Risk of Developing Seizures in Children With Abnormal EEG Findings During Polysomnography.

BACKGROUND: Polysomnography (PSG) utilizes abbreviated electroencephalogram (EEG) to stage sleep. The aim of this study was to determine whether epileptiform abnormalities on this limited EEG coverage correlated with abnormalities on routine EEG (rEEG) and an increased risk for seizures in children without a prior diagnosis of epilepsy. METHODS: A six-year retrospective chart review was performed assessing children with abnormalities on EEG during PSG. Children who underwent subsequent rEEG were included; children with a prior diagnosis of seizures were excluded. The main outcome measures were rEEG results and subsequent diagnosis of epilepsy. RESULTS: A total of 67 children met inclusion criteria. Average age was six years, and 43 (64%) were male. rEEG was normal in 16 (24%). Epileptiform abnormalities were focal in 36 (54%), generalized in eight (12%), and mixed in five (8%). An additional two (3%) had slow background rhythm without epileptiform discharges. Thirty-one patients had neurology clinic follow-up with an average duration of 31 months (range 4 to 65 months). Of these, nine (29%) developed seizures, including all three with generalized epileptiform discharges, four of 19 (21%) with focal epileptiform discharges, and two of five (40%) with mixed epileptiform discharges or background slowing. None of the four patients with a normal rEEG had seizures. Eight of the nine patients with seizures were treated with antiepileptic drugs. CONCLUSIONS: Children with no history of seizures found to have abnormal EEG during PSG are likely to have an abnormal rEEG. Additionally, they have an increased risk for developing seizures.

A Case Report of Myelopathy Following Heroin Overdose in a Child.

Neurologic complications secondary to heroin abuse in the adult population have been widely described in the literature. With the recent opioid epidemic and increasing rates of heroin abuse in adolescents, pediatricians are now encountering the diagnostic and management challenge of similar complications in children. We report a case of a 16-year-old girl who presented with complete paraplegia after a heroin overdose. Spinal magnetic resonance imaging showed diffuse thoracic spinal cord abnormalities. She rapidly recovered after high dose intravenous corticosteroids and, upon hospital discharge 2 weeks later, required minimal assistance with ambulation. This case represents the youngest patient reported with the rare complication of myelopathy associated with heroin use.

A case report of hypersomnia in tetrasomy X improved with medical therapy.

Tetrasomy X is a rare chromosomal anomaly in which sleep disorders have not been previously reported. We report on one patient with tetrasomy X and hypersomnia successfully treated with psychostimulant therapy. Sleep disorders are rarely reported in chromosomal anomalies. Clinicians should screen patients for sleep disorders and manage them appropriately.

Tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal-dominant or sporadic multisystem disorder that results from mutations in either TSC1 or TSC2. The primary organs affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. There are over 2000 known allelic variants for TSC, including nonsense and misssense mutation, and all pathogenic mutations are inactivating, leading to loss-of-function effects on the encoded proteins, TSC1 and TSC2. These proteins form a complex to constitutively inhibit the mammalian target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce renal and brain lesion size, and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. The clinical application of mTOR inhibitors in TSC has provided one of the first examples of precision medicine in a neurodevelopmental disorder.

Genetics of tuberous sclerosis complex: implications for clinical practice.

Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in either TSC1 or TSC2. The primary organ systems that are affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. Neurological features include epilepsy, autism, and intellectual disability. There are more than 1,500 known pathogenic variants for TSC1 and TSC2, including deletion, nonsense, and missense mutations, and all pathogenic mutations are inactivating, leading to loss of function effects on the encoded proteins TSC1 and TSC2. These proteins form a complex to constitutively inhibit mechanistic target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce the size of renal and brain lesions and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. The clinical application of mTOR inhibitors in TSC has provided one of the first examples of precision medicine in a neurodevelopmental disorder.

Efficacy and Tolerability of Lacosamide in the Treatment of Children With Refractory Generalized Epilepsy.

Lacosamide is FDA-approved in patients 17 years or older with partial-onset epilepsy. We evaluated the efficacy and tolerability of lacosamide in children with refractory generalized epilepsy. We retrospectively reviewed records of 21 children with refractory generalized epilepsy treated with lacosamide in our institution from 2009-2013 divided into 2 subgroups- I, Lennox-Gastaut Syndrome, and II, other generalized epilepsies. Efficacy was defined as seizure freedom or ≥50% seizure reduction. Descriptive data analysis including seizure freedom was compared using c(2) analysis. There were eleven females and ten males with a mean age, of 11.9 years. Five patients became seizure free, nine had ≥50% seizure reduction, and seven had no response. Group I: seven had ≥50% improvement, one did not respond. Group II: five became seizure free, two had ≥50% improvement, five had no response. Lacosamide is effective and well tolerated in children with refractory generalized epilepsy particularly patients with Lennox-Gastaut Syndrome.

Status epilepticus: immunologic and inflammatory mechanisms.

Status epilepticus (SE) can be difficult to treat, particularly if refractory, and lead to significant morbidity and mortality. Prolonged seizures are also a risk factor for the subsequent diagnosis of epilepsy. Activation of the immune system and inflammation are areas of recent interest in the field of epilepsy, and there is growing evidence that these may be involved in the pathogenesis of ongoing SE and subsequent epileptogenesis. We review the current data on this topic in both animal models and human disease. We conclude that there is evidence suggesting a role for immunologic and inflammatory mechanisms in SE. Further research, especially human studies, is necessary to determine whether targeting the immune system would improve control of SE and prevent sequelae such as epileptogenesis.

Nonconvulsive electrographic seizures are common in children with abusive head trauma*.

OBJECTIVE: To determine the prevalence of nonconvulsive seizures in children with abusive head trauma. DESIGN: Retrospective study of children with abusive head trauma undergoing clinically indicated continuous electroencephalographic monitoring. SETTING: PICU of a tertiary care hospital. SUBJECTS: Children less than or equal to 2 years old with evidence of abusive head trauma determined by neuroimaging, physical examination, and determination of abuse by the Child Protection Team. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-two children with abusive head trauma were identified with a median age of 4 months (interquartile range 3, 5.5 months). Twenty-one of 32 children (66%) underwent electroencephalographic monitoring. Those monitored were more likely to have a lower admission Glasgow Coma Scale (8 vs 15, p = 0.05) and be intubated (16 vs 2, p = 0.002). Electrographic seizures occurred in 12 of 21 children (57%) and constituted electrographic status epilepticus in 8 of 12 children (67%). Electrographic seizures were entirely nonconvulsive in 8 of 12 children (67%). Electroencephalographic background category (discontinuous and slow-disorganized) (p = 0.02) and neuroimaging evidence of ischemia were associated with the presence of electrographic seizures (p = 0.05). Subjects who had electrographic seizures were no more likely to have clinical seizures at admission (67% electrographic seizures vs 33% none, p = 0.6), parenchymal imaging abnormalities (61% electrographic seizures vs 39% none, p = 0.40), or extra-axial imaging abnormalities (56% electrographic seizures vs 44% none, p = 0.72). Four of 21 (19%) children died prior to discharge; none had electrographic seizures, but all had attenuated-featureless electroencephalographic backgrounds. Follow-up outcome data were available for 16 of 17 survivors at a median duration of 9.5 months following PICU admission, and the presence of electrographic seizures or electrographic status epilepticus was not associated with the Glasgow Outcome Scale score (p = 0.10). CONCLUSIONS: Electrographic seizures and electrographic status epilepticus are common in children with abusive head trauma. Most seizures have no clinical correlate. Further study is needed to determine whether seizure identification and management improves outcome.

Wld(S) mice are protected against the Parkinsonian mimetic MPTP.

The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. Because terminal field loss appears to precede cell body loss, we tested whether the mouse mutant Wld(S), which delays axonal degeneration in a variety of disorders, would ameliorate nigrostriatal degeneration following treatment with the Parkinsonian mimetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present findings show that the Wld(S) gene product enhances survival, prevents nigrostriatal axon degeneration, and attenuates neurotransmitter loss but does not rescue cell bodies. As MPTP is thought to impair mitochondrial energy production, these data suggest that disease pathology due to metabolic dysfunction could be improved by the Wld(S) gene product. These results suggest new therapeutic avenues for Parkinson's disease.

Dopamine depletion does not protect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in vivo.

Dopamine (DA) has been postulated to play a role in the loss of dopaminergic substantia nigra (SN) neurons in Parkinson's disease because of its propensity to oxidize and form quinones and other reactive oxygen species that can alter cellular function. Moreover, DA depletion can attenuate dopaminergic cell loss in vitro. To test the contribution of DA to SN impairment in vivo, we used DA-deficient mice, which lack the enzyme tyrosine hydroxylase in dopaminergic cells, and mice pharmacologically depleted of DA by alpha-methyl-p-tyrosine pretreatment. Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that produces parkinsonian pathology in humans, nonhuman primates, and rodents. In contrast to in vitro results, genetic or pharmacologic DA depletion did not attenuate loss of dopaminergic neurons in the SN or dopaminergic neuron terminals in the striatum. These results suggest that DA does not contribute to acute MPTP toxicity in vivo.

SM-20, EGL-9, and the EGLN family of hypoxia-inducible factor prolyl hydroxylases.

Key to the transduction of signals from the environment to the cell nucleus are enzymes that post-translationally modify proteins. Modifications such as protein phosphorylation have long been known to regulate protein interactions, stability, and localization, as well as enzyme activity. Recent investigations into how cells respond to varying oxygen levels have identified a new mechanism for regulating signal transduction involving the post-translational hydroxylation of proline. The enzymes that catalyze this reaction comprise a novel family of prolyl hydroxylases, which include a growth-factor-responsive and cell-death-related protein (SM-20) in mammals, and a protein (EGL-9) in C. elegans important for normal egg laying.