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SCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic SCN2A variants are associated with a diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. SCN2A is a high confidence risk gene for autism spectrum disorder and a commonly discovered cause of neonatal onset epilepsy. This remarkable clinical heterogeneity is mirrored by extensive allelic heterogeneity and complex genotype-phenotype relationships partially explained by divergent functional consequences of pathogenic variants. Emerging therapeutic strategies targeted to specific patterns of NaV1.2 dysfunction offer hope to improving the lives of individuals affected by SCN2A-related disorders. This Element provides a review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these genetic conditions authored by leading experts in the field and accompanied by perspectives shared by affected families. This title is also available as Open Access on Cambridge Core.
KCNQ2 and KCNQ3 encode subunits (KV7.2, KV7.3) that combine to form a voltage-gated potassium ion (K+) channel responsible for generating an ionic current (M-current) important for controlling activity in the nervous system. Pathogenic variants in both genes are associated with a spectrum of genetic neurological disorders that feature epilepsy of variable severity and can be accompanied by debilitating impaired neurodevelopment. These two genes were among the first discovered causes of monogenic epilepsy, and are frequently identified in persons with early-life epilepsy. This Element provides a comprehensive review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these prototypical neurological disorders accompanied by perspectives shared by affected families and scientists who have made seminal contributions to the field. This title is also available as Open Access on Cambridge Core.
Neonatal seizures are usually considered of epileptic origin, although some may be generated by non-epileptic mechanisms. Neonatal seizures may be classified by clinical features: focal clonic, focal tonic, myoclonic, spasms, generalized tonic and motor automatisms. The main categories of etiological factors of neonatal seizures include hypoxic- ischemic encephalopathy, central nervous system (CNS) infections, structural brain abnormalities, and metabolic disturbances. Early neuroimaging studies, particularly magnetic resonance imaging (MRI) with diffusion imaging, should show acute diffuse abnormalities consistent with hypoxia/ischemia. Some neonatal seizures result from long-standing disorders. These disorders include cerebral dysgenesis, neurocutaneous syndromes, genetic disorders, or very early onset epilepsy in association with well-defined epileptic syndromes. Clinical examination and seizure characterization are initial points of reference in the evaluation of infants suspected of early myoclonic encephalopathy (EME). Benzodiazepines are frequently used as alternative secondline antiepileptic drugs (AEDs), although more often they are given following phenobarbital and in place of phenytoin.
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SECTION V
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PEDIATRIC NEUROLOGICAL EMERGENCIES
By
Mont R. Roberts, Sparrow Healthcare System Sparow Hospital/MSU Emergency Medicine Residency Program Lansing, Michigan,
Rae R. Hanson, Midelfort Clinic Eau Claire, Wisconsin
The average age of childhood status epilepticus (SE) is under 3 years old. The acute management requires a planned treatment schedule and a specific time line. The duration of SE is the greatest risk to the patient; the longer SE lasts, the more difficult it is to treat. The three goals of treatment are to control seizures, to preserve vital functions, and to diagnose the underlying pathology. Absence SE, partial absence SE, or complex partial SE may present as nonconvulsive SE. Neonatal seizures occur in patients under 29 days old, and they are usually related to significant neurological disease. Pediatric patients are unique in that several characteristic epileptic syndromes have an age-dependent appearance, one or more characteristic seizure types, a natural history, and a prognosis. Some major syndromes include febrile seizures, infantile spasms, Lennox-Gastaut syndrome, and benign rolandic epilepsy (BRE).
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