Brief Communication
Successful Treatment of Refractory Seizures With Rufinamide in Children With Schizencephaly: Report of 3 Cases
Journal of Child Neurology 2015, Vol. 30(8) 1079-1083 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814542951 jcn.sagepub.com
Alberto Verrotti, MD, PhD1, Giulia Loiacono, MD2, Alessandra Rossi, MD2, Armando Tartaro, MD3, Andrea Delli Pizzi, MD3, and Giangennaro Coppola, MD4
Abstract Schizencephaly is an uncommon malformation of cortical development. Patients with schizencephaly present with a broad range of severe neurologic symptoms including pharmacoresistant epilepsy. Rufinamide is a new antiepileptic drug approved for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome and it is also effective for refractory partial seizures. We report 3 cases of pediatric patients aged 7.2, 8.1, and 10.1 years, respectively, with intractable epilepsy associated with bilateral open-lip schizencephaly and septo-optic dysplasia. The follow-up ranged from 3.8 to 4.1 years. In our patients, the introduction of rufinamide as adjunctive drug led to a dramatic decline in the number of seizures and an improvement in EEG epileptic activity without side effects. Rufinamide seems to be efficacious and safe in patients with epileptic encephalopathies associated with pharmacoresistant epilepsy; further and larger clinical reports and controlled studies could confirm the usefulness of this anticonvulsant drug. Keywords epilepsy, rufinamide, schizencephaly, septo-optic dysplasia, antiepileptic drugs Received December 10, 2013. Received revised May 20, 2014. Accepted for publication June 06, 2014.
Schizencephaly, an uncommon malformation of cortical development, was first described by Yakovlev and Wadsworth in 2 different studies: the first one1 described closed-lip schizencephaly as a fused cleft that did not permit cerebrospinal fluid to pass, whereas the second one2 described open-lip schizencephaly as a cleft of irregular width permitting cerebrospinal fluid to pass between ventricular cavity and subarachnoid space. Neuroimaging studies showed unilateral or bilateral fullthickness gray matter–lined clefts of the cerebral hemispheres. Patients with schizencephaly present a broad range of severe neurologic symptoms, including developmental delay, hemiparesis or quadriparesis, and seizures. About epilepsy, the most common type is complex partial, although infantile spasms, tonic, atonic, and tonic-clonic seizures are reported.3 Studies have shown that rufinamide (Inovelon in the European Union, Banzel in North America), a relatively new antiepileptic drug approved by European Medicine Agency in 2007 and by the Food and Drug Administration (FDA) in 2008 for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome,4,5 is also effective for refractory partial seizures6,7 and it is a valid adjunctive therapeutic option for children with epileptic spasms8 and when either ACTH or vigabatrin is not effective.9
Here we report 3 cases of bilateral open-lip schizencephaly with accompanying septo-optic dysplasia, in which the introduction of rufinamide as adjunctive drug led to a rapid reduction in the number of seizures. The electroclinical features and course of epilepsy were prospectively followed up for a period ranging from 3.8 to 4.1 years.
Case 1 An 8-year-1-month-old male child, was referred to the Department of Pediatrics of Chieti with diagnosis of psychomotor delay, West syndrome, and generalized tonic-clonic seizures. 1
Department of Pediatrics, University of Perugia, Perugia, Italy Department of Pediatrics, University of Chieti, Chieti, Italy 3 Department of Neuroscience and Imaging, Institute of Advanced Technology, G. d’Annunzio University, Chieti, Italy 4 Child Neuropsychiatry Clinic, Medical School, University of Salerno, Salerno, Italy 2
Corresponding Author: Alberto Verrotti, MD, PhD, Department of Pediatrics, University of Perugia, Loc. S. Andrea Fratte, 06134, Perugia, PG, Italy. Email: [email protected]
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
1080
Journal of Child Neurology 30(8)
He was born at term, by caesarean delivery because of deceleration in cardiotocography, and he was the only child of a non-consanguineous couple with no family history of genetic or neurologic diseases. At 6 months of age, the child presented infantile spasms (more than 20/d); the child was treated previously with tetracosactide, trazodone, vigabatrin, oxcarbazepine, and levetiracetam, but seizures were poorly controlled. The child showed worsening of asymmetric spasms and onset of partial seizures often with secondary generalization (30-40 seizures per day). Physical examination showed microcephaly, gross hypotonia, severe intellectual disability, spastic quadriplegia, blindness, and hearing loss. Electroencephalography (EEG) showed lack of background activity without posterior alpha rhythm, with multifocal spikewave activity: this pattern was prevalent in the left hemisphere, but it was also present asynchronously in the contralateral hemisphere (Figure 1). Brain magnetic resonance imaging (MRI) examination was performed with Philips Achieva (3-Tesla; Philips, Holland) and showed optic dysplasia associated with bilateral open-lip schizencephaly (Figure 2). Because of worsening seizures, rufinamide (16 mg/kg/d) was added to previous therapy (valproic acid and vigabatrin) and it was discharged with 40 mg/kg/d, with a good response. In the next 7 days, the number of seizures decreased from 30 per day to about 3 per day, without major side effects. EEG persisted abnormal but the spikes were very rare. At the last neurologic examination (age: 11.9 years), his seizures were very rare (2/month) and very brief (less than 10 seconds) with the following therapy (rufinamide 40 mg/kg/d and valproic acid 25 mg/kg/d).
Case 2 A 10-year-1-month-old boy, born at term of nonconsanguineous parentage in good health, presented with recurrent seizures characterized by asymmetric spasms and generalized tonic-clonic seizures. There was no adverse prenatal exposure. Septo-optic dysplasia and bilateral schizencephaly with very open lips were diagnosed based on 3-Tesla MRI. Neurologic follow-up identified a delay in acquisition of motor and language developmental milestones. The patient was referred to the Department of Child and Adolescent Neuropsychiatry of Salerno because of poor seizure control, with 30 to 40 episodes of epileptic seizures per day, in spite of antiepileptic polytherapy (valproic acid, vigabatrin, and levetiracetam). Physical examination demonstrated microcephaly and quadriplegia, whereas ophthalmologic evaluation showed bilateral optic disk hypoplasia and nystagmus. EEG revealed diffuse bioelectrical depression with highvoltage, asynchronous bilateral spike-wave, generalized 3 to 4 Hz spike-waves discharges. Because of pharmacoresistant epilepsy (asymmetric spasms and generalized tonic-clonic seizures), rufinamide was administered (dosage of 34 mg/kg/d) as adjunctive therapy, with excellent results: number of seizures decreased to 3 or 4 per
week. After 3 years 8 months from beginning of rufinamide treatment, seizures were well controlled (1 seizure/mo) without side effects. The last EEG recording showed very rare spikes.
Case 3 A 7-year-2-month-old boy was born at term gestation after an uncomplicated pregnancy and delivery; there was no history of consanguinity. Signs of early developmental lag were noticed by the parents. At the age of 26 months, he showed mental retardation, asymmetric spasms, and generalized tonic seizures. Seizures were very frequent, with 20 to 30 episodes per day, in spite of the association of valproic acid and vigabatrin, received from 2 years. At neuropsychological examination, he showed short stature, microcephaly, spastic quadriplegia, severe intellectual disability, bilateral nystagmus, and blindness. EEG recordings during wakefulness and sleep showed generalized high-voltage sharp and slow-wave complexes: the latter were more evident in the left hemisphere. There was activation of the discharges in sleep. Brain MRI, performed with a 1.5-Tesla Siemens Symphony MRI system, showed a small pituitary gland, absence of septum pellucidum, and hypoplasia of the optic nerves (more evident in the right nerve), suggestive of septo-optic dysplasia, and bilateral open-lip schizencephaly, with polymicrogyric gray matter surrounding the clefts bilaterally. Because of the persistence of asymmetric spasms and generalized tonic seizures, rufinamide therapy was started with dramatic decrease in the number of seizures from 20-30 to 2-5 per day. The adjunctive therapy was not only efficacious, but also well tolerated, without side effects. Actually, after 4.1 years from the first hospital admission, he was maintained on rufinamide (35 mg/kg/d) and other antiepileptic drugs were gradually discontinued. With this treatment, the number of seizures decreased to 1 every 2 months and EEG showed, in the left hemisphere, very rare slow-wave complexes.
Discussion We have documented a clear efficacy in the treatment with rufinamide of 3 patients with bilateral open-lip schizencephaly, septo-optic dysplasia, and pharmacoresistent epilepsy, with significant improvement in both seizure control and EEG epileptiform activity. In particular, this drug seems to be efficacious in patients with epileptic encephalopathies associated with asymmetric spasms and refractory generalized epilepsy. In the last years, there is a growing evidence of the efficacy of rufinamide in children with pharmacoresistant epilepsy.8,9 Rufinamide has been reported to be effective in a variety of drug-resistant seizure types in children and adults.10,11 In particular, Kluger et al11 found the highest response rate in patients with Lennox-Gastaut syndrome (54.8%), the lowest in patients with partial epilepsy (23.5%) and an unexpectedly high rate of responders in patients with unclassified generalized epilepsy (42.8%), and the results of the study suggest that the efficacy
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
Verrotti et al
1081
Figure 1. (A) EEG recording shows frequent spikes in the left cerebral regions and poorly developed alpha activity. (B) Spikes are absent but the poorly developed background alpha activity persists.
of rufinamide in patients with generalized epilepsy might be comparable to that in patients with Lennox-Gastaut syndrome. Recently Kim et al12 confirmed efficacy and tolerability of
rufinamide add-on therapy in children with refractory generalized epilepsy. Efficacy and tolerability of rufinamide have been also proven in drug-resistant childhood epileptic
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
1082
Journal of Child Neurology 30(8) 69 patients, 3 had bilateral schizencephaly. After a follow-up period ranging from 0.2 to 4.1 years, 62.3% had 50% to 99% seizure reduction and, interestingly, the better response was obtained in children from 8 to 18 years; 3% became seizurefree, whereas seizure frequency was unchanged in 26% and worsened in 8.7%. During the therapy with rufinamide, generally mild and transient adverse side effects were reported in 42% of children.
Our Data Seem to Confirm Those Recently Reported in Literature
Figure 2. Turbo spin echo magnetic resonance imaging (MRI) (15 000 ms TR, 90 ms TE, 90 FA) acquired on axial plane shows bilateral ‘‘open lip’’ schizencephaly (arrows) with the clefts communicating the lateral ventricles with the temporoparietal convexity; adjacent cortex is dysplastic.
Rufinamide appears to be well tolerated: the most common adverse events are somnolence, vomiting, headache, poor appetite, and fatigue,4,9,17,18 and they are transient or resolve spontaneously after discontinuing therapy.12,19 Our data confirmed the tolerability of this drug: none of our 3 patients had adverse effects. Considering the difficulties in decreasing epileptic activity in brain malformations in general as well as in these 3 cases with intractable epilepsy, rufinamide has demonstrated to be efficacious. Interestingly, our patients showed the same type of epilepsy at the beginning of therapy with rufinamide: asymmetric spasms and generalized seizures with typical interictal EEG abnormalities. We understand that only 3 cases do not prove rufinamide efficacy and safety in this severe condition, but further and larger clinical reports and controlled studies could confirm the usefulness of this anticonvulsant drug. Author Contributions
encephalopathies and generalized epilepsies other than Lennox-Gastaut syndrome.13 In the study by Olson et al,9 the responder rate, defined as 50% decrease in spasms, was 53%. To date, several cases of pharmacoresistant epilepsy associated with schizencephaly are reported in the literature, and rufinamide has been used to treat children with intractable epilepsy due to malformations of cortical development.13-16 A prospective open-label add-on study13 showed a reduction of overall seizure frequency in approximately 40% of patients with refractory childhood-onset epileptic encephalopathies other than Lennox-Gastaut syndrome and, among 38 patients with these catastrophic epilepsies who received rufinamide, 6 of them had neuronal migration disorders. In a recent study15 with the aim to assess efficacy and tolerability of rufinamide as adjunctive drug for refractory focal seizures, 8 of 13 symptomatic subjects with a more than 50% seizure decrease had seizures starting from the frontal lobe, and 3 of them had a cortical migration disorder (perisylvian polymicrogyria and schizencephaly) or a genetic disorder. In most of these studies, patients have been recruited according to seizure semiology, thus grouping severe different etiologies, whereas Cusmai et al16 recently restricted the use of rufinamide to children with pharmacoresistant epilepsy symptomatic because of neuronal migration disorders; focal cortical dysplasia, lissencephaly/pachygyria, and bilateral polymicrogyria have been the most investigated forms, and among the
AV and GC designed the study and were responsible for critical revision. GL and AR acquired the data and were responsible for data interpretation and manuscript writing. AT and ADP acquired and interpreted the brain magnetic resonance images.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Patients were enrolled following informed consent signed by parents of the children under protocols approved by the Institutional Review Board of the University of Chieti, Italy.
References 1. Yakovlev PI, Wadsworth RC. Schizencephalies: a study of the congenital clefts in the cerebral mantle, I: clefts with fused lips. J Neuropathol Exp Neurol. 1946;5:116-130. 2. Yakovlev PI, Wadsworth RC. Schizencephalies: a study of the congenital clefts in the cerebral mantle, II: clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol. 1946;5: 169-206.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
Verrotti et al
1083
3. Leventer RJ, Guerrini R, Dobyns WB. Malformations of cortical development and epilepsy. Dialogues Clin Neurosci. 2008;10:47-62. 4. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70:1950-1958. 5. Kluger G, Glauser T, Krauss G, et al. Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study. Acta Neurol Scand. 2010;122:202-208. 6. Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia. 2009;50:1899-1909. 7. Elger CE, Stefan H, Mann A, et al. A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Res. 2010;88:255-263. 8. Vendrame M, Loddenkemper T, Gooty VD, et al. Experience with rufinamide in a pediatric population: a single center’s experience. Pediatr Neurol. 2010;43:155-158. 9. Olson HE, Loddenkemper T, Vendrame M, et al. Rufinamide for the treatment of epileptic spasms. Epilepsy Behav. 2011;20:344-348. 10. Joseph JR, Schultz RJ, Wilfong AA. Rufinamide for refractory epilepsy in a pediatric and young adult population. Epilepsy Res. 2011;93:87-89. 11. Kluger G, Kurlemann G, Haberlandt E, et al. Effectiveness and tolerability of rufinamide in children and adults with refractory
12.
13.
14.
15.
16.
17.
18.
19.
epilepsy: first European experience. Epilepsy Behav. 2009;14: 491-495. Kim SH, Lee JH, Ryu HW, et al. Short-term efficacy and tolerability of rufinamide adjunctive therapy in children with refractory generalised epilepsy. Epileptic Disord. 2013;15:49-54. Coppola G, Grosso S, Franzoni E, et al. Rufinamide in refractory childhood epileptic encephalopathies other than Lennox-Gastaut syndrome. Eur J Neurol. 2011;18:246-251. Kim JY, Lee CG, Yu HJ, et al. The efficacy and tolerability of rufinamide in intractable pediatric epilepsy. J Epilepsy Res. 2012;2:33-37. Coppola G, Zamponi N, Kluger G, et al. Rufinamide for refractory focal seizures: an open-label, multicenter European study. Seizure. 2013;22:33-36. Cusmai R, Verrotti A, Moavero R, et al. Rufinamide for the treatment of refractory epilepsy secondary to neuronal migration disorders. Epilepsy Res. 2014;108:542-546. Wheless J, Conry J, Krauss G, et al. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol. 2009;24:1520-1525. Verrotti A, Loiacono G, Ballone E, et al. Efficacy of rufinamide in drug-resistant epilepsy: a meta-analysis. Pediatr Neurol. 2011;44: 347-349. Kim S, Eun S, Kang H, et al. Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome. Seizure. 2012;21:288-291.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
Successful Treatment of Refractory Seizures With Rufinamide in Children With Schizencephaly: Report of 3 Cases
Journal of Child Neurology 2015, Vol. 30(8) 1079-1083 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814542951 jcn.sagepub.com
Alberto Verrotti, MD, PhD1, Giulia Loiacono, MD2, Alessandra Rossi, MD2, Armando Tartaro, MD3, Andrea Delli Pizzi, MD3, and Giangennaro Coppola, MD4
Abstract Schizencephaly is an uncommon malformation of cortical development. Patients with schizencephaly present with a broad range of severe neurologic symptoms including pharmacoresistant epilepsy. Rufinamide is a new antiepileptic drug approved for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome and it is also effective for refractory partial seizures. We report 3 cases of pediatric patients aged 7.2, 8.1, and 10.1 years, respectively, with intractable epilepsy associated with bilateral open-lip schizencephaly and septo-optic dysplasia. The follow-up ranged from 3.8 to 4.1 years. In our patients, the introduction of rufinamide as adjunctive drug led to a dramatic decline in the number of seizures and an improvement in EEG epileptic activity without side effects. Rufinamide seems to be efficacious and safe in patients with epileptic encephalopathies associated with pharmacoresistant epilepsy; further and larger clinical reports and controlled studies could confirm the usefulness of this anticonvulsant drug. Keywords epilepsy, rufinamide, schizencephaly, septo-optic dysplasia, antiepileptic drugs Received December 10, 2013. Received revised May 20, 2014. Accepted for publication June 06, 2014.
Schizencephaly, an uncommon malformation of cortical development, was first described by Yakovlev and Wadsworth in 2 different studies: the first one1 described closed-lip schizencephaly as a fused cleft that did not permit cerebrospinal fluid to pass, whereas the second one2 described open-lip schizencephaly as a cleft of irregular width permitting cerebrospinal fluid to pass between ventricular cavity and subarachnoid space. Neuroimaging studies showed unilateral or bilateral fullthickness gray matter–lined clefts of the cerebral hemispheres. Patients with schizencephaly present a broad range of severe neurologic symptoms, including developmental delay, hemiparesis or quadriparesis, and seizures. About epilepsy, the most common type is complex partial, although infantile spasms, tonic, atonic, and tonic-clonic seizures are reported.3 Studies have shown that rufinamide (Inovelon in the European Union, Banzel in North America), a relatively new antiepileptic drug approved by European Medicine Agency in 2007 and by the Food and Drug Administration (FDA) in 2008 for use as adjunctive therapy of seizures associated with Lennox-Gastaut syndrome,4,5 is also effective for refractory partial seizures6,7 and it is a valid adjunctive therapeutic option for children with epileptic spasms8 and when either ACTH or vigabatrin is not effective.9
Here we report 3 cases of bilateral open-lip schizencephaly with accompanying septo-optic dysplasia, in which the introduction of rufinamide as adjunctive drug led to a rapid reduction in the number of seizures. The electroclinical features and course of epilepsy were prospectively followed up for a period ranging from 3.8 to 4.1 years.
Case 1 An 8-year-1-month-old male child, was referred to the Department of Pediatrics of Chieti with diagnosis of psychomotor delay, West syndrome, and generalized tonic-clonic seizures. 1
Department of Pediatrics, University of Perugia, Perugia, Italy Department of Pediatrics, University of Chieti, Chieti, Italy 3 Department of Neuroscience and Imaging, Institute of Advanced Technology, G. d’Annunzio University, Chieti, Italy 4 Child Neuropsychiatry Clinic, Medical School, University of Salerno, Salerno, Italy 2
Corresponding Author: Alberto Verrotti, MD, PhD, Department of Pediatrics, University of Perugia, Loc. S. Andrea Fratte, 06134, Perugia, PG, Italy. Email: [email protected]
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
1080
Journal of Child Neurology 30(8)
He was born at term, by caesarean delivery because of deceleration in cardiotocography, and he was the only child of a non-consanguineous couple with no family history of genetic or neurologic diseases. At 6 months of age, the child presented infantile spasms (more than 20/d); the child was treated previously with tetracosactide, trazodone, vigabatrin, oxcarbazepine, and levetiracetam, but seizures were poorly controlled. The child showed worsening of asymmetric spasms and onset of partial seizures often with secondary generalization (30-40 seizures per day). Physical examination showed microcephaly, gross hypotonia, severe intellectual disability, spastic quadriplegia, blindness, and hearing loss. Electroencephalography (EEG) showed lack of background activity without posterior alpha rhythm, with multifocal spikewave activity: this pattern was prevalent in the left hemisphere, but it was also present asynchronously in the contralateral hemisphere (Figure 1). Brain magnetic resonance imaging (MRI) examination was performed with Philips Achieva (3-Tesla; Philips, Holland) and showed optic dysplasia associated with bilateral open-lip schizencephaly (Figure 2). Because of worsening seizures, rufinamide (16 mg/kg/d) was added to previous therapy (valproic acid and vigabatrin) and it was discharged with 40 mg/kg/d, with a good response. In the next 7 days, the number of seizures decreased from 30 per day to about 3 per day, without major side effects. EEG persisted abnormal but the spikes were very rare. At the last neurologic examination (age: 11.9 years), his seizures were very rare (2/month) and very brief (less than 10 seconds) with the following therapy (rufinamide 40 mg/kg/d and valproic acid 25 mg/kg/d).
Case 2 A 10-year-1-month-old boy, born at term of nonconsanguineous parentage in good health, presented with recurrent seizures characterized by asymmetric spasms and generalized tonic-clonic seizures. There was no adverse prenatal exposure. Septo-optic dysplasia and bilateral schizencephaly with very open lips were diagnosed based on 3-Tesla MRI. Neurologic follow-up identified a delay in acquisition of motor and language developmental milestones. The patient was referred to the Department of Child and Adolescent Neuropsychiatry of Salerno because of poor seizure control, with 30 to 40 episodes of epileptic seizures per day, in spite of antiepileptic polytherapy (valproic acid, vigabatrin, and levetiracetam). Physical examination demonstrated microcephaly and quadriplegia, whereas ophthalmologic evaluation showed bilateral optic disk hypoplasia and nystagmus. EEG revealed diffuse bioelectrical depression with highvoltage, asynchronous bilateral spike-wave, generalized 3 to 4 Hz spike-waves discharges. Because of pharmacoresistant epilepsy (asymmetric spasms and generalized tonic-clonic seizures), rufinamide was administered (dosage of 34 mg/kg/d) as adjunctive therapy, with excellent results: number of seizures decreased to 3 or 4 per
week. After 3 years 8 months from beginning of rufinamide treatment, seizures were well controlled (1 seizure/mo) without side effects. The last EEG recording showed very rare spikes.
Case 3 A 7-year-2-month-old boy was born at term gestation after an uncomplicated pregnancy and delivery; there was no history of consanguinity. Signs of early developmental lag were noticed by the parents. At the age of 26 months, he showed mental retardation, asymmetric spasms, and generalized tonic seizures. Seizures were very frequent, with 20 to 30 episodes per day, in spite of the association of valproic acid and vigabatrin, received from 2 years. At neuropsychological examination, he showed short stature, microcephaly, spastic quadriplegia, severe intellectual disability, bilateral nystagmus, and blindness. EEG recordings during wakefulness and sleep showed generalized high-voltage sharp and slow-wave complexes: the latter were more evident in the left hemisphere. There was activation of the discharges in sleep. Brain MRI, performed with a 1.5-Tesla Siemens Symphony MRI system, showed a small pituitary gland, absence of septum pellucidum, and hypoplasia of the optic nerves (more evident in the right nerve), suggestive of septo-optic dysplasia, and bilateral open-lip schizencephaly, with polymicrogyric gray matter surrounding the clefts bilaterally. Because of the persistence of asymmetric spasms and generalized tonic seizures, rufinamide therapy was started with dramatic decrease in the number of seizures from 20-30 to 2-5 per day. The adjunctive therapy was not only efficacious, but also well tolerated, without side effects. Actually, after 4.1 years from the first hospital admission, he was maintained on rufinamide (35 mg/kg/d) and other antiepileptic drugs were gradually discontinued. With this treatment, the number of seizures decreased to 1 every 2 months and EEG showed, in the left hemisphere, very rare slow-wave complexes.
Discussion We have documented a clear efficacy in the treatment with rufinamide of 3 patients with bilateral open-lip schizencephaly, septo-optic dysplasia, and pharmacoresistent epilepsy, with significant improvement in both seizure control and EEG epileptiform activity. In particular, this drug seems to be efficacious in patients with epileptic encephalopathies associated with asymmetric spasms and refractory generalized epilepsy. In the last years, there is a growing evidence of the efficacy of rufinamide in children with pharmacoresistant epilepsy.8,9 Rufinamide has been reported to be effective in a variety of drug-resistant seizure types in children and adults.10,11 In particular, Kluger et al11 found the highest response rate in patients with Lennox-Gastaut syndrome (54.8%), the lowest in patients with partial epilepsy (23.5%) and an unexpectedly high rate of responders in patients with unclassified generalized epilepsy (42.8%), and the results of the study suggest that the efficacy
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
Verrotti et al
1081
Figure 1. (A) EEG recording shows frequent spikes in the left cerebral regions and poorly developed alpha activity. (B) Spikes are absent but the poorly developed background alpha activity persists.
of rufinamide in patients with generalized epilepsy might be comparable to that in patients with Lennox-Gastaut syndrome. Recently Kim et al12 confirmed efficacy and tolerability of
rufinamide add-on therapy in children with refractory generalized epilepsy. Efficacy and tolerability of rufinamide have been also proven in drug-resistant childhood epileptic
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
1082
Journal of Child Neurology 30(8) 69 patients, 3 had bilateral schizencephaly. After a follow-up period ranging from 0.2 to 4.1 years, 62.3% had 50% to 99% seizure reduction and, interestingly, the better response was obtained in children from 8 to 18 years; 3% became seizurefree, whereas seizure frequency was unchanged in 26% and worsened in 8.7%. During the therapy with rufinamide, generally mild and transient adverse side effects were reported in 42% of children.
Our Data Seem to Confirm Those Recently Reported in Literature
Figure 2. Turbo spin echo magnetic resonance imaging (MRI) (15 000 ms TR, 90 ms TE, 90 FA) acquired on axial plane shows bilateral ‘‘open lip’’ schizencephaly (arrows) with the clefts communicating the lateral ventricles with the temporoparietal convexity; adjacent cortex is dysplastic.
Rufinamide appears to be well tolerated: the most common adverse events are somnolence, vomiting, headache, poor appetite, and fatigue,4,9,17,18 and they are transient or resolve spontaneously after discontinuing therapy.12,19 Our data confirmed the tolerability of this drug: none of our 3 patients had adverse effects. Considering the difficulties in decreasing epileptic activity in brain malformations in general as well as in these 3 cases with intractable epilepsy, rufinamide has demonstrated to be efficacious. Interestingly, our patients showed the same type of epilepsy at the beginning of therapy with rufinamide: asymmetric spasms and generalized seizures with typical interictal EEG abnormalities. We understand that only 3 cases do not prove rufinamide efficacy and safety in this severe condition, but further and larger clinical reports and controlled studies could confirm the usefulness of this anticonvulsant drug. Author Contributions
encephalopathies and generalized epilepsies other than Lennox-Gastaut syndrome.13 In the study by Olson et al,9 the responder rate, defined as 50% decrease in spasms, was 53%. To date, several cases of pharmacoresistant epilepsy associated with schizencephaly are reported in the literature, and rufinamide has been used to treat children with intractable epilepsy due to malformations of cortical development.13-16 A prospective open-label add-on study13 showed a reduction of overall seizure frequency in approximately 40% of patients with refractory childhood-onset epileptic encephalopathies other than Lennox-Gastaut syndrome and, among 38 patients with these catastrophic epilepsies who received rufinamide, 6 of them had neuronal migration disorders. In a recent study15 with the aim to assess efficacy and tolerability of rufinamide as adjunctive drug for refractory focal seizures, 8 of 13 symptomatic subjects with a more than 50% seizure decrease had seizures starting from the frontal lobe, and 3 of them had a cortical migration disorder (perisylvian polymicrogyria and schizencephaly) or a genetic disorder. In most of these studies, patients have been recruited according to seizure semiology, thus grouping severe different etiologies, whereas Cusmai et al16 recently restricted the use of rufinamide to children with pharmacoresistant epilepsy symptomatic because of neuronal migration disorders; focal cortical dysplasia, lissencephaly/pachygyria, and bilateral polymicrogyria have been the most investigated forms, and among the
AV and GC designed the study and were responsible for critical revision. GL and AR acquired the data and were responsible for data interpretation and manuscript writing. AT and ADP acquired and interpreted the brain magnetic resonance images.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Patients were enrolled following informed consent signed by parents of the children under protocols approved by the Institutional Review Board of the University of Chieti, Italy.
References 1. Yakovlev PI, Wadsworth RC. Schizencephalies: a study of the congenital clefts in the cerebral mantle, I: clefts with fused lips. J Neuropathol Exp Neurol. 1946;5:116-130. 2. Yakovlev PI, Wadsworth RC. Schizencephalies: a study of the congenital clefts in the cerebral mantle, II: clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol. 1946;5: 169-206.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
Verrotti et al
1083
3. Leventer RJ, Guerrini R, Dobyns WB. Malformations of cortical development and epilepsy. Dialogues Clin Neurosci. 2008;10:47-62. 4. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70:1950-1958. 5. Kluger G, Glauser T, Krauss G, et al. Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study. Acta Neurol Scand. 2010;122:202-208. 6. Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia. 2009;50:1899-1909. 7. Elger CE, Stefan H, Mann A, et al. A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Res. 2010;88:255-263. 8. Vendrame M, Loddenkemper T, Gooty VD, et al. Experience with rufinamide in a pediatric population: a single center’s experience. Pediatr Neurol. 2010;43:155-158. 9. Olson HE, Loddenkemper T, Vendrame M, et al. Rufinamide for the treatment of epileptic spasms. Epilepsy Behav. 2011;20:344-348. 10. Joseph JR, Schultz RJ, Wilfong AA. Rufinamide for refractory epilepsy in a pediatric and young adult population. Epilepsy Res. 2011;93:87-89. 11. Kluger G, Kurlemann G, Haberlandt E, et al. Effectiveness and tolerability of rufinamide in children and adults with refractory
12.
13.
14.
15.
16.
17.
18.
19.
epilepsy: first European experience. Epilepsy Behav. 2009;14: 491-495. Kim SH, Lee JH, Ryu HW, et al. Short-term efficacy and tolerability of rufinamide adjunctive therapy in children with refractory generalised epilepsy. Epileptic Disord. 2013;15:49-54. Coppola G, Grosso S, Franzoni E, et al. Rufinamide in refractory childhood epileptic encephalopathies other than Lennox-Gastaut syndrome. Eur J Neurol. 2011;18:246-251. Kim JY, Lee CG, Yu HJ, et al. The efficacy and tolerability of rufinamide in intractable pediatric epilepsy. J Epilepsy Res. 2012;2:33-37. Coppola G, Zamponi N, Kluger G, et al. Rufinamide for refractory focal seizures: an open-label, multicenter European study. Seizure. 2013;22:33-36. Cusmai R, Verrotti A, Moavero R, et al. Rufinamide for the treatment of refractory epilepsy secondary to neuronal migration disorders. Epilepsy Res. 2014;108:542-546. Wheless J, Conry J, Krauss G, et al. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol. 2009;24:1520-1525. Verrotti A, Loiacono G, Ballone E, et al. Efficacy of rufinamide in drug-resistant epilepsy: a meta-analysis. Pediatr Neurol. 2011;44: 347-349. Kim S, Eun S, Kang H, et al. Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome. Seizure. 2012;21:288-291.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on August 8, 2015
