Dinesh Talwar

De Novo Pathogenic SCN8A Mutation Identified by Whole-Genome Sequencing of a Family Quartet Affected by Infantile Epileptic Encephalopathy and SUDEP

Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

Exome sequencing reveals new causal mutations in children with epileptic encephalopathies

The management of epilepsy in children is particularly challenging when seizures are resistant to antiepileptic medications, or undergo many changes in seizure type over time, or have comorbid cognitive, behavioral, or motor deficits. Despite efforts to classify such epilepsies based on clinical and electroencephalographic criteria, many children never receive a definitive etiologic diagnosis. Whole exome sequencing (WES) is proving to be a highly effective method for identifying de novo variants that cause neurologic disorders, especially those associated with abnormal brain development. Herein we explore the utility of WES for identifying candidate causal de novo variants in a cohort of children with heterogeneous sporadic epilepsies without etiologic diagnoses.

EEG Changes and Seizure Exacerbation in Young Children Treated with Carbamazepine

Summary: Carbamazepine (CBZ) has been reported to exacerbate some seizure types in children. We studied the correlation between CBZ‐associated EEG changes and seizure exacerbation in 59 children aged <6 years treated with CBZ. All patients had EEGs before and after initiation of treatment; initial EEGs were not significantly different among the patients. In 33 children (56%), the subsequent EEGs were either unchanged or improved or demonstrated minor changes (Group I), and excellent to complete seizure control was achieved in 67% of patients. In 26 children (44%), the EEG became significantly more abnormal and was characterized predominantly by new appearance of generalized spikelpolyspike‐and‐wave discharges (group 11). The majority of these patients (65%) experienced seizure exacerbation (p <0.001). For group I, symptomatic partial epilepsy, idiopathic focal epilepsy, and complex febrile seizures were significantly more common; in group 11, cryptogenic seizure disorders were more common (p < 0.005). Children in group I were more likely to remain on CBZ or to be weaned from medication after successful treatment, whereas children in group II required additional medication(s) or complete discontinuation of CBZ. Our results suggest that new appearance of generalized paroxysmal discharges after treatment is highly correlated with seizure exacerbation or suboptimal control as well as with adverse outcome. Conversely, absence of significant EEG deterioration on CBZ is usually associated with good seizure control.

Exacerbation of partial seizures and onset of nonepileptic myoclonus with carbamazepine

Summary: A child had two to three generalized tonic‐clonic (GTC) seizures per week unresponsive to pheno‐barbital (PB) and valproate (VPA). Interictal EEG demonstrated left occipital spikes. When carbamazepine (CBZ) therapy was started, he developed very frequent (4–6/day) complex partial seizures (CPS) characterized on ictal EEG by focal right temporal lobe discharges. The seizure exacerbation, which was associated with development of nonepileptic, multifocal myoclonus, resolved 24 h after CBZ was discontinued. The exacerbation occurred with therapeutic CBZ serum levels, but may have been related to the toxic levels of carbamazepine‐10, 11‐epoxide (CBZE).

Nonepileptic events in normal and neurologically handicapped children: A video-EEG study

Nonepileptic episodic phenomena are reported in 27 of 124 children (21.8%) who had video-electroencephalographic studies performed. Mean age was 7.4 years (S.D.: 6.0; range: 0.1-19). Nineteen (70%) were neurologically impaired (Group 1) and 8 (30%) neurologically normal (Group 2). The final diagnoses included movement sequences (48%), conversion disorder (22%), behavioral staring (18%), sleep disorder (11%), behavioral episodes (8%), and central apnea (8%). In Group 1, abnormal movements (58%) and staring (26%) were most common; conversion disorder (62.5%) was most common in Group 2. Unnecessary medication therapy was prevented in many children. Video-electroencephalography is valuable in preventing over-medication and misdiagnosis.

Clinical Manifestations in Children with Occipital Spike‐Wave Paroxysms

Summary: The pattern of occipital‐posterotemporal spike‐wave paroxysms (O‐PT SWPs), is a distinctive EEG abnormality observed primarily with occipital epilepsy of childhood and basilar artery migraine. We studied EEG and clinical features in 30 children and young adults with this EEG pattern. Prolonged and brief O‐PT SWPs were observed. Prolonged discharges (>6 s) were observed only in children with seizures (p < 0.001), and brief discharges (1–6 s) were observed immediately after eye closure. Generalized SWPs (11 patients, 37%) and background abnormalities (17 patients, 57%) were common. Photic activation of O‐PT SWPs was not observed. Twenty‐four patients (80%) manifested paroxysmal phenomena‐seizures (20 patients, 67%) and migraine (12 patients, 40%, 4 alone and 8 with seizures). Fifteen patients (75%) had partial seizures, and 5 (25%) had absence seizures. In 7 patients with partial seizures, an etiology was evident. Neurologic examination was more often abnormal in patients with secondary partial seizures than in those with idiopathic partial seizures (p < 0.05) and absence seizures. Conversely, migraine was more often associated with idiopathic partial seizures than with secondary partial seizures (p < 0.05) and absence seizures. Six children (20%) had no paroxysmal events. Generalized SWPs were uncommon in patients with idiopathic partial seizures. We conclude that 0‐PT SWPs is a nonspecific epileptiform abnormality that may occur in children with (a) idiopathic partial, (b) symptomatic partial, and (c) absence epilepsies, but it may also occur in patients with no evidence of seizures.

Factors influencing serum levels of carbamazepine and carbamazepine-10,11-epoxide in children

Carbamazepine-10,11-epoxide (CBZ-E), the principal metabolite of carbamazepine (CBZ), is reported to have antiepileptic and toxic effects similar to CBZ. Steady-state CBZ and CBZ-E levels (high performance liquid chromatography, HPLC assay) were reviewed in 225 outpatient children and young adults taking CBZ with or without other antiepileptic drugs (AEDs). In patients on CBZ alone, mean serum concentration of CBZ was 7.9 +/- 1.9 micrograms/ml and of CBZ-E was 1.5 +/- 0.6 micrograms/ml. The CBZ-E/CBZ ratio was 19.6 +/- 2.4%. Serum CBZ increased with increasing age and with CBZ dose. CBZ-E increased with increasing CBZ dose but was unaffected by age. The CBZ-E/CBZ ratio progressively declined with age. Co-medication with barbiturates or valproic acid significantly increased CBZ-E. Phenytoin showed a similar trend while ethosuximide caused the least change. Patients on CBZ and two or more other AEDs had highest CBZ-E levels and CBZ-E/CBZ ratio. CBZ and CBZ-E levels are variably affected by age, CBZ dose, and co-medication with other AEDs. When other AEDs are administered, careful monitoring is especially indicated in order to avoid toxicity.

Continuous electrophysiologic monitoring of cerebral function in the pediatric intensive care unit

The brains of children admitted to intensive care units are at considerable risk. Electrophysiologic techniques are the most suitable of available methods for uninterrupted surveillance of brain function. Although the use of routine electroencephalography for this purpose is impractical, automated electroencephalographic signal analysis and application of digital computer technology have made continuous monitoring of cerebral function feasible. Various methods of displaying modified electroencephalographic data in an understandable and interpretable form have been developed; the most commonly used devices are the cerebral function monitor and the compressed spectral array. Practical clinical applications and limitations of continuous cerebral function monitoring are discussed.

EEG and Seizures in Children with Hemolytic–Uremic Syndrome

Summary: The EEG results of 11 children, ages 1–15 years, who presented with hemolytic‐uremic syndrome complicated by seizures 3–10 days after the prodrome were studied. In four children who experienced generalized tonic‐clonic seizures, the EEGs demonstrated diffuse delta slowing with no focality. All recovered without neurological deficits or a residual seizure disorder. Of seven children who experienced partial seizures, six had structural lesions on cranial computed tomography and residual focal neurological deficits with epilepsy. The EEGs in two patients revealed focal spikes and slowing consistent with the lateralization of the partial seizures, in four it was characterized by atypical “burst suppression,” and in one showed epochs of high‐amplitude delta slowing alternating with generalized suppression. Although episodic and generalized burst suppression is usually regarded as a grave prognostic indicator, all four subjects recovered.

Mechanisms of antiepileptic drug action

Animal seizure models, in vitro preparations of cell cultures and tissue slices, and an unravelling of some of the basic mechanisms underlying epileptogenesis and epilepsy have furthered the understanding of mechanisms of action of antiepileptic drugs at the cellular and subcellular levels. Nevertheless, the mechanism of action of most antiepileptic drugs in clinical use is incompletely understood. Multiple physiologic mechanisms are altered by antiepileptic drugs. Some of these drugs, such as phenytoin and carbamazepine, decrease sustained repetitive firing and post-tetanic potentiation through their blocking effects on the sodium channel. Benzodiazepines and barbiturates enhance GABA-mediated inhibition. Many antiepileptic drugs inhibit calcium influx and calcium-mediated secondary effects at supratherapeutic concentrations. Newer drugs that inhibit excitatory receptors or enhance various forms of inhibition are presently under investigation.