DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
ORIGINAL ARTICLE
Dravet syndrome in Sweden: a population-based study CECILIA ROSANDER
€ | TOVE HALLB O€ OK
Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden. Correspondence to Tove Hallb€o€ok at Department of Pediatrics, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, University of Gothenburg, S-416 85 G€oteborg, Sweden. E-mail: [email protected] This article is commented on by Dravet on page 593 of this issue.
PUBLICATION DATA
Accepted for publication 26th December 2014. Published online 13th March 2015
AIM To assess the prevalence and incidence of Dravet syndrome in children diagnosed in Sweden between 2007 and 2011, and to describe neurological comorbidity, disease course, phenotypes, and treatment effects. METHOD All neuropaediatricians at university and county hospitals were asked to supply information for patients that matched the electro-clinical profile of Dravet syndrome. Genetic laboratories and referral clinicians were also contacted and requested to supply information. RESULTS The estimated incidence was one in 33 000 live births (95% CI 1:20 400–1:56 200) and prevalence on December 31, 2011 was one in 45 700 children aged less than 18 years of age (95% CI 1:33 800–1:63 400). The median age of the 42 children (18 males, 24 females) was 7 years (range 1–17y), the median age at seizure onset was 6 months (range 0–12mo), and the median age at diagnosis was 3 years (range 1–14y). A mutation in the SCN1A gene was found in 37 patients (88%), four were familial. Intellectual disability was diagnosed in 28 (67%) children, and 18 out of 30 patients investigated had autism spectrum disorder. Thirty participants had neurological deficits. Stiripentol, as an add-on medication, was used in 18 patients. Among these patients, seven were seizure free, six had >50% seizure reduction, and five 50% reduction in seizure frequency, 5y
42 24 (57) 8 (19)
17 8 (47) 4 (23)
25 16 (64) 4 (16)
6 37 28 24 4 30 27 12 10
2 15 15 15 0 9 8 8 7
4 22 13 9 4 21 19 4 3
(14) (88) (19) (57) (9) (71) (64) (29) (24)
(12) (88) (88) (88) (0) (53) (47) (47) (41)
(16) (88) (52) (36) (16) (84) (76) (16) (12)
Quartiles
Median
Mean
3.5–12 4.4–9 1.5–8.5
7 6 3
7.8 6.4 4.9
a
No myoclonic seizures.
atypical absences, or myoclonic seizures, and 35 children (83%) had convulsive status epilepticus. Nineteen (45%) children had ataxia and nine (21%) had developed a ‘crouch gait’. Another three children had more severe neurological deficits. One child suffered from hypoxic brain injury after an episode of status epilepticus. One child had a progressive course and diffused white-matter abnormalities on MRI and a remarkable sensitivity to side effects of either antiepileptic drugs or from a ketogenic diet. The third child had a large deletion in the SCN1A gene and a severe motor deficit and intellectual disability. Their MRI was considered normal. Changes on MRI were seen in another three children with a Dravet syndrome phenotype and an SCN1A mutation. One of these children had hydrocephalus and a ventriculoperitoneal shunt, another had a hippocampus atrophy, and the third child had a left hemisphere atrophy, diagnosed after a varicellae-encephalitis. In total, 40 out of 42 children had been investigated with MRI. Intellectual disability was diagnosed in 28 (67%) children. Nine children were not tested for intellectual disability – eight because they were considered to have a normal development and one for unknown reasons/had yet to be tested. In addition, five children between 2 years and 5 years were reported only to have language impairment. Nine children had a mild, eight a moderate, and eight a severe intellectual disability; the level of intellectual disability was not specified in three children. Of the 30 children assessed for autism spectrum disorder, 18 (60%) were diagnosed with an autism spectrum disorder. In line with clinical course where year 1 to 5 have been described as the ‘catastrophic stage’, we divided the children in two groups, older than 5 years and younger than 5 years of age at assessment, which might illustrate the progressive course of this disease.1 Seventeen children were 5 years of age or under, with a median of 2 years (range
1–5y), and 25 children older than 5 years of age, with a median of 10 years (range 6–17y). A summary of clinical features of the two groups is presented in Table II. Of the 25 children older than 5 years of age, seven were seizure free for at least 3 months, but experienced sporadic myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli. Thirteen children had stiripentol as an add-on to other antiepileptic drugs. Three of these children were considered seizure free with sporadic seizures provoked by fever or other stimuli and three had >50% seizure reduction; the other patient had atypical absences and generalized tonic–clonic seizures but no convulsive status epilepticus. In the group of children 5 years of age and under, 3 out of 17 were seizure free for at least 3 months but experienced sporadic myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli. One of them was treated with a ketogenic diet and had no other antiepileptic drugs. None of these seizure-free children had stiripentol as an add-on medication. Of the 17 children 5 years of age and under, five had stiripentol in combination with other antiepileptic drugs; they all had >50% seizure reduction (Table II). Ten children had tried a
Table II: Clinical features in 42 children with Dravet syndrome
Median age (range) Total number Autism (%) Autistic traits (%) No autism (%) Not investigated (%) Intellectual disability Mild Moderate Severe Not specified Not investigateda Neurological deficit Ataxia Crouch gait Other EEG Normal Abnormalb No information Seizures Febrile As initial seizure Generalized tonic–clonic/generalized clonic Focal Myoclonic Atypical absence Convulsive status epilepticus Seizure freec Stiripentol as add-on Seizure free >50% reduction 5y
2 17 1 2 4 10 6 5 0 1 0 5 8 7 0 1
10 25 14 1 8 2 22 4 8 7 3 4 22 12 9 2
(1–5) (6) (12) (23) (59) (35) (29) (0) (6) (0) (29) (47) (41) (0) (6)
(6–17) (56) (4) (32) (8) (88) (16) (32) (28) (12) (16) (88) (48) (48) (8)
14 (82) 3 (18) 0 (0)
4 (16) 20 (80) 1 (4)
17 16 14 14 8 8 13 3 5 0 5 0
24 15 24 17 22 23 22 7 13 3 3 7
(100) (94) (82) (82) (47) (47) (76) (18) (29) (0) (29) (0)
(96) (60) (96) (68) (88) (92) (88) (28) (52) (12) (12) (28)
Of the nine children not tested, eight were considered typically developing, without intellectual disability. bLast performed, interictal EEG. Spike wave, sharp wave, slow wave, increased background slowing. cMyoclonic, focal, and generalized tonic–clonic seizures provoked by fever or other stimuli were still reported.
ketogenic diet. Two had >50% seizure reduction and one was seizure free without any other antiepileptic drugs. Vagus nerve stimulation therapy was used in four children and was considered effective (>50% seizure reduction) in two children, with a significant improvement in behaviour. An increase in EEG abnormalities with age was seen. Of the 25 children older than 5 years of age, four had a normal interictal EEG in the last recording compared with 14 out of 17 of the children in the younger group (Table II). Rehabilitation services were well functioning. Three children and their families had no contact with a rehabilitation unit. One child was older than 5 years old with a milder course of scarce febrile seizures and mild behavioural problems after the first years, with a more typical Dravet syndrome course. Two were younger than 5 years and not yet accepted for a rehabilitation unit.
DISCUSSION This study is the first population-based study of Dravet syndrome in Sweden. All Swedish citizens are included in an official census at birth and there is a state-oriented medical care system that is transparent and able to access clinical information. This is especially true in paediatric epilepsy that is mostly centralized to paediatric neurologists at county and/or university hospitals. The incidence of new cases of Dravet syndrome in the 5-year birth cohort (2007–2011) was estimated to one in 33 000 live births. This rate corroborates previous approximations, for example, Hurst et al.4 approximated the incidence to one in 40 000. In another study by Yakoub et al.6 in 1992, 17 out of 329 children with epilepsy met the criteria for Dravet syndrome with an approximated incidence of one in 20 000–30 000 children, and in a recent study by Brunklaus et al.5 an incidence of one in 40 900 was reported. These reports from the USA and France were not population-based studies.4,6 The Brunklaus study from the UK was the first systematic population-based evaluation estimating the incidence of SCN1A mutation-positive patients.5 Their findings might be an underestimation since 20% to 30% of cases were mutation negative. There is also a systematic increase in and widening of the spectrum of genetically proven cases including cases of germinal and somatic mosaicism.7,9,13,30 The difference in incidence and prevalence might be explained by under diagnosis in the older age group, death, or that the difference is not significant because the confidence intervals of both incidence and prevalence could overlap in the small sample size. In our study, the included children all shared the diagnostic features of Dravet syndrome according to international criteria.3,31 Both SCN1A mutation-positive and mutation-negative children were included. One could expect false negative cases because of reluctance of keeping the clinical diagnosis records when the genotype is negative. To avoid this we have included both groups. A weakness with this study is that Dravet syndrome is a relatively unknown disorder in Sweden. This is a challenge in all Dravet Syndrome in Sweden Cecilia Rosander and Tove Hallbo€o€k
631
population-based studies of rare diseases. As a reflection of increased awareness and knowledge of the disorder, there have been an increasing number of referrals for genetic testing during the last years. We therefore chose the last 5 years (between 2007 and 2011) for the estimation of incidence. When calculating the prevalence of Dravet syndrome among Swedish children to one in 45 700, we found no children had died as a result of the syndrome. One could expect that all families seek medical attendance because of the severity of the epilepsy in Dravet syndrome. The emigration rate of families with a severe disease and dependency on the healthcare system is negligible. The systematic methodology for recruiting patients to the study group, together with an increased knowledge about Dravet syndrome minimized the risk of missing cases because of diagnostic difficulties. However, as Sweden has a relatively small population and Dravet syndrome is a rare disease, the prevalence estimate must be interpreted with caution. The confidence interval of this study was narrow. In contrast to earlier studies, we observed a slightly lower male to female ratio of 1:1.33. This was in line with more recent studies where no significant differences between sexes have been found.5,32 As described in earlier studies, we found a family background in 9.5% of our patients.1,33 Inheritance for febrile seizures and epilepsy were described by Mancardi et al.,10 who found that febrile seizures and epilepsy occurred in 20 out of 74 (27%) families with severe myoclonic epilepsy in infancy, and did not differ significantly from matched controls where 13 out of 70 (18.6%) families were affected. Similar data was presented in the populationbased study by Brunklaus et al. In this study, 7 out of 42 patients (17%) had a family history of febrile seizures.5 In line with the earlier described clinical course and year 1 to 5 being the ‘catastrophic stage’, we divided the children in our assessment into two groups: older than 5 years of age and younger than 5 years of age; to see if this would illustrate the progressive course of the disease.1 One limitation in the comparison of the two groups is that they are not equivalent in terms of duration of the disease, which varies during the periods of childhood and adolescence. Intellectual disability was seen in 88% of the older age group compared with 35% of the younger age group. Five children in the younger group were reported to have language impairment. This might be an early sign of affected development and future neuropsychiatric pathology as
described in early symptomatic syndromes eliciting neurodevelopment clinical examinations.33 In the group of children older than 5 years of age, 15 out of 23 patients assessed had autism spectrum disorder (60%). In concordance with earlier studies, an increase in EEG abnormalities with age was seen.21,34 Only four out of 25 children in the older group compared with 14 out of 17 children in the younger group had a normal interictal EEG in the last recording. The absence of myoclonic seizures has already been reported in patients as a possible factor for a less severe cognitive impairment.19,35 The role of status epilepticus for prognosis remains unclear.5,19 In our study seven participants had no status epilepticus, three were older than 5 years of age and four were 5 years old or younger. All had initial febrile seizures, four had myoclonic seizures that stopped in one participant, and two had atypical absences. Four had mild intellectual disability, one had language impairment, and no-one had autism spectrum disorder. Two in the older group were using stiripentol. These data suggest a milder course. Ten children (24%) were seizure free for at least 3 months but experienced myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli. Three children were using stiripentol as an add-on medication and one had a ketogenic diet.
CONCLUSION The incidence of Dravet syndrome in this 5-year birth cohort (2007 and 2011) was estimated to be one in 33 000 and the prevalence was one in 45 700 children. This is the first population-based study of Dravet syndrome in Sweden. Our data confirms international findings of incidence, and highlights the severe and progressive course of this genetic epilepsy syndrome. A CK N O W L E D G E M E N T S This work was supported by the Department of Pediatrics, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, Sahlgrenska Academy Gothenburg, Margarethahemmet and Bertha and Felix Neuberghs Foundation. We thank statistician Fredrik Nilsson PhD, who performed all calculations. We also thank the parents of the affected children. The authors have stated that they had no interests that might be perceived as posing a conflict or bias.
REFERENCES 1. Dravet C. The core Dravet syndrome phenotype. Epilepsia 2011; 52(Suppl. 2): 3–9. 2. Dravet C. Les epilepsies graves de l’enfant. Vie Med 1978; 8: 543–8. 3. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–99. 4. Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990; 31: 397–400.
SCN1A mutation-positive Dravet syndrome. Brain 2012; 135: 2329–36. 6. Yakoub M, Dulac O, Jambaque I, Chiron C, Plouin P. Early diagnosis of severe myoclonic epilepsy in infancy. Brain Dev 1992; 14: 299–303.
implications for molecular diagnosis. Epilepsia 2009; 50: 1670–8. 9. Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia 2011; 52(Suppl. 2): 24–9. 10. Mancardi MM, Striano P, Gennaro E, et al. Familial
7. Harkin LA, McMahon JM, Iona X, et al. The spectrum
occurrence of febrile seizures and epilepsy in severe
of SCN1A-related infantile epileptic encephalopathies.
myoclonic epilepsy of infancy (SMEI) patients with
Brain 2007; 130: 843–52.
SCN1A mutations. Epilepsia 2006; 47: 1629–35.
5. Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi
8. Marini C, Scheffer IE, Nabbout R, et al. SCN1A dupli-
11. Kassai B, Chiron C, Augier S, et al. Severe myoclonic
SM. Prognostic, clinical and demographic features in
cations and deletions detected in Dravet syndrome:
epilepsy in infancy: a systematic review and a meta-
632 Developmental Medicine & Child Neurology 2015, 57: 628–634
analysis of individual patient data. Epilepsia 2008; 49:
cents with Dravet syndrome. Arch Neurol 2012; 69:
343–8.
873–8.
29. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934; 26: 404–13.
12. Guerrini R, Falchi M. Dravet syndrome and SCN1A
21. Specchio N, Balestri M, Trivisano M, et al. Electroen-
gene mutation related-epilepsies: cognitive impairment
cephalographic features in dravet syndrome: five-year
30. Depienne C, Trouillard O, Saint-Martin C, et al. Spec-
and its determinants. Dev Med Child Neurol 2011; 53
follow-up study in 22 patients. J Child Neurol 2012; 27:
trum of SCN1A gene mutations associated with Dravet
(Suppl. 2): 11–5.
439–44.
13. Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes
GH.
Genotype–phenotype
associations
in
SCN1A-related epilepsies. Neurology 2011; 76: 594–600. 14. Guerrini R, Cellini E, Mei D, et al. Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene. Epilepsia 2010; 51: 2474–7. 15. Singh NA, Pappas C, Dahle EJ, et al. A role of SCN9A
syndrome: analysis of 333 patients. J Med Genet 2009;
22. Striano P, Mancardi MM, Biancheri R, et al. Brain MRI
46: 183–91.
findings in severe myoclonic epilepsy in infancy and
31. Berg AT, Berkovic SF, Brodie MJ, et al. Revised termi-
genotype–phenotype correlations. Epilepsia 2007; 48:
nology and concepts for organization of seizures and epi-
1092–6.
lepsies: report of the ILAE Commission on Classification
23. Guerrini R, Striano P, Catarino C, Sisodiya SM. Neu-
and Terminology, 2005–2009. Epilepsia 2010; 51: 676–85.
roimaging and neuropathology of Dravet syndrome. Epi-
32. Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P.
lepsia 2011; 52(Suppl. 2): 30–4.
Dravet syndrome and parent associations: the IDEA
in human epilepsies, as a cause of febrile seizures and as
24. Chiron C, Marchand MC, Tran A, et al. Stiripentol in
League experience with comorbid conditions, mortality,
a potential modifier of Dravet syndrome. PLoS Genet
severe myoclonic epilepsy in infancy: a randomised pla-
management, adaptation, and grief. Epilepsia 2011; 52
2009; 5: e1000649.
cebo-controlled
16. Depienne C, LeGuern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat 2012; 33: 627–34.
syndrome-dedicated
trial.
STICLO
study group. Lancet 2000; 356: 1638–42. 25. Nabbout R, Copioli C, Chipaux M, et al. Ketogenic diet
(Suppl. 2): 95–101. 33. Gillberg C. The ESSENCE in child psychiatry: early symptomatic syndromes eliciting neurodevelopmental
also benefits Dravet syndrome patients receiving stirip-
clinical examinations. Res Dev Disabil 2010; 31: 1543–51.
17. Carvill GL, Weckhuysen S, McMahon JM, et al.
entol: a prospective pilot study. Epilepsia 2011; 52: e54–7.
34. Bureau M, Dalla Bernardina B. Electroencephalographic
GABRA1 and STXBP1: novel genetic causes of Dravet
26. Caraballo RH, Cersosimo RO, Sakr D, Cresta A, Esco-
characteristics of Dravet syndrome. Epilepsia 2011; 52
syndrome. Neurology 2014; 82: 1245–53. 18. Ragona F, Brazzo D, De Giorgi I, et al. Dravet syndrome: early clinical manifestations and cognitive outcome in 37 Italian patients. Brain Dev 2010; 32: 71–7. 19. Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia 2011; 52: 386–92. 20. Rodda JM, Scheffer IE, McMahon JM, Berkovic SF,
bal N, Fejerman N. Ketogenic diet in patients with Dravet syndrome. Epilepsia 2005; 46: 1539–44. 27. Diagnoskoder (ICD-10) (2010). ISBN: 978-91-8658563-1. Available from: http://www.socialstyrelsen.se/klassi
(Suppl. 2): 13–23. 35. Takayama R, Fujiwara T, Shigematsu H, et al. Longterm course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014; 55: 528–38.
ficeringochkoder/diagnoskoder (1 January 2015). 28. The International Classification of Diseases, 10th Edition (ICD-10) changeover is coming. Optometry 2010; 81: 551–3.
Graham HK. Progressive gait deterioration in adoles-
Dravet Syndrome in Sweden Cecilia Rosander and Tove Hallbo€o€k
633
ORIGINAL ARTICLE
Dravet syndrome in Sweden: a population-based study CECILIA ROSANDER
€ | TOVE HALLB O€ OK
Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden. Correspondence to Tove Hallb€o€ok at Department of Pediatrics, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, University of Gothenburg, S-416 85 G€oteborg, Sweden. E-mail: [email protected] This article is commented on by Dravet on page 593 of this issue.
PUBLICATION DATA
Accepted for publication 26th December 2014. Published online 13th March 2015
AIM To assess the prevalence and incidence of Dravet syndrome in children diagnosed in Sweden between 2007 and 2011, and to describe neurological comorbidity, disease course, phenotypes, and treatment effects. METHOD All neuropaediatricians at university and county hospitals were asked to supply information for patients that matched the electro-clinical profile of Dravet syndrome. Genetic laboratories and referral clinicians were also contacted and requested to supply information. RESULTS The estimated incidence was one in 33 000 live births (95% CI 1:20 400–1:56 200) and prevalence on December 31, 2011 was one in 45 700 children aged less than 18 years of age (95% CI 1:33 800–1:63 400). The median age of the 42 children (18 males, 24 females) was 7 years (range 1–17y), the median age at seizure onset was 6 months (range 0–12mo), and the median age at diagnosis was 3 years (range 1–14y). A mutation in the SCN1A gene was found in 37 patients (88%), four were familial. Intellectual disability was diagnosed in 28 (67%) children, and 18 out of 30 patients investigated had autism spectrum disorder. Thirty participants had neurological deficits. Stiripentol, as an add-on medication, was used in 18 patients. Among these patients, seven were seizure free, six had >50% seizure reduction, and five 50% reduction in seizure frequency, 5y
42 24 (57) 8 (19)
17 8 (47) 4 (23)
25 16 (64) 4 (16)
6 37 28 24 4 30 27 12 10
2 15 15 15 0 9 8 8 7
4 22 13 9 4 21 19 4 3
(14) (88) (19) (57) (9) (71) (64) (29) (24)
(12) (88) (88) (88) (0) (53) (47) (47) (41)
(16) (88) (52) (36) (16) (84) (76) (16) (12)
Quartiles
Median
Mean
3.5–12 4.4–9 1.5–8.5
7 6 3
7.8 6.4 4.9
a
No myoclonic seizures.
atypical absences, or myoclonic seizures, and 35 children (83%) had convulsive status epilepticus. Nineteen (45%) children had ataxia and nine (21%) had developed a ‘crouch gait’. Another three children had more severe neurological deficits. One child suffered from hypoxic brain injury after an episode of status epilepticus. One child had a progressive course and diffused white-matter abnormalities on MRI and a remarkable sensitivity to side effects of either antiepileptic drugs or from a ketogenic diet. The third child had a large deletion in the SCN1A gene and a severe motor deficit and intellectual disability. Their MRI was considered normal. Changes on MRI were seen in another three children with a Dravet syndrome phenotype and an SCN1A mutation. One of these children had hydrocephalus and a ventriculoperitoneal shunt, another had a hippocampus atrophy, and the third child had a left hemisphere atrophy, diagnosed after a varicellae-encephalitis. In total, 40 out of 42 children had been investigated with MRI. Intellectual disability was diagnosed in 28 (67%) children. Nine children were not tested for intellectual disability – eight because they were considered to have a normal development and one for unknown reasons/had yet to be tested. In addition, five children between 2 years and 5 years were reported only to have language impairment. Nine children had a mild, eight a moderate, and eight a severe intellectual disability; the level of intellectual disability was not specified in three children. Of the 30 children assessed for autism spectrum disorder, 18 (60%) were diagnosed with an autism spectrum disorder. In line with clinical course where year 1 to 5 have been described as the ‘catastrophic stage’, we divided the children in two groups, older than 5 years and younger than 5 years of age at assessment, which might illustrate the progressive course of this disease.1 Seventeen children were 5 years of age or under, with a median of 2 years (range
1–5y), and 25 children older than 5 years of age, with a median of 10 years (range 6–17y). A summary of clinical features of the two groups is presented in Table II. Of the 25 children older than 5 years of age, seven were seizure free for at least 3 months, but experienced sporadic myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli. Thirteen children had stiripentol as an add-on to other antiepileptic drugs. Three of these children were considered seizure free with sporadic seizures provoked by fever or other stimuli and three had >50% seizure reduction; the other patient had atypical absences and generalized tonic–clonic seizures but no convulsive status epilepticus. In the group of children 5 years of age and under, 3 out of 17 were seizure free for at least 3 months but experienced sporadic myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli. One of them was treated with a ketogenic diet and had no other antiepileptic drugs. None of these seizure-free children had stiripentol as an add-on medication. Of the 17 children 5 years of age and under, five had stiripentol in combination with other antiepileptic drugs; they all had >50% seizure reduction (Table II). Ten children had tried a
Table II: Clinical features in 42 children with Dravet syndrome
Median age (range) Total number Autism (%) Autistic traits (%) No autism (%) Not investigated (%) Intellectual disability Mild Moderate Severe Not specified Not investigateda Neurological deficit Ataxia Crouch gait Other EEG Normal Abnormalb No information Seizures Febrile As initial seizure Generalized tonic–clonic/generalized clonic Focal Myoclonic Atypical absence Convulsive status epilepticus Seizure freec Stiripentol as add-on Seizure free >50% reduction 5y
2 17 1 2 4 10 6 5 0 1 0 5 8 7 0 1
10 25 14 1 8 2 22 4 8 7 3 4 22 12 9 2
(1–5) (6) (12) (23) (59) (35) (29) (0) (6) (0) (29) (47) (41) (0) (6)
(6–17) (56) (4) (32) (8) (88) (16) (32) (28) (12) (16) (88) (48) (48) (8)
14 (82) 3 (18) 0 (0)
4 (16) 20 (80) 1 (4)
17 16 14 14 8 8 13 3 5 0 5 0
24 15 24 17 22 23 22 7 13 3 3 7
(100) (94) (82) (82) (47) (47) (76) (18) (29) (0) (29) (0)
(96) (60) (96) (68) (88) (92) (88) (28) (52) (12) (12) (28)
Of the nine children not tested, eight were considered typically developing, without intellectual disability. bLast performed, interictal EEG. Spike wave, sharp wave, slow wave, increased background slowing. cMyoclonic, focal, and generalized tonic–clonic seizures provoked by fever or other stimuli were still reported.
ketogenic diet. Two had >50% seizure reduction and one was seizure free without any other antiepileptic drugs. Vagus nerve stimulation therapy was used in four children and was considered effective (>50% seizure reduction) in two children, with a significant improvement in behaviour. An increase in EEG abnormalities with age was seen. Of the 25 children older than 5 years of age, four had a normal interictal EEG in the last recording compared with 14 out of 17 of the children in the younger group (Table II). Rehabilitation services were well functioning. Three children and their families had no contact with a rehabilitation unit. One child was older than 5 years old with a milder course of scarce febrile seizures and mild behavioural problems after the first years, with a more typical Dravet syndrome course. Two were younger than 5 years and not yet accepted for a rehabilitation unit.
DISCUSSION This study is the first population-based study of Dravet syndrome in Sweden. All Swedish citizens are included in an official census at birth and there is a state-oriented medical care system that is transparent and able to access clinical information. This is especially true in paediatric epilepsy that is mostly centralized to paediatric neurologists at county and/or university hospitals. The incidence of new cases of Dravet syndrome in the 5-year birth cohort (2007–2011) was estimated to one in 33 000 live births. This rate corroborates previous approximations, for example, Hurst et al.4 approximated the incidence to one in 40 000. In another study by Yakoub et al.6 in 1992, 17 out of 329 children with epilepsy met the criteria for Dravet syndrome with an approximated incidence of one in 20 000–30 000 children, and in a recent study by Brunklaus et al.5 an incidence of one in 40 900 was reported. These reports from the USA and France were not population-based studies.4,6 The Brunklaus study from the UK was the first systematic population-based evaluation estimating the incidence of SCN1A mutation-positive patients.5 Their findings might be an underestimation since 20% to 30% of cases were mutation negative. There is also a systematic increase in and widening of the spectrum of genetically proven cases including cases of germinal and somatic mosaicism.7,9,13,30 The difference in incidence and prevalence might be explained by under diagnosis in the older age group, death, or that the difference is not significant because the confidence intervals of both incidence and prevalence could overlap in the small sample size. In our study, the included children all shared the diagnostic features of Dravet syndrome according to international criteria.3,31 Both SCN1A mutation-positive and mutation-negative children were included. One could expect false negative cases because of reluctance of keeping the clinical diagnosis records when the genotype is negative. To avoid this we have included both groups. A weakness with this study is that Dravet syndrome is a relatively unknown disorder in Sweden. This is a challenge in all Dravet Syndrome in Sweden Cecilia Rosander and Tove Hallbo€o€k
631
population-based studies of rare diseases. As a reflection of increased awareness and knowledge of the disorder, there have been an increasing number of referrals for genetic testing during the last years. We therefore chose the last 5 years (between 2007 and 2011) for the estimation of incidence. When calculating the prevalence of Dravet syndrome among Swedish children to one in 45 700, we found no children had died as a result of the syndrome. One could expect that all families seek medical attendance because of the severity of the epilepsy in Dravet syndrome. The emigration rate of families with a severe disease and dependency on the healthcare system is negligible. The systematic methodology for recruiting patients to the study group, together with an increased knowledge about Dravet syndrome minimized the risk of missing cases because of diagnostic difficulties. However, as Sweden has a relatively small population and Dravet syndrome is a rare disease, the prevalence estimate must be interpreted with caution. The confidence interval of this study was narrow. In contrast to earlier studies, we observed a slightly lower male to female ratio of 1:1.33. This was in line with more recent studies where no significant differences between sexes have been found.5,32 As described in earlier studies, we found a family background in 9.5% of our patients.1,33 Inheritance for febrile seizures and epilepsy were described by Mancardi et al.,10 who found that febrile seizures and epilepsy occurred in 20 out of 74 (27%) families with severe myoclonic epilepsy in infancy, and did not differ significantly from matched controls where 13 out of 70 (18.6%) families were affected. Similar data was presented in the populationbased study by Brunklaus et al. In this study, 7 out of 42 patients (17%) had a family history of febrile seizures.5 In line with the earlier described clinical course and year 1 to 5 being the ‘catastrophic stage’, we divided the children in our assessment into two groups: older than 5 years of age and younger than 5 years of age; to see if this would illustrate the progressive course of the disease.1 One limitation in the comparison of the two groups is that they are not equivalent in terms of duration of the disease, which varies during the periods of childhood and adolescence. Intellectual disability was seen in 88% of the older age group compared with 35% of the younger age group. Five children in the younger group were reported to have language impairment. This might be an early sign of affected development and future neuropsychiatric pathology as
described in early symptomatic syndromes eliciting neurodevelopment clinical examinations.33 In the group of children older than 5 years of age, 15 out of 23 patients assessed had autism spectrum disorder (60%). In concordance with earlier studies, an increase in EEG abnormalities with age was seen.21,34 Only four out of 25 children in the older group compared with 14 out of 17 children in the younger group had a normal interictal EEG in the last recording. The absence of myoclonic seizures has already been reported in patients as a possible factor for a less severe cognitive impairment.19,35 The role of status epilepticus for prognosis remains unclear.5,19 In our study seven participants had no status epilepticus, three were older than 5 years of age and four were 5 years old or younger. All had initial febrile seizures, four had myoclonic seizures that stopped in one participant, and two had atypical absences. Four had mild intellectual disability, one had language impairment, and no-one had autism spectrum disorder. Two in the older group were using stiripentol. These data suggest a milder course. Ten children (24%) were seizure free for at least 3 months but experienced myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli. Three children were using stiripentol as an add-on medication and one had a ketogenic diet.
CONCLUSION The incidence of Dravet syndrome in this 5-year birth cohort (2007 and 2011) was estimated to be one in 33 000 and the prevalence was one in 45 700 children. This is the first population-based study of Dravet syndrome in Sweden. Our data confirms international findings of incidence, and highlights the severe and progressive course of this genetic epilepsy syndrome. A CK N O W L E D G E M E N T S This work was supported by the Department of Pediatrics, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, Sahlgrenska Academy Gothenburg, Margarethahemmet and Bertha and Felix Neuberghs Foundation. We thank statistician Fredrik Nilsson PhD, who performed all calculations. We also thank the parents of the affected children. The authors have stated that they had no interests that might be perceived as posing a conflict or bias.
REFERENCES 1. Dravet C. The core Dravet syndrome phenotype. Epilepsia 2011; 52(Suppl. 2): 3–9. 2. Dravet C. Les epilepsies graves de l’enfant. Vie Med 1978; 8: 543–8. 3. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–99. 4. Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia 1990; 31: 397–400.
SCN1A mutation-positive Dravet syndrome. Brain 2012; 135: 2329–36. 6. Yakoub M, Dulac O, Jambaque I, Chiron C, Plouin P. Early diagnosis of severe myoclonic epilepsy in infancy. Brain Dev 1992; 14: 299–303.
implications for molecular diagnosis. Epilepsia 2009; 50: 1670–8. 9. Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia 2011; 52(Suppl. 2): 24–9. 10. Mancardi MM, Striano P, Gennaro E, et al. Familial
7. Harkin LA, McMahon JM, Iona X, et al. The spectrum
occurrence of febrile seizures and epilepsy in severe
of SCN1A-related infantile epileptic encephalopathies.
myoclonic epilepsy of infancy (SMEI) patients with
Brain 2007; 130: 843–52.
SCN1A mutations. Epilepsia 2006; 47: 1629–35.
5. Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi
8. Marini C, Scheffer IE, Nabbout R, et al. SCN1A dupli-
11. Kassai B, Chiron C, Augier S, et al. Severe myoclonic
SM. Prognostic, clinical and demographic features in
cations and deletions detected in Dravet syndrome:
epilepsy in infancy: a systematic review and a meta-
632 Developmental Medicine & Child Neurology 2015, 57: 628–634
analysis of individual patient data. Epilepsia 2008; 49:
cents with Dravet syndrome. Arch Neurol 2012; 69:
343–8.
873–8.
29. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934; 26: 404–13.
12. Guerrini R, Falchi M. Dravet syndrome and SCN1A
21. Specchio N, Balestri M, Trivisano M, et al. Electroen-
gene mutation related-epilepsies: cognitive impairment
cephalographic features in dravet syndrome: five-year
30. Depienne C, Trouillard O, Saint-Martin C, et al. Spec-
and its determinants. Dev Med Child Neurol 2011; 53
follow-up study in 22 patients. J Child Neurol 2012; 27:
trum of SCN1A gene mutations associated with Dravet
(Suppl. 2): 11–5.
439–44.
13. Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes
GH.
Genotype–phenotype
associations
in
SCN1A-related epilepsies. Neurology 2011; 76: 594–600. 14. Guerrini R, Cellini E, Mei D, et al. Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene. Epilepsia 2010; 51: 2474–7. 15. Singh NA, Pappas C, Dahle EJ, et al. A role of SCN9A
syndrome: analysis of 333 patients. J Med Genet 2009;
22. Striano P, Mancardi MM, Biancheri R, et al. Brain MRI
46: 183–91.
findings in severe myoclonic epilepsy in infancy and
31. Berg AT, Berkovic SF, Brodie MJ, et al. Revised termi-
genotype–phenotype correlations. Epilepsia 2007; 48:
nology and concepts for organization of seizures and epi-
1092–6.
lepsies: report of the ILAE Commission on Classification
23. Guerrini R, Striano P, Catarino C, Sisodiya SM. Neu-
and Terminology, 2005–2009. Epilepsia 2010; 51: 676–85.
roimaging and neuropathology of Dravet syndrome. Epi-
32. Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P.
lepsia 2011; 52(Suppl. 2): 30–4.
Dravet syndrome and parent associations: the IDEA
in human epilepsies, as a cause of febrile seizures and as
24. Chiron C, Marchand MC, Tran A, et al. Stiripentol in
League experience with comorbid conditions, mortality,
a potential modifier of Dravet syndrome. PLoS Genet
severe myoclonic epilepsy in infancy: a randomised pla-
management, adaptation, and grief. Epilepsia 2011; 52
2009; 5: e1000649.
cebo-controlled
16. Depienne C, LeGuern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat 2012; 33: 627–34.
syndrome-dedicated
trial.
STICLO
study group. Lancet 2000; 356: 1638–42. 25. Nabbout R, Copioli C, Chipaux M, et al. Ketogenic diet
(Suppl. 2): 95–101. 33. Gillberg C. The ESSENCE in child psychiatry: early symptomatic syndromes eliciting neurodevelopmental
also benefits Dravet syndrome patients receiving stirip-
clinical examinations. Res Dev Disabil 2010; 31: 1543–51.
17. Carvill GL, Weckhuysen S, McMahon JM, et al.
entol: a prospective pilot study. Epilepsia 2011; 52: e54–7.
34. Bureau M, Dalla Bernardina B. Electroencephalographic
GABRA1 and STXBP1: novel genetic causes of Dravet
26. Caraballo RH, Cersosimo RO, Sakr D, Cresta A, Esco-
characteristics of Dravet syndrome. Epilepsia 2011; 52
syndrome. Neurology 2014; 82: 1245–53. 18. Ragona F, Brazzo D, De Giorgi I, et al. Dravet syndrome: early clinical manifestations and cognitive outcome in 37 Italian patients. Brain Dev 2010; 32: 71–7. 19. Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia 2011; 52: 386–92. 20. Rodda JM, Scheffer IE, McMahon JM, Berkovic SF,
bal N, Fejerman N. Ketogenic diet in patients with Dravet syndrome. Epilepsia 2005; 46: 1539–44. 27. Diagnoskoder (ICD-10) (2010). ISBN: 978-91-8658563-1. Available from: http://www.socialstyrelsen.se/klassi
(Suppl. 2): 13–23. 35. Takayama R, Fujiwara T, Shigematsu H, et al. Longterm course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014; 55: 528–38.
ficeringochkoder/diagnoskoder (1 January 2015). 28. The International Classification of Diseases, 10th Edition (ICD-10) changeover is coming. Optometry 2010; 81: 551–3.
Graham HK. Progressive gait deterioration in adoles-
Dravet Syndrome in Sweden Cecilia Rosander and Tove Hallbo€o€k
633
