DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
COMMENTARIES
Dravet syndrome in Sweden CHARLOTTE DRAVET Universita Cattolica del Sacro Cuore, Roma, Italy. doi: 10.1111/dmcn.12731 This commentary is on the original article by Rosander and Hallb€o€ok on pages 628–633 of this issue.
€k provides a good corpus The paper by Rosander and Hallb€ oo of information on the epidemiology and clinical/cognitive outcome of 42 children aged 1 to 17 years, diagnosed with Dravet syndrome in Sweden between 2007 and 2012.1 All the patients had a genetic analysis. The authors did not exclude 12% who were negative for both SCN1A and PCDH19 mutations. To our knowledge, it is the first truly national-based epidemiological study of Dravet syndrome. Interestingly, the estimated incidence of 1 in 33 000 live births was comprised in the range (approximately 1/20–30 000 and 1/40 000) found in previous studies before the discovery of the genetic aetiology, and also in the more recent British study2 which included only the patients with mutations (1/40 900). So, it appears that in spite of an increasing knowledge of the syndrome, Dravet syndrome remains a rare disease. To compare the youngest patients to the oldest was a judicious decision and allowed the group to study the outcome in adolescence. The authors highlighted a trend towards improvement in the seizure severity because there were more seizure-free periods in the oldest group than in the youngest. However, I disagree with their definition of these periods where the children ‘. . . were seizure free for at least 3 months but they experienced sporadic myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli’. Various seizure types provoked by fever and other stimuli are a characteristic feature of this epilepsy and cannot be considered apart.3 A true seizure-free period should last at least 1 year and should be without these provoked seizures to be significant. These short periods do not correspond to a real ‘good outcome’ and I do not believe some patients were misdiagnosed and were affected by GEFS+ syndrome. It is known that the seizure frequency and severity tend to decrease during the course of Dravet syndrome. This has been shown in adulthood and, particularly, after the age of 25 years according to Akiyama et al.4 It would be good if
this improvement in the Swedish adolescents were better documented because there is no other study of this age range in the literature. The absence of neuroimaging abnormalities at the onset is part of the definition of Dravet syndrome. Before the development of magnetic resonance imaging (MRI), neuroimaging remained normal during the course of the disease in the majority of the patients. In some of them, it could display slight diffuse cerebral or cerebellar atrophy, increased white matter signal, and arachnoid cysts. However, from 2005 on, several studies have reported other types of anomalies. On one hand, severe hypoxic-ischemic lesions were observed in patients having suffered from encephalitis or status epilepticus. On the other hand, structural changes such as hippocampal sclerosis and cortical dysplasia were discovered in a small subset of patients, raising discussion about their role in the expression of epilepsy and the reciprocal relationship between these malformations and the SCN1A mutation.5 In the present study, the authors report five children with MRI changes. In three of them they were similar to those previously reported: post-status epilepticus and postencephalitic hypoxic brain injury, and hippocampal sclerosis. In the remaining they were different. One patient had ‘a progressive course and diffuse white-matter abnormalities’. As the authors do not have details and do not indicate if he carries a mutation, we do not know the meaning of the ‘progressive course’ in that case. We were more puzzled by the last patient who had hydrocephaly and a ventriculoperitoneal shunt. Once more, the authors do not have further information so it is impossible to understand this peculiar and unique association and to make any kind of hypothesis. However, these cases do add further questions regarding the discovery of brain anomalies in patients with Dravet syndrome as discussed by Barba et al.5 In practice, when possible, it would be useful to repeat MRI in childhood or adolescence. On the whole, the advances in MRI and genetics technology allow a better knowledge of this disease but also the emergence of new findings, making the disease more complex than we had initially thought and pushing us to go forward and more deeply into the scientific research.
REFERENCES €k T. Dravet syndrome in Sweden: 1. Rosander C, Hallb€ oo a population-based study. Dev Med Child Neurol 2015; 57: 628–33. 2. Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Prognostic, clinical and demographic features in
3. Dravet C. The core Dravet syndrome phenotype. Epilepsia 2011; 52(Suppl. 2): 3–9. 4. Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y.
5. Barba C, Parrini E, Coras R, et al. Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 2014; 55: 1009–19.
A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 2010; 51: 1043–52.
SCN1A mutation-positive Dravet syndrome. Brain 2012; 135: 2329–36.
© 2015 Mac Keith Press
593
COMMENTARIES
Dravet syndrome in Sweden CHARLOTTE DRAVET Universita Cattolica del Sacro Cuore, Roma, Italy. doi: 10.1111/dmcn.12731 This commentary is on the original article by Rosander and Hallb€o€ok on pages 628–633 of this issue.
€k provides a good corpus The paper by Rosander and Hallb€ oo of information on the epidemiology and clinical/cognitive outcome of 42 children aged 1 to 17 years, diagnosed with Dravet syndrome in Sweden between 2007 and 2012.1 All the patients had a genetic analysis. The authors did not exclude 12% who were negative for both SCN1A and PCDH19 mutations. To our knowledge, it is the first truly national-based epidemiological study of Dravet syndrome. Interestingly, the estimated incidence of 1 in 33 000 live births was comprised in the range (approximately 1/20–30 000 and 1/40 000) found in previous studies before the discovery of the genetic aetiology, and also in the more recent British study2 which included only the patients with mutations (1/40 900). So, it appears that in spite of an increasing knowledge of the syndrome, Dravet syndrome remains a rare disease. To compare the youngest patients to the oldest was a judicious decision and allowed the group to study the outcome in adolescence. The authors highlighted a trend towards improvement in the seizure severity because there were more seizure-free periods in the oldest group than in the youngest. However, I disagree with their definition of these periods where the children ‘. . . were seizure free for at least 3 months but they experienced sporadic myoclonic, focal, or generalized tonic–clonic seizures provoked by fever or other stimuli’. Various seizure types provoked by fever and other stimuli are a characteristic feature of this epilepsy and cannot be considered apart.3 A true seizure-free period should last at least 1 year and should be without these provoked seizures to be significant. These short periods do not correspond to a real ‘good outcome’ and I do not believe some patients were misdiagnosed and were affected by GEFS+ syndrome. It is known that the seizure frequency and severity tend to decrease during the course of Dravet syndrome. This has been shown in adulthood and, particularly, after the age of 25 years according to Akiyama et al.4 It would be good if
this improvement in the Swedish adolescents were better documented because there is no other study of this age range in the literature. The absence of neuroimaging abnormalities at the onset is part of the definition of Dravet syndrome. Before the development of magnetic resonance imaging (MRI), neuroimaging remained normal during the course of the disease in the majority of the patients. In some of them, it could display slight diffuse cerebral or cerebellar atrophy, increased white matter signal, and arachnoid cysts. However, from 2005 on, several studies have reported other types of anomalies. On one hand, severe hypoxic-ischemic lesions were observed in patients having suffered from encephalitis or status epilepticus. On the other hand, structural changes such as hippocampal sclerosis and cortical dysplasia were discovered in a small subset of patients, raising discussion about their role in the expression of epilepsy and the reciprocal relationship between these malformations and the SCN1A mutation.5 In the present study, the authors report five children with MRI changes. In three of them they were similar to those previously reported: post-status epilepticus and postencephalitic hypoxic brain injury, and hippocampal sclerosis. In the remaining they were different. One patient had ‘a progressive course and diffuse white-matter abnormalities’. As the authors do not have details and do not indicate if he carries a mutation, we do not know the meaning of the ‘progressive course’ in that case. We were more puzzled by the last patient who had hydrocephaly and a ventriculoperitoneal shunt. Once more, the authors do not have further information so it is impossible to understand this peculiar and unique association and to make any kind of hypothesis. However, these cases do add further questions regarding the discovery of brain anomalies in patients with Dravet syndrome as discussed by Barba et al.5 In practice, when possible, it would be useful to repeat MRI in childhood or adolescence. On the whole, the advances in MRI and genetics technology allow a better knowledge of this disease but also the emergence of new findings, making the disease more complex than we had initially thought and pushing us to go forward and more deeply into the scientific research.
REFERENCES €k T. Dravet syndrome in Sweden: 1. Rosander C, Hallb€ oo a population-based study. Dev Med Child Neurol 2015; 57: 628–33. 2. Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Prognostic, clinical and demographic features in
3. Dravet C. The core Dravet syndrome phenotype. Epilepsia 2011; 52(Suppl. 2): 3–9. 4. Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y.
5. Barba C, Parrini E, Coras R, et al. Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 2014; 55: 1009–19.
A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 2010; 51: 1043–52.
SCN1A mutation-positive Dravet syndrome. Brain 2012; 135: 2329–36.
© 2015 Mac Keith Press
593
