GRAY MATTERS to date. Clearly, the addition of the Korean, German, Greek, and Arabic versions points to the recognition by the medical community of this user-friendly and valuable tool in the screening of major depressive episodes in patients with epilepsy by all clinicians. Finally, we hope that a timely recognition of this severe form of mood disorder will also result in its effective treatment that can be incorporated into the comprehensive management of seizure disorder in these patients. DISCLOSURE Dr. Alfredo Thomson has received honoraria for lectures given on behalf of the following pharmaceutical companies: Abbott, Novartis, GlaxoSmithKline, Pfizer, UCB Pharma, Jansen-Cilag, Gador and Raffo laboratories. In addition he has received honoraria for participation in clinical trials from the following pharmaceutical companies: Novartis, Jansen-Cilag, Eisai, and Upsher-Smith. Dr. Analia Calle has no disclosure to report. 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.
Alfredo E. Thomson1,2,3 [email protected] Analıa Calle1 1 Department of Neurology, Institute of Neurosciences at Favaloro University, Buenos Aires, Argentina; 2 Institute of Cognitive Neurology (INECO), Buenos Aires, Argentina; and 3 Department of Neurology, British Hospital, Buenos Aires, Argentina REFERENCE 1. Thomson AE, Calle A, Fontela ME, et al. Screening of major depression in epilepsy: The Neurologic Depression Disorders Inventory in Epilepsy-Spanish version (Argentina). Epilepsia 2014;55:331–334.
Terminology and prognosis of Dravet syndrome To the Editors: I read with great interest the article by Takayama et al.,1 ”Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.” This study brings us new and precise information on the course of Dravet syndrome (DS) in adulthood. Electroencephalography (EEG) data were particularly detailed, showing variability between the patients and confirming the positive relationship between a posterior alpha rhythm and a relatively favorable outcome. I thank the authors for the terminology they have used: replacing “borderline” forms with “atypical” forms. I agree that since the name “Dravet syndrome” was adopted by the International League Against Epilepsy (ILAE) Task Force on terminology2 to include the different forms, Epilepsia, 55(6):941–947, 2014
with and without the complete symptomatology, the incomplete forms intrinsically belong to the syndrome and there is no more reason to consider them as borderline.3 One argument for eliminating the separation is the presence of an SCN1A mutation in most of the different forms. However, this study confirms the previous hypothesis that patients who have the complete form with prominent myoclonic seizures have a less favorable outcome in terms of epileptic seizures and cognitive functions. In 1987, Dalla Bernardina et al.4 found that the presence of myoclonus negatively influenced the cognitive course during childhood and adolescence. Ragona et al.5 reported only one patient with myoclonic seizures among seven patients who had a slight cognitive decline during the course of DS, opposed to 12 among 19 who had a moderate or severe decline, even though this difference did not reach statistical significance. In a recent study,6 the authors found that the cognitive skills were significantly lower in patients older than 3 years of age who presented with myoclonic seizures (p ≤ 0.03) or focal seizures (p ≤ 0.03) when compared to the whole group of patients older than 3 years. Thus if they seem to be minor in their semiology, the myoclonic seizures are not really minor in their consequences. My third comment addresses the roles of epilepsy and genetic alterations in cognitive impairment that are still in discussion. Catarino et al.7 deeply studied 22 adult patients, with an extensive neuropathologic examination of three patients who died. The autopsy did not reveal morphological abnormalities in the central nervous system or specific histopathological changes that could explain the cognitive decline characteristic of DS. Moreover, some patients benefited from an adaptation of their antiepileptic treatment, which resulted in seizure reduction and a marked cognitive improvement. The authors concluded that their data support the assertion that DS is at least partially an epileptic encephalopathy. However, I agree with the authors of the present study who have underscored the complexity of the factors at stake in the general outcome of this syndrome. I believe that the genetic background also plays a key role in the comprehension of this outcome. Only prospective studies of a large number of patients would allow establishing correlations between genetics, epilepsy, and cognitive functions, without overlooking the environmental factors. DISCLOSURES The author is appointed by Biocodex as an occasional expert. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with these guidelines.
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Charlotte Dravet [email protected] Child Neuropsychiatry, Catholic University, Roma, Italy
GRAY MATTERS REFERENCES 1. Takayama R, Fujiwara T, Shigematsu H, et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014 Feb 6 [Epub ahead of print]. 2. Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001; 42:796–803. 3. Guerrini R, Oguni H. Borderline Dravet syndrome: a useful diagnostic category? Epilepsia 2011; 52(Suppl. 2):10–12. 4. Dalla Bernardina B, Capovilla G, Chiamenti C, et al. Cryptogenic myoclonic epilepsies of infancy and early childhood: nosological and prognostic approach. In: Wolf P, Dam M, Janz D, Dreifuss FE (Eds) Advances in epileptology. Raven Press, New-York, 1987, pp. 175–180 5. Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a retrospective multi center study of 26 patients. Epilepsia 2011; 52:386–392 6. Nabbout R, Chemaly N, Chipaux M, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis 2013; 8:176. 7. Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 2011; 134(Pt 10):2982–3010.
In response to terminology and prognosis of Dravet syndrome
cephalography (EEG) examinations are useful to evaluate and foresee clinical outcome of DS. Myoclonic seizure: We agree with Dr. Dravet that myoclonic seizures are not really minor in their consequences. Although our study and previous studies have elucidated that the extent of damage from convulsion plays an important role in outcomes, neuropsychological sequelae of minor generalized seizure such as myoclonic seizure are not well studied. Possibly the existence of myoclonic seizures may indicate severity of epileptic encephalopathy. Outcomes: We think that there is a complex interplay of many factors in the general outcome of DS, including the genetic background. As Dr. Dravet notes, cognitive and seizure outcomes in some patients benefited from new antiepileptic medications. With such treatment, the longterm outcome of DS might become less severe in the future. In addition, the understanding of clinical picture of DS prompts us to earlier recognition of this condition and introduction of neuropsychological and educational interventions as well as modification of the environment, which could contribute to improved cognitive and developmental outcome. DISCLOSURE
To the Editors: We deeply thank Dr. Dravet for her warm interest in our recent article1 and for her thoughtful comments, with which we agree entirely. Herein we add some explanations and comments. Terminology: We previously advocated the term “intractable childhood epilepsy with generalized tonic– clonic seizure” (ICEGTC) for a group of patients who manifest only major generalized seizures with/without additional complex focal seizures.2,3 However, because the older terminologies such as borderline severe myoclonic epilepsy in infancy (SMEB) and ICEGTC are somewhat confusing, in this article we used the term “typical DS” for core SMEI and “atypical DS” for ICEGTC and SMEB. Atypical DS refers to patients without minor generalized seizures. Currently, these related epilepsies are known to have high frequencies of SCNIA mutations; they are positioned on the Dravet syndrome (DS).4 We agree with Dr. Dravet that the incomplete form intrinsically belongs to the syndrome, and that there is no more reason to consider them as borderline. Posterior alpha rhythm: In this study, the freedom from seizures significantly correlated with appearance of occipital alpha rhythms in the background activity (p = 0.0008). Akiyama et al.5 reported a correlation between the presence of occipital alpha rhythms and mild intellectual disability. We reconfirmed a trend of milder intellectual disability in patients with occipital alpha rhythms compared to those without. We think consecutive electroen-
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. None of the authors has any conflicts of interest to disclose.
Rumiko Takayama1 Tateki Fujiwara1 Hideo Shigematsu1 Katsumi Imai1 Yukitoshi Takahashi1 Kazuhiro Yamakawa2 Yushi Inoue1 [email protected] 1 National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan; and 2 Laboratory for Neurogenetics, RIKEN, Brain Science Institute, Saitama, Japan REFERENCES 1. Takayama R, Fujiwara T, Shigematsu H, et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014;54:1–11. 2. Watanabe M, Fujiwara T, Terauchi N, et al. Intractable grand mal epilepsy developed in the first year of life. In Manelis J, Bentol E, Loever JN, Dreifuss FE (Eds) Advances in epileptology: the 17th Epilepsy International Symposium. New York, NY: Raven Press, 1989:327–329. 3. Watanabe M, Fujiwara T, Yagi K, et al. Intractable childhood epilepsy with generalized tonic–clonic seizures. J Jpn Epil Soc 1989;7:96–105 (In Japanese). 4. Fujiwara T, Sugawara T, Mazaki-Miyazaki E, et al. Mutations of sodium channel a subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures. Brain 2003;126:531–546. 5. Akiyama M, Kobayashi K, Yoshinaga H, et al. (2010) A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 51:1043–1052.
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Epilepsia, 55(6):941–947, 2014
Alfredo E. Thomson1,2,3 [email protected] Analıa Calle1 1 Department of Neurology, Institute of Neurosciences at Favaloro University, Buenos Aires, Argentina; 2 Institute of Cognitive Neurology (INECO), Buenos Aires, Argentina; and 3 Department of Neurology, British Hospital, Buenos Aires, Argentina REFERENCE 1. Thomson AE, Calle A, Fontela ME, et al. Screening of major depression in epilepsy: The Neurologic Depression Disorders Inventory in Epilepsy-Spanish version (Argentina). Epilepsia 2014;55:331–334.
Terminology and prognosis of Dravet syndrome To the Editors: I read with great interest the article by Takayama et al.,1 ”Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.” This study brings us new and precise information on the course of Dravet syndrome (DS) in adulthood. Electroencephalography (EEG) data were particularly detailed, showing variability between the patients and confirming the positive relationship between a posterior alpha rhythm and a relatively favorable outcome. I thank the authors for the terminology they have used: replacing “borderline” forms with “atypical” forms. I agree that since the name “Dravet syndrome” was adopted by the International League Against Epilepsy (ILAE) Task Force on terminology2 to include the different forms, Epilepsia, 55(6):941–947, 2014
with and without the complete symptomatology, the incomplete forms intrinsically belong to the syndrome and there is no more reason to consider them as borderline.3 One argument for eliminating the separation is the presence of an SCN1A mutation in most of the different forms. However, this study confirms the previous hypothesis that patients who have the complete form with prominent myoclonic seizures have a less favorable outcome in terms of epileptic seizures and cognitive functions. In 1987, Dalla Bernardina et al.4 found that the presence of myoclonus negatively influenced the cognitive course during childhood and adolescence. Ragona et al.5 reported only one patient with myoclonic seizures among seven patients who had a slight cognitive decline during the course of DS, opposed to 12 among 19 who had a moderate or severe decline, even though this difference did not reach statistical significance. In a recent study,6 the authors found that the cognitive skills were significantly lower in patients older than 3 years of age who presented with myoclonic seizures (p ≤ 0.03) or focal seizures (p ≤ 0.03) when compared to the whole group of patients older than 3 years. Thus if they seem to be minor in their semiology, the myoclonic seizures are not really minor in their consequences. My third comment addresses the roles of epilepsy and genetic alterations in cognitive impairment that are still in discussion. Catarino et al.7 deeply studied 22 adult patients, with an extensive neuropathologic examination of three patients who died. The autopsy did not reveal morphological abnormalities in the central nervous system or specific histopathological changes that could explain the cognitive decline characteristic of DS. Moreover, some patients benefited from an adaptation of their antiepileptic treatment, which resulted in seizure reduction and a marked cognitive improvement. The authors concluded that their data support the assertion that DS is at least partially an epileptic encephalopathy. However, I agree with the authors of the present study who have underscored the complexity of the factors at stake in the general outcome of this syndrome. I believe that the genetic background also plays a key role in the comprehension of this outcome. Only prospective studies of a large number of patients would allow establishing correlations between genetics, epilepsy, and cognitive functions, without overlooking the environmental factors. DISCLOSURES The author is appointed by Biocodex as an occasional expert. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with these guidelines.
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Charlotte Dravet [email protected] Child Neuropsychiatry, Catholic University, Roma, Italy
GRAY MATTERS REFERENCES 1. Takayama R, Fujiwara T, Shigematsu H, et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014 Feb 6 [Epub ahead of print]. 2. Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001; 42:796–803. 3. Guerrini R, Oguni H. Borderline Dravet syndrome: a useful diagnostic category? Epilepsia 2011; 52(Suppl. 2):10–12. 4. Dalla Bernardina B, Capovilla G, Chiamenti C, et al. Cryptogenic myoclonic epilepsies of infancy and early childhood: nosological and prognostic approach. In: Wolf P, Dam M, Janz D, Dreifuss FE (Eds) Advances in epileptology. Raven Press, New-York, 1987, pp. 175–180 5. Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a retrospective multi center study of 26 patients. Epilepsia 2011; 52:386–392 6. Nabbout R, Chemaly N, Chipaux M, et al. Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy. Orphanet J Rare Dis 2013; 8:176. 7. Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain 2011; 134(Pt 10):2982–3010.
In response to terminology and prognosis of Dravet syndrome
cephalography (EEG) examinations are useful to evaluate and foresee clinical outcome of DS. Myoclonic seizure: We agree with Dr. Dravet that myoclonic seizures are not really minor in their consequences. Although our study and previous studies have elucidated that the extent of damage from convulsion plays an important role in outcomes, neuropsychological sequelae of minor generalized seizure such as myoclonic seizure are not well studied. Possibly the existence of myoclonic seizures may indicate severity of epileptic encephalopathy. Outcomes: We think that there is a complex interplay of many factors in the general outcome of DS, including the genetic background. As Dr. Dravet notes, cognitive and seizure outcomes in some patients benefited from new antiepileptic medications. With such treatment, the longterm outcome of DS might become less severe in the future. In addition, the understanding of clinical picture of DS prompts us to earlier recognition of this condition and introduction of neuropsychological and educational interventions as well as modification of the environment, which could contribute to improved cognitive and developmental outcome. DISCLOSURE
To the Editors: We deeply thank Dr. Dravet for her warm interest in our recent article1 and for her thoughtful comments, with which we agree entirely. Herein we add some explanations and comments. Terminology: We previously advocated the term “intractable childhood epilepsy with generalized tonic– clonic seizure” (ICEGTC) for a group of patients who manifest only major generalized seizures with/without additional complex focal seizures.2,3 However, because the older terminologies such as borderline severe myoclonic epilepsy in infancy (SMEB) and ICEGTC are somewhat confusing, in this article we used the term “typical DS” for core SMEI and “atypical DS” for ICEGTC and SMEB. Atypical DS refers to patients without minor generalized seizures. Currently, these related epilepsies are known to have high frequencies of SCNIA mutations; they are positioned on the Dravet syndrome (DS).4 We agree with Dr. Dravet that the incomplete form intrinsically belongs to the syndrome, and that there is no more reason to consider them as borderline. Posterior alpha rhythm: In this study, the freedom from seizures significantly correlated with appearance of occipital alpha rhythms in the background activity (p = 0.0008). Akiyama et al.5 reported a correlation between the presence of occipital alpha rhythms and mild intellectual disability. We reconfirmed a trend of milder intellectual disability in patients with occipital alpha rhythms compared to those without. We think consecutive electroen-
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. None of the authors has any conflicts of interest to disclose.
Rumiko Takayama1 Tateki Fujiwara1 Hideo Shigematsu1 Katsumi Imai1 Yukitoshi Takahashi1 Kazuhiro Yamakawa2 Yushi Inoue1 [email protected] 1 National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan; and 2 Laboratory for Neurogenetics, RIKEN, Brain Science Institute, Saitama, Japan REFERENCES 1. Takayama R, Fujiwara T, Shigematsu H, et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia 2014;54:1–11. 2. Watanabe M, Fujiwara T, Terauchi N, et al. Intractable grand mal epilepsy developed in the first year of life. In Manelis J, Bentol E, Loever JN, Dreifuss FE (Eds) Advances in epileptology: the 17th Epilepsy International Symposium. New York, NY: Raven Press, 1989:327–329. 3. Watanabe M, Fujiwara T, Yagi K, et al. Intractable childhood epilepsy with generalized tonic–clonic seizures. J Jpn Epil Soc 1989;7:96–105 (In Japanese). 4. Fujiwara T, Sugawara T, Mazaki-Miyazaki E, et al. Mutations of sodium channel a subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures. Brain 2003;126:531–546. 5. Akiyama M, Kobayashi K, Yoshinaga H, et al. (2010) A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 51:1043–1052.
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