Epilepsy & Behavior 47 (2015) 11–16

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Autism and behavior in adult patients with Dravet syndrome (DS) J.J.L. Berkvens a, I. Veugen a, M.J.B.M. Veendrick-Meekes a, F.M. Snoeijen-Schouwenaars a, H.J. Schelhaas b, M.H. Willemsen c, I.Y. Tan a,⁎, A.P. Aldenkamp a,b a b c

Department of Residential Care, Epilepsy Center Kempenhaeghe, Heeze, The Netherlands Department of Neurology, Academic Center for Epileptology Kempenhaeghe/Maastricht University Medical Center, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

a r t i c l e

i n f o

Article history: Received 24 February 2015 Revised 22 April 2015 Accepted 23 April 2015 Available online 23 May 2015 Keywords: Dravet syndrome Severe Myoclonic Epilepsy in Infancy (SMEI) Adulthood Behavior Autism

a b s t r a c t Introduction: Autism and behavioral characteristics in adults with Dravet syndrome (DS) have rarely been systematically studied. Method: Three scales were used to assess the outcomes of DS in adulthood in terms of autism and behavior. All the adult patients with DS, nine male and four female, aged between 18 and 60 years, living at the Epilepsy Center Kempenhaeghe in The Netherlands were included in the study. In addition, the past medical history of each patient was systematically screened for diagnoses like autism, Pervasive Development DisorderNot Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD), hyperactivity, Attention Deficit Hyperactivity Disorder (ADHD), and self-mutilation. Information concerning past and current use of psychoactive drugs was also evaluated. Results: Eight patients (61.5%) were classified as having autism spectrum disorder (ASD) according to the AVZ-R or according to the medical record. Self-mutilation was seen in four patients (30.8%), hyperactivity in none. Three patients (23.1%) currently used psychoactive drugs. Conclusion: Autism spectrum disorders persist in adult patients with DS, while certain characteristics associated with behavioral problems, such as hyperactivity or use of psychoactive medication, seem to be less prominent than in childhood. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Dravet syndrome (DS), also known as Severe Myoclonic Epilepsy in Infancy (SMEI), was first described in 1978 [1]. The onset of Dravet syndrome is during the first year of life, typical signs being febrile seizures, followed by frequent convulsive seizures. Later, other seizure types occur, such as myoclonic seizures, atypical absences, and partial seizures. Prior to the onset of seizures, development of the child is normal [1]. The majority (70–80%) of patients with DS have mutations in the SCN1A gene [2]. Dravet syndrome is rare, and even though recognition of the syndrome has increased in the last decade, its actual frequency is not accurately known [1]. Incidence is estimated at 1/20,000 to 1/40,000 of the general population [3,4].

⁎ Corresponding author at: Department of Residential Care, Epilepsy Center Kempenhaeghe, P.O. Box 61, NL-5590 AB Heeze, The Netherlands. Tel.: +31 402279440; fax: +31 402279477. E-mail address: [email protected] (I.Y. Tan).

http://dx.doi.org/10.1016/j.yebeh.2015.04.057 1525-5050/© 2015 Elsevier Inc. All rights reserved.

Dravet syndrome in childhood has been the subject of frequent studies. At a younger age, behavioral problems are common and are characterized by hyperactivity [1,5–9], attention deficit [1,6,10], limited concentration [11], short temper [10], mood instability [8], opposing behavior [1,7], perseveration [9], and impulsive actions [11]. Besides behavioral problems, many autistic-like features are described in children with DS, such as having unusual/restricted interests and obsessions [7,9,10], repetitive behavior (for example, watching the same cartoon over and over again) [1,10], adherence to routines [10], abnormal eye contact [7], and a lack of/poor ability to express emotions [7,10]. Even though children with DS have difficulties dealing with social rules and struggle to have normal peer relationships [1,5,7,8], they often show a lack of social reserve and are excessively familiar with strangers [7,9]. They also tend to have better socialization skills than usually described in autism [7,11]. In contrast to the younger population, much less is known about the long-term outcomes of DS related to behavior and autism in adults. Studies that do focus on behavior or autism have not systematically used scales or structured assessments. In order to extend this knowledge, we present systematically gathered data on autism features and behavioral aspects in 13 patients with DS, aged between 18 and 60 years.

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J.J.L. Berkvens et al. / Epilepsy & Behavior 47 (2015) 11–16

2. Methods 2.1. Study design This was a cross-sectional, descriptive study focusing on the longterm outcomes of Dravet syndrome related to autism and behavior in adulthood. 2.2. Inclusion All adults with DS, living at Epilepsy Center Kempenhaeghe, a tertiary care facility for people with epilepsy and an intellectual disability in The Netherlands, were included in the study. 2.3. Instruments Three Dutch scales were used to assess several aspects of autism and behavior. These scales are specifically designed for the evaluation of patients with an intellectual disability (ID). 2.3.1. AVZ-R (Pervasive developmental disorder in mental retardation scale-Revised) The AVZ-R is a screening tool for autism and related disorders [12, 13]. It is designed for people between the ages of 2–70 years, with ID (regardless of the severity). The scale consists of 12 items: 1 item about contact with adults, 1 about contact with peers, 3 about speech and language, and 7 about other behaviors. For each item, two observers have to indicate whether or not a particular type of behavior was present. The scale still uses the term ‘pervasive developmental disorder’ (PDD). The total score can be classified according to the AVZ-R: no PDD (score of 0–6), uncertain whether or not someone has a PDD (score 7–9), and PDD (score 10–19). Because of the systematic approach of this scale, it can be helpful in diagnosing autism and related disorders [13]. The inter-rater reliability (r = 0.83–0.89), test–retest stability (r = 0.7–0.86), internal consistency (Cronbach's alpha = 0.81–0.86), and construct validity of the AVZ-R have been described as good [12]. Criterion validity has been described as adequate [12]. 2.3.2. SGZ (Maladaptive behavior scale for individuals with ID) The SGZ is a scale that can be used to assess disturbing behavior in institutionalized individuals with ID, over the age of three years [13]. The scale consists of 32 items and can be divided into subscales: aggressive disturbing behavior (8 items), verbally disturbing behavior (5 items), and a combination of both behaviors (19 items). For each item, two observers have to indicate the frequency of occurrence of a particular behavior, ranging from not, once a month, once a week, multiple times a week, to once a day or more. Lower scores on the SGZ (transfigured to higher norm scores) indicate better functioning. The inter-rater reliability (r = 0.75–0.79), test–retest stability (r = 0.68–0.70), internal consistency (Cronbach's alpha = 0.80–0.85), construct validity, and criterion validity of the SGZ have been described as good [14]. 2.3.3. TVZ (Temperament scale for individuals with ID) The TVZ is derived from the American Parent and Teacher Questionnaire and adjusted for institutionalized people with a moderate to severe ID, aged 10 to 55 years [13,15]. The TVZ consists of 56 items and 7 subscales to assess the dimensions of ‘Temperament’ and ‘the Focus on other people’. The subscales: ‘Intensity’ (9 items), ‘Soothability’ (7 items), ‘Mood’ (8 items), and ‘Adaptability’ (9 items) add up to a total score for temperament. A higher score indicates an easier temperament. The subscales: ‘Approach’ (7 items), ‘Threshold of responsiveness’ (8 items), and ‘Persistence’ (8 items) are used to quantify the focus on other people. A higher score indicates a better focus on others. For each item, two observers have to indicate the frequency of occurrence

of a particular behavior (never, hardly ever, sometimes, often, and always). The inter-rater reliability (r = 0.62–0.73), test–retest stability (r = 0.81–0.87), internal consistency (Cronbach's alpha = 0.72–0.85), and construct validity of the TVZ have been described as good [15]. 2.4. Procedure The digital medical records of all the adult patients living at Epilepsy Center Kempenhaeghe with a genetically confirmed diagnosis of DS were reviewed. We identified a series of 13 adult patients. Information concerning gender, age, age at onset, type of SCN1A mutation, severity of intellectual disability, and functional outcome were documented. The past medical history of each patient was then systematically screened for diagnoses (like autism, PDD-NOS, ASD, self-mutilation, hyperactivity, and ADHD) and information concerning the past and current use of psychoactive medication (see Table 1 — Characteristics). In addition, the nursing staff of each patient was trained to fill in the AVZ-R, the SGZ, and the TVZ. 3. Results 3.1. Patient characteristics Thirteen patients, 9 male and 4 female, were included in the study. Demographic and clinical characteristics of the patients are summarized in Table 1. Ages ranged from 18 to 60 years (mean = 34.7 years). Age at epilepsy onset ranged from 4 to 18 months (mean = 8.1 months). Intellectual disability was moderate (IQ 35–50) in 4 (30.8%) patients, severe (IQ 20–35) in 6 (46.1%), and profound (IQ b 20) in 3 (23.1%). Eleven patients had used psychoactive medication in the past, whereas three patients currently used psychoactive medication (pipamperone, citalopram, and promethazine). 3.2. AVZ-R According to the AVZ-R, six patients were classified as having PDD (patients 3, 4, 5, 6, 8, and 12) and six as having no PDD (Table 2). One patient (patient 2) was classified as ‘uncertain’ of having PDD. Four patients did score on the item ‘presence of self-mutilation’. 3.3. SGZ Table 2 also summarizes the total scores on the SGZ. In 5 of the 13 patients (patients 3, 4, 5, 8, and 12), the score was high, indicating that they showed more disturbing behavior compared to institutionalized individuals of the same age and sex. All five were classified as having PDD according to the AVZ-R. Four patients scored low on the SGZ, indicating that they showed less disturbing behavior compared to their norm group. The other four patients had average scores. Furthermore, all patients did score on the statement: “Not willing to respond to a request”: in one patient once a month, in 3 once a week, in 7 multiple times a week, and in 2 once a day or more. 3.4. TVZ According to the total scores on temperament, six patients (patients 3, 5, 6, 8, 11, and 12) had a below average score, which indicates a difficult temperament. Of these six patients, five were classified as having PDD according to the AVZ-R, and four of them had scored low on the SGZ. Only one patient scored above average on the TVZ, indicating a more even temperament. The other six patients had average scores. With respect to being focused on themselves or on someone else, nine patients scored below average, which means they are more likely to focus on themselves than on others. Only one patient scored above

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Table 1 Characteristics. Sex

Age (yrs)

Epilepsy onset (months)

Cognitive impairment

Types of seizures in adulthood

AED history

Psychoactive medications History

1

F

45

8

Severe

CP, GTC, MY, GC

LEV, CLN, CBZ, VPA, VGB, ESM, LTG, Diamox

2

M

50

6

Profound

CP, GTC, MY, GC

STP, CLN, PHB, VPA, LEV, CLB, TPM, CBZ, LTG

3

M

35

18

Severe

GTC, MY

STP, TPM, VPA, CLB, GBP, LEV, PHB, LTG, VGB

4

M

32

4

Profound

CP, GTC, MY, GC

LEV, CLN, CBZ, VPA, TPM, GBP, LTG, VGB

5

F

26

4

Moderate

GTC, MY

LTG, VPA, GBP, ESM, VGB, Diamox

6

F

60

9

Moderate

GTC

LTG, CLB, CBZ, VPA, VGB, OXC

7 8

F M

35 20

7 5

Moderate Profound

“Drops”, MY GC, GTC, ‘Drops’,

9

M

19

9

Moderate

FS, CP

CLB, TPM, CLN, VPA, VGB, ESM ZNS, VPA, LEV, CLN, CLB, CBZ, STP, GBP, TPM, LTG, PHB, VGB TPM, CLN, LTG, CBZ, PHB, VPA

10

M

18

6

Severe

MY

11

M

25

9

Severe

GTC, FO

ZNS, LEV, TPM, PHB, CLN, LTG, FBM, CLB, PHT, CBZ, VPA VPA, OXC, LEV, TPM, CLN, CLB

12

M

49

6

Severe

GTC, “Drops”

VPA, CLB, PHT, LTG, GBP, CBZ

13

M

37

14

Severe

GTC, MY

LEV, VPA, TPM, LTG, FBM, CLB, VGB, OXC

Citalopram Oxazepam Oxazepam Haloperidol Droperidol Citalopram Paroxetine Lorazepam Zopiclone Risperidone Levomepromazine Pipamperone Promethazine Trifluoperazine Zuclopentixol Zolpidem Zopiclone Citalopram Aripiprazol Methylphenidate Periciazine Pimozide Pipamperone Risperidone Nortriptyline Temazepam Haloperidol Pipamperone Promethazine

Current

Pipamperone

Methylphenidate Risperidone Oxazepam Methylphenidate Oxazepam Citalopram Pipamperone Citalopram Clomipramine Buspirone Lormetazepam Oxazepam Droperidol Haloperidol Promethazine

Functional outcome

Deceased

Deceased Citalopram Citalopram Promethazine

M = male, F = female. CP = complex partial, FO = focal, FS = febrile seizures, GC = generalized clonic, GTC = generalized tonic–clonic, MY = myoclonic, ‘Drops’ = ‘drop-attacks’. CBZ = carbamazepine, CLB = clobazam, CLN = clonazepam, ESM = ethosuximide, FBM = felbamate, GBP = gabapentin, LEV = levetiracetam, LTG = lamotrigine, OXC = oxcarbazepine, PHB = phenobarbital, PHT = phenytoin, STP = stiripentol, TPM = topiramate, VGB = vigabatrin, VPA = valproate, ZNS = zonisamide.

average, suggesting she is more likely to focus on others. The other three patients had average scores. 3.5. Medical records Of the 7 patients who were not classified as having autism according to the AVZ-R, the medical records revealed that in two patients, a clinical diagnosis of ASD had been established (patient 9 at age 15 years and patient 11 at age 25 years). Another patient was described as having autistic features (patient 7). In general, the medical records showed that the patients exhibited autistic features, although they were not formally classified as having ASD. Repetitive behavior/language (5/13), short temper/mood instability (9/13), continuing behavior (5/13), difficulties with transitions (3/13), obsessive interests (2/13), adherence to routine (1/13), and abnormal eye contact (1/13) were mentioned. In the medical records, neither hyperactivity nor ADHD were described in adulthood. Self-mutilation, on the other hand, was reported

spontaneously in three patients (patients 5, 8, and 12) and consisted of scratching wounds, pulling fingernails, biting the hand, and vomiting. In one patient (patient 5), self-mutilation was related to stress. In addition, the same patient was found to have psychogenic nonepileptic seizures (PNES). 3.6. Mutation types Nine patients had a missense mutation, three patients had a frameshift mutation, and one patient had a mutation affecting the splice donor site of intron 14 (Table 3). The SCN1A protein contains four homologous domains (I–IV) which each contain six transmembrane segments (S1–S6), and an N- and C-terminal domain. The mutations in these patients are scattered throughout different domains (Table 3). We observed that all three patients with a frameshift mutation (patients 7, 10, and 11) were not diagnosed with disturbing behaviors or PDD according to the AVZ-R. The same observation can be made for the

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J.J.L. Berkvens et al. / Epilepsy & Behavior 47 (2015) 11–16

Table 2 Results.

1

2

3

4

5

6

7

8

9

10

11

12

13

6

7

14

16

13

12

2

16

6

4

5

10

0

N

T

PDD

PDD

PDD

PDD

N

PDD

N

N

N

PDD

N

Contact adults

+

+

–

––

–

––

+

––

+

+

+

–

+

Peer contact

–

–

–

–

–

–

+

–

+

–

+

–

+

Speech/language

+/–

+/–

–

–

+/–

+

+/–

–

+/–

–

–

+/–

+

Obsessive interests

+

+

+

+

+

–

–

+

+

–

+

+

–

Stereotype use of objects

–

–

+

+

–

–

–

+

–

–

–

–

–

Stereotype use of own body

–

–

+

+

+

+

–

+

–

–

–

+

–

Adherence to routine

–

–

+

+

–

+

–

+

+

–

+

–

–

Self–mutilation

–

–

–

+

+

–

–

+

–

–

–

+

–

Unpredictable behavior

–

–

+

–

+

+

–

+

–

–

+

–

–

Abnormal anxiety/panic

–

–

–

+

–

+

–

–

–

–

–

–

–

AVZ–R total* Classification

+ = Present, +/– = Present, but impaired, – = Absent, –– = Severely impaired PDD = Pervasive Developmental Disorder, N = no PDD, T = Uncertain SGZ total**

7

Norm

11

126

102

76

27

17

87

33

75

46

70

23

8L

7H

3–

3

4

7L

7H

4

6H

6L

6L

4

6H

More disturbing behavior***

81%

68%

0%

0%

2%

55%

68%

2%

41%

27%

27%

2%

41%

Equal disturbing behavior***

7%

13%

2%

2%

7%

13%

13%

7%

14%

14%

14%

7%

14%

Less disturbing behavior***

12%

19%

98%

98%

91%

32%

19%

91%

45%

59%

59%

91%

45%

Aggressive disturbing

0

0

31

26

5

2

2

21

9

36

8

12

5

7

7

3

4

6

6

6

4

5

5

5

5

5

0

0

0

0

18

10

6

0

14

9

2

6

14

7

7

7

7

4

5

6

7

4

5

6

5

4

7

11

95

76

53

15

9

66

10

30

36

52

4

8

7

3

3

5

7

7

4

7

7

6

4

7

Norm Verbally disturbing Norm Both behaviors Norm

On a scale of 3–9: 3 = the most disturbing behavior, 9 = the least disturbing behavior L = Low, H = High TVZ total: temperament**

5

6

4

6

1

1

5

4

6

7

1

3

6

Intensity

4

6

6

4

10

9

5

9

4

3

8

7

3

Soothability

5

5

3

7

1

1

3

7

4

4

2

5

6

Mood

3

5

4

7

1

2

4

4

10

7

2

3

4

Adaptability

4

9

3

3

2

1

7

6

3

7

1

2

6

TVZ total: focus on others

4

4

1

2

7

6

4

4

6

2

2

1

5

Approach

2

5

4

3

9

2

5

5

6

2

2

1

4

Threshold to responsiveness

6

2

2

2

6

10

3

3

4

2

3

5

5

Persistence

7

10

1

6

3

5

6

3

9

5

3

3

8

On a scale of 1–10: 1 = Difficult temperament, 10 = Easy temperament, except for Intensity

On a scale of 1–10: 1 = Focus on themselves, 10 = Focus on others a

Colors: red = PDD, orange = uncertain, green = no PDD. Colors: red = scored worse, orange = scored average, green = scored better than institutionalized individuals of the same age and sex. c Percentages: e.g., 81% ‘more disturbing behavior’ means that this person belongs to the best behaving 19% of his/her norm group. b

patients with a mutation in the C-terminal domain (patients 1, 2, and 13): none of them were diagnosed with either disturbing behavior or PDD.

4. Discussion The long-term prognosis of DS is usually unfavorable. In general, seizures persist and become drug resistant [16]. However, seizures tend to become less frequent and less severe after childhood [16–18]. Motor function tends to worsen with age, often due to signs such as ataxia, kyphosis, scoliosis, feet deformations, or gait disturbances [16, 18]. All patients with DS are reported to be cognitively impaired, often severely, and language remains poor [16]. Our study population

matches this profile, with the majority of patients (9 out of 13) having either a severe or a profound ID. The aim of this study was to describe the long-term outcome of DS related to autism and behavior in adulthood. As far as we are aware, this is the first time that scales have been systematically administered in adult patients with DS. Several findings are of interest. First of all, according to the AVZ-R, six patients were classified as having PDD and six as having no PDD. Of the latter, the medical records demonstrated that two of them were actually diagnosed as having ASD according to their clinical characteristics and one had autistic features. These three patients were not classified as having PDD according to the AVZ-R. This is probably due to the seemingly adequate contact with other adults, which results in better scores on the AVZ-R and, consequently, does not lead to a diagnosis

J.J.L. Berkvens et al. / Epilepsy & Behavior 47 (2015) 11–16 Table 3 Mutation characteristics. Patient

SCN1A mutation

Exon

Mutation type

Protein alteration

Domain location

1 2 3 4 5 6 7 8 9 10 11 12 13

c.5422 T N C c.5604 A N C c.248 A N G c.4094 G N A c.2589 + 3 A N T c.2425 G N A c.1258dup c.2686 G N T c.580 G N A c.3370–3371delTT c.2202 C N A c.4628 T N C c.5564 C N A

26 26 1 21 Intron 14 14 9 15 4 16 13 25 26

Missense Missense Missense Missense Splice donor site Missense Frameshift Missense Missense Frameshift Frameshift Missense Missense

p.F1808L p.L1868F p.Y83C p.G1365D

C-terminal C-terminal N-terminal DIIIS5 DIIS4 DIIS2 DIS6 DIIS5 D1S3 DII–DIII DI–DII DIVS1 C-terminal

p.G809R p.A420 p.V896F p.D194N p.F1124 p.C734 p.F1543S p.1855H

D1–DIV: homologous domains I–IV, S1–S6: transmembrane segments 1–6.

of PDD. As described before, patients with DS have higher scores on socialization skills and are, for this reason, not always considered to have autism [7,11]. This result is consistent with the findings in the literature. The relationship between epilepsy, ID, and autism is complex and difficult to entangle. Literature shows that there is a strong association between epilepsy, ID, and autism. In general, the prevalence of autism increases with the severity of the ID. Furthermore, ID is very common in patients with epilepsy [19] and, specifically, in patients with DS. The high prevalence of autism/autistic features in our patients with DS might, therefore, reflect the presence of intellectual disability rather than that it is specific for DS. Nor did we find evidence for a typical DS-profile for autistic features, other than the discrepancy that has been mentioned between “regular” autistic features and the seemingly inappropriate familiarity with strangers. Of interest, we observed that none of the patients with frameshift mutations and mutations in the C-terminal domain of SCN1A were formally diagnosed with PDD and/or disturbing behavior. However, the number of patients in this cohort is too small to draw any conclusions about genotype–phenotype correlations with respect to autism and behavior. According to the AVZ-R and the medical records, self-mutilation was seen in 4 out of 13 patients in this study. This is remarkable, because no other studies have been found that described self-mutilation in children or adults with DS. Background information in the medical records was limited and did not allow for further analysis of this phenomenon. The findings on the SGZ and the TVZ are more difficult to interpret. The TVZ suggests, on average, a difficult temperament, but the clinical meaning of these scores is unclear. Table 2 clearly shows that the subjects with the worst scores on the TVZ were not those with the worst scores on the SGZ, the behavior scale. On the SGZ, 8 out of 13 patients performed as well as or better than comparable individuals. In this study design, comparison with childhood scores was not available, but given that behavioral problems are common in youth, one might have expected that many of these 13 patients would have continued to demonstrate behavioral problems in adulthood. The outcome can, therefore, be considered to be not unfavorable. Hyperactivity is common in children with DS [5–9,20], but none of the patients in the current study were considered to be hyperactive during adulthood. This is underscored by the fact that although, according to their medical history, methylphenidate had been prescribed to three of them, at the start of this research study, they were no longer using methylphenidate. This seems to be in line with findings in the literature: hyperactivity is common in childhood but is not described in adulthood. According to the medical records, only 3 out of 13 patients (23.1%) participating in this study used psychoactive medication at the time of the research, namely pipamperone, citalopram, and promethazine. This is remarkable for two reasons. In an earlier study in the same

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center, Leunissen et al. had demonstrated that 41.5% of the total adult population took psychotropic drugs [21], and secondly, the medication history of the 13 patients showed that there had been substantial use of psychoactive medication in the past; therefore, higher rates would have been expected in adulthood. This would seem to indicate that upon becoming an adult, behavioral aspects tend to be milder and are less likely to necessitate the use of psychoactive medication. Though the medical records do not show documentation in this direction, an alternative explanation could be that prescribing physicians might have been reluctant to continue these drugs because of their propensity to worsen seizure control. No other studies that mentioned the use of psychoactive medication in patients with DS were found. Although we included all our institutionalized patients with DS, the small number of thirteen patients is still a limitation of the current study. Consequently, the results should be interpreted with caution. It is uncertain whether these patients are representative of adult DS patients in general. One might contend that this study only consisted of ‘severe’ cases living in an institution. If so, it is possible that another cohort of adult patients might show fewer features of behavioral problems than ours did, as patients with multiple problems will be more likely to be admitted to an institution. Another limitation is that types, frequency, and severity of seizures and the use of different AEDs were not taken into account and could have influenced some of the results. For instance, epileptic seizures tend to become less frequent and less severe in adults with DS [16,17,22]. Further research is needed to clarify the impact of these factors on behavior. Moreover, this study includes some longitudinal data, but it remains a cross-sectional study. We did not systematically study the patients in their childhood and are, therefore, not able to draw conclusions about the individuals themselves. We could only compare them to children with DS as reported in the literature. Future prospective studies on a cohort of children with DS might give a better insight into behavior and autism in individuals. Despite the limitations of the current study, the data available do generate new insights and directions for future research. 5. Conclusion Our results confirm that adults with DS exhibit many autistic-like features, though these may be ID-related rather than DS-related, but behavioral problems, which are reported in children with DS, are not frequently seen. Thus, the overall behavior of patients with DS seems to become milder in adulthood. Acknowledgments The authors thank S. Raijmakers (MSc) for her contribution in collecting the data. Disclosure The authors have no conflicts of interest to declare. References [1] Dravet C, Guerrini R. Dravet syndrome. United Kingdom: John Libbey Eurotext; 2011. [2] Claes L, Ceulemans B, Audenaert D, Smets K, Löfgren A, Del-Favero J, et al. De novo mutations in the sodium-channel gene SCN1A cause Severe Myoclonic Epilepsy of Infancy. Am J Hum Genet 2001;68(6):1327–32. [3] Martin P, Rautenstrauβ B, Abicht A, Fahrbach J, Koster S. Severe Myoclonic Epilepsy in Infancy — adult phenotype with bradykinesia, hypomimia, and perseverative behavior: report of five cases. Mol Syndromol 2010;1(5):231–8. [4] Dravet C, Bureau M, Engel J. Dravet syndrome. San Diego: Medlink Neurology; 2010. [5] Brunklaus A, Dorris L, Zuberi SM. Assessment and predictors of health-related quality of life in Dravet syndrome. Dev Med Child Neurol 2011;53:15. [6] Ragona F. Cognitive development in children with Dravet syndrome. Epilepsia 2011; 52 Suppl. 2:39–43.

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[7] Villeneuve N, Laguitton V, Viellard M, Lépine A, Chabrol B, Dravet C, et al. Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome. Epilepsy Behav 2014;31:143–8. [8] Wolff M, Casse-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Epilepsia 2006;47 Suppl. 2:45–8. [9] Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia 2011;52 Suppl. 2:95–101. [10] Chieffo D, Ricci D, Baranello G, Martinelli D, Veredice C, Lettori D, et al. Early development in Dravet syndrome; visual function impairment precedes cognitive decline. Epilepsy Res 2011;93(1):73–9. [11] Ceulemans B. Overall management of patients with Dravet syndrome. Dev Med Child Neurol 2011;53 Suppl. 2:19–23. [12] Kraijer DW. AVZ-R handleiding. 4 ed. Amsterdam: Harcourt Test Publishers; 2004. [13] Kraijer DW, Plas JJ. Handboek psychodiagnostiek en beperkte begaafdheid: classificatie, test- en schaalgebruik, vol. 5. Amsterdam: Pearson Assessment and Information B.V.; 2014. [14] Kraijer DW, Kema GN. Handleiding storend gedragsschaal (SGZ). 3 ed. Amsterdam: Harcourt Assessment B.V.; 1994.

[15] Blok JB, van den Berg PTh, Feij JA. Handleiding temperamentsschaal voor zwakzinnigen (TVZ). Lisse: Swets & Zeitlinger; 1990. [16] Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome. Epilepsia 2011;52 Suppl. 2:44–9. [17] Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y. A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 2010;51(6):1043–52. [18] Jansen FE, Sadleir LG, Harkin LA, Vadlamudi L, McMahon JM, Mulley JC, et al. Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults. Neurology 2006;67(12):2224–6. [19] Berg AT, Plioplys S. Epilepsy and autism: is there a special relationship? Epilepsy Behav 2012;23(3):193–8. [20] Ragona F, Brazzo D, De Giorgi I, Morbi M, Freri E, Teutonico F, et al. Dravet syndrome: early clinical manifestations and cognitive outcome in 37 Italian patients. Brain Dev 2010;32(1):71–7. [21] Leunissen CL, de la Parra NM, Tan IY, Rentmeester TW, Vader CI, Veendrick-Meekes MJ, et al. Antiepileptic drugs with mood stabilizing properties and their relation with psychotropic drug use in institutionalized epilepsy patients with intellectual disability. Res Dev Disabil 2011;32(6):2660–8. [22] Takayama R, Fujiwara T, Shigematsu H, Imai K, Takahashi Y, Yamakawa K. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014; 55(4):528–38.