Caregiver perceptions of the impact of Dravet syndrome on the family, current supports and hopes and fears for the future: A qualitative study.

BACKGROUND: Dravet syndrome (DS) is a Developmental and Epileptic Encephalopathy (DEE) with onset typically in infancy. Seizures are pharmaco-resistant, and neurodevelopment is compromised in almost all children. There is limited data on the impact of the condition on the family, support needs and hopes and fears in Sweden. METHODS: Interviews were undertaken with the caregivers of 36 of 48 (75%) living children with DS in Sweden focusing on the perceived impact on the family, current supports and hopes and fears for the future. Data from the interviews were analyzed by two raters using reflexive thematic analysis. RESULTS: The analysis revealed seven main themes focusing on the perceived negative impact the disease has on caregivers and family functioning. These negative impacts concerned: caregiver sleep (e.g., frequent night waking), siblings (e.g., gets less attention/time), social life (e.g., limited vacations), family finances (e.g., limited career progression), parental health (both mental and physical) and need for constant supervision (e.g., child's need for constant supervision for fear of seizures). Another theme concerned the impact on family relationships. Whilst some caregivers perceived the impact to be negative (e.g., limited time for each other) others felt that having a child with DS lead to stronger relationships and more 'teamwork'. With respect to supports, the caregivers identified a number of areas where they felt the family could access appropriate supports. Themes regarding supports included: support from the wider family and friends, support from DS support groups (online or in-person), support from the child's hospital or disability service and respite care (e.g., child was looked after on weekends or had paid carers in the home). Regarding hopes and fears for the future, responses focused mainly on fears, including concerns about premature death of the child, transition to adult healthcare services and care arrangements for child when parents are dead. Hopes for the future included better treatment for epilepsy and associated neurodevelopmental problems and finding a cure for DS. CONCLUSIONS: Caregivers of children with DS report that the disease can have a very comprehensive negative impact on caregiver and family functioning. Identifying and providing the supports to ameliorate these negative impacts is vital to optimize caregiver and family wellbeing and quality of life.

Autism and attention-deficit/hyperactivity disorder in children with Dravet syndrome: A population-based study.

AIM: To identify on a population basis the prevalence of autism and attention-deficit/hyperactivity disorder (ADHD) in children with Dravet syndrome and factors associated with symptoms of autism and ADHD. METHOD: Forty-one of 48 children with Dravet syndrome living in Sweden, born between 1st January 2000 and 31st December 2018 underwent assessment including measures of autism and ADHD. Diagnoses of autism and ADHD were made with respect to DSM-5 criteria. Factors associated with features of autism and ADHD were analysed via regression. RESULTS: Twenty-five of the 41 children fulfilled DSM-5 criteria for autism spectrum disorder and 12 of 37 children considered for an ADHD diagnosis fulfilled DSM-5 criteria for ADHD. Severe intellectual disability was significantly associated with a greater degree of autistic features (p < 0.001) and a DSM-5 diagnosis of autism spectrum disorder (p = 0.029). Younger children had significantly more features of ADHD (p = 0.004) and features of inattention were significantly more common than features of hyperactivity/impulsivity (p < 0.001). INTERPRETATION: Children with Dravet syndrome often have significant features of autism and ADHD, primarily inattentive type. Screening for autism and ADHD should be routine in children with Dravet syndrome.

Diagnosis, epilepsy treatment and supports for neurodevelopment in children with Dravet Syndrome: Caregiver reported experiences and needs.

BACKGROUND: Dravet syndrome is a rare infantile onset epilepsy syndrome encompassing treatment resistant epilepsy and neurodevelopmental difficulties. There is limited data regarding caregiver experiences of diagnosis, treatment and supports for the associated neurodevelopmental problems. METHOD: Semi-structured interviews were conducted with caregivers of 36/48 children (75% of total population in Sweden) with Dravet syndrome. Data was analysed using thematic analysis. RESULTS: Regarding the diagnostic experience, themes were: Delays in diagnostic process, genetic testing not optimal, communication of Dravet syndrome diagnosis and support and information soon after diagnosis. Caregivers felt that delays in diagnosis and testing could have been avoided whilst experiences of communication of diagnosis and support after diagnosis varied. In terms of treatment for seizures, the themes were: Satisfied with treatment, emergency treatment, treatment with antiseizure medications, strategies to control seizures via temperature regulation/avoidance of infections and use of equipment and aids. Caregivers were in the main accepting that seizures in Dravet syndrome are very difficult to treat and that seizure freedom is often an unachievable goal. Many felt frustrated that they were expected to take responsibility with respect to choice of medication. They often employed strategies (e.g., avoidance of physical activity) to reduce seizures or their impact. In terms of supports for neurodevelopmental problems, the themes were: Struggled to access support, lack of integrated healthcare and satisfaction with school. Many caregivers felt that accessing necessary supports for their children and developmental and behavioural needs was a struggle and that the provision of support often lacked integration e.g., lack of collaboration between child's disability service and school. Caregivers also expressed a desire that there would be better knowledge of Dravet syndrome in emergency departments and schools, that care would be better integrated and that there would be more supports for assessment and interventions regarding the associated neurodevelopmental problems. CONCLUSION: The responses of caregivers of children with Dravet syndrome highlight the need for supports from diagnosis for both epilepsy and neurodevelopmental problems. Good examples of provision were identified but parents often felt they lacked support and support often came from providers who lacked knowledge of the syndrome. Collaboration between medical, disability and school services was often lacking.

Caregiver reported behavior, sleep and quality of life in children with Dravet syndrome: A population-based study.

OBJECTIVE: The aim of this population-based study was to assess behavior, sleep, and quality of life, and explore factors associated with these in children with Dravet syndrome. METHODS: The Developmental Behavior Checklist, the Insomnia Severity Index, and a global question regarding quality of life from the Epilepsy and Learning Disabilities Quality of Life scale were completed by primary caregivers of 42/48 Swedish children with Dravet syndrome, born 2000-2018. Factors associated with problems with insomnia, behavior and quality of life were analyzed using multivariable linear regression. RESULTS: Scores indicating significant behavioral problems were seen in 29/40 (72 %) children, scores indicating moderate or severe clinical insomnia in 18/42 (43 %) and scores indicating poor or very poor quality of life in 7/41 (17 %). On multivariable analysis, autistic symptoms were significantly associated with behavioral problems (p = 0.013), side-effects of anti-seizure medications (ASMs) were associated with insomnia (p = 0.038), whilst insomnia was significantly associated with poor quality of life (p = 0.016). SIGNIFICANCE: Dravet syndrome in children is associated with significant problems with behavior, sleep and quality of life. There is a need to optimize treatment via ASMs and develop and evaluate interventions to treat behavioral and sleep difficulties to optimize outcomes.

Intellectual functioning and adaptive behaviour in children with Dravet syndrome: A population-based study.

AIM: To identify, on a population basis, the prevalence of intellectual disability in children with Dravet syndrome, profiles on a measure of adaptive behaviour, and factors associated with intellectual functioning and adaptive behaviour. METHOD: Forty-two out of 48 children with Dravet syndrome living in Sweden, born between 1st January 2000 and 31st December 2018, underwent assessment of intellectual functioning and adaptive behaviour. Factors associated with level of intellectual functioning and adaptive behaviour were analysed. RESULTS: Eight-six per cent (n = 36) of the children fulfilled DSM-5 criteria for intellectual disability (29% [n = 12] mild intellectual disability, 24% [n = 10] moderate intellectual disability, 33% [n = 14] severe intellectual disability, 0% profound intellectual disability) and 93% (n = 39) had an adaptive behaviour composite more than two standard deviations below the mean. Communication was a significant weakness compared with daily living skills (p < 0.001; mean difference 95% confidence interval [CI] -8.193 to -4.092) and socialization (p = 0.001; mean difference 95% CI 6.511 to -1.775) on the Vineland Adaptive Behavior Scales, Second Edition. The only factors significantly associated with both decreased adaptive behaviour and presence of severe intellectual disability was the presence of increased autistic symptoms and younger age. INTERPRETATION: Children with Dravet syndrome have a very high level of intellectual disability and almost all have significant deficits in adaptive behaviour. Greater deficits in adaptive behaviour and greater severity of intellectual disability are associated with the presence of increased autistic symptoms, highlighting the need for comprehensive neurodevelopmental assessment for all affected children. WHAT THIS PAPER ADDS: Eighty-six per cent (n = 36) of children with Dravet syndrome fulfilled criteria for intellectual disability. Ninety-three per cent (n = 39) of children with Dravet syndrome had significant deficits in adaptive behaviour. Communication was a significant weakness on a measure of adaptive behaviour. Increased autistic symptoms were associated with greater deficits in cognition/adaptive behaviour. Older age and earlier status epilepticus were associated with decreased adaptive behaviour.

Caregiver reported seizure precipitants and measures to prevent seizures in children with Dravet syndrome.

OBJECTIVE: The aim of this population-based, cross-sectional study was to describe caregiver-reported seizure precipitants, measures taken to prevent seizures and rescue therapies in children with Dravet Syndrome (DS). METHODS: In a population-based study, caregivers of 42/48 Swedish children with DS born between 2000 and 2018 were interviewed. Frequency of precipitants, preventive measures, and rescue therapies were compared between children born 2000-2009 and 2010-2018 and between `severe´ and `less severe´ epilepsy. RESULTS: All children had experienced precipitants. Preventive measures were employed in all. Seizures had been provoked by a median of seven (range 2-11) out of 13 factors. A median of eight (range 1-17) preventive measures out of 19 were reported. The most common precipitants were fever (n=42, 100%), and afebrile infections (n=39/42, 93%). Afebrile infections (p=0.014) and reduced ambient temperature (p=0.006) were more common precipitants in younger children, and bright light in children with severe epilepsy (p=0.013). The most common factors avoided were warm weather (n=35/42, 83%) and physical activity (n=27/42, 64%). It was more common to avoid strong emotions (p=0.035) and reduced temperature (p=0.002) in younger children, and to avoid infections (p=0.024) and crowds (p=0.046) in children with 'severe' epilepsy. Many children (n=28/42, 67%) or their siblings (n=16/34, 47% of individuals with siblings) had stayed home to avoid infections in school/day-care. Use of emergency medicines was more frequent in younger children (p=0.006) and in children with 'severe' epilepsy (p=0.007). SIGNIFICANCE: Caregiver-reported seizure precipitants are common in DS. Caregivers employ a range of measures to avoid seizures, restricting family life.

Dravet syndrome in children-A population-based study.

OBJECTIVE: The aim was to describe age at diagnosis, cumulative incidence, SCN1A variants, mortality, seizure types and treatments in children with Dravet Syndrome (DS) in Sweden. METHODS: Children diagnosed with DS, born between January 1st 2000 and December 31st 2018 were included in a population-based study. Clinical data, frequency of seizure types and treatments were collected from caregivers and medical records in 42 children. Age at diagnosis, cumulative incidence and treatment were compared between children born in Sweden 2000-2009 and 2010-2018. RESULTS: We identified 55 children with DS, 53 were born in Sweden. Three children had died of definite, probable, or possible sudden unexpected death in epilepsy, one of acute anoxic brain injury and three of pneumonia or pneumonitis. Median age at death was 4.7 (range 3.3-11) years. In 49/53 children with known SCN1A status, a pathogenic/likely pathogenic variant of SCN1A was detected. In two a SCN1A variant of unknown significance was found. For children born in Sweden 2010-2018, median age at DS diagnosis was lower (1.6 vs 4.5 years, p = 0.001) and cumulative incidence higher (1/33,000 vs 1/46,000 live-born children, p = 0.03), compared to children born in 2000-2009. The most common seizure types were focal to bilateral tonic clonic (n = 41/42) and myoclonic (n = 35/42). Tonic seizures were reported in 25/42 children. Sodium-channel inhibitors had been used in 9/24 children born in 2010-2018 and 17/18 children born in 2000-2009 (p = 0.001). SIGNIFICANCE: A SCN1A variant that could explain the syndrome was found in over 90% of children. Tonic seizures seem to be more frequent than earlier described. Median age at diagnosis was lower, cumulative incidence higher and use of contra-indicated sodium-channel inhibitors less common for children born in 2010-2018 compared with children born in 2000-2009. This could indicate an increased awareness of DS.

Potassium citrate and metabolic acidosis in children with epilepsy on the ketogenic diet: a prospective controlled study.

AIM: To investigate if potassium citrate, a mild alkaline compound, can prevent metabolic acidosis in children with epilepsy treated with the ketogenic diet without reducing antiepileptic efficacy. METHOD: In this prospective controlled study, we investigated the frequency of initial uncompensated metabolic acidosis in 51 participants. There were 22 participants with and 29 without potassium citrate supplementation. The ketogenic diet was used as add-on treatment to children with drug resistant epilepsy. We also estimated the proportion of participants with a greater than 50% seizure reduction after 7 months. RESULTS: None of the 22 participants (15 males, seven females; median age 1y 7mo, interquartile range [IQR] 3y 3mo) with, and 10 of 29 (12 males, 17 females; median age 6y 1mo, IQR 4y 8mo) without potassium citrate developed metabolic acidosis (odds ratio=0.04, 95% CI 0.00-0.75 [p<0.01]); median pH 7.32 vs 7.24; [p<0.001]), and median bicarbonate 19.7mmol/L vs 14.0mmol/L (p<0.001). The number of seizures was reduced by more than 50% in 9 of 22 with potassium citrate and 8 of 29 participants without potassium citrate, 7 months after introducing a ketogenic diet (p=0.4). INTERPRETATION: In the ketogenic diet, potassium citrate supplementation can prevent metabolic acidosis, without reducing antiepileptic efficacy. WHAT THIS PAPER ADDS: Citrate supplementation prevents metabolic acidosis in children treated with a ketogenic diet. Efficacy of the ketogenic diet is not affected by supplementation with citrate. Citrate supplementation does not affect beta-hydroxybuturate concentration. Potassium citrate reduces the time needed to reach an optimal ketogenic ratio. This article is commented on by Schoeler on page 8 of this issue.

Effectiveness of the ketogenic diet used to treat resistant childhood epilepsy in Scandinavia.

BACKGROUND: This Scandinavian collaborative retrospective study of children treated with ketogenic diet (KD) highlights indications and effectiveness over two years follow-up. METHODS: Five centres specialised in KD collected data retrospectively on 315 patients started on KD from 1999 to 2009. Twenty-five patients who stopped the diet within four weeks because of compliance-problems and minor side-effects were excluded. Seizure-type(s), seizure-frequency, anti-epileptic drugs and other treatments, mental retardation, autism-spectrum disorder and motor-dysfunction were identified and treatment-response was evaluated. RESULTS: An intention-to-treat analysis was used. Responders (>50% seizure-frequency reduction) at 6, 12 and 24 months were 50%, 46% and 28% respectively, seizure-free were 16%, 13% and 10%. Still on the diet were 80%, 64% and 41% after 6, 12 and 24 months. No child had an increased seizure-frequency. The best seizure outcome was seen in the group with not-daily seizures at baseline (n = 22), where 45%, 41% and 32% became seizure-free at 6, 12 and 24 months A significant improvement in seizure-frequency was seen in atonic seizures at three months and secondary generalised seizures at three and six months. Side-effects were noted in 29 subjects; most could be treated and only two stopped due to hyperlipidaemia and two due to kidney-stones. In 167 patients treated with potassium-citrate, one developed kidney-stones, compared with six of 123 without potassium-citrate treatment (relative risk = 8.1). CONCLUSIONS: As the first study of implementing KD in children in the Scandinavian countries, our survey of 290 children showed that KD is effective and well tolerated, even in such severe patients with therapy-resistant epilepsy, more than daily seizures and intellectual disability in the majority of patients. Long-term efficacy of KD was comparable or even better than reported in newer AEDs. Addition of potassium citrate reduced risk of kidney-stones. Our data indicate that the response might be predicted by seizure-frequency before initiation of the diet but not by age, seizure-type or aetiology.

Severe ALG8-CDG (CDG-Ih) associated with homozygosity for two novel missense mutations detected by exome sequencing of candidate genes.

Posttranslationally glycosylated proteins are important in many biological processes in humans and Congenital disorders of glycosylation (CDGs) are associated with a broad range of phenotypes. Type I CDGs are a group of rare autosomal recessive conditions. To date 17 subtypes have been enzymatically and molecularly characterized. Impaired function of the enzyme dolichyl pyrophosphate Glc(1)Man(9)GlcNAc(2) alpha-1,3-glucosyltransferase encoded by the ALG8 gene, causes ALG8-CDG (CDG-Ih, OMIM #608104). This enzyme facilitates the transfer of a second glucose molecule to a growing lipid-linked oligosaccharide chain, a process that transpires in the endoplasmic reticulum (ER). We present a female patient of consanguineous parents, with pre- and postnatal growth retardation, dysmorphic features, significant developmental delay, visual impairment and an electrophoretic serum transferrin pattern indicative of a type I CDG. Type I CDG subgroup was determined by exome sequencing facilitated by homozygosity analysis. The patient was homozygous for two variants, nine nucleotides apart, in exon 8 of ALG8; c.799T > C [p.Ser267Pro] and c.808T > C [p.Phe270Leu]. Both missense mutations are predicted to affect a conserved region of an intraluminal ER loop of dolichyl pyrophosphate Glc(1)Man(9)GlcNAc(2) alpha-1,3-glucosyltransferase. To our knowledge, the current report describes the ninth published case of ALG8-CDG, contributing to the further delineation of this rare and variable disorder.

Niemann-Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue.

BACKGROUND: Niemann-Pick disease type C1 (NPC1) and type C2 (NPC2) display the same pattern of neurovisceral storage due to deficiencies within lysosomes. NPC2 is a much rarer condition, and as reports on the pathological changes are scarce, the morphological findings in the lungs and brain in two siblings who died at an early age from pulmonary involvement are described. The diagnosis of NPC2 was confirmed at postmortem mutational analysis. CASE REPORTS: Both siblings presented with postnatal conjugated hyperbilirubinemia. They subsequently developed progressive respiratory insufficiency with opacification of the lungs on X-ray examination and died at the ages of 8 and 13 months. The lungs contained intra-alveolar accumulation of periodic acid-Schiff positive material, foamy macrophages, and hyperplasia of the alveolar cells, consistent with pulmonary alveolar lipoproteinosis. On neuropathological examination, storage material in swollen perikarya in the deep cerebellar nuclei, thalamus, medulla oblongata, and in the paravertebral ganglion cells was found. Meganeurites were present in the cerebral cortex. A few axonal spheroids were also observed. There seemed to be a reduced number of Purkinje cells in the cerebellum. CONCLUSIONS: Evidence that NPC2 is associated with severe pulmonary alveolar lipoproteinosis is supported. There were extensive neuropathological changes with storage material in swollen perikarya and a few axonal spheroids.

Incidence rates of progressive childhood encephalopathy in Oslo, Norway: a population based study.

BACKGROUND: Progressive encephalopathy (PE) in children is a heterogeneous group of diseases mainly composed of metabolic diseases, but it consists also of neurodegenerative disorders where neither metabolic nor other causes are found. We wanted to estimate the incidence rate and aetiology of PE, as well as the age of onset of the disease. METHODS: We included PE cases born between 1985 and 2003, living in Oslo, and registered the number presenting annually between 1985 and 2004. Person-years at risk between 0 and 15 years were based on the number of live births during the observation period which was divided into four 5-year intervals. We calculated incidence rates according to age at onset which was classified as neonatal (0-4 weeks), infantile (1-12 months), late infantile (1-5 years), and juvenile (6-12 years). RESULTS: We found 84 PE cases representing 28 diagnoses among 1,305,997 person years, giving an incidence rate of 6.43 per 100,000 person years. The age-specific incidence rates per 100,000 were: 79.89 (<1 year), 8.64 (1-2 years), 1.90 (2-5 years), and 0.65 (>5 years). 66% (55/84) of the cases were metabolic, 32% (27/54) were neurodegenerative, and 2% (2/84) had HIV encephalopathy. 71% (60/84) of the cases presented at < 1 year, 24% (20/84) were late infantile presentations, and 5% (4/84) were juvenile presentations. Neonatal onset was more common in the metabolic (46%) (25/55) compared to the neurodegenerative group (7%) (2/27). 20% (17/84) of all cases were classified as unspecified neurodegenerative disease. CONCLUSION: The overall incidence rate of PE was 6.43 per 100,000 person years. There was a strong reduction in incidence rates with increasing age. Two-thirds of the cases were metabolic, of which almost half presented in the neonatal period.