A Sense of Humor is Especially Important During Difficult Times.

Artist-critic Clive James said: "Common sense and a sense of humor are the same thing, moving at different speeds. A sense of humor is just common sense, dancing. Those who lack humor are without judgment and should be trusted with nothing."

Child neurology in the 21st century: More than the sum of our RVUs.

In September 2017, the Child Neurology Society (CNS) convened a special task force to review the practice of child neurology in the United States. This was deemed a necessity by our membership, as our colleagues expressed discouragement and burnout by the increase in workload without additional resources; reliance on work relative value units (wRVUs) as the sole basis of compensation; a push by administrators for providers to see more patients with less allotted time; and lack of administrative, educational, and research support. The CNS Task Force designed and distributed a survey to multiple academic divisions of various sizes, as well as to private practices. Our findings were strikingly similar across different practices, demonstrating high workloads, lack of resources, poor electronic medical record support, and high provider symptoms of fatigue and burnout. From the results, the CNS Task Force has concluded that wRVUs cannot be the sole basis of compensation for child neurology. We have also made several specific recommendations for alleviating the current situation, including innovative ways to fund child neurology as well as ways to enhance job satisfaction.

Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses.

BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. OBJECTIVE: To identify rare, causal CNV in patients with RE. METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

Neuroinflammation-Related Encephalopathy in an Infant Born Preterm Following Exposure to Maternal Diabetic Ketoacidosis.

A pregnant woman with new-onset type 1 diabetes and ketoacidosis delivered an infant at 28 weeks of gestation who died with multiple organ failure and severe cerebral vasculopathy with extensive hemorrhage, diffuse microgliosis, and edema. This illustrates that antenatal metabolic and inflammatory stressors may be associated with neonatal encephalopathy and cerebral hemorrhage.

Adverse Structural and Functional Effects of Marijuana on the Brain: Evidence Reviewed.

The growing use and legalization of cannabis are leading to increased exposures across all age groups, including in adolescence. The touting of its medicinal values stems from anecdotal reports related to treatment of a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer disease, Parkinson disease, post-traumatic stress, inflammatory bowel disease, and anxiety. However, anecdotal data and the high level of interest in this treatment must not obscure objective assessments of any potential and realized short- and long-term adverse effects of cannabis, particularly with respect to age of onset and chronicity of exposure. This critical review focuses on evidence-based research designed to assess both therapeutic benefits and harmful effects of cannabis exposure and is combined with an illustration of the neuropathologic findings in a fatal case of cannabis-induced psychosis. The literature and reported case provide strong evidence that chronic cannabis abuse causes cognitive impairment and damages the brain, particularly white matter, where cannabinoid 1 receptors abound. Contrary to popular perception, there are few objective data supporting preferential use of cannabis over conventional therapy for restoration of central nervous system structure and function in disease states such as multiple sclerosis, epilepsy, or schizophrenia. Additional research is needed to determine if subsets of individuals with various neurological and psychiatric diseases derive therapeutic benefits from cannabis.

A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.

OBJECTIVE: Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome-wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4-PAX6 locus in two independent US and Canadian case-control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array. METHODS: We fine-mapped the ELP4-PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome-12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance. RESULTS: Homozygosity at the T allele of SNP rs662702 in the 3' untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20-47.22), P = 2.6 × 10(-4) and is seen in 3.9% of cases but only 0.3% of controls. INTERPRETATION: The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.

Risk factors for reading disability in families with rolandic epilepsy.

OBJECTIVE: The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. METHODS: An observational study of 108 probands with RE (age range: 3.6-22 years) and their 159 siblings (age range: 1-29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case-control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. RESULTS: Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45-37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15-49.44), and male sex (OR: 3.62, 95% CI: 1.11-11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42-13.0) and not with the presence of interictal EEG focal sharp waves. SIGNIFICANCE: The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions.

Association of head circumference and shoulder dystocia in macrosomic neonates.

To determine whether asymmetric macrosomia (disproportionately large body size in comparison to head circumference) could be demonstrated in a population of infants suffering shoulder dystocia during delivery relative to those that did not suffer from shoulder dystocia. A case-control study was conducted as a retrospective chart review over 3 years at a large maternity hospital in an urban setting. Among infants over 4,000 g, those that suffered from shoulder dystocia during delivery had a smaller mean head circumference than infants of a similar size that did not suffer from shoulder dystocia. A statistically significant difference was also present when cases of documented gestational diabetes were excluded. Asymmetric macrosomia is more likely to be present in a population of infants who suffered shoulder dystocia during delivery. This knowledge could be used in designing tools to predict which pregnancies are at highest risk for shoulder dystocia during delivery.

The genetics of reading disability in an often excluded sample: novel loci suggested for reading disability in Rolandic epilepsy.

BACKGROUND: Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating "pure" dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE. METHODS: We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus. RESULTS: In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation. DISCUSSION: Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in "pure" dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.

Myoclonic astatic epilepsy and the role of the ketogenic diet.

The ketogenic diet remains one of the most effective treatments for medically refractory childhood epilepsy. In spite of the long history of its use, relatively little is known about the mechanism of action. The diet's efficacy in a wide range of epilepsy syndromes suggests that it may have multiple mechanisms of action, each of which may be more relevant to a specific disease state. Further research is necessary to define the mechanism of action, which may, in turn, lead to easier means to provide the therapeutic benefit.

Polyspike and waves do not predict generalized tonic-clonic seizures in childhood absence epilepsy.

About 40% of children with childhood absence epilepsy develop generalized tonic-clonic seizures. It is commonly held that polyspike-wave pattern on the electroencephalogram (EEG) can predict this development of generalized tonic-clonic seizures. However, there is no firm evidence in support of this proposition. To test this assumption, we used survival analysis and compared the incidence of generalized tonic-clonic seizures in 115 patients with childhood absence epilepsy having either isolated 3-Hz spike-wave or coexisting 3 Hz and polyspike-waves and other variables. There was no evidence that polyspike-waves predicted development of generalized tonic-clonic seizures in patients with childhood absence epilepsy. Later age of onset (> or =8 years) and family histories of generalized tonic-clonic seizures were the only independent predictors. These results have implications for counseling and in the choice of first-line antiepileptic drugs used for childhood absence epilepsy, especially if valproate is chosen based on the observation of polyspike-waves.

Baseline cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy.

AIM: Epilepsy is associated with difficulties in cognition and behavior in children. These problems have been attributed to genetics, ongoing seizures, psychosocial issues, underlying abnormality of the brain, and/or antiepileptic drugs. In a previous study, we found baseline cognitive differences between children with partial versus generalized and convulsive versus non-convulsive seizures. Measures in that study focused primarily on IQ scores. In the present study, we assessed baseline function with respect to new learning, attention, and memory, thus providing a more comprehensive profile than our previous study. METHOD: We examined 57 children (42 females, 15 males), aged 6 to 17 years (mean 10y 1mo, SD 2y 9mo), with new-onset, idiopathic epilepsy, using tests of cognitive function reflective of new learning, memory, and attention. Seizures were classified as generalized convulsive (n=5), generalized non-convulsive (n=18), or focal (n=34). Focal seizures were divided into unilateral versus bilateral independent foci, and presence versus absence of secondary generalization. RESULTS: Attention was a particular area of weakness across all groups. The Vocabulary score of an intelligence screen was higher for the focal seizure groups (p=0.012), primarily because of a difference between the unilateral focal and the primary generalized groups (p<0.047). Children with generalized, non-convulsive seizures performed significantly worse than the focal group on a measure of short-term auditory memory (p=0.019). All groups performed poorly on a test of visual-motor speed. INTERPRETATION: These findings suggest intrinsic abnormalities in children with new-onset, idiopathic epilepsy at baseline.

Impact of antiepileptic drugs on cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy.

OBJECTIVE: As treatment options for epilepsy have increased, there has been a commensurate increase in interest in the side effect profiles of these drugs. METHODS: In this study, children between the ages of 6 and 17 with a diagnosis of new-onset, idiopathic epilepsy were evaluated at baseline (n=57) and 6 (n=45) and 12 (n=31) months after initiation of antiepileptic drug therapy. RESULTS: There was improvement in the cognitive functioning of children after 12 months of treatment. A transient drop in performance of children with generalized seizures (10 of 11 of whom had absence seizures) at 6 months may have been due to persistent seizures, the drugs used to treat them (predominantly ethosuximide), or both. Worsening of reaction time and reaction time variability in the focal seizure group, the only scores showing persistent deterioration over 12 months, may be attributable to the medications used for this group, the most common of which was carbamazepine. CONCLUSIONS: There were few adverse effects of antiepileptic drug treatment in the group followed over 12 months. Carbamazepine may have been responsible for persistent impairment of reaction time and reaction time variability.

Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4).

Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.