, and the ketogenic diet [
]. However, caregivers rated stiripentol, sodium valproate, dietary therapy, and CBD (non-pharmaceutical preparations) highest. Dietary therapy was preferred over most other medications, and three of the top four caregiver-rated medications (stiripentol, CBD (non-pharmaceutical preparations), and Epidiolex) are not currently US FDA-approved. Indeed, there are no FDA-approved medications specifically indicated for treatment of Dravet syndrome, which suggests barriers to approval in the US remain quite difficult for a rare disease to overcome. With two Dravet-specific clinical trials underway whose primary outcome measures are a reduction in convulsive seizures, the need for patient-centered outcomes in research is prominent and well positioned for inclusion.
4.5 Limitations and bias
Limitations of this study include the caregiver-reported nature of the survey, the potential for caregivers misunderstanding terms or questions, and the lack of response validation by physicians. Some categories, such as degree of developmental delay, were not defined and therefore included subjective assessments by caregivers that may not be representative of a physician's well-defined assessment. Sources of potential bias include caregiver perception and response, the online format of the survey, the English-only presentation of the survey, the web-based requests for participation, the potential for caregivers of severely affected patients to be overrepresented in the support group, and survey design due to the authors being parents of patients with Dravet syndrome.
5. Conclusion
Dravet syndrome is a multifaceted disease that affects not only the patient but also the caregiver and family unit as a whole. Caregiver feedback suggests treatment and management must not be limited to pharmacological seizure management but should address behavior, development, communication, and the caregiver as well. Ideally, future research will seek to address these areas of caregiver concern and elucidate the natural history of the disease as it relates to the whole patient.
The following are the supplementary data related to this article.
This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements
The authors thank the parents and caregivers of patients with Dravet syndrome for their participation in this survey and online dialogue, as well as Charlotte Dravet, MD, for her generous contributions and continued concern that the entire patient be studied. Special thanks to Kelly Knupp, MD, for her editorial assistance and the DSF Medical Advisory Board and Scientific Advisory Board for their guidance and support of DSF's mission.
Disclosures
None of the authors has any conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
The European patient with Dravet syndrome: results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome.
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