Migrating partial seizures in infancy: expanding the phenotype of a rare seizure syndrome.
TL;DR: A constellation of early‐onset, unprovoked, alternating electroclinical seizures and neurodevelopmental devastation was first described by Coppola et al and the prospect of a more optimistic developmental outcome is reported.
Abstract: Summary: Purpose: The constellation of early-onset, unprovoked, alternating electroclinical seizures and neurodevelopmental devastation was first described by Coppola et al. We report six new patients and the prospect of a more optimistic developmental outcome.
Methods: Retrospective chart reviews were performed on six infants evaluated at the Children's Hospital of Philadelphia (five patients) and at Hershey Medical Center (one patient) who had electroclinically alternating seizures before age 6 months of age. Electroclinical characteristics and long-term follow-up were recorded.
Results: All had unprovoked, early-onset (range, 1 day to 3 months; mean, 25 days) intractable electroclinical seizures that alternated between the two hemispheres. Each patient underwent comprehensive brain imaging and neurometabolic workups, which were unrevealing. In all patients, subsequently intractable partial seizures developed and often a progressive decline of head circumference percentile occurred with age. Three demonstrated severe developmental delay and hypotonia. All survived, and 7-year follow-up on one patient was quite favorable.
Conclusions: Our patients satisfied the seven major diagnostic criteria first described by Coppola et al. The prognosis of this rare neonatal-onset epilepsy syndrome from the original description and subsequent case reports was very poor, with 28% mortality, and the majority of survivors were profoundly retarded and nonambulatory. Our patient data validate the diagnostic criteria of this syndrome and further quantify a previously described observation of progressive decline of head circumference percentiles with age. Our data also suggest that the prognosis of this syndrome, although poor, is not as uniformly grim as the cases reported previously in the literature.
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TL;DR: Exome sequencing in three probands with MMPSI and de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel were identified, which led to constitutive activation of the channel.
Abstract: Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.
406 citations
TL;DR: The case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine was reported, with a marked reduction in seizure frequency and improved psychomotor development.
Abstract: Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically resistant to treatment. The most common cause is a gain of function mutation in the potassium channel KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate drug for treatment of this condition. We report the case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was correlated with a marked reduction in seizure frequency and improved psychomotor development.
206 citations
Cites background from "Migrating partial seizures in infan..."
...rodevelopmental outcomes, and life expectancy, although some variability has been reported.(2,3) The disorder begins...
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TL;DR: Transplantation of mutant immature interneurons into a wild-type brain demonstrated that loss of either Dlx5 or DlX5&6 preferentially reduced the number of mature parvalbumin+ interneeurons; those parval bumin+interneuron that were present had increased dendritic branching.
Abstract: Dlx5 and Dlx6 homeobox genes are expressed in developing and mature cortical interneurons. Simultaneous deletion of Dlx5 and 6 results in exencephaly of the anterior brain; despite this defect, prenatal basal ganglia differentiation appeared largely intact, while tangential migration of Lhx6+ and Mafb+ interneurons to the cortex was reduced and disordered. The migration deficits were associated with reduced CXCR4 expression. Transplantation of mutant immature interneurons into a wild-type brain demonstrated that loss of either Dlx5 or Dlx5&6 preferentially reduced the number of mature parvalbumin+ interneurons; those parvalbumin+ interneurons that were present had increased dendritic branching. Dlx5/6+/− mice, which appear normal histologically, show spontaneous electrographic seizures and reduced power of gamma oscillations. Thus, Dlx5&6 appeared to be required for development and function of somal innervating (parvalbumin+) neocortical interneurons. This contrasts with Dlx1, whose function is required for dendrite innervating (calretinin+, somatostatin+, and neuropeptide Y+) interneurons (Cobos et al., 2005).
161 citations
Cites background from "Migrating partial seizures in infan..."
..., 2008) and more recently, in mutant mice (Powell et al., 2003; Cobos et al., 2005; Marsh et al., 2005; Glickstein et al., 2007; Butt et al., 2008; Marsh et al., 2009)....
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...…a critical aspect of this impairment and has been observed in tissue sections from patients with intractable epilepsy (Knopp et al., 2008) and more recently, in mutant mice (Powell et al., 2003; Cobos et al., 2005; Marsh et al., 2005; Glickstein et al., 2007; Butt et al., 2008; Marsh et al., 2009)....
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TL;DR: The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression.
Abstract: Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100 000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.
136 citations
Cites background from "Migrating partial seizures in infan..."
...The prognosis for psychomotor development is extremely poor for those surviving infancy, although six cases had a relatively better outcome (Marsh et al., 2005)....
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...…in the literature (Coppola et al., 1995, 2005, 2007; Okuda et al., 2000; Wilmshurst et al., 2000; Veneselli et al., 2001; Gross-Tsur et al., 2004; Marsh et al., 2005; Hmaimess et al., 2006; Hahn et al., 2007; Caraballo et al., 2008; Jocic-Jakubi and Lagae, 2008; Cilio et al., 2009; Bedoyan et…...
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...MPSI appears to be rare with 100 cases reported in the literature (Coppola et al., 1995, 2005, 2007; Okuda et al., 2000; Wilmshurst et al., 2000; Veneselli et al., 2001; Gross-Tsur et al., 2004; Marsh et al., 2005; Hmaimess et al., 2006; Hahn et al., 2007; Caraballo et al., 2008; Jocic-Jakubi and Lagae, 2008; Cilio et al., 2009; Bedoyan et al., 2010; Nabatame et al., 2010; Carranza Rojo et al., 2011; Djuric et al., 2011; Freilich et al., 2011; Gilhuis et al., 2011; Irahara et al., 2011; Lee et al., 2012; Poduri et al., 2011, 2012; Sharma et al., 2011; Vendrame et al., 2011; Barcia et al., 2012; Chien et al., 2012; Fasulo et al., 2012; Merdariu et al., 2013)....
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TL;DR: The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology.
Abstract: The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene‐related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self‐limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology‐specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology‐defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource‐limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.
119 citations
References
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Book•
01 Jan 1981
TL;DR: Neural Tube Formation and Prosencephalic, Neuronal Proliferation, Migration, Organization and Myelination.
Abstract: Neural Tube Formation and Prosencephalic Neuronal Proliferation, Migration, Organization and Myelination The Neurological Examination: Normal and Abnormal Features Specialized Studies in the Neurological Evaluation Neonatal Seizures Hypoxic-Ischemic Encephalopathy: Biochemical and Physiological Aspects Hypoxic-Ischemic Encephalopathy: Intrauterine Assessment Hypoxic-Ischemic Encephalopathy: Neuropathology and Pathogenesis Hypoxic-Ischemic Encephalopathy: Clinical Aspects Intracranial Hemorrhage: Subdural, Primary Subarachnoid, Intracerebellar, Intraventricular (Term Infant) and Miscellaneous Intracranial Hemorrhage: Germinal Matrix Intraventricular Hemorrhage or the Premature Infant Hypoglycemia and Brain Injury Bilirubin and Brain Injury Hyperammonemia and Other Disorders of Amino Acid Metabolism Disorders of Organic Acid Metabolism Degenerative Diseases of the Newborn Neuromuscular Disorders: Motor System, Evaluation and Arthrogryposis Multiplex Congenita Neuromuscular Disorders: Levels Above the Lower Motor Neuron to the Neuromuscular Junction Neuromuscular Disorders: Muscle Improvement and Restricted Disorders Viral, Protozoan and Related Intracranial Infections Bacterial and Fungal Intracranial Infections Injuries of Extracranial, Cranial, Intracranial, Spinal Cord and Peripheral Nervous System Structures Brain Tumors and Vein of Galen Malformations Teratogenic Effects of Drugs and Passive Addiction
3,453 citations
"Migrating partial seizures in infan..." refers background in this paper
...Cortical microdysgenesis could be a mechanism; however, no dysgenesis was observed in postmortem examinations limited to the hippocampi in two patients in the original case series (1)....
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...Multifocal electrographic seizures in the neonate are common after a multitude of acute diffuse brain insults, including infections, metabolic disorders, and hypoxia– ischemia (1)....
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...(1) described 14 infants with unprovoked seizures that began before age 6 months and electrographically migrated between the two hemispheres....
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TL;DR: Fourteen infants of both sexes had a previously unreported epileptic condition characterized by nearly continuous multifocal seizures, and extensive investigation failed to determine an etiology, and there was no familial recurrence.
Abstract: Fourteen infants of both sexes had a previously unreported epileptic condition characterized by nearly continuous multifocal seizures. The first seizures occurred at a mean age of 3 months, without antecedent risk factors. At 1 to 10 months, the seizures became very frequent. They were partial with variable clinical expression, and the EEG showed that the discharges randomly involved multiple independent sites, moving from one cortical area to another in consecutive seizures. Although their topography varied, the EEG ictal pattern of each seizure was very similar. It consisted of rhythmic alpha or theta activity which spread to involve an increasing area of the cortical surface. Patients regressed developmentally and became quadriplegic with severe axial hypotonia. Three patients died at age 7 months and at age 7 and 8 years, respectively. Seizures were controlled in only 2 patients, and only 3 children resumed psychomotor development. Extensive investigation failed to determine an etiology, and there was no familial recurrence. Neuropathological examination of the brain in two cases showed only severe hippocampal neuronal loss and accompanying gliosis.
244 citations
"Migrating partial seizures in infan..." refers background in this paper
...infantile epileptic encephalopathy (3,9)....
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...(3) described in 1995 a new syndrome with multifocal seizures and a characteristic EEG pattern, an important addition was made to the recognition of a new early-onset epilepsy syndrome....
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TL;DR: This review provides a simple classification of seizures and emphasizes that many abnormal intermittent behaviors in this age group are not accompanied by ictal EEG patterns, and ≤50% of neonatal seizures are not associated with abnormal clinical behavior.
Abstract: Summary: Neonatal seizures frequently accompany neonatal encephalopathies. Seizures occur in ∼1.8–5/1,000 live births in this country and are caused by virtually any condition that affects neonatal brain function. This review provides a simple classification of seizures and emphasizes that many abnormal intermittent behaviors in this age group are not accompanied by ictal EEG patterns. Additionally, ≤50% of neonatal seizures are not associated with abnormal clinical behavior. This is a common phenomenon, particularly after anticonvulsant treatment in which the clinical seizures are suppressed but electrographic seizures continue unabated. Seizures also may be caused by genetic disorders, several of which are benign, familial, and caused by channelopathies involving potassium channels. The review also discusses the epileptic syndromes seen in neonates, including early myoclonic encephalopathy, Ohtahara syndrome, pyridoxine dependency, and glucose transporter type 1 syndrome.
74 citations
"Migrating partial seizures in infan..." refers background in this paper
...Multifocal seizures also can be observed in cerebral dysgenesis and with some of the known neonatal seizure syndromes (2)....
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TL;DR: There is no direct evidence in humans to suggest that the occurrence of seizures themselves in the neonate is the main determinant of long-term outcome, but experimental data suggests that some epileptic seizures eventually may have physiological, histological, metabolic, or behavioral consequences.
Abstract: The determination of the developmental consequences of seizure syndromes in the neonate is based upon a number of factors which include: understanding of the clinical and electroencephalographic (EEG) features of neonatal seizures; current theories of the mechanisms by which neonatal seizures are generated; a current classification of neonatal seizures; potential etiologic and risk factors for seizures; and therapies. In addition, different seizure types, mechanisms of generation and etiologies of cerebral dysfunction may vary with conceptional age of the infant. There are a few distinct neonatal epileptic syndromes, which are rare, have been well described: benign neonatal convulsions; benign neonatal familial convulsions; early myoclonic encephalopathy and early infantile epileptic encephalopathy. The prognosis for the first two is relatively good while the outcome for the other two with encephalopathy is catastrophic. However, the majority of neonatal seizures occur as acute, reactive events in association with a wide range of etiologic factors. These etiologic factors, as well as those of the more traditionally defined syndromes, are the main determinants of eventual developmental outcome of neonates who experience seizures. Although experimental data suggests that some epileptic seizures eventually may have physiological, histological, metabolic, or behavioral consequences, there is yet direct evidence in humans to suggest that the occurrence of seizures themselves in the neonate is the main determinant of long-term outcome. MRDD Research Reviews 2000;6:229–241. © 2000 Wiley-Liss, Inc.
74 citations
Additional excerpts
...infantile epileptic encephalopathy (3,9)....
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TL;DR: The potassium bromide therapy resulted in complete control of seizures in one patient, and more than 95% reduction in seizure frequency in the other.
Abstract: A 3-month-old male and a 4-month-old female infant with intractable seizures were diagnosed as having malignant migrating partial seizures in infancy (MMPSI) with developmental arrest on the basis of characteristics of symptoms, clinical courses and EEGs. We treated these two patients with potassium bromide (80 mg/kg) after conventional antiepileptic drugs failed to adequately control the seizures. The potassium bromide therapy resulted in complete control of seizures in one patient, and more than 95% reduction in seizure frequency in the other.
73 citations