Novel premature termination codon in the FOXP3 gene as the cause of familial hydrops fetalis in males.

A 19-year-old, G1P0, pregnant person was referred at 20w2d gestation for evaluation due to non-immune hydrops fetalis (NIHF), which was confirmed at the time of evaluation. Amniocentesis was performed at 20 w4d, and FISH, karyotype, chromosomal microarray, and exome sequencing (ES) were ordered. Trio ES identified a novel hemizygous c.142 C > T (p.Arg48*; maternally inherited) variant in the FOXP3 gene, resulting in a premature termination codon and establishing the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Intrauterine fetal demise (IUFD) was diagnosed at 21w3d. CVS was performed at 12w1d in a subsequent pregnancy (male fetus) and the known familial variant was identified. NIHF was identified at 18w1d. Ultrasound at 19w2d revealed IUFD. This is the first report of this variant in a diagnosis of IPEX syndrome, presenting with NIHF and male fetal demise. Genotype-phenotype correlations are not available in many cases of IPEX syndrome, as the same genotype can be present with variable severity in different individuals. Given the near identical presentations in this family, we anticipate a more severe phenotype with this variant. We propose a novel variant resulting in an early premature termination codon as an explanation for the severe presentation of IPEX syndrome in two successive fetuses in this family.

Repeat testing enhances long-term verbal memory in children with epilepsy.

To (i) determine whether accelerated long-term forgetting (ALF) can be found using standardized verbal memory test materials in children with genetic generalized epilepsy (GGE) and temporal lobe epilepsy (TLE), and (ii) to establish whether ALF is impacted by executive skills and repeat testing over long delays. One hundred and twenty-three children aged 8 to 16, (28 with GGE, 23 with TLE, and 72 typically developing; TD) completed a battery of standardized tests assessing executive functioning and memory for two stories. Stories were recalled immediately and after a 30-min delay. To examine whether repeat testing impacts long-term forgetting, one story was tested via free recall at 1-day and 2-weeks, and the other at 2-weeks only. Recognition was then tested for both stories at 2-weeks. Children with epilepsy recalled fewer story details, both immediately and after 30-min relative to TD children. Compared to TD children, the GGE group, but not the TLE group, showed ALF, having significantly poorer recall of the story tested only at the longest delay. Poor executive skills were significantly correlated with ALF for children with epilepsy. Standard story memory materials can detect ALF in children with epilepsy when administered over long delays. Our findings suggest that (i) ALF is related to poor executive skills in children with epilepsy, and (ii) repeated testing may ameliorate ALF in some children.

Accelerated long-term forgetting in children with temporal lobe epilepsy: A timescale investigation of material specificity and executive skills.

Recently, children with temporal lobe epilepsy (TLE) were found to be at risk of accelerated long-term forgetting (ALF). In this study, we examined the temporal trajectory of ALF, while exploring the relationship between ALF, executive skills, and epilepsy variables. Fifty-one children, (23 with TLE and 28 typically developing) completed a battery of neuropsychological tests of verbal and visual memory, executive skills, and two experimental memory tasks (verbal and visual) involving recall after short (30-min) and extended (1-day and 2-week) delays. Side of seizure focus and hippocampal integrity were considered. On the visual task (Scene Memory), children with TLE performed comparably to typically developing children following a 30-min and 1-day delay, although worse than typically developing children at 2 weeks: ALF was observed in children with right TLE focus. The two groups did not differ on the experimental verbal memory task. Children with TLE also had worse performance than typically developing children on standardized verbal memory test and on tests of executive skills (i.e., verbal generativity, inhibition, working memory, complex attention). Only complex attention was associated with visual ALF. ALF was present for visuo-spatial materials in children with TLE at two weeks, and children with right TLE were most susceptible. A relationship was identified between complex attention and long-term forgetting. The findings extend our understanding of difficulties in long-term memory formation experienced by children with TLE.

The Oscillatory Basis of Working Memory Function and Dysfunction in Epilepsy.

Working memory (WM) deficits are pervasive co-morbidities of epilepsy. Although the pathophysiological mechanisms underpinning these impairments remain elusive, it is thought that WM depends on oscillatory interactions within and between nodes of large-scale functional networks. These include the hippocampus and default mode network as well as the prefrontal cortex and frontoparietal central executive network. Here, we review the functional roles of neural oscillations in subserving WM and the putative mechanisms by which epilepsy disrupts normative activity, leading to aberrant oscillatory signatures. We highlight the particular role of interictal epileptic activity, including interictal epileptiform discharges and high frequency oscillations (HFOs) in WM deficits. We also discuss the translational opportunities presented by greater understanding of the oscillatory basis of WM function and dysfunction in epilepsy, including potential targets for neuromodulation.

Indications and expectations for neuropsychological assessment in epilepsy surgery in children and adults.

In our first paper in this series (Epilepsia 2015; 56(5): 674-681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence-based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long-term assessment of these changes following surgery should form an integral part of the postoperative follow-up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.

Indications and expectations for neuropsychological assessment in routine epilepsy care: Report of the ILAE Neuropsychology Task Force, Diagnostic Methods Commission, 2013-2017.

The International League Against Epilepsy (ILAE) Diagnostic Methods Commission charged the Neuropsychology Task Force with the job of developing a set of recommendations to address the following questions: (1) What is the role of a neuropsychological assessment? (2) Who should do a neuropsychological assessment? (3) When should people with epilepsy be referred for a neuropsychological assessment? and (4) What should be expected from a neuropsychological assessment? The recommendations have been broadly written for health care clinicians in established epilepsy settings as well as those setting up new services. They are based on a detailed survey of neuropsychological assessment practices across international epilepsy centers, and formal ranking of specific recommendations for advancing clinical epilepsy care generated by specialist epilepsy neuropsychologists from around the world. They also incorporate the latest research findings to establish minimum standards for training and practice, reflecting the many roles of neuropsychological assessment in the routine care of children and adults with epilepsy. The recommendations endorse routine screening of cognition, mood, and behavior in new-onset epilepsy, and describe the range of situations when more detailed, formal neuropsychological assessment is indicated. They identify a core set of cognitive and psychological domains that should be assessed to provide an objective account of an individual's cognitive, emotional, and psychosocial functioning, including factors likely contributing to deficits identified on qualitative and quantitative examination. The recommendations also endorse routine provision of feedback to patients, families, and clinicians about the implications of the assessment results, including specific clinical recommendations of what can be done to improve a patient's cognitive or psychosocial functioning and alleviate the distress of any difficulties identified. By canvassing the breadth and depth of scope of neuropsychological assessment, this report demonstrates the pivotal role played by this noninvasive and minimally resource intensive investigation in the care of people with epilepsy.

Absent CNKSR2 causes seizures and intellectual, attention, and language deficits.

Synaptic function is central to brain function. Understanding the synapse is aided by studies of patients lacking individual synaptic proteins. Common neurological diseases are genetically complex. Their understanding is likewise simplified by studies of less common monogenic forms. We detail the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike-waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders.

Cognitive and language outcomes in HIV-uninfected infants exposed to combined antiretroviral therapy in utero and through extended breast-feeding.

OBJECTIVE: To determine whether there is a higher risk for cognitive or language delay among HIV-exposed uninfected (HEU) children exposed to cART (zidovudine/lamivudine/lopinavir/ritonavir) in utero and through 1 year of breast-feeding (World health Organization Option B+), compared with the control children born to HIV-uninfected mothers. DESIGN: This is a double cohort study from Lusaka, Zambia. METHODS: HEU (n = 97) and control (n = 103) children aged 15-36 months were assessed on their early nonverbal problem-solving and language skills using the standardized Capute Scales. A score of less than 85 on the Capute Full-Scale Developmental Quotient (FSDQ) was considered indicative of developmental delay and was the primary outcome of interest. RESULTS: An FSDQ of less than 85 was found in eight (8.3%) of HEU participants and 15 (14.6%) of controls. In univariate logistic regressions, lower income [odds ratio (OR) = 0.93, P = 0.02], older infant age (OR = 1.08, P = 0.03), lower birth weight (OR = 0.16, P < 0.001), and less maternal education (OR = 0.41, P = 0.047) were associated with the probability of FSDQ less than 85, whereas Group (control/HEU) was not (OR = 1.88, P = 0.16). In the multivariable analysis, only lower birth weight (OR = 0.15, P < 0.001) remained associated with FSDQ less than 85. CONCLUSIONS: Our study did not support the presence of an adverse effect on cognitive and language development with prolonged antepartum and postpartum cART e/xposure. Larger studies and studies of older HEU children will be required to confirm these reassuring findings.

The significance of ear plugging in localization-related epilepsy.

PURPOSE: The localizing value of ear plugging in the treatment of auditory onset partial seizures, to our knowledge, has not been previously described. We propose that ear plugging is a clinical response to a sensory seizure manifested as an auditory hallucination and a tool for identifying the seizure focus in the auditory cortex on the superior temporal gyrus. METHODS: We report on three children who had prior epilepsy surgery for recurrent symptomatic localization-related epilepsy and who, subsequent to their surgery, displayed stereotyped unilateral or bilateral ear plugging at the onset of partial seizures. We studied scalp video electroencephalography (VEEG), magnetoencephalography (MEG), and magnetic resonance imaging (MRI) in all three. Additionally, we used electrocorticography (ECoG) in two patients, intracranial VEEG monitoring in one patient, and functional MRI language mapping in two patients. RESULTS: All three patients plugged their ears with their hands during auditory auras that localized to the superior temporal gyrus and were followed by partial seizures that spread to a wider field, as shown on scalp and intracranial VEEG. All three patients had MEG interictal discharges in the superior temporal gyrus. One patient who was nonverbal and unable to describe an auditory phenomenon plugged the ear contralateral to where temporal lobe-onset seizures and MEG interictal discharges occurred. CONCLUSIONS; Ear-plugging seizures indicate an auditory aura and may also lateralize seizure onset to the contralateral temporal lobe auditory cortex. Stereotyped behaviors accompanied by epileptic seizures in children who have poor communication skills are important in the seizure semiology of localization-related epilepsy.