Epilepsy & Behavior 31 (2014) 143–148
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome Nathalie Villeneuve a,b,c, Virginie Laguitton a, Marine Viellard b, Anne Lépine a,c, Brigitte Chabrol c, Charlotte Dravet d, Mathieu Milh c,e,⁎ a
CINAPSE, Hôpital Henri Gastaut Centre Saint Paul, 13009 Marseille, France Centre Ressource Autisme, Hopital Sainte Marguerite, 13009 Marseille, France APHM, Service de neurologie pédiatrique, Hôpital de la Timone, 13005 Marseille, France d Child Neurology and Psychiatry, Catholic University, Rome, Italy e INSERM, UMR 910, Aix-Marseille Université, 13005 Marseille, France b c
a r t i c l e
i n f o
Article history: Received 13 June 2013 Revised 15 November 2013 Accepted 21 November 2013 Available online 8 January 2014 Keywords: Dravet syndrome Cognitive evaluation Epilepsy SCN1A
a b s t r a c t In order to assess the cognitive and adaptive profiles of school-aged patients with Dravet syndrome (DS), we proposed to evaluate the intelligence and adaptive scores in twenty-one 6- to 10-year-old patients with DS followed in our institution between 1997 and 2013. Fourteen patients were tested using the Wechsler Intelligence Scale for Children (WISC) and the Vineland Adaptive Behavioral Scales (VABS); 6 patients could not be tested with the WISC and were tested with the VABS only, and one was tested with the WISC only. Data regarding the epilepsy were retrospectively collected. Statistical analysis (Spearman rank order and Pearson correlation coefficient) was used to correlate early epilepsy characteristics with the cognitive and adaptive scores. Sodium channel, neuronal alpha-subunit type 1 (SCN1A) was mutated in 19 out of 21 patients. After the age of 6 years, none of the DS patients had a normal intelligence quotient (IQ) using WISC (age at the testing period: mean = 100 ± 5; median = 105 months; mean total IQ = 47 ± 3; n = 15). Only five patients had a verbal and/or a non verbal IQ of more than 60 (points). Their cognitive profile was characterized by an attention deficit, an inability to inhibit impulsive responses, perseverative responses and deficit in planning function. Administering the Vineland Adaptive Behavioral Scales in the same period, we showed that socialization skills were significantly higher than communication and autonomy skills (age at the testing period: mean = 100 ± 4; median = 100 months; n = 20). We did not find any significant correlation between the IQ or developmental quotient assessed between 6 and 10 years of age and the quantitative and qualitative parameters of epilepsy during the first two years of life in this small group of patients. Despite an overall moderate cognitive deficit in this group of patients, the Vineland Adaptive Behavioral Scales described an adaptive/behavioral profile with low communication and autonomy capacities, whereas the socialization skills were more preserved. This profile was different from the one usually found in young patients with autism and may require specific interventions. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is a rare, chronic epileptic syndrome occurring within the first years of life in a previously normal infant. Patients endure recurrent and prolonged hemiclonic or generalized tonic–clonic seizures, mostly febrile ones, and usually develop other seizure types including atypical absence seizures, focal seizures, and myoclonic jerks that usually emerge between 1 and 4 years of age [1]. SCN1A encoding
⁎ Corresponding author at: Service de neurologie pédiatrique, Hopital Timone-Enfants, 264 Rue Saint Pierre, 13005 Marseille, France. Fax: +33 491 38 68 09. 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.021
a voltage sensitive sodium channel has been found mutated or deleted in 70–80% of the patients with DS [2]. A singular time course of psychomotor development has been classically described in DS [3]. Before the age of two years, children who have been tested by the Brunet–Lezine scale [4] or the Griffiths scale [5] displayed a normal or subnormal developmental quotient (DQ). In older children, cognitive evaluation indicated a low DQ in most cases, characterized by poor visuomotor skills, heterogeneous language, and behavioral disorders such as hyperactivity, poor relational capacities and gestural stereotypies [4,5]. Behavioral disturbance such as hyperactivity and autistic behavior was frequently observed, as well as speech disturbance [4–6]. The cognitive outcome was usually poor, and seizures remained anti-epileptic drugs even in adulthood [7,8], although
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seizure frequency usually decreased [9,10]. Despite overall cognitive deficiency, some degree of heterogeneity has been reported and noticed in our clinical experience [3–5]. In order to describe its extent, we administered the Wechsler Intelligence Scale for Children (WISC) and the Vineland Adaptive Behavioral Scales (VABS) between the ages of six and ten in 21 patients with DS who were followed in our institution from the beginning of the illness. 2. Participants and methods Out of a total of 47 patients born between 1986 and 2012 (16 months–27 years) with DS who are still followed in our institution, 10 patients were born before 1993, and 10 were born after 2006 and could not be evaluated using the WISC and the VABS between 6 and 10 years. Among 27 consecutive patients with DS born between 1993 and 2006, 2 endured very severe SE followed by anoxic encephalopathy and spastic tetraplegia; 4 died before entering the study (SUDEP). Finally, twenty-one patients were included and tested in a prospective way between 2003 and 2012, and data on epilepsy were retrospectively studied. None of the patients had been reported in previous studies. Diagnosis of DS was suspected on the following criteria: no previous personal history of disease; seizures beginning in the first year of life or slightly later in the form of generalized or unilateral clonic seizures or myoclonic seizures; sensitivity to fever; presence of afebrile seizures; normal interictal EEG, or slight slowing in the central regions and normal brain MRI at the onset [1,4]. Diagnosis of DS was then confirmed with the emergence of the other following symptoms: ataxic gait, pyramidal signs, slowing or arrest of cognitive development after 2 years old, persistence of clonic seizures, and sensitivity to fever. We distinguished between typical DS when other seizure types were present, including myoclonias, mild or incomplete DS (IDS) [11,12], i.e., borderline SMEI without myoclonias [13], and intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC), in which the patients have only one type of seizure [14]. Status epilepticus (SE) was defined by a duration of more than 30 min of clonic seizure. We also defined a group of “long-lasting seizures”, between 20 and 30 min, since all of these seizures required a medical intervention (rectal diazepam). Other types of seizures were noted between 0 and 2 years old. Electroencephalogram was not systematically performed at each visit. The parents' consent was obtained for all the patients. Cognitive evaluation was assessed for each patient by a single neuropsychologist (VL), using the Wechsler Intelligence Scale for Children (WISC III; WISC IV) between 6 and 10 years of age. The Vineland Adaptive Behavioral Scales (VABS) [15], a semistructured interview, was administrated in 20/21 patients by a trained child psychiatrist certified in the procedure (MV) to assess the cognitive and social integration scaling. The characteristics of the epilepsy and the treatments were collected. A brain MRI was performed in all patients between 1 and 5 years of age. SCN1A was screened for all the patients included in the study. Pearson correlation coefficient and Spearman rank order were used to calculate the correlation coefficient between normally and not normally distributed data, respectively. Mann–Whitney Rank Sum Test and t test were used to compare two groups.
Table 1 Genetics of the patients. Patient, gender
Type of SCN1A mutation
Familial history of epilepsy
1, F 2, F 3, F 4, M 5, F 6, F 7, F 8, F 9, F 10, M 11, M 12, M 13, F 14, F 15, F 16, F 17, F 18, M 19, M 20, M 21, F
c.2686GNA/p.Trp873X c.1171-2ANG (intron 9) c.5656CNT/p.Arg1886X c.1377+1GNA (intron 9) c.1177CNT/p.Arg393Cys c.602+1GNT (intron4) c.1702CNT/p.Arg568X c.5641GNT/p.Glu1881X c.152081523delAAGA/p.LysSerfsX36 n c.272_273delITA/p.ile91SrfsX4 c.429_430delGT/p.Phe144TyrfsX148 c.5743GNT/p.Glu1915X c.840GNC/p.Trp280Cys c.2837GNA/p.Arg946His c.4091TNA/p.Met1364Lys n c.5673_5676dupGCGA/p.Phe1893AlafsX53 c.1511_1515delGAAA/p.Arg504ThrfsX12 c.5346CNG/p.IIe1782Met c.2092CNT/p.His698Tyr
Yes (FS) Yes (PS) Yes (FS) Yes (PS) No No No Yes (GTCS) No Yes (FS) No Yes (FS) No No Yes (FS) No No No No Yes (FS) No
FS: febrile seizure; PS: partial seizure; GTCS: generalized tonic–clonic seizure.
3.1. Epilepsy history between the age of diagnosis and 6 years old (Table 2) Nine patients had a typical DS (9/9 with a SCN1A mutation), 10 patients never had any myoclonias (incomplete DS, 9/10 with a SCN1A mutation), and 2 patients had only generalized, febrile, and afebrile tonic–clonic seizures (ICEGTC, 1/2 with a SCN1A mutation). The average age at the first seizure was 6 ± 1 month (mean ± standard error). Eleven patients displayed at least one SE before the age of two (mean age at first SE: 9 ± 2 months; range: 3–19 months; n = 11), and 19/21 patients endured at least one seizure lasting more than 20 min during the first two years of age. The two patients who never endured any seizure of more than 20 min had an incomplete form of DS (IDS, patients 6 and 11, Table 2). 3.2. Developmental and neurological evaluation before 3 years of age The mean walking age was 16 ± 2 months (range: 12–24 months; n = 21). Only one child was not able to walk at the age of 18 months because of ataxic gait. The cranial circumference was normal for all patients. Children produced their first words at the mean age of 20 ± 4 months (range: 12–36 months; n = 21). Only one child was able to produce sentences before the age of 36 months. After the age of 3, sentences stayed simple, short, and often stereotyped in all patients. The first clinical abnormalities were noted before the age of two in half of the children in the form of poor visual interaction, i.e., the eye contact was possible but did not reflect any normal exchange between physicians and patients, according to their age. At the age of two, 10/21children had a significant motor hyperactivity. At the age of three, 17/21 patients had ataxic gait and slight pyramidal signs. 3.3. Wechsler Intelligence Scale for Children
3. Results Twenty-six patients born between 1993 and 2006 were eligible. Two children died before the age of 6 years, one died at the age of 8, and two endured a severe, long-lasting SE followed by an anoxic encephalopathy with severe cognitive and motor impairment. These five patients were excluded. Finally, 21 patients (7 boys) aged 6 to 20 years were included in this study. SCN1A gene was mutated in 19 patients (Table 1). Brain MRIs did not reveal any congenital structural abnormalities.
The Wechsler Intelligence Scale for Children III or the Wechsler Intelligence Scale for Children IV was planned for use in all the patients between 6 and 10 years old, (n = 21, Table 3). It was not possible to administer the tests in 6/21 patients because of major behavioral problems and lack of any possible interaction with the neuropsychologist. These patients were profoundly cognitively impaired; 3 of them had typical DS, and 3 had IDS. None of the remaining 15 testable patients had a normal global IQ between 6 and 10 years old (average full IQ: 47 ± 2 (average standard score ± standard error), range: 40–73;
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Table 2 Age at diagnosis of DS, genetics, and early epilepsy of the patients. Patient, gender
Date of birth(m/y)
1, F 2, F 3, F 4, M 5, F 6, F 7, F 8, F 9, F 10, M 11, M 12, M 13, F 14, F 15, F 16, F 17, F 18, M 19, M 20, M 21, F
Nov-93 Apr-94 Mar-98 Nov-99 Dec-99 Mar-00 Apr-00 Jul-00 Sep-00 Jan-01 Feb-01 Apr-01 Jun-01 Dec-01 Apr-02 Mar-02 Mar-03 Mar-03 Nov-03 Nov-05 Nov-06
Age at diagnosis (y)
Age at seizure onset (m), and type
Age at first SE (m)
Nb of b20-min seizures/y
Nb of 20- to 30-min seizures/y
Nb of SE/y
b1 y
1–2 y
b1 y
1–2 y
b1 y
1–2 y
4 3 2.2 1 5.5 0.7 6 2.5 1.5 1.5 2 2.5 0.8 0.8 0.8 5 2 2.8 0.8 1.5 2
4; F; G 5.5; F; HC 7; F; HC 4; U; M 8; F; G 5; F; HC 3; F; G 8; F; G 4; U; G 6; F; G 10; F; G 4.5; F; G 6; F; HC 5; F; HC 6.5; F; HC 15; U; HC 6; F; G 6; F; G 4.2; F; HC 4; F; HC 10; F; G
na 5.5 na 14 na na 3 na na na na 14.5 na 5 6.5 19 na 6 4.2 4 18
24 10 3 0 3 20 8 3 2 4 2 7 4 7 5 0 6 10 7 4 2
50 10 12 50 40 10 4 5 6 15 30 100 30 20 6 6 10 20 50 20 13
1 0 1 0 1 0 0 1 1 2 0 3 2 2 0 0 1 0 1 2 2
0 1 0 0 0 0 0 0 0 1 0 0 1 0 0 4 1 0 0 0 2
0 1 0 0 0 0 1 0 0 0 0 0 0 3 2 0 0 2 4 1 0
0 1 0 1 0 0 0 0 0 0 0 1 0 0 0 2 0 1 0 0 1
DS type
IDS DS IDS DS IDS IDS ICEGTC IDS IDS IDS IDS DS IDS DS DS DS ICEGTC DS DS DS IDS
AED received b1 y
1–2 y
pb vpa cbz clb vpa pb esm vpa vpa 0 vpa clb stp vpa vpa vpa pb vpa vpa clb vpa clb vpa cbz vgb clb stp vpa clb stp 0 vpa pb vpa czp vpa cbz vpa cbz
vpa clb esm vpa vpa czp vpa czp pb vpa cbz tpm vpa clb stp tpm vpa vpa vpa clb pb vpa cbz pb vpa czp vpa tpm cbz vpa clb stp vpa clb tpm vpa clb stp tpm vpa vpa clb vpa czp vpa clb stp vpa cbz clb stp cbz ltg
F: febrile; G: generalized; HC: hemiclonic; U: unfebrile; M: myoclonic; Nb: number. DS: Dravet syndrome; IDS: incomplete Dravet syndrome; ICEGTC: childhood epilepsy with generalized tonic-clonic seizures. AED: antiepileptic drugs. PB: phonobarbital; VPA: sodium valpraote; CBZ: carbamazepine; CLB: clobazam; ESM: ethosuximide; STP: stiripentol; VGB: vigabatrin; CZP: clonozepam; LTG: lamotrigine; TPM: topiramate.
verbal IQ: 54 ± 2; nonverbal IQ: 54 ± 2; n = 15, Table 3). We did not find any significant difference in the total IQ within DS versus IDS (44 ± 3 versus 46 ± 5; p = 0.7), in DS versus IGTLC (44 ± 3 versus 53 ± 10; p = 0.7), and in IDS versus IGTLC (46 ± 5 versus 53 ± 10; p = 0.6). Only 5 patients out of 21 had a verbal IQ and/or a nonverbal IQ of more than 60 between 6 and 10 years old, allowing us to draw a cognitive profile. In these patients, we found a language disorder characterized by an articulatory dysfunction. The speech was characterized by a reduced verbal fluency, a poor lexical and syntactic naming, perseverance, stereotyped answers, and a deficit in planning capacity and
Table 3 Intelligence quotient using the WISC and adaptive scores using the VABS. Patient WISC
VABS
Total Verbal NonVerbal QD Communication Autonomy Socialization IQ IQ IQ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
40 40 40 40 60 na 73 40 53 na na na 46 na 40 61 43 40 na 45 42
46 45 45 46 69 na 74 45 63 na na na 55 na 45 74 55 45 na 59 51
41 45 45 46 63 na 82 45 65 na na na 67 na 45 61 45 45 na 56 57
33 36 35 nd 66 39 76 56 51 28 50 30 55 43 53 76 60 54 42 71 51
30 27 37 nd 75 40 83 50 51 26 50 29 43 42 53 74 65 50 42 67 45
20 32 22 nd 58 27 67 54 46 20 44 20 55 36 47 66 51 54 32 68 44
50 48 47 nd 65 51 79 64 46 38 56 42 67 51 60 89 65 67 53 78 63
conceptual elaboration (vocabulary: 4 ± 2.3; information: 3.6 ± 2.3, Table 4). The verbal comprehension was poor (comprehension: 3.8 ± 1.9), as well as the comprehension of social conventions. Speech fluency was below normal limits in letter and semantic fluency tasks. Numeric reasoning was severely impaired (arithmetic: 2.4 ± 2). Major disturbances of auditory working memory were observed in 3 of the 5 patients (number strings backwards: 3.6 ± 3.8). The level of general knowledge was poor and restricted to series (week days) learned in an automatic mode. In contrast, receptive language skills were just below normal limits (DEN48: 38.5 ± 3.5), and auditory immediate memory was relatively preserved in 4 of the 5 patients (number strings forward, mean average score: 6.2 ± 2.8). Nonverbal capacities were characterized by a deficient visual–motor speed (coding: 2.8 ± 2), nonverbal reasoning ability (4.4 ± 2), and matrix reasoning (4.8 ± 2.4). The visual discrimination abilities were more preserved (symbol: 6.2 ± 2.95) (Table 4). Overall, these findings put the light on a contrast between a relative preservation of some instrumental functions (confrontation naming and visuo-perceptive abilities) and a significant deficit of executive functions (significant difficulties in verbal planning, auditory working memory, visuomotor abilities, visuospatial organization, and fine motor skills). In the remaining 10 testable patients, the cognitive deficits were severe and homogeneous for each subtest of the IQ (Table 4). Speech productions were limited to words without any grammatical construction, and receptive language skills were limited to simple orders. Count, verbal and nonverbal reasoning, and graphing were not possible. Their cognitive profile was dominated by pronounced attention difficulties, inability to inhibit impulsive responses, perseverance, and deficits in planning, suggesting a major executive disturbance. We then investigated whether the characteristics of the initial epilepsy before the age of 2 years were correlated with later cognitive development. We did not find any statistically significant correlation between full IQ and the age of epilepsy onset (p = 0.66; n = 15, Spearman rank order), the total number of seizures during the first year of life (p = 0.3), and between 1 and 2 years (p = 0.4). Seizures lasting 20–30 min did not correlate with full IQ (p = 0.5 during the first year of life; p = 0.3 between 1 and 2 years). Status epilepticus lasting
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Table 4 Scores obtained at each subtest of the WISC (gray, standard score) and other cognitive tests (raw score).
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more than 30 min also did not correlate with full IQ (p = 0.5 during the first year; p = 0.6 between 1 and 2 years). We then investigated whether the seizure type before the age of 2 years could be associated with a different cognitive profile. We did not find any significant correlation between the presence of myoclonias (p = 0.2, Mann–Whitney Rank Sum Test), focal nonfebrile seizures (p = 0.3), and absence seizures (p = 0.1) occurring before the age of 2 years and the global IQ at the age of six. Thus, the global IQ assessed after the age of six was not correlated with the main characteristics of the early epilepsy. 3.4. Vineland Adaptive Behavioral Scales (Table 3) Twenty patients were tested using the Vineland rating scale between 6 and 10 years old. The adaptive and behavioral developmental quotient was low in all the children (QD: 50 ± 3 in average; n = 20; range: 28– 76). However, socialization skills were significantly higher than autonomy (59 ± 3 versus 43 ± 4; p = 0.002, t test, n = 20) and communication (59 ± 3 versus 50 ± 3; p = 0.04; n = 20). Some autistic features were observed for all children. The eye contact was not normal. The children failed to establish friendships and had difficulties in dealing with social rules. They had unusual and restricted interests (e.g., TV weather forecasts). They also had a poor ability in expressing emotions. Behavioral disorders were characterized by hyperactivity, opposing and provocative behavior, excessive familiarity with strangers, and poor danger awareness. Communication capacities in general were low, and the daily living skills were particularly deficient. Thus, patients with DS had on average a moderate to severe mental retardation, with significantly lower communication and autonomy capacities than socialization ones. We did not find any statistically significant correlation between QD obtained by the Vineland assessment and the age of epilepsy onset (p = 0.2, Pearson correlation coefficient; n = 20); the total number of seizures before the age of one year (p = 0.1), between 1 and 2 years old (p = 0.1), the age at first SE (p = 0.3); the number of long-lasting seizures before 1 year (p = 0.2), between 1 and 2 years (p = 0.2); and the number of SE before 1 year old (p = 0.9), between 1 and 2 years (p = 0.6). Developmental quotient was similar in the 10 patients who did not endure any SE before 2 years of age, when
compared with the 10 patients who endured at least one SE before two years of age (47 ± 4, n = 10 versus 53 ± 5, n = 10; , p = 0.4). We did not see any statistically significant correlation between global DQ assessed with the Vineland rating scale and the presence of myoclonias (p = 0.2, t test, n = 20), afebrile focal seizures (p = 0.8), and absence seizures (p = 0.1). 4. Discussion We did an analysis of the cognitive performances of 21 patients with DS between 6 and 10 years old in order to assess a global cognitive evaluation using the Wechsler and/or Vineland scales. The diagnosis of DS was suspected on early epilepsy history and confirmed later with the emergence of neurological symptoms (ataxic gait and/or pyramidal signs and slowing or arrest of cognitive development). There are several obvious limitations of this study. The first one is the small number of patients. Given that, the attempted correlation of WISC and VABS results with epilepsy phenotype should be interpreted with caution. The second limitation is that type and time of nonpharmacological intervention and educational level of the parents have not been assessed here and could influence the WISC and VABS results. The third limitation is that we did not perform a systematic review of the brain MRIs at different ages looking for nonspecific abnormalities that have previously been described in about 10% of patients with DS [16]. These abnormalities did not, however, correlate with behavioral problems or autistic features [16]. Moreover, we did not study the EEG features during the course of the disease, and we did not take into account the AEDs in our statistics. Finally, we did not assess whether the nature of the SCN1A mutation in our cohort could influence the cognitive evolution. However, it has been reported that among patients with a phenotype of DS, the type of mutation (missense versus nonsense), if correlated with the degree of severity of the epilepsy, was not correlated with the cognitive evolution or behavior [16,17]. The role of intrinsic, complex genetic modifiers in the cognitive outcome of DS is, however, probably more influential than extrinsic ones (e.g., treatments and nontherapeutic interventions). The criteria for making the diagnosis of DS were the same for all patients and allowed us to strongly suspect the diagnosis before the age of two in all children. Despite a stereotyped initial history, the evolution of
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the patients we tested was heterogeneous, especially in terms of cognitive and behavioral state. An important proportion (12/21) of the patients with DS we studied never had any myoclonias and could be considered as having incomplete DS. This proportion is relatively similar to what is usually described in recent series [11,13,18]. Patients who had either verbal or nonverbal IQ of more than 60 displayed a remarkable cognitive qualitative profile characterized by deficient verbal planning, auditory working memory, visuomotor abilities, visuospatial organization, and déficient fine motor skills, with more preserved visual perception and discrimination. How such a profile emerges is not known. We propose that cognitive deficiency in DS can be almost entirely due to a disruption of the development of the executive functions. Executive functions normally emerge after the age of two, with the progressive maturation of the frontal lobe regions until adolescence [19,20]. Early disruption of frontal lobe development can lead to global cognitive impairment because of “dysexecutive syndrome” [21]. This is in line with several characteristics of patients with DS: i) the difficulty to acquire any new skill after the age of two [22]; ii) the impression of regression, which is rather due to a lack of any progression after 2 years old; and iii) the relative preservation of visual perception by contrast with the massive impairment of abilities linked to visual– motor integration [4,5]. Moreover, the weakness in expressive language skills is not a primary language disorder but may result from an underlying executive deficit. The role of cerebellar dysfunction in the cognitive profile of patients with DS is also plausible [23] and could participate in the dysexecutive syndrome [24]. For the first time, the Vineland Adaptive Behavioral Scales were systematically administrated in patients with DS between 6 and 10 years old. The Vineland scores reflect on adaptive behavior competency. This instrument provides an overall composite score for communication, daily living skills, and socialization. It focuses on behaviors expected to operate in an age-dependent manner. In children, the behaviors assessed are usually closely correlated with developmental milestones (domain “day living skills”). The particularly limited autonomy of the patients with DS, demonstrated here, may be explained by their parents' fear of seizures, their global and fine motor difficulties, and their opposing character and poor capacity of verbal understanding. On the other hand, their capacities in socialization are significantly more preserved than in communication ones, thus, confirming that patients with DS can display some autistic features but cannot be considered as autistic [4,25,26]. The use of patients with autism scales in future studies should clarify this point. Why and how such a deep executive impairment arises still has to be elucidated. Obviously, it is not possible to specifically study the role of the AEDs in the cognitive state of the patients since the severity of the epilepsy prevents us from stopping any medication. However, it is plausible that the AED, especially when multiple, has an impact on the psychomotor speed of the patients during the tests, as previously shown in children with epilepsy [27]. The possible role of interictal electroencephalogram (EEG) is not easy to investigate since interictal abnormalities and background abnormalities may be transitory in DS and can be easily overestimated or overlooked [28]. However, Brunklaus et al. have shown that the interictal EEG abnormalities in the first year were correlated with a worse developmental outcome in their cohort of 241 SCN1A mutation-positive patients [16]. In our patients, we did not find any significant correlation between the seizure frequency and duration in the first two years and severity of cognitive impairment. Lack of any significant correlation does not mean that the epileptic activity does not play any role in the occurrence of developmental impairment but that intellectual disability of patients with DS cannot be considered as linearly related to early epileptic activity. We did not find any statistically significant difference in the cognitive or adaptive scores in typical patients with DS versus those with IDS or ICEGTC in general. However, among patients with VIQ and/or NVIQ of more than 60, only 1 patient had typical DS (11% of patients with DS), whereas 3 patients had IDS (33% of patients with IDS), and 1 patient had ICEGTC (50% of patients
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with ICEGTC), consistent with a more severe prognosis of patients with typical DS. Other studies have found that the number of convulsive seizures [3,4], or the presence of myoclonic seizures [5] or that of SE [7,14], tended to be associated with bad outcome. Ours was also a small series of patients, and the results are difficult to compare as we restricted our study of epileptic features to the first two years of age. Recently, a larger prospective study found three clinical features significantly predicting a worse developmental outcome: occurrence of status epilepticus, interictal electroencephalography abnormalities in the first year of life, and motor disorder (ataxia, hypotonia, dystonia, and spasticity) [16]. The apparent contradiction with our conclusions regarding SE could be related to the fact that we excluded patients with post-SE ischemic encephalopathy, and also with the fact that we did not take SE occurring after 2 years of age into account. However, the overall IQ and DQ of patients with DS were low even for patients who did not endure any SE in our study. Is the cognitive profile we described specific to DS or due to early onset seizures? Early age of onset of epilepsy is classically associated with a higher risk of cognitive impairment in general [29,30], but to our knowledge, there is no specific cognitive profile that can be distinguished depending only on the age of onset of epilepsy [31]. Studies comparing cognitive profile of DS versus other early onset epileptic syndromes would be of great interest. In our study, DS was the result of a mutation of SCN1A gene in more than 90% of the cases, resulting in a heterozygous loss of function of the protein NaV1.1 [2]. This alteration was demonstrated to increase cortical excitability through a reduction of sodium channel density in GABAergic interneurons but not in excitatory glutamatergic neurons [32,33]. This increased excitability may explain the severity of the epileptic activity in patients with DS. On the other hand, NaV1.1 dysfunction also impairs network properties in animal models, independently from seizures [34]. Since cognitive processes are largely supported by various network oscillations, permanent NaV1-1 dysfunction may exert a negative effect on cognition, independent from seizures, in patients with DS [35]. 5. Conclusion None of the 21 patients with a DS that we tested had a normal IQ between 6 and 10 years old, and only a quarter of them had an verbal and/ or non verbal IQ of more than 60. Using the Vineland Adaptive Behavioral Scales, we showed that patients with DS, however deficient, displayed a peculiar adaptive profile, with significantly higher socialization than communication and autonomy capacities in contrast to what is usually described in patients with autism. Acknowledgements MM is funded by INSERM contrat interface. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Dravet C. The core Dravet syndrome phenotype. Epilepsia 2011;52(Suppl. 2):3–9. [2] Claes L, Del-Favero J, Ceulemans B, Lagae L, Van BC, De JP. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001;68:1327–32. [3] Cassé-Perrot C, Wolf M, Dravet C. Neuropsychological aspects of severe myoclonic epilepsy in infancy. In: Jambaqué I, Lassonde M, Dulac O, editors. Neuropsychology of childhood epilepsy. New York: Kluwer Academic/ Plenum Publishers; 2001. p. 131–40. [4] 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. [5] Ragona F, Granata T, Dalla Bernardina B, Offredi F, Darra F, Battaglia D, et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia 2011;52:386–92.
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[22] 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;93:73–9. [23] Kalume F, Yu FH, Westenbroek RE, Scheuer T, Catterall WA. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. J Neurosci 2007;27:11065–74. [24] Baillieux H, De Smet HJ, Paquier PF, De Deyn PP, Marien P. Cerebellar neurocognition: insights into the bottom of the brain. Clin Neurol Neurosurg 2008;110:763–73. [25] Guzzetta F. Cognitive and behavioral characteristics of children with Dravet syndrome: an overview. Epilepsia 2011;52(Suppl. 2):35–8. [26] Li BM, Liu XR, Yi YH, Deng YH, Su T, Zou X, et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav 2011;21:291–5. [27] Aldenkamp AP, Alpherts WC, Blennow G, Elmqvist D, Heijbel J, Nilsson HL, et al. Withdrawal of antiepileptic medication in children—effects on cognitive function: the multicenter Holmfrid study. Neurology 1993;43(1):41–50. [28] Bureau M, Dalla Bernardina B. Electroencephalographic characteristics of Dravet syndrome. Epilepsia 2011;52(Suppl. 2):13–23. [29] Hermann B, Seidenberg M, Jones J. The neurobehavioural comorbidities of epilepsy: can a natural history be developed? Lancet Neurol 2008;7(2):151–60. [30] Sabbagh SE, Soria C, Escolano S, Bulteau C, Dellatolas G. Impact of epilepsy characteristics and behavioral problems on school placement in children. Epilepsy Behav 2006;9(4):573–8. [31] Reijs RP, van Mil SG, Arends JB, van Hall MH, Weber JW, Renier WO, et al. Cryptogenic localization related epilepsy in children from a tertiary outpatient clinic: is neurological and neuropsychological outcome predictable? Clin Neurol Neurosurg 2007;109(5):422–30. [32] Kalume F, Yu FH, Westenbroek RE, Scheuer T, Catterall WA. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. J Neurosci 2007;27(41):11065–74. [33] Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol 2010;588(Pt 11):1849–59. [34] Bender AC, Natola H, Ndong C, Holmes GL, Scott RC, Lenck-Santini PP. Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 2013;54:297–303. [35] Bender AC, Morse RP, Scott RC, Holmes GL, Lenck-Santini PP. SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 2012;23:177–86.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome Nathalie Villeneuve a,b,c, Virginie Laguitton a, Marine Viellard b, Anne Lépine a,c, Brigitte Chabrol c, Charlotte Dravet d, Mathieu Milh c,e,⁎ a
CINAPSE, Hôpital Henri Gastaut Centre Saint Paul, 13009 Marseille, France Centre Ressource Autisme, Hopital Sainte Marguerite, 13009 Marseille, France APHM, Service de neurologie pédiatrique, Hôpital de la Timone, 13005 Marseille, France d Child Neurology and Psychiatry, Catholic University, Rome, Italy e INSERM, UMR 910, Aix-Marseille Université, 13005 Marseille, France b c
a r t i c l e
i n f o
Article history: Received 13 June 2013 Revised 15 November 2013 Accepted 21 November 2013 Available online 8 January 2014 Keywords: Dravet syndrome Cognitive evaluation Epilepsy SCN1A
a b s t r a c t In order to assess the cognitive and adaptive profiles of school-aged patients with Dravet syndrome (DS), we proposed to evaluate the intelligence and adaptive scores in twenty-one 6- to 10-year-old patients with DS followed in our institution between 1997 and 2013. Fourteen patients were tested using the Wechsler Intelligence Scale for Children (WISC) and the Vineland Adaptive Behavioral Scales (VABS); 6 patients could not be tested with the WISC and were tested with the VABS only, and one was tested with the WISC only. Data regarding the epilepsy were retrospectively collected. Statistical analysis (Spearman rank order and Pearson correlation coefficient) was used to correlate early epilepsy characteristics with the cognitive and adaptive scores. Sodium channel, neuronal alpha-subunit type 1 (SCN1A) was mutated in 19 out of 21 patients. After the age of 6 years, none of the DS patients had a normal intelligence quotient (IQ) using WISC (age at the testing period: mean = 100 ± 5; median = 105 months; mean total IQ = 47 ± 3; n = 15). Only five patients had a verbal and/or a non verbal IQ of more than 60 (points). Their cognitive profile was characterized by an attention deficit, an inability to inhibit impulsive responses, perseverative responses and deficit in planning function. Administering the Vineland Adaptive Behavioral Scales in the same period, we showed that socialization skills were significantly higher than communication and autonomy skills (age at the testing period: mean = 100 ± 4; median = 100 months; n = 20). We did not find any significant correlation between the IQ or developmental quotient assessed between 6 and 10 years of age and the quantitative and qualitative parameters of epilepsy during the first two years of life in this small group of patients. Despite an overall moderate cognitive deficit in this group of patients, the Vineland Adaptive Behavioral Scales described an adaptive/behavioral profile with low communication and autonomy capacities, whereas the socialization skills were more preserved. This profile was different from the one usually found in young patients with autism and may require specific interventions. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is a rare, chronic epileptic syndrome occurring within the first years of life in a previously normal infant. Patients endure recurrent and prolonged hemiclonic or generalized tonic–clonic seizures, mostly febrile ones, and usually develop other seizure types including atypical absence seizures, focal seizures, and myoclonic jerks that usually emerge between 1 and 4 years of age [1]. SCN1A encoding
⁎ Corresponding author at: Service de neurologie pédiatrique, Hopital Timone-Enfants, 264 Rue Saint Pierre, 13005 Marseille, France. Fax: +33 491 38 68 09. 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.021
a voltage sensitive sodium channel has been found mutated or deleted in 70–80% of the patients with DS [2]. A singular time course of psychomotor development has been classically described in DS [3]. Before the age of two years, children who have been tested by the Brunet–Lezine scale [4] or the Griffiths scale [5] displayed a normal or subnormal developmental quotient (DQ). In older children, cognitive evaluation indicated a low DQ in most cases, characterized by poor visuomotor skills, heterogeneous language, and behavioral disorders such as hyperactivity, poor relational capacities and gestural stereotypies [4,5]. Behavioral disturbance such as hyperactivity and autistic behavior was frequently observed, as well as speech disturbance [4–6]. The cognitive outcome was usually poor, and seizures remained anti-epileptic drugs even in adulthood [7,8], although
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seizure frequency usually decreased [9,10]. Despite overall cognitive deficiency, some degree of heterogeneity has been reported and noticed in our clinical experience [3–5]. In order to describe its extent, we administered the Wechsler Intelligence Scale for Children (WISC) and the Vineland Adaptive Behavioral Scales (VABS) between the ages of six and ten in 21 patients with DS who were followed in our institution from the beginning of the illness. 2. Participants and methods Out of a total of 47 patients born between 1986 and 2012 (16 months–27 years) with DS who are still followed in our institution, 10 patients were born before 1993, and 10 were born after 2006 and could not be evaluated using the WISC and the VABS between 6 and 10 years. Among 27 consecutive patients with DS born between 1993 and 2006, 2 endured very severe SE followed by anoxic encephalopathy and spastic tetraplegia; 4 died before entering the study (SUDEP). Finally, twenty-one patients were included and tested in a prospective way between 2003 and 2012, and data on epilepsy were retrospectively studied. None of the patients had been reported in previous studies. Diagnosis of DS was suspected on the following criteria: no previous personal history of disease; seizures beginning in the first year of life or slightly later in the form of generalized or unilateral clonic seizures or myoclonic seizures; sensitivity to fever; presence of afebrile seizures; normal interictal EEG, or slight slowing in the central regions and normal brain MRI at the onset [1,4]. Diagnosis of DS was then confirmed with the emergence of the other following symptoms: ataxic gait, pyramidal signs, slowing or arrest of cognitive development after 2 years old, persistence of clonic seizures, and sensitivity to fever. We distinguished between typical DS when other seizure types were present, including myoclonias, mild or incomplete DS (IDS) [11,12], i.e., borderline SMEI without myoclonias [13], and intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC), in which the patients have only one type of seizure [14]. Status epilepticus (SE) was defined by a duration of more than 30 min of clonic seizure. We also defined a group of “long-lasting seizures”, between 20 and 30 min, since all of these seizures required a medical intervention (rectal diazepam). Other types of seizures were noted between 0 and 2 years old. Electroencephalogram was not systematically performed at each visit. The parents' consent was obtained for all the patients. Cognitive evaluation was assessed for each patient by a single neuropsychologist (VL), using the Wechsler Intelligence Scale for Children (WISC III; WISC IV) between 6 and 10 years of age. The Vineland Adaptive Behavioral Scales (VABS) [15], a semistructured interview, was administrated in 20/21 patients by a trained child psychiatrist certified in the procedure (MV) to assess the cognitive and social integration scaling. The characteristics of the epilepsy and the treatments were collected. A brain MRI was performed in all patients between 1 and 5 years of age. SCN1A was screened for all the patients included in the study. Pearson correlation coefficient and Spearman rank order were used to calculate the correlation coefficient between normally and not normally distributed data, respectively. Mann–Whitney Rank Sum Test and t test were used to compare two groups.
Table 1 Genetics of the patients. Patient, gender
Type of SCN1A mutation
Familial history of epilepsy
1, F 2, F 3, F 4, M 5, F 6, F 7, F 8, F 9, F 10, M 11, M 12, M 13, F 14, F 15, F 16, F 17, F 18, M 19, M 20, M 21, F
c.2686GNA/p.Trp873X c.1171-2ANG (intron 9) c.5656CNT/p.Arg1886X c.1377+1GNA (intron 9) c.1177CNT/p.Arg393Cys c.602+1GNT (intron4) c.1702CNT/p.Arg568X c.5641GNT/p.Glu1881X c.152081523delAAGA/p.LysSerfsX36 n c.272_273delITA/p.ile91SrfsX4 c.429_430delGT/p.Phe144TyrfsX148 c.5743GNT/p.Glu1915X c.840GNC/p.Trp280Cys c.2837GNA/p.Arg946His c.4091TNA/p.Met1364Lys n c.5673_5676dupGCGA/p.Phe1893AlafsX53 c.1511_1515delGAAA/p.Arg504ThrfsX12 c.5346CNG/p.IIe1782Met c.2092CNT/p.His698Tyr
Yes (FS) Yes (PS) Yes (FS) Yes (PS) No No No Yes (GTCS) No Yes (FS) No Yes (FS) No No Yes (FS) No No No No Yes (FS) No
FS: febrile seizure; PS: partial seizure; GTCS: generalized tonic–clonic seizure.
3.1. Epilepsy history between the age of diagnosis and 6 years old (Table 2) Nine patients had a typical DS (9/9 with a SCN1A mutation), 10 patients never had any myoclonias (incomplete DS, 9/10 with a SCN1A mutation), and 2 patients had only generalized, febrile, and afebrile tonic–clonic seizures (ICEGTC, 1/2 with a SCN1A mutation). The average age at the first seizure was 6 ± 1 month (mean ± standard error). Eleven patients displayed at least one SE before the age of two (mean age at first SE: 9 ± 2 months; range: 3–19 months; n = 11), and 19/21 patients endured at least one seizure lasting more than 20 min during the first two years of age. The two patients who never endured any seizure of more than 20 min had an incomplete form of DS (IDS, patients 6 and 11, Table 2). 3.2. Developmental and neurological evaluation before 3 years of age The mean walking age was 16 ± 2 months (range: 12–24 months; n = 21). Only one child was not able to walk at the age of 18 months because of ataxic gait. The cranial circumference was normal for all patients. Children produced their first words at the mean age of 20 ± 4 months (range: 12–36 months; n = 21). Only one child was able to produce sentences before the age of 36 months. After the age of 3, sentences stayed simple, short, and often stereotyped in all patients. The first clinical abnormalities were noted before the age of two in half of the children in the form of poor visual interaction, i.e., the eye contact was possible but did not reflect any normal exchange between physicians and patients, according to their age. At the age of two, 10/21children had a significant motor hyperactivity. At the age of three, 17/21 patients had ataxic gait and slight pyramidal signs. 3.3. Wechsler Intelligence Scale for Children
3. Results Twenty-six patients born between 1993 and 2006 were eligible. Two children died before the age of 6 years, one died at the age of 8, and two endured a severe, long-lasting SE followed by an anoxic encephalopathy with severe cognitive and motor impairment. These five patients were excluded. Finally, 21 patients (7 boys) aged 6 to 20 years were included in this study. SCN1A gene was mutated in 19 patients (Table 1). Brain MRIs did not reveal any congenital structural abnormalities.
The Wechsler Intelligence Scale for Children III or the Wechsler Intelligence Scale for Children IV was planned for use in all the patients between 6 and 10 years old, (n = 21, Table 3). It was not possible to administer the tests in 6/21 patients because of major behavioral problems and lack of any possible interaction with the neuropsychologist. These patients were profoundly cognitively impaired; 3 of them had typical DS, and 3 had IDS. None of the remaining 15 testable patients had a normal global IQ between 6 and 10 years old (average full IQ: 47 ± 2 (average standard score ± standard error), range: 40–73;
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Table 2 Age at diagnosis of DS, genetics, and early epilepsy of the patients. Patient, gender
Date of birth(m/y)
1, F 2, F 3, F 4, M 5, F 6, F 7, F 8, F 9, F 10, M 11, M 12, M 13, F 14, F 15, F 16, F 17, F 18, M 19, M 20, M 21, F
Nov-93 Apr-94 Mar-98 Nov-99 Dec-99 Mar-00 Apr-00 Jul-00 Sep-00 Jan-01 Feb-01 Apr-01 Jun-01 Dec-01 Apr-02 Mar-02 Mar-03 Mar-03 Nov-03 Nov-05 Nov-06
Age at diagnosis (y)
Age at seizure onset (m), and type
Age at first SE (m)
Nb of b20-min seizures/y
Nb of 20- to 30-min seizures/y
Nb of SE/y
b1 y
1–2 y
b1 y
1–2 y
b1 y
1–2 y
4 3 2.2 1 5.5 0.7 6 2.5 1.5 1.5 2 2.5 0.8 0.8 0.8 5 2 2.8 0.8 1.5 2
4; F; G 5.5; F; HC 7; F; HC 4; U; M 8; F; G 5; F; HC 3; F; G 8; F; G 4; U; G 6; F; G 10; F; G 4.5; F; G 6; F; HC 5; F; HC 6.5; F; HC 15; U; HC 6; F; G 6; F; G 4.2; F; HC 4; F; HC 10; F; G
na 5.5 na 14 na na 3 na na na na 14.5 na 5 6.5 19 na 6 4.2 4 18
24 10 3 0 3 20 8 3 2 4 2 7 4 7 5 0 6 10 7 4 2
50 10 12 50 40 10 4 5 6 15 30 100 30 20 6 6 10 20 50 20 13
1 0 1 0 1 0 0 1 1 2 0 3 2 2 0 0 1 0 1 2 2
0 1 0 0 0 0 0 0 0 1 0 0 1 0 0 4 1 0 0 0 2
0 1 0 0 0 0 1 0 0 0 0 0 0 3 2 0 0 2 4 1 0
0 1 0 1 0 0 0 0 0 0 0 1 0 0 0 2 0 1 0 0 1
DS type
IDS DS IDS DS IDS IDS ICEGTC IDS IDS IDS IDS DS IDS DS DS DS ICEGTC DS DS DS IDS
AED received b1 y
1–2 y
pb vpa cbz clb vpa pb esm vpa vpa 0 vpa clb stp vpa vpa vpa pb vpa vpa clb vpa clb vpa cbz vgb clb stp vpa clb stp 0 vpa pb vpa czp vpa cbz vpa cbz
vpa clb esm vpa vpa czp vpa czp pb vpa cbz tpm vpa clb stp tpm vpa vpa vpa clb pb vpa cbz pb vpa czp vpa tpm cbz vpa clb stp vpa clb tpm vpa clb stp tpm vpa vpa clb vpa czp vpa clb stp vpa cbz clb stp cbz ltg
F: febrile; G: generalized; HC: hemiclonic; U: unfebrile; M: myoclonic; Nb: number. DS: Dravet syndrome; IDS: incomplete Dravet syndrome; ICEGTC: childhood epilepsy with generalized tonic-clonic seizures. AED: antiepileptic drugs. PB: phonobarbital; VPA: sodium valpraote; CBZ: carbamazepine; CLB: clobazam; ESM: ethosuximide; STP: stiripentol; VGB: vigabatrin; CZP: clonozepam; LTG: lamotrigine; TPM: topiramate.
verbal IQ: 54 ± 2; nonverbal IQ: 54 ± 2; n = 15, Table 3). We did not find any significant difference in the total IQ within DS versus IDS (44 ± 3 versus 46 ± 5; p = 0.7), in DS versus IGTLC (44 ± 3 versus 53 ± 10; p = 0.7), and in IDS versus IGTLC (46 ± 5 versus 53 ± 10; p = 0.6). Only 5 patients out of 21 had a verbal IQ and/or a nonverbal IQ of more than 60 between 6 and 10 years old, allowing us to draw a cognitive profile. In these patients, we found a language disorder characterized by an articulatory dysfunction. The speech was characterized by a reduced verbal fluency, a poor lexical and syntactic naming, perseverance, stereotyped answers, and a deficit in planning capacity and
Table 3 Intelligence quotient using the WISC and adaptive scores using the VABS. Patient WISC
VABS
Total Verbal NonVerbal QD Communication Autonomy Socialization IQ IQ IQ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
40 40 40 40 60 na 73 40 53 na na na 46 na 40 61 43 40 na 45 42
46 45 45 46 69 na 74 45 63 na na na 55 na 45 74 55 45 na 59 51
41 45 45 46 63 na 82 45 65 na na na 67 na 45 61 45 45 na 56 57
33 36 35 nd 66 39 76 56 51 28 50 30 55 43 53 76 60 54 42 71 51
30 27 37 nd 75 40 83 50 51 26 50 29 43 42 53 74 65 50 42 67 45
20 32 22 nd 58 27 67 54 46 20 44 20 55 36 47 66 51 54 32 68 44
50 48 47 nd 65 51 79 64 46 38 56 42 67 51 60 89 65 67 53 78 63
conceptual elaboration (vocabulary: 4 ± 2.3; information: 3.6 ± 2.3, Table 4). The verbal comprehension was poor (comprehension: 3.8 ± 1.9), as well as the comprehension of social conventions. Speech fluency was below normal limits in letter and semantic fluency tasks. Numeric reasoning was severely impaired (arithmetic: 2.4 ± 2). Major disturbances of auditory working memory were observed in 3 of the 5 patients (number strings backwards: 3.6 ± 3.8). The level of general knowledge was poor and restricted to series (week days) learned in an automatic mode. In contrast, receptive language skills were just below normal limits (DEN48: 38.5 ± 3.5), and auditory immediate memory was relatively preserved in 4 of the 5 patients (number strings forward, mean average score: 6.2 ± 2.8). Nonverbal capacities were characterized by a deficient visual–motor speed (coding: 2.8 ± 2), nonverbal reasoning ability (4.4 ± 2), and matrix reasoning (4.8 ± 2.4). The visual discrimination abilities were more preserved (symbol: 6.2 ± 2.95) (Table 4). Overall, these findings put the light on a contrast between a relative preservation of some instrumental functions (confrontation naming and visuo-perceptive abilities) and a significant deficit of executive functions (significant difficulties in verbal planning, auditory working memory, visuomotor abilities, visuospatial organization, and fine motor skills). In the remaining 10 testable patients, the cognitive deficits were severe and homogeneous for each subtest of the IQ (Table 4). Speech productions were limited to words without any grammatical construction, and receptive language skills were limited to simple orders. Count, verbal and nonverbal reasoning, and graphing were not possible. Their cognitive profile was dominated by pronounced attention difficulties, inability to inhibit impulsive responses, perseverance, and deficits in planning, suggesting a major executive disturbance. We then investigated whether the characteristics of the initial epilepsy before the age of 2 years were correlated with later cognitive development. We did not find any statistically significant correlation between full IQ and the age of epilepsy onset (p = 0.66; n = 15, Spearman rank order), the total number of seizures during the first year of life (p = 0.3), and between 1 and 2 years (p = 0.4). Seizures lasting 20–30 min did not correlate with full IQ (p = 0.5 during the first year of life; p = 0.3 between 1 and 2 years). Status epilepticus lasting
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Table 4 Scores obtained at each subtest of the WISC (gray, standard score) and other cognitive tests (raw score).
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more than 30 min also did not correlate with full IQ (p = 0.5 during the first year; p = 0.6 between 1 and 2 years). We then investigated whether the seizure type before the age of 2 years could be associated with a different cognitive profile. We did not find any significant correlation between the presence of myoclonias (p = 0.2, Mann–Whitney Rank Sum Test), focal nonfebrile seizures (p = 0.3), and absence seizures (p = 0.1) occurring before the age of 2 years and the global IQ at the age of six. Thus, the global IQ assessed after the age of six was not correlated with the main characteristics of the early epilepsy. 3.4. Vineland Adaptive Behavioral Scales (Table 3) Twenty patients were tested using the Vineland rating scale between 6 and 10 years old. The adaptive and behavioral developmental quotient was low in all the children (QD: 50 ± 3 in average; n = 20; range: 28– 76). However, socialization skills were significantly higher than autonomy (59 ± 3 versus 43 ± 4; p = 0.002, t test, n = 20) and communication (59 ± 3 versus 50 ± 3; p = 0.04; n = 20). Some autistic features were observed for all children. The eye contact was not normal. The children failed to establish friendships and had difficulties in dealing with social rules. They had unusual and restricted interests (e.g., TV weather forecasts). They also had a poor ability in expressing emotions. Behavioral disorders were characterized by hyperactivity, opposing and provocative behavior, excessive familiarity with strangers, and poor danger awareness. Communication capacities in general were low, and the daily living skills were particularly deficient. Thus, patients with DS had on average a moderate to severe mental retardation, with significantly lower communication and autonomy capacities than socialization ones. We did not find any statistically significant correlation between QD obtained by the Vineland assessment and the age of epilepsy onset (p = 0.2, Pearson correlation coefficient; n = 20); the total number of seizures before the age of one year (p = 0.1), between 1 and 2 years old (p = 0.1), the age at first SE (p = 0.3); the number of long-lasting seizures before 1 year (p = 0.2), between 1 and 2 years (p = 0.2); and the number of SE before 1 year old (p = 0.9), between 1 and 2 years (p = 0.6). Developmental quotient was similar in the 10 patients who did not endure any SE before 2 years of age, when
compared with the 10 patients who endured at least one SE before two years of age (47 ± 4, n = 10 versus 53 ± 5, n = 10; , p = 0.4). We did not see any statistically significant correlation between global DQ assessed with the Vineland rating scale and the presence of myoclonias (p = 0.2, t test, n = 20), afebrile focal seizures (p = 0.8), and absence seizures (p = 0.1). 4. Discussion We did an analysis of the cognitive performances of 21 patients with DS between 6 and 10 years old in order to assess a global cognitive evaluation using the Wechsler and/or Vineland scales. The diagnosis of DS was suspected on early epilepsy history and confirmed later with the emergence of neurological symptoms (ataxic gait and/or pyramidal signs and slowing or arrest of cognitive development). There are several obvious limitations of this study. The first one is the small number of patients. Given that, the attempted correlation of WISC and VABS results with epilepsy phenotype should be interpreted with caution. The second limitation is that type and time of nonpharmacological intervention and educational level of the parents have not been assessed here and could influence the WISC and VABS results. The third limitation is that we did not perform a systematic review of the brain MRIs at different ages looking for nonspecific abnormalities that have previously been described in about 10% of patients with DS [16]. These abnormalities did not, however, correlate with behavioral problems or autistic features [16]. Moreover, we did not study the EEG features during the course of the disease, and we did not take into account the AEDs in our statistics. Finally, we did not assess whether the nature of the SCN1A mutation in our cohort could influence the cognitive evolution. However, it has been reported that among patients with a phenotype of DS, the type of mutation (missense versus nonsense), if correlated with the degree of severity of the epilepsy, was not correlated with the cognitive evolution or behavior [16,17]. The role of intrinsic, complex genetic modifiers in the cognitive outcome of DS is, however, probably more influential than extrinsic ones (e.g., treatments and nontherapeutic interventions). The criteria for making the diagnosis of DS were the same for all patients and allowed us to strongly suspect the diagnosis before the age of two in all children. Despite a stereotyped initial history, the evolution of
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the patients we tested was heterogeneous, especially in terms of cognitive and behavioral state. An important proportion (12/21) of the patients with DS we studied never had any myoclonias and could be considered as having incomplete DS. This proportion is relatively similar to what is usually described in recent series [11,13,18]. Patients who had either verbal or nonverbal IQ of more than 60 displayed a remarkable cognitive qualitative profile characterized by deficient verbal planning, auditory working memory, visuomotor abilities, visuospatial organization, and déficient fine motor skills, with more preserved visual perception and discrimination. How such a profile emerges is not known. We propose that cognitive deficiency in DS can be almost entirely due to a disruption of the development of the executive functions. Executive functions normally emerge after the age of two, with the progressive maturation of the frontal lobe regions until adolescence [19,20]. Early disruption of frontal lobe development can lead to global cognitive impairment because of “dysexecutive syndrome” [21]. This is in line with several characteristics of patients with DS: i) the difficulty to acquire any new skill after the age of two [22]; ii) the impression of regression, which is rather due to a lack of any progression after 2 years old; and iii) the relative preservation of visual perception by contrast with the massive impairment of abilities linked to visual– motor integration [4,5]. Moreover, the weakness in expressive language skills is not a primary language disorder but may result from an underlying executive deficit. The role of cerebellar dysfunction in the cognitive profile of patients with DS is also plausible [23] and could participate in the dysexecutive syndrome [24]. For the first time, the Vineland Adaptive Behavioral Scales were systematically administrated in patients with DS between 6 and 10 years old. The Vineland scores reflect on adaptive behavior competency. This instrument provides an overall composite score for communication, daily living skills, and socialization. It focuses on behaviors expected to operate in an age-dependent manner. In children, the behaviors assessed are usually closely correlated with developmental milestones (domain “day living skills”). The particularly limited autonomy of the patients with DS, demonstrated here, may be explained by their parents' fear of seizures, their global and fine motor difficulties, and their opposing character and poor capacity of verbal understanding. On the other hand, their capacities in socialization are significantly more preserved than in communication ones, thus, confirming that patients with DS can display some autistic features but cannot be considered as autistic [4,25,26]. The use of patients with autism scales in future studies should clarify this point. Why and how such a deep executive impairment arises still has to be elucidated. Obviously, it is not possible to specifically study the role of the AEDs in the cognitive state of the patients since the severity of the epilepsy prevents us from stopping any medication. However, it is plausible that the AED, especially when multiple, has an impact on the psychomotor speed of the patients during the tests, as previously shown in children with epilepsy [27]. The possible role of interictal electroencephalogram (EEG) is not easy to investigate since interictal abnormalities and background abnormalities may be transitory in DS and can be easily overestimated or overlooked [28]. However, Brunklaus et al. have shown that the interictal EEG abnormalities in the first year were correlated with a worse developmental outcome in their cohort of 241 SCN1A mutation-positive patients [16]. In our patients, we did not find any significant correlation between the seizure frequency and duration in the first two years and severity of cognitive impairment. Lack of any significant correlation does not mean that the epileptic activity does not play any role in the occurrence of developmental impairment but that intellectual disability of patients with DS cannot be considered as linearly related to early epileptic activity. We did not find any statistically significant difference in the cognitive or adaptive scores in typical patients with DS versus those with IDS or ICEGTC in general. However, among patients with VIQ and/or NVIQ of more than 60, only 1 patient had typical DS (11% of patients with DS), whereas 3 patients had IDS (33% of patients with IDS), and 1 patient had ICEGTC (50% of patients
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with ICEGTC), consistent with a more severe prognosis of patients with typical DS. Other studies have found that the number of convulsive seizures [3,4], or the presence of myoclonic seizures [5] or that of SE [7,14], tended to be associated with bad outcome. Ours was also a small series of patients, and the results are difficult to compare as we restricted our study of epileptic features to the first two years of age. Recently, a larger prospective study found three clinical features significantly predicting a worse developmental outcome: occurrence of status epilepticus, interictal electroencephalography abnormalities in the first year of life, and motor disorder (ataxia, hypotonia, dystonia, and spasticity) [16]. The apparent contradiction with our conclusions regarding SE could be related to the fact that we excluded patients with post-SE ischemic encephalopathy, and also with the fact that we did not take SE occurring after 2 years of age into account. However, the overall IQ and DQ of patients with DS were low even for patients who did not endure any SE in our study. Is the cognitive profile we described specific to DS or due to early onset seizures? Early age of onset of epilepsy is classically associated with a higher risk of cognitive impairment in general [29,30], but to our knowledge, there is no specific cognitive profile that can be distinguished depending only on the age of onset of epilepsy [31]. Studies comparing cognitive profile of DS versus other early onset epileptic syndromes would be of great interest. In our study, DS was the result of a mutation of SCN1A gene in more than 90% of the cases, resulting in a heterozygous loss of function of the protein NaV1.1 [2]. This alteration was demonstrated to increase cortical excitability through a reduction of sodium channel density in GABAergic interneurons but not in excitatory glutamatergic neurons [32,33]. This increased excitability may explain the severity of the epileptic activity in patients with DS. On the other hand, NaV1.1 dysfunction also impairs network properties in animal models, independently from seizures [34]. Since cognitive processes are largely supported by various network oscillations, permanent NaV1-1 dysfunction may exert a negative effect on cognition, independent from seizures, in patients with DS [35]. 5. Conclusion None of the 21 patients with a DS that we tested had a normal IQ between 6 and 10 years old, and only a quarter of them had an verbal and/ or non verbal IQ of more than 60. Using the Vineland Adaptive Behavioral Scales, we showed that patients with DS, however deficient, displayed a peculiar adaptive profile, with significantly higher socialization than communication and autonomy capacities in contrast to what is usually described in patients with autism. Acknowledgements MM is funded by INSERM contrat interface. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Dravet C. The core Dravet syndrome phenotype. Epilepsia 2011;52(Suppl. 2):3–9. [2] Claes L, Del-Favero J, Ceulemans B, Lagae L, Van BC, De JP. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001;68:1327–32. [3] Cassé-Perrot C, Wolf M, Dravet C. Neuropsychological aspects of severe myoclonic epilepsy in infancy. In: Jambaqué I, Lassonde M, Dulac O, editors. Neuropsychology of childhood epilepsy. New York: Kluwer Academic/ Plenum Publishers; 2001. p. 131–40. [4] 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. [5] Ragona F, Granata T, Dalla Bernardina B, Offredi F, Darra F, Battaglia D, et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. Epilepsia 2011;52:386–92.
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