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Migrating Focal Seizures During Infancy: A Case Report and Pathologic Study
Pediatric Neurology 46 (2012) 182e184
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Migrating Focal Seizures During Infancy: A Case Report and Pathologic Study Lorena Fasulo MD a, *, Silvia Saucedo MD b, Lidia Cáceres MD a, Silvana Solis MD c, Roberto Caraballo MD d a
Department of Neuropediatrics, Prof. Dr. A. Posadas Hospital, Buenos Aires, Argentina Department of Anatomopathology, Prof. Dr. A. Posadas Hospital, Buenos Aires, Argentina Department of Neurophysiology, Prof. Dr. A. Posadas Hospital, Buenos Aires, Argentina d Department of Neurology, Children’s Hospital Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina b c
article information
abstract
Article history: Received 7 November 2011 Accepted 22 December 2011
Migrating focal seizures in infancy are an unusual and often overlooked epilepsy syndrome, with onset before age 6 months, in which nearly continuous seizures involve multiple, independent areas of both hemispheres with an arrest of psychomotor development. We describe a patient with migrating focal seizures in infancy whose seizures began at age 45 days. The seizures were refractory to common antiepileptic drugs. At age 6 months, the infant received potassium bromide and became almost seizurefree. The infant developed severe neurologic impairment, with marked axial hypotonia and an absence of visual contact and head control. At age 8 months, the child suddenly died. Pathologic findings included multiple malformations of cortical development, polymicrogyria, and focal cortical dysplasia associated with hippocampal sclerosis. Ó 2012 Elsevier Inc. All rights reserved.
Introduction Migrating focal seizures in infancy constitute an unusual, often overlooked epilepsy syndrome with onset before age 6 months, in which nearly continuous seizures involve multiple, independent areas of both hemispheres, with an arrest of psychomotor development [1]. Their etiology is unknown, and the seizures are drugresistant. Computed tomography scans and magnetic resonance imaging generally produce normal results. Caraballo et al. reported on 17 patients with migrating focal seizures in infancy, in three of whom magnetic resonance imaging indicated mesial temporal lobe sclerosis [2]. Coppola et al. described left temporal lobe hippocampal sclerosis and cortical-subcortical blurring in one patient [3]. We report on the pathologic findings of a patient with migrating focal seizures in infancy. Case Report A 2-month-old girl was admitted to our hospital with marked hypotonia and seizures. The pregnancy and perinatal course had been uneventful. The seizures consisted of clonic twitches of the eyelids and clonic jerks of either upper or lower limbs or both, alternatively associated with flushing, tachycardia, hyperthermia, and perioral cyanosis, usually lasting 1-3 minutes. Seizures became evident from age 45 days, occurring once a day, and their frequency had gradually increased to 20-30 per
day by age 3 months. The infant was treated with phenobarbital, carbamazepine, pyridoxine, clonazepam, and levetiracetam, without success. When levetiracetam was added, the seizure frequency increased to 60 per day. At age 6 months, the infant received potassium bromide and became almost seizure-free. At age 4 months, magnetic resonance imaging produced normal results (Fig 1), and funduscopy, visual evoked potentials, and an electroretinogram revealed no pathology. Alterations were evident in the brainstem auditory evoked potentials. Tests for congenital infections (human immunodeficiency virus, toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) produced negative results, and the patient’s karyotype, serum, urine and cerebrospinal fluid amino acids, urinary organic acids, carnitine, and acylcarnitine were normal. The first electroencephalogram, performed at age 2 months, produced normal results. A month later, an electroencephalogram revealed high-amplitude spikes and sharp waves over the left centrotemporal region. A subsequent electroencephalogram indicated rhythmic d-q activity in the right frontotemporal region, with spreading to the left homologous region in the form of paroxysms of spikes. At age 5 months, an ictal video polysomnography recording demonstrated high-frequency (13-14 Hz) rhythms with interspersed isolated spikes in the left temporo-occipital region, migrating to the homologous region of the other hemisphere. Over the ictal pattern, central apneas of 40-60 seconds’ duration were evident, and they remained unchanged during electrocardiography. The infant developed severe neurologic impairment, with marked axial hypotonia and an absence of visual contact and head control. At age 8 months, she suddenly died. She manifested heart and respiratory failure witnessed by doctors, without evidence of seizures before sudden death. She was immediately intubated, but did not respond to adrenaline therapy. As a result of the close doctor-patient relationship, the family agreed to an autopsy. Pathologic findings
* Communications should be addressed to: Dr. Fasulo; Department of Neuropediatrics; Hospital Posadas; Pte. Illia s/n y Marconi; El Palomar 1684, Buenos Aires, Argentina. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2011.12.004
The autopsy indicated pulmonary edema. Macroscopic features in the brain cortex included multifocal polymicrogyria, a thickened cortex, and blurring of the interface between the cortex and white matter (Fig 2).
L. Fasulo et al. / Pediatric Neurology 46 (2012) 182e184
183
Figure 2. Multifocal polymicrogyria, thickened cortex, and blurring of the interface between the cortex and white matter.
Figure 1. Cranial magnetic resonance imaging T2-weighted sequence, without evidence of pathology.
Microscopic features consisted of laminar disorganization and neuronal aggregates, hypertrophic and dysmorphic neurons with an enlarged neuronal cell diameter, abnormal somatodendritic morphology and malorientation (Fig 3), and excessive cellular gliosis, characteristic of focal cortical dysplasia. The main features in the hippocampal area included neuronal loss and cellular gliosis in subareas CA1, CA3, CA4, and the subiculum, whereas subzone CA2 was spared (Fig 4). These findings were compatible with hippocampal sclerosis. According to the consensus classification proposed by an ad hoc Task Force of the International League Against Epilepsy Diagnostic Methods Commission, our findings are compatible with focal cortical dysplasia associated with hippocampal sclerosis (focal cortical dysplasia type IIIa).
resonance imaging may explain the normal neuroradiologic findings in our patient. In our patient, the malformation of cortical development could explain the electroclinical picture. In patients with migrating focal seizures in infancy, the electroclinical pattern suggests that the entire cerebral cortex is abnormally excitable [7], thus explaining this particular agedependent picture in an abnormally developing brain. Our patient responded well to bromides, as reported in previous patients [2,3,8,9]. Other antiepileptic drugs, such as stiripentol [9,10], levetiracetam [2,9,11], and rufinamide [12], have also been proven useful in the treatment of migrating focal seizures in infancy. Unfortunately, at age 8 months, our patient suddenly died. She manifested heart and respiratory failure witnessed by doctors, without evidence of seizures before sudden death. She was immediately intubated, but did not respond to adrenaline
Discussion Migrating focal seizures in infancy constitute a rare epileptic syndrome with a devastating course. Despite extensive investigation, their underlying cause has not been identified [4,5]. The electroclinical features of our patient were compatible with migrating focal seizures in infancy with a severe course, and our pathologic study macroscopically demonstrated multifocal polymicrogyria. Microscopic features in the cortex included altered lamination with dysmorphic neurons and abnormal somatodenditric morphology. The hippocampal area exhibited neuronal loss in subareas CA1, CA3, CA4, and the subiculum, associated with cellular gliosis compatible with hippocampal sclerosis (focal cortical dysplasia type IIIa). Autopsy results were reported in five previous patients [4,6]. Coppola et al. [4] observed neuronal loss and gliosis of the CA1 sector in the pyramidal layer of the hippocampus in two patients. Our patient manifested the same features, except in CA1, CA3, CA4, and subiculum. Our patient manifested not only hippocampal pathology, but malformations of cortical development as well. On the other hand, Wilmshurst et al. [6] observed no brain abnormalities in three patients. The low resolution of magnetic
Figure 3. Laminar disorganization, hypertrophic and dysmorphic neurons with enlarged neuronal cell diameter, abnormal somatodendritic morphology, and malorientation.
184
L. Fasulo et al. / Pediatric Neurology 46 (2012) 182e184
migrating focal seizures in infancy could be included in the group of epileptic encephalopathies. References
Figure 4. Neuronal loss in subareas CA1, CA3, CA4, and the subiculum (S), associated with cellular gliosis and the sparing of CA2.
therapy. The autopsy indicated pulmonary edema. Pulmonary edema is a common finding at autopsy after sudden death in epilepsy [13,14]. However, it is often associated with other causes of death, and is nonspecific. Recently, sudden death was reported in a patient with Dravet syndrome and an SCNIA mutation [15]. To the best of our knowledge, this report is the first to document multiple malformations of cortical development, polymicrogyria, and focal cortical dysplasia associated with hippocampal sclerosis in a patient with migrating focal seizures in infancy. Although they are rare, migrating focal seizures in infancy constitute a well-defined epileptic syndrome, and based on the cognitive deterioration observed in our patient and in others [2,4],
[1] Dulac O. Malignant migrating partial seizures in infancy. In: Roger J, editor. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. Eastleigh, UK: John Libbey & Co., Ltd.; 2002. p. 65e8. [2] Caraballo RH, Fontana E, Darra F, et al. Migrating focal seizures in infancy: Analysis of the electroclinical patterns in 17 patients. J Child Neurol 2008;23:497e506. [3] Coppola G, Operto FF, Auricchio G, D’Amico A, Fortunato D, Pascotto A. Temporal lobe dual pathology in malignant migrating partial seizures in infancy. Epileptic Disord 2007;9:145e8. [4] Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: A malignant disorder with developmental arrest. Epilepsia 1995;36:1017e24. [5] Coppola G, Veggiotti P, Del Giudice EM, et al. Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. Brain Dev 2006;28:76e9. [6] Wilmshurst JM, Appleton DB, Grattan-Smith PJ. Migrating partial seizures in infancy: Two new cases. J Child Neurol 2000;15:717e22. [7] Veneselli E, Perrone MV, Di Rocco M, Gaggero R, Biancheri R. Malignant migrating partial seizures in infancy. Epilepsy Res 2001;46:27e32. [8] Okuda K, Yasuhara A, Kamei A, Araki A, Kitamura N, Kobayashi Y. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev 2000;22:56e9. [9] Djuric M, Kravljanac R, Kovacevic G, Martic J. The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic Disord 2011;13:22e6. [10] Perez J, Chiron C, Musial C, et al. Stiripentol: Efficacy and tolerability in children with epilepsy. Epilepsia 1999;40:1618e26. [11] Hmaimess G, Kadhim H, Nassogne MC, Bonnier C, Van Rijckevorsel K. Levetiracetam in a neonate with malignant migrating partial seizures. Pediatr Neurol 2006;34:55e9. [12] Vendrame M, Poduri A, Loddenkemper T, Kluger G, Coppola G, Kothare SV. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: Report of five cases. Epileptic Disord 2011;13:18e21. [13] Milroy CM. Sudden unexpected death in epilepsy in childhood. Forensic Sci Med Pathol 2011;7:336e40. [14] Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: Current knowledge and future directions. Lancet Neurol 2008;7:1021e31. [15] Le Gal F, Korff C, Monso-Hinard C, Mund M, Morris M, Malafosse A, SchmittMechelke T. A case of SUDEP in a patient with Dravet syndrome with SCNIA mutation. Epilepsia 2010;51:1915e8.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Migrating Focal Seizures During Infancy: A Case Report and Pathologic Study Lorena Fasulo MD a, *, Silvia Saucedo MD b, Lidia Cáceres MD a, Silvana Solis MD c, Roberto Caraballo MD d a
Department of Neuropediatrics, Prof. Dr. A. Posadas Hospital, Buenos Aires, Argentina Department of Anatomopathology, Prof. Dr. A. Posadas Hospital, Buenos Aires, Argentina Department of Neurophysiology, Prof. Dr. A. Posadas Hospital, Buenos Aires, Argentina d Department of Neurology, Children’s Hospital Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina b c
article information
abstract
Article history: Received 7 November 2011 Accepted 22 December 2011
Migrating focal seizures in infancy are an unusual and often overlooked epilepsy syndrome, with onset before age 6 months, in which nearly continuous seizures involve multiple, independent areas of both hemispheres with an arrest of psychomotor development. We describe a patient with migrating focal seizures in infancy whose seizures began at age 45 days. The seizures were refractory to common antiepileptic drugs. At age 6 months, the infant received potassium bromide and became almost seizurefree. The infant developed severe neurologic impairment, with marked axial hypotonia and an absence of visual contact and head control. At age 8 months, the child suddenly died. Pathologic findings included multiple malformations of cortical development, polymicrogyria, and focal cortical dysplasia associated with hippocampal sclerosis. Ó 2012 Elsevier Inc. All rights reserved.
Introduction Migrating focal seizures in infancy constitute an unusual, often overlooked epilepsy syndrome with onset before age 6 months, in which nearly continuous seizures involve multiple, independent areas of both hemispheres, with an arrest of psychomotor development [1]. Their etiology is unknown, and the seizures are drugresistant. Computed tomography scans and magnetic resonance imaging generally produce normal results. Caraballo et al. reported on 17 patients with migrating focal seizures in infancy, in three of whom magnetic resonance imaging indicated mesial temporal lobe sclerosis [2]. Coppola et al. described left temporal lobe hippocampal sclerosis and cortical-subcortical blurring in one patient [3]. We report on the pathologic findings of a patient with migrating focal seizures in infancy. Case Report A 2-month-old girl was admitted to our hospital with marked hypotonia and seizures. The pregnancy and perinatal course had been uneventful. The seizures consisted of clonic twitches of the eyelids and clonic jerks of either upper or lower limbs or both, alternatively associated with flushing, tachycardia, hyperthermia, and perioral cyanosis, usually lasting 1-3 minutes. Seizures became evident from age 45 days, occurring once a day, and their frequency had gradually increased to 20-30 per
day by age 3 months. The infant was treated with phenobarbital, carbamazepine, pyridoxine, clonazepam, and levetiracetam, without success. When levetiracetam was added, the seizure frequency increased to 60 per day. At age 6 months, the infant received potassium bromide and became almost seizure-free. At age 4 months, magnetic resonance imaging produced normal results (Fig 1), and funduscopy, visual evoked potentials, and an electroretinogram revealed no pathology. Alterations were evident in the brainstem auditory evoked potentials. Tests for congenital infections (human immunodeficiency virus, toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) produced negative results, and the patient’s karyotype, serum, urine and cerebrospinal fluid amino acids, urinary organic acids, carnitine, and acylcarnitine were normal. The first electroencephalogram, performed at age 2 months, produced normal results. A month later, an electroencephalogram revealed high-amplitude spikes and sharp waves over the left centrotemporal region. A subsequent electroencephalogram indicated rhythmic d-q activity in the right frontotemporal region, with spreading to the left homologous region in the form of paroxysms of spikes. At age 5 months, an ictal video polysomnography recording demonstrated high-frequency (13-14 Hz) rhythms with interspersed isolated spikes in the left temporo-occipital region, migrating to the homologous region of the other hemisphere. Over the ictal pattern, central apneas of 40-60 seconds’ duration were evident, and they remained unchanged during electrocardiography. The infant developed severe neurologic impairment, with marked axial hypotonia and an absence of visual contact and head control. At age 8 months, she suddenly died. She manifested heart and respiratory failure witnessed by doctors, without evidence of seizures before sudden death. She was immediately intubated, but did not respond to adrenaline therapy. As a result of the close doctor-patient relationship, the family agreed to an autopsy. Pathologic findings
* Communications should be addressed to: Dr. Fasulo; Department of Neuropediatrics; Hospital Posadas; Pte. Illia s/n y Marconi; El Palomar 1684, Buenos Aires, Argentina. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2011.12.004
The autopsy indicated pulmonary edema. Macroscopic features in the brain cortex included multifocal polymicrogyria, a thickened cortex, and blurring of the interface between the cortex and white matter (Fig 2).
L. Fasulo et al. / Pediatric Neurology 46 (2012) 182e184
183
Figure 2. Multifocal polymicrogyria, thickened cortex, and blurring of the interface between the cortex and white matter.
Figure 1. Cranial magnetic resonance imaging T2-weighted sequence, without evidence of pathology.
Microscopic features consisted of laminar disorganization and neuronal aggregates, hypertrophic and dysmorphic neurons with an enlarged neuronal cell diameter, abnormal somatodendritic morphology and malorientation (Fig 3), and excessive cellular gliosis, characteristic of focal cortical dysplasia. The main features in the hippocampal area included neuronal loss and cellular gliosis in subareas CA1, CA3, CA4, and the subiculum, whereas subzone CA2 was spared (Fig 4). These findings were compatible with hippocampal sclerosis. According to the consensus classification proposed by an ad hoc Task Force of the International League Against Epilepsy Diagnostic Methods Commission, our findings are compatible with focal cortical dysplasia associated with hippocampal sclerosis (focal cortical dysplasia type IIIa).
resonance imaging may explain the normal neuroradiologic findings in our patient. In our patient, the malformation of cortical development could explain the electroclinical picture. In patients with migrating focal seizures in infancy, the electroclinical pattern suggests that the entire cerebral cortex is abnormally excitable [7], thus explaining this particular agedependent picture in an abnormally developing brain. Our patient responded well to bromides, as reported in previous patients [2,3,8,9]. Other antiepileptic drugs, such as stiripentol [9,10], levetiracetam [2,9,11], and rufinamide [12], have also been proven useful in the treatment of migrating focal seizures in infancy. Unfortunately, at age 8 months, our patient suddenly died. She manifested heart and respiratory failure witnessed by doctors, without evidence of seizures before sudden death. She was immediately intubated, but did not respond to adrenaline
Discussion Migrating focal seizures in infancy constitute a rare epileptic syndrome with a devastating course. Despite extensive investigation, their underlying cause has not been identified [4,5]. The electroclinical features of our patient were compatible with migrating focal seizures in infancy with a severe course, and our pathologic study macroscopically demonstrated multifocal polymicrogyria. Microscopic features in the cortex included altered lamination with dysmorphic neurons and abnormal somatodenditric morphology. The hippocampal area exhibited neuronal loss in subareas CA1, CA3, CA4, and the subiculum, associated with cellular gliosis compatible with hippocampal sclerosis (focal cortical dysplasia type IIIa). Autopsy results were reported in five previous patients [4,6]. Coppola et al. [4] observed neuronal loss and gliosis of the CA1 sector in the pyramidal layer of the hippocampus in two patients. Our patient manifested the same features, except in CA1, CA3, CA4, and subiculum. Our patient manifested not only hippocampal pathology, but malformations of cortical development as well. On the other hand, Wilmshurst et al. [6] observed no brain abnormalities in three patients. The low resolution of magnetic
Figure 3. Laminar disorganization, hypertrophic and dysmorphic neurons with enlarged neuronal cell diameter, abnormal somatodendritic morphology, and malorientation.
184
L. Fasulo et al. / Pediatric Neurology 46 (2012) 182e184
migrating focal seizures in infancy could be included in the group of epileptic encephalopathies. References
Figure 4. Neuronal loss in subareas CA1, CA3, CA4, and the subiculum (S), associated with cellular gliosis and the sparing of CA2.
therapy. The autopsy indicated pulmonary edema. Pulmonary edema is a common finding at autopsy after sudden death in epilepsy [13,14]. However, it is often associated with other causes of death, and is nonspecific. Recently, sudden death was reported in a patient with Dravet syndrome and an SCNIA mutation [15]. To the best of our knowledge, this report is the first to document multiple malformations of cortical development, polymicrogyria, and focal cortical dysplasia associated with hippocampal sclerosis in a patient with migrating focal seizures in infancy. Although they are rare, migrating focal seizures in infancy constitute a well-defined epileptic syndrome, and based on the cognitive deterioration observed in our patient and in others [2,4],
[1] Dulac O. Malignant migrating partial seizures in infancy. In: Roger J, editor. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. Eastleigh, UK: John Libbey & Co., Ltd.; 2002. p. 65e8. [2] Caraballo RH, Fontana E, Darra F, et al. Migrating focal seizures in infancy: Analysis of the electroclinical patterns in 17 patients. J Child Neurol 2008;23:497e506. [3] Coppola G, Operto FF, Auricchio G, D’Amico A, Fortunato D, Pascotto A. Temporal lobe dual pathology in malignant migrating partial seizures in infancy. Epileptic Disord 2007;9:145e8. [4] Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: A malignant disorder with developmental arrest. Epilepsia 1995;36:1017e24. [5] Coppola G, Veggiotti P, Del Giudice EM, et al. Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. Brain Dev 2006;28:76e9. [6] Wilmshurst JM, Appleton DB, Grattan-Smith PJ. Migrating partial seizures in infancy: Two new cases. J Child Neurol 2000;15:717e22. [7] Veneselli E, Perrone MV, Di Rocco M, Gaggero R, Biancheri R. Malignant migrating partial seizures in infancy. Epilepsy Res 2001;46:27e32. [8] Okuda K, Yasuhara A, Kamei A, Araki A, Kitamura N, Kobayashi Y. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain Dev 2000;22:56e9. [9] Djuric M, Kravljanac R, Kovacevic G, Martic J. The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic Disord 2011;13:22e6. [10] Perez J, Chiron C, Musial C, et al. Stiripentol: Efficacy and tolerability in children with epilepsy. Epilepsia 1999;40:1618e26. [11] Hmaimess G, Kadhim H, Nassogne MC, Bonnier C, Van Rijckevorsel K. Levetiracetam in a neonate with malignant migrating partial seizures. Pediatr Neurol 2006;34:55e9. [12] Vendrame M, Poduri A, Loddenkemper T, Kluger G, Coppola G, Kothare SV. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: Report of five cases. Epileptic Disord 2011;13:18e21. [13] Milroy CM. Sudden unexpected death in epilepsy in childhood. Forensic Sci Med Pathol 2011;7:336e40. [14] Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: Current knowledge and future directions. Lancet Neurol 2008;7:1021e31. [15] Le Gal F, Korff C, Monso-Hinard C, Mund M, Morris M, Malafosse A, SchmittMechelke T. A case of SUDEP in a patient with Dravet syndrome with SCNIA mutation. Epilepsia 2010;51:1915e8.