Dravet syndrome history

Transcription

1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW Dravet syndrome history CHARLOTTE DRAVET Centre Saint-Paul-Hôpital Henri Gastaut, Marseille, France. Correspondence to Charlotte Dravet, 4a, Avenue Toussaint Samat, Marseille, France. PUBLICATION DATA Accepted for publication 7 March 2011 Severe myoclonic epilepsy of infancy (SMEI) is a complex form of epilepsy that was first described in France in Because the myoclonic component of this epilepsy is not always present and because some variability has been observed in the symptomatology, the name was changed to Dravet syndrome in The genetic aetiology of this epilepsy was discovered in 2001, and since then numerous studies have contributed to a better knowledge of the disease. Around 70% of affected patients are carriers of a mutation on the alpha subunit of the SCN1A gene. An accurate analysis of the clinical features leads to the distinction between typical and atypical forms, both with the same unfavourable prognosis and the same genetic background. However, many studies are being conducted in order to establish correlations between phenotypes and genotypes, and to understand the factors underlying the cognitive impairment of the affected patients. Severe myoclonic epilepsy of infancy (SMEI) was first described in France in 1978 and has been progressively recognised in many other countries. With the increasing number of cases, the characteristics of this epilepsy were more accurately defined, leading to a change in its name to Dravet syndrome in In this review we aim to explain this evolution and to underline the main advances which have been made in the knowledge of this syndrome. The first paper was published in a small French medical journal. 1 After that publication, we published our series of 42 cases at the XIIIth Epilepsy International Congress in Kyoto. 2 Simultaneously, B. Dalla Bernardina in Italy recognised the same clinical features in other patients. 3 In 1983, an international workshop was organized in Marseille by the members of the Commission on Classification and Terminology of the International League against Epilepsy in order to clarify the different types of epilepsy in infancy, childhood, and adolescence; these proceedings were published in 1984 in French 4 and 1985 in English. 5 In the following years, several authors confirmed our observations. 6 8 CRITERIA At this time, we proposed the following diagnostic criteria for SMEI: family history of epilepsy or febrile convulsions; no previous personal history of disease; seizures beginning in the first year of life in the form of generalized or unilateral febrile clonic seizures; secondary appearance of myoclonic jerks and often partial seizures; EEG showing generalized spike-wave (SW) and polyspike-wave (PolySW), early photosensitivity and focal abnormalities (Fig.1); retarded psychomotor development from the second year of life; simultaneous ataxia, pyramidal signs, and interictal myoclonus; resistance to all forms of treatment; intellectual deficiency and personality disorders in all affected children. On the whole, these electro-clinical criteria remain valid in 2010 and define the typical form of SMEI. We have only slightly modified them: one family history of epilepsy or febrile convulsions is not constant but variable according to the authors (25 71%); the initial seizures are not always generalized or unilateral clonic but may be focal or myoclonic; they are not always febrile and the clonic seizures often evolve to status epilepticus; not only myoclonic jerks and focal seizures appear secondarily but also atypical absences and obtundation statuses; photosensitivity may be associated with pattern-sensitivity; neurological signs are not always present but are frequently observed: ataxia (60%), pyramidal signs (20%) and interictal myoclonus (36 85%); themriisnormalattheonset; cognitive deficiency and personality disorders are present in all affected children during the course of the disease, but they are of variable degrees, from slight to severe, and may be detected only at the age when entering elementary school. THE ATYPICAL (BORDERLINE) FORMS Soon after our first publications, it appeared that a number of patients that did not present all these criteria were reported ª The Author. Developmental Medicine & Child Neurology ª 2011 Mac Keith Press DOI: /j x 1

2 Figure 1: EEG recording of a 5-year-old girl while awake. Two bursts of massive myoclonic jerks recorded on the upper limb muscles, accompanied by fast generalized spike-waves. Association of multifocal spikes and spike-waves. and defined as the atypical or borderline forms, which are more difficult to define. The first atypical feature is the absence of myoclonic seizures, which was first underlined by Japanese authors 9 who proposed to separate the borderline form, and then by others. 10,11 As the number of diagnosed patients increased however, other symptomatological differences became apparent: onset with afebrile seizures or focal seizures, rarity of febrile seizures, absence of focal seizures, absence of atypical absences, absence of neurological signs, and almost normal psychomotor development in the first 4 years. The greatest symptomatological variation of SMEI occurs with the high voltage slow wave-grand mal syndrome (HVSW- GM) described in Japan: 12 these patients have only clonic or tonic-clonic seizures (GTCS), without the other seizure types and without myoclonia but with a specific EEG pattern. We have rarely encountered such patients in our practice. The severe idiopathic generalized epilepsy of infancy with GTCS reported by Doose et al. 13 is rather heterogeneous. It comprises patients who also have myoclonic and focal seizures, probably corresponding to SMEI, patients with only GTCS and also patients with a later onset, up to 5 years. All the patients with these different presentations, excluding the latter, share the same other characteristics and have the same outcomes in terms of drug resistance and cognitive deficits. For this reason, the terminology was changed by the Commission from SMEI to Dravet syndrome, 14 with typical (core) and atypical (borderline) forms. The most dramatic advance in the understanding of Dravet syndrome was the discovery of its genetic alteration. In 2001, Claes et al. 15 demonstrated that de novo mutations in the sodium-channel gene SCN1A were present in seven children affected by the syndrome. Since then, many researchers have performed genetic studies and it appears that around 70% of affected patients carry a SCN1A mutation in the gene encoding the a 1 subunit of the Na + channel, 16 whereas the others do not. It is now well known that there are different types of SCN1A mutations (truncating, missense, nonsense, etc.), which are located at different sites in the gene. However, until now the attempts to clarify correlations between phenotypes and genotypes have remained inconclusive. Recently, a mutation encompassing the PCDH19 gene was discovered in a subset of female patients presenting clinical features similar to those of Dravet syndrome in its borderline form, with differences in the outcome, which is less severe. 17 This new gene was also recently found in a familial epileptic syndrome known as Epilepsy and mental retardation limited to females 18 and in other patients with cryptogenic focal epilepsy 19 ). These findings raise the question as to the limits of the Dravet syndrome and justify the molecular testing of this gene in patients, especially females, diagnosed as having Dravet syndrome and who are negative for the SCN1A gene. NEUROPSYCHOLOGICAL OUTCOME In the first neuropsychological study performed in Marseille, 20 the global developmental quotient (DQ) declined quickly to a level of 60 to 95 in children aged 1 to 3 years, and a level of severe deficit, 25 to 40, in children older than 6 years. In this study, the degree of impairment appeared to be correlated with the severity of epilepsy during the first 2 years of life. Thirty years later, our experience shows there are different outcomes and the affected patients do not all have severe cognitive impairment. In 2006 a case of one patient with a normal intellectual quotient and normal schooling was published. 21 This case remains unique, but there are several ongoing studies in Italy that focus on the neuropsychological outcome of patients with Dravet syndrome and show their heterogeneity. In one of them, 22 a group of 26 subjects were followed from 2 Developmental Medicine & Child Neurology 2011, 53 (Suppl. 2): 1 6

3 the onset of the seizures and regularly assessed by standardized tests up to the age of at least 4 years (range 48 60mo). The majority of the patients presented a rapid slowing down and their mean DQ declined by 39.8 ± 16 points; in a small group of seven patients however, this decline was less rapid and less significant, with a mean loss of only ± 5 points (Fig. 2). In another unpublished study performed in Rome on 12 patients (eight of whom were examined before the age of 3 years) followed with repeated tests up to the age of at least 4 years (range 4 10y), the global DQ and IQ were all above 50 and were above 60 for six patients, corresponding to a slight deficit or a low normal range (personal experience). Why do some children have gross and early retardation from the second year, whereas others have only slight retardation during the first 3 or 4 years and are able to attend elementary school? The correlation with the severity of epilepsy could not be confirmed in these recent studies, and the respective roles of epilepsy, genetic alterations and treatment in determining the final outcomes still need to be elucidated. TREATMENT Drug resistance is one of the main features of Dravet syndrome. It is known that the antiepileptic drugs (AEDs), which target the sodium channel, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, must be avoided because of the risk of aggravating the condition. The list of classical AEDs that are truly useful for this epilepsy is short: benzodiazepines, valproate, ethosuximide and bromides. Progress now in pharmacological treatment is very encouraging due to the arrival of new AEDs, two of which are actually more a G Q Months b G Q Months Figure 2: Changes in the global quotient (GQ) in 26 patients with Dravet syndrome. (From Ragona et al., Multicentric Italian study on 26 patients [in press], with permission). (a) Group 1: 19 children with a mean GQ decrease of (b) Group 2: seven children with a mean GQ decrease of Review 3

4 efficacious than the old AEDs, and one is promising. Stiripentol has proven its efficacy in shortening the longest convulsive seizures and avoiding status epilepticus, which has changed the quality of life for many families. It is now considered an orphan drug by the European Medicines Agency and can be obtained in all countries of the European Union. No controlled trial has been done for topiramate, but several publications have shown its efficacy in reducing the seizure number by more than 50% in about half of the patients. 23 It must be considered a first-line drug in spite of the risk of mild to moderate side effects in some children (22.2%), which need to be carefully explained to the parents and monitored. Levetiracetam deserves to be used, but its efficacy needs to be better evaluated. Another recent option is the ketogenic diet (KD). Studies that have focused on this epilepsy type are rare, retrospective, and comprise a small number of patients. Caraballo et al. 24 reported on 20 children with Dravet syndrome treated by KD, 13 of whom were responders and remained on the diet for at least 1 year and up to 4 years. Two were seizure-free, eight had a 75 to 99% seizure reduction, and three had a 50 to 74% seizure reduction. This reduction was observed for all the different seizure types. Seven patients stopped the KD within the first year, either due to lack of efficacy (five) or for side effects (persistent vomiting in two). In the other children, the KD was well tolerated. Dressler et al. 25 applied the KD in a series of fifty children affected by drug-resistant epilepsy. The follow-up duration was variable, longer than 1 year in 43 children. No discontinuation of the KD was necessary because of side effects. Eight children presented with Dravet syndrome. Details are lacking but the best results were obtained in this group, with five responders who had a seizure reduction of 50% or more. These findings show that the KD deserves to be proposed when the appropriate AEDs fail to improve the seizure control in Dravet patients. However, although treating patients with Dravet syndrome has become easier, there are no data, except for stiripentol, predicting the effect of these treatments in individual patients, and the results are still uncertain. Moreover, many cases of status epilepticus are resistant to the protocols applied in the emergency rooms, but there is not yet a consensus for establishing specific recommendations for those related to Dravet syndrome. Through the years, early mortality has appeared to be a great concern in the course of the disease. In 2005, in our review of the literature 26 we estimated the mortality rate to be 17.5%, with four cases of sudden unexpected death (SUDEP) in 26 patients who had died (15.3% of the deaths) and eleven cases of status epilepticus (42.3% of the deaths). Two studies were recently conducted. In Japan, Sakauchi et al. 27 conducted a national retrospective survey and collected 623 patients from 91 hospitals and centres. They found a rate of 10.1%. Thirtyone deaths out of 63 were caused by SUDEP, i.e., 53%. The other main cause of death was the occurrence of acute encephalopathy with status epilepticus in 36% of cases. We personally conducted a retrospective multicentric study and collected 903 patients from 36 hospitals and centres in 13 countries. We found a rate of 5.75%. Twenty-eight deaths out of 52 were caused by SUDEP, i.e., 53.8%, and six by status epilepticus (11.5%) (personal unpublished observations). Mortality has also been studied by Watts et al. in the Dravet Syndrome Family Network, a support group for parents with affected children associated with the International Dravet Syndrome Epilepsy Action League (IDEA League). The authors performed a survey of mortality in this group and presented its results at the Verona workshop (2009). These results were updated in May At this time, 727 individual children with Dravet syndrome from 44 different countries were represented by their families. Since 2000, at least 32 children known to the Dravet Syndrome Family Network have died (4.4%). Information about the children was collected from the parents through interviews and questionnaires. The causes of death were SUDEP in 18 patients (56%), status epilepticus in 11 patients (34%), ketoacidosis, seizure accident, and unknown for one patient each. Figure 3 summarizes these data, showing that although the global mortality rate has tended to decrease, the rate of SUDEP has increased from 15.3 to around 50% of the deaths, a rate that is remarkably similar in all three studies. The role of status epilepticus remains important. It is likely that SUDEP is better recognised because of the increasing interest of the epileptologists and families and the high number of published studies on this topic. In order to better understand the mechanisms of SUDEP, Delogu et al. 28 performed a cardiological study of heart rate variability (HRV) in patients affected by Dravet syndrome. HRV is an important factor of cardiac functioning and can be modified in patients suffering from epilepsy. The authors studied it by recording electrocardiogram (ECG) and longterm Holter ECG (12 24h) in four groups of children: 20 children with Dravet syndrome receiving AEDs; 20 children with another type of epilepsy and receiving AEDs; 20 children with yet another type of epilepsy but not receiving AEDs; and Number % Deaths: number and causes Deaths SUDEP ES Causes Dravet 2005 Japan 2009 Dravet 2009 IDEAL 2010 Figure 3: Mortality in patients with Dravet syndrome. Percentages of patients who died and causes of death in four studies. Dravet 2005 = literature review before ; Japan 2009 = retrospective multicenter national study 27 ; Dravet 2009 = multicenter survey by Dravet, 2009 (unpublished observations); IDEAL 2010 = survey in an international family network by Watts et al. (unpublished material). SUDEP = Sudden unexpected death in epileptic patients; SE = status epilepticus. 4 Developmental Medicine & Child Neurology 2011, 53 (Suppl. 2): 1 6

5 20 healthy children without AEDs. The statistical analysis of these four groups demonstrated that the HRV was significantly different between the patients with Dravet syndrome and all the other three groups. This could be a factor that partially explains the risk of SUDEP in patients with Dravet syndrome. Until now, it has not been possible to draw practical conclusions for individual patients. Further studies with a greater number of patients should be performed. DIFFERENTIAL DIAGNOSIS In spite of the knowledge of its genetic aetiology, the diagnosis of Dravet syndrome remains a clinical diagnosis, based on the above criteria. As the clinical symptomatology appears progressively between the first and the fourth year, an early diagnosis is difficult. In 2008, some Japanese authors 29 proposed a screening test for the prediction of the syndrome before 1 year of age by comparing two groups of infants who presented with febrile seizures before 1 year, the first group later diagnosed with Dravet syndrome (46 patients) and the second not diagnosed with Dravet syndrome (50 patients). The items encompassed in the calculation of a risk score were as follows: onset at or before 7 months = 2, 5 or more convulsive seizures in the first year = 3, hemiconvulsions = 3, focal seizures = 1, prolonged (more than 10min) seizures = 3, hot-water induced seizures = 2, presence of an SCN1A missense mutation = 1, presence of an SCN1A truncating mutation = 2. A total clinical score of six or above was the cutoff value indicating a high risk. This screening test has not been validated by a prospective study, but it matches our experience well. It could be useful for general paediatricians who do not have the same expertise as the child neurologists. It is applicable in infants who present with a first febrile seizure in the first year. The absence of mutation on the SCN1A gene does not preclude this diagnosis since about 30% of the patients with a typical or borderline form are found to be negative. Conversely, the presence of such a mutation does not enable the diagnosis to be established if the clinical features do not fit the clinical criteria. Indeed, we know that SCN1A mutations are present in patients with several other epilepsy types, 30 either as part of genetic epilepsy with febrile seizures plus (GEFS+) or in the form of cryptogenic focal epilepsy. One confusing situation is that of an infant who presents as borderline Dravet syndrome but with stereotypical focal seizures and constant localization of the abnormalities on the EEGs. In this case, even if the genetic screening reveals an SCN1A mutation, focal epilepsy cannot be ruled out and the imaging investigations must be repeated to search for a subtle brain lesion. Moreover, some clinical features of the syndrome have been reported in other situations that deserve further studies, such as the girls carrying a mutation on the PCDH19 gene (see above). To summarise therefore, while the number of publications is steadily growing, the diagnosis of Dravet syndrome has become increasingly difficult. FAMILY ASSOCIATIONS Other developments concern the social aspects of the disease and the emergence of an international association of families who have a child affected by Dravet syndrome: the International Dravet Epilepsy Action League (IDEA League), which has gathered together more than 600 families from the Americas, Europe and other countries. British- and French-speaking branches, as well as Spanish, German and Italian groups also exist. They constitute highly valuable help for the families and a good stimulus for doctors and researchers. In conclusion, we discovered an epileptic syndrome of unknown aetiology in 1978, different from other infantile epileptic encephalopathies. In 2010, we now know this syndrome is due to a channelopathy, which causes a complex form of epilepsy and more or less severe cognitive impairment, the factors of which are still unclear. The relationships between phenotype and genotype have not yet been clarified and need additional studies. While the histories of the affected children are very similar, their individual characteristics (seizure types, triggering factors, psychomotor development and cognitive skills, behaviour, response to drugs) are variable. We would like to especially underline the variability of the long-term outcomes leading to severe motor and cognitive disability in some patients, whereas others have mild cognitive impairment and are able to participate in social activities in a sheltered environment. 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