- Email: [email protected]
Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy
Brain & Development xxx (2016) xxx–xxx www.elsevier.com/locate/braindev
Case Report
Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy Robertino Dilena a,⇑, Pasquale Striano b, Elena Gennaro c, Laura Bassi d, Sara Olivotto e, Laura Tadini a, Fabio Mosca d, Sergio Barbieri a, Federico Zara f, Monica Fumagalli d a
Service of Pediatric Epileptology – Unit of Clinical Neurophysiology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy b Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, Institute ‘‘G. Gaslini” University of Genova, Genoa, Italy c Laboratory of Genetics, E.O. Ospedali Galliera, Genova, Italy d NICU, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Universita` degli Studi di Milano, Milan, Italy e Child and Adolescent Neuropsychiatric Service (UONPIA), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy f Pediatric Neurology and Muscular Diseases Unit, Laboratory of Neurogenetics, Institute ‘‘G. Gaslini”, Genoa, Italy Received 12 July 2016; received in revised form 15 October 2016; accepted 29 October 2016
Abstract Background: Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. Patient description: A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p. [Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. Conclusions: Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: SCN2A; Early infantile epileptic encephalopathy; Sodium channel blockers; Carbamazepine; Phenytoin
1. Introduction ⇑ Corresponding author at: Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Servizio di Epilettologia e Neurofisiopatologia Pediatrica, Clinica Mangiagalli, via Commenda 12, 20122 Milan, Italy. Fax: +39 0255032155. E-mail address: [email protected] (R. Dilena).
Early infantile epileptic encephalopathy (EIEE) due to SCN2A mutations (EIEE 11) is attributed to dysfunction of the brain sodium channel Na(V)1.2 [1,2]. In some patients with EIEE 11 in vitro
http://dx.doi.org/10.1016/j.braindev.2016.10.015 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
2
R. Dilena et al. / Brain & Development xxx (2016) xxx–xxx
electrophysiological studies have demonstrated a gain of function mutation of the sodium channel. In these cases sodium channel blockers might specifically reverse the epileptogenic dysfunction, although the benefit might vary from case to case [3]. 2. Case history A male infant was born at term to unrelated healthy parents following uncomplicated pregnancy and delivery. On the second day of life seizures characterized by asymmetric tonic posture with alternating side, apnea and clonic movements were observed. They lasted 1–2 min and recurred 20–25 times per day. The neurological evaluation showed lethargy, hypotonia, poor general movements, inconstant eye contact, feeding difficulties requiring nasogatric tube feeding. The electroencephalogram (EEG) showed a burst-suppression pattern, characterized by periodic burst of high-amplitude polispikes and slow-waves lasting 2–5 s separated by lowamplitude activity intervals lasting 3–4 s (Fig. 1). The seizures (Fig. 2) were characterized by abrupt interruption of the burst-suppression activity and appearance of a low-amplitude fast activity more expressed in one hemisphere related to asymmetric tonic posture and apnea, followed by spike-wave activity related to clonic movements, then the seizure often migrated to the contralateral side repeating with a similar sequence. Postnatal brain MRI showed neither structural nor acquired brain abnormalities. Extended metabolic blood and cerebrospinal fluid work-up yielded negative findings. Phenobarbital (PB) was ineffective in controlling seizures, despite adequate serum doses (PB blood levels: 30–40 mcg/ml). The addiction of levetiracetam (LEV) at 40 mg/kg/day led to transient seizure freedom (for six days), but with persistence of severe EEG abnormalities. After one week seizures relapsed (LEV blood level: 15 mcg/ml) and no benefit was obtained from increasing
LEV to 80 mg/kg/day. Intravenous pyridoxine (100 mg) and oral pyridoxal phosphate (30 mg/kg/day) for three days were ineffective. Conversely, a dramatic change was observed after the administration of an intravenous dose of 20 mg/kg of phenytoin (PHT). The video-EEG monitoring showed an immediate seizure interruption and, within few hours, the remission of the burstsuppression activity along with the appearance of sleep-wake patterns with sporadic multifocal spikes (Fig. 3). PB and LEV were withdrawn and a high PHT dosage (12–18 mg/kg in four daily doses), able to maintain blood level concentration close to the upper limit of the therapeutic range, was pursued leading to complete seizure control, marked improvement of EEG background and neurological status with improved eye contact and oral feeding. Due to unstable PHT blood levels, seizures recurred when PHT serum concentration fell under 13 mcg/ml. Considering the overall good response to adequate PHT levels, oral CBZ was introduced and progressively increased to 30 mg/kg/day divided in 4 doses (CBZ blood levels: 8–10 mcg/ml) reaching a complete and stable seizure freedom. On CBZ monotherapy the patient has remained seizure-free but for an episode of febrile seizure at the age of 1 year. Control EEGs demonstrated normal wake and sleep patterns with sporadic frontocentral spikes during NREM sleep. The last neurological examination performed at two years and three months of age showed strabismus, hypotonia, clumsiness, ataxic gait requiring bilateral support, hand stereotypies, scarce babbling and comprehension difficulties. A developmental assessment through the Griffiths Mental Development Scale showed a marked developmental delay (General Quotient-GQ: 47) with more pronounced difficulties in the performance (39), eye and hand coordination (43) and locomotor (45) subscales compared to personal and social (54) and hearing and language/speech (54) subscales.
Fig. 1. Interictal EEG at age 2 days showing burst-suppression background pattern and frequent generalized and multifocal polymorphic epileptiform discharges.
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
R. Dilena et al. / Brain & Development xxx (2016) xxx–xxx
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Fig. 2. Ictal EEG of a migrating partial seizure at age 2 days. The upper trace shows the first part of the seizure: an ictal low amplitude beta activity arises from the left hemisphere together with contralateral muscle artifact due to the right-sided tonic phase of the seizure (asymmetric posturing with head deviation, hypertonic extended right extremities and some tremors in left side extremities ascribable to reactive movements in the side free to move). The lower trace shows the second part of the seizure: the previous left hemisphere ictal fast activity is followed by a spike-wave activity in the left frontal regions (related to slight right-sided clonic movements), during which an intraictal focal activation of a contralateral ictal rhythm of different frequency recruits in the right posterior leads. This second discharge is characterized by the same frequency sequence seen previously in the first discharge: at the beginning a recruiting focal low amplitude fast (beta-alpha) activity during the partial tonic phase (clinically related to a specular change of the asymmetric tonic posture with appearance of contralateral head turning and hypertonic extension of the left extremities) and later by a rhythmic spike-wave activity in the same region.
Target resequencing of 19 genes (ALDH7A1, PNPO, ARHGEF9, SLC25A22, PLCB1, TBC1D24, PNKP, KCNT1, KCNQ2, SCN2A, SCN8A, STXBP1, SCN1A, PCDH19, CDKL5, SPTAN1, SLC2A1, ST3GAL3, GRIN2A, STXBP1) identified in SCN2A a novel heterozygous mutation (c.[4633A>G]p.[Met1545Val]) occurring de novo and involving a highly conserved aminoacid with a probable damaging functional effect. 3. Discussion We report a patient with EIEE with burstsuppression and tonic-clonic migrating partial seizures due to a novel SCN2A mutation, in whom EEG monitoring showed a specific dose-dependent efficacy of sodium channel blockers. The electro-clinical features
and therapeutic response are consistent with those reported in other SCN2A patients [1–3]. Previous studies have shown that SCN2A mutations alter the channel electrophysiological properties and may lead to neuronal hyperexcitation through different mechanisms depending on the specific mutation. Mutations may produce channels with both augmented and reduced hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation channel activities. In our case, pathogenicity of the identified SCN2A change is supported by evolutionary conservation, its de novo origin, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in the domain IV [3]. Our case suggests that in severe epileptic encephalopathy with features compatible with EIEE
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
4
R. Dilena et al. / Brain & Development xxx (2016) xxx–xxx
Fig. 3. EEG at age 20 days (at seizure remission following phenytoin therapy) showing striking improvement of background activity and appearance of physiological wake and sleep pattern. However, sporadic multifocal spikes are still observed.
11 intravenous PHT load is suitable as first option to rapidly test the efficacy of sodium channel blockers. It is recommended to obtain high PHT blood levels with very high daily maintenance dosage. If seizure remission is induced, a caution switch to another sodium channel blocker (e.g., carbamazepine) should be considered for maintenance therapy due to the poor pharmacokinetics and severe safety profile of phenytoin. Despite the complete and early epilepsy control, the patient manifested a developmental delay. This demonstrate that in the epileptic encephalopathies epilepsy burden may account for a part of the disability, but the outcome is highly dependent on the underlying substrate. Efficacy of sodium channel blockers has been recently described also for KCNQ2 encephalopathy [4]. Sodium and potassium channels cooperate in the regulation of action potential firing. SCN2A and KCNQ2 mutations can share a similar phenotype, characterized by EIEE with asymmetric tonic seizures and a variable abnormal EEG. A response to sodium channel blockers in the context of such an electro-clinical presentation is a diagnostic clue for sodium or potassium channel mutations. Finally, our case also exemplified that pharmacological refractoriness needs to be related to the underlying cause. When dealing with genetic EIEE, complete seizure control might still be obtained with a specific therapy [4–6]. The novel genetic methods, that are able to analyze all known genes at a reasonable price, are of paramount importance to discover novel therapeutic avenues and individualized medicine [6]. Collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.
Acknowledgement The authors declared no potential conflict of interest and no financial support for the research, the authorship and publication of this article. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.braindev.2016.10.015. References [1] Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, et al. De novo mutations of voltage-gated sodium channel alpha II gene SCN2A in intractable epilepsies. Neurology 2009;73:1046–53. [2] Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, et al. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology 2010;75:1454–8. [3] Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-Casero V, et al. SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015;85:958–66. [4] Weckhuysen S, Ivanovic V, Hendrickx R, Van Coster R, Hjalgrim H, Møller RS, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013;81:1697–703. [5] Dilena R, Striano P, Traverso M, Viri M, Cristofori G, Tadini L, et al. Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation. Brain Dev 2016;38:128–31. [6] Striano P, Vari MS, Mazzocchetti C, Verrotti A, Zara F. Management of genetic epilepsies: from empirical treatment to precision medicine. Pharmacol Res 2016;107:426–9.
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
Case Report
Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy Robertino Dilena a,⇑, Pasquale Striano b, Elena Gennaro c, Laura Bassi d, Sara Olivotto e, Laura Tadini a, Fabio Mosca d, Sergio Barbieri a, Federico Zara f, Monica Fumagalli d a
Service of Pediatric Epileptology – Unit of Clinical Neurophysiology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy b Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, Institute ‘‘G. Gaslini” University of Genova, Genoa, Italy c Laboratory of Genetics, E.O. Ospedali Galliera, Genova, Italy d NICU, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Universita` degli Studi di Milano, Milan, Italy e Child and Adolescent Neuropsychiatric Service (UONPIA), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy f Pediatric Neurology and Muscular Diseases Unit, Laboratory of Neurogenetics, Institute ‘‘G. Gaslini”, Genoa, Italy Received 12 July 2016; received in revised form 15 October 2016; accepted 29 October 2016
Abstract Background: Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. Patient description: A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p. [Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. Conclusions: Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: SCN2A; Early infantile epileptic encephalopathy; Sodium channel blockers; Carbamazepine; Phenytoin
1. Introduction ⇑ Corresponding author at: Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Servizio di Epilettologia e Neurofisiopatologia Pediatrica, Clinica Mangiagalli, via Commenda 12, 20122 Milan, Italy. Fax: +39 0255032155. E-mail address: [email protected] (R. Dilena).
Early infantile epileptic encephalopathy (EIEE) due to SCN2A mutations (EIEE 11) is attributed to dysfunction of the brain sodium channel Na(V)1.2 [1,2]. In some patients with EIEE 11 in vitro
http://dx.doi.org/10.1016/j.braindev.2016.10.015 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
2
R. Dilena et al. / Brain & Development xxx (2016) xxx–xxx
electrophysiological studies have demonstrated a gain of function mutation of the sodium channel. In these cases sodium channel blockers might specifically reverse the epileptogenic dysfunction, although the benefit might vary from case to case [3]. 2. Case history A male infant was born at term to unrelated healthy parents following uncomplicated pregnancy and delivery. On the second day of life seizures characterized by asymmetric tonic posture with alternating side, apnea and clonic movements were observed. They lasted 1–2 min and recurred 20–25 times per day. The neurological evaluation showed lethargy, hypotonia, poor general movements, inconstant eye contact, feeding difficulties requiring nasogatric tube feeding. The electroencephalogram (EEG) showed a burst-suppression pattern, characterized by periodic burst of high-amplitude polispikes and slow-waves lasting 2–5 s separated by lowamplitude activity intervals lasting 3–4 s (Fig. 1). The seizures (Fig. 2) were characterized by abrupt interruption of the burst-suppression activity and appearance of a low-amplitude fast activity more expressed in one hemisphere related to asymmetric tonic posture and apnea, followed by spike-wave activity related to clonic movements, then the seizure often migrated to the contralateral side repeating with a similar sequence. Postnatal brain MRI showed neither structural nor acquired brain abnormalities. Extended metabolic blood and cerebrospinal fluid work-up yielded negative findings. Phenobarbital (PB) was ineffective in controlling seizures, despite adequate serum doses (PB blood levels: 30–40 mcg/ml). The addiction of levetiracetam (LEV) at 40 mg/kg/day led to transient seizure freedom (for six days), but with persistence of severe EEG abnormalities. After one week seizures relapsed (LEV blood level: 15 mcg/ml) and no benefit was obtained from increasing
LEV to 80 mg/kg/day. Intravenous pyridoxine (100 mg) and oral pyridoxal phosphate (30 mg/kg/day) for three days were ineffective. Conversely, a dramatic change was observed after the administration of an intravenous dose of 20 mg/kg of phenytoin (PHT). The video-EEG monitoring showed an immediate seizure interruption and, within few hours, the remission of the burstsuppression activity along with the appearance of sleep-wake patterns with sporadic multifocal spikes (Fig. 3). PB and LEV were withdrawn and a high PHT dosage (12–18 mg/kg in four daily doses), able to maintain blood level concentration close to the upper limit of the therapeutic range, was pursued leading to complete seizure control, marked improvement of EEG background and neurological status with improved eye contact and oral feeding. Due to unstable PHT blood levels, seizures recurred when PHT serum concentration fell under 13 mcg/ml. Considering the overall good response to adequate PHT levels, oral CBZ was introduced and progressively increased to 30 mg/kg/day divided in 4 doses (CBZ blood levels: 8–10 mcg/ml) reaching a complete and stable seizure freedom. On CBZ monotherapy the patient has remained seizure-free but for an episode of febrile seizure at the age of 1 year. Control EEGs demonstrated normal wake and sleep patterns with sporadic frontocentral spikes during NREM sleep. The last neurological examination performed at two years and three months of age showed strabismus, hypotonia, clumsiness, ataxic gait requiring bilateral support, hand stereotypies, scarce babbling and comprehension difficulties. A developmental assessment through the Griffiths Mental Development Scale showed a marked developmental delay (General Quotient-GQ: 47) with more pronounced difficulties in the performance (39), eye and hand coordination (43) and locomotor (45) subscales compared to personal and social (54) and hearing and language/speech (54) subscales.
Fig. 1. Interictal EEG at age 2 days showing burst-suppression background pattern and frequent generalized and multifocal polymorphic epileptiform discharges.
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
R. Dilena et al. / Brain & Development xxx (2016) xxx–xxx
3
Fig. 2. Ictal EEG of a migrating partial seizure at age 2 days. The upper trace shows the first part of the seizure: an ictal low amplitude beta activity arises from the left hemisphere together with contralateral muscle artifact due to the right-sided tonic phase of the seizure (asymmetric posturing with head deviation, hypertonic extended right extremities and some tremors in left side extremities ascribable to reactive movements in the side free to move). The lower trace shows the second part of the seizure: the previous left hemisphere ictal fast activity is followed by a spike-wave activity in the left frontal regions (related to slight right-sided clonic movements), during which an intraictal focal activation of a contralateral ictal rhythm of different frequency recruits in the right posterior leads. This second discharge is characterized by the same frequency sequence seen previously in the first discharge: at the beginning a recruiting focal low amplitude fast (beta-alpha) activity during the partial tonic phase (clinically related to a specular change of the asymmetric tonic posture with appearance of contralateral head turning and hypertonic extension of the left extremities) and later by a rhythmic spike-wave activity in the same region.
Target resequencing of 19 genes (ALDH7A1, PNPO, ARHGEF9, SLC25A22, PLCB1, TBC1D24, PNKP, KCNT1, KCNQ2, SCN2A, SCN8A, STXBP1, SCN1A, PCDH19, CDKL5, SPTAN1, SLC2A1, ST3GAL3, GRIN2A, STXBP1) identified in SCN2A a novel heterozygous mutation (c.[4633A>G]p.[Met1545Val]) occurring de novo and involving a highly conserved aminoacid with a probable damaging functional effect. 3. Discussion We report a patient with EIEE with burstsuppression and tonic-clonic migrating partial seizures due to a novel SCN2A mutation, in whom EEG monitoring showed a specific dose-dependent efficacy of sodium channel blockers. The electro-clinical features
and therapeutic response are consistent with those reported in other SCN2A patients [1–3]. Previous studies have shown that SCN2A mutations alter the channel electrophysiological properties and may lead to neuronal hyperexcitation through different mechanisms depending on the specific mutation. Mutations may produce channels with both augmented and reduced hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation channel activities. In our case, pathogenicity of the identified SCN2A change is supported by evolutionary conservation, its de novo origin, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in the domain IV [3]. Our case suggests that in severe epileptic encephalopathy with features compatible with EIEE
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015
4
R. Dilena et al. / Brain & Development xxx (2016) xxx–xxx
Fig. 3. EEG at age 20 days (at seizure remission following phenytoin therapy) showing striking improvement of background activity and appearance of physiological wake and sleep pattern. However, sporadic multifocal spikes are still observed.
11 intravenous PHT load is suitable as first option to rapidly test the efficacy of sodium channel blockers. It is recommended to obtain high PHT blood levels with very high daily maintenance dosage. If seizure remission is induced, a caution switch to another sodium channel blocker (e.g., carbamazepine) should be considered for maintenance therapy due to the poor pharmacokinetics and severe safety profile of phenytoin. Despite the complete and early epilepsy control, the patient manifested a developmental delay. This demonstrate that in the epileptic encephalopathies epilepsy burden may account for a part of the disability, but the outcome is highly dependent on the underlying substrate. Efficacy of sodium channel blockers has been recently described also for KCNQ2 encephalopathy [4]. Sodium and potassium channels cooperate in the regulation of action potential firing. SCN2A and KCNQ2 mutations can share a similar phenotype, characterized by EIEE with asymmetric tonic seizures and a variable abnormal EEG. A response to sodium channel blockers in the context of such an electro-clinical presentation is a diagnostic clue for sodium or potassium channel mutations. Finally, our case also exemplified that pharmacological refractoriness needs to be related to the underlying cause. When dealing with genetic EIEE, complete seizure control might still be obtained with a specific therapy [4–6]. The novel genetic methods, that are able to analyze all known genes at a reasonable price, are of paramount importance to discover novel therapeutic avenues and individualized medicine [6]. Collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.
Acknowledgement The authors declared no potential conflict of interest and no financial support for the research, the authorship and publication of this article. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.braindev.2016.10.015. References [1] Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, et al. De novo mutations of voltage-gated sodium channel alpha II gene SCN2A in intractable epilepsies. Neurology 2009;73:1046–53. [2] Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, et al. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology 2010;75:1454–8. [3] Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-Casero V, et al. SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015;85:958–66. [4] Weckhuysen S, Ivanovic V, Hendrickx R, Van Coster R, Hjalgrim H, Møller RS, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013;81:1697–703. [5] Dilena R, Striano P, Traverso M, Viri M, Cristofori G, Tadini L, et al. Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation. Brain Dev 2016;38:128–31. [6] Striano P, Vari MS, Mazzocchetti C, Verrotti A, Zara F. Management of genetic epilepsies: from empirical treatment to precision medicine. Pharmacol Res 2016;107:426–9.
Please cite this article in press as: Dilena R et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.10.015