Richard E. Rosch

Analysis of rare copy number variation in absence epilepsies

Objective: To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum. Methods: We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE). Results: We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes. Conclusions: Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures.

Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management.

Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the worlds attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities.

Temperature-dependent changes in neuronal dynamics in a patient with an SCN1A mutation and hyperthermia induced seizures

Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures. The patient carries a heterozygous missense variant (c3818C > T; pAla1273Val) in the NaV1.1 brain sodium channel. We compared the functional effects of the variant vs. wild type NaV1.1 using patch clamp recordings from channels expressed in Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40 °C). The variant channels produced a temperature-dependent destabilization of activation and fast inactivation. Implementing these empirical abnormalities in a computational model predicts a higher threshold for depolarization block in the variant, particularly at 40 °C, suggesting a failure to autoregulate at high-input states. These results reveal direct effects of abnormalities in NaV1.1 biophysical properties on neuronal dynamics. They illustrate the value of combining cellular measurements with computational models to integrate different observational scales (gene/channel to patient).

Calcium imaging and dynamic causal modelling reveal brain-wide changes in effective connectivity and synaptic dynamics during epileptic seizures

Pathophysiological explanations of epilepsy typically focus on either the micro/mesoscale (e.g. excitation-inhibition imbalance), or on the macroscale (e.g. network architecture). Linking abnormalities across spatial scales remains difficult, partly because of technical limitations in measuring neuronal signatures concurrently at the scales involved. Here we use light sheet imaging of the larval zebrafish brain during acute epileptic seizure induced with pentylenetetrazole. Spectral changes of spontaneous neuronal activity during the seizure are then modelled using neural mass models, allowing Bayesian inference on changes in effective network connectivity and their underlying synaptic dynamics. This dynamic causal modelling of seizures in the zebrafish brain reveals concurrent changes in synaptic coupling at macro- and mesoscale. Fluctuations of both synaptic connection strength and their temporal dynamics are required to explain observed seizure patterns. These findings highlight distinct changes in local (intrinsic) and long-range (extrinsic) synaptic transmission dynamics as a possible seizure pathomechanism and illustrate how our Bayesian model inversion approach can be used to link existing neural mass models of seizure activity and novel experimental methods.

Use of a bibliometric literature review to assess medical research capacity in post‐conflict and developing countries: Somaliland 1991–2013

Effective healthcare systems require high‐quality research to guide evidence‐based interventions and strategic planning. In low‐ and middle‐income countries, especially those emerging from violent conflict, research capacity often lags behind other aspects of health system development. Here, we sought to bibliometrically review health‐related research output in Somaliland, a post‐conflict self‐declared, autonomous nation on the Horn of Africa, as a means of assessing research capacity.

NMDA receptor blockade causes selective prefrontal disinhibition in a roving auditory oddball paradigm

N-methyl-D-aspartate receptors (NMDARs) are expressed widely throughout the human cortex. Yet disturbances in NMDAR transmission – as implicated in patients with schizophrenia or pharmacologically induced – can cause a regionally specific set of electrophysiological effects. Here, we present a double-blind placebo-controlled study of the effects of the NMDAR blocker ketamine in human volunteers. We employ a marker of auditory learning and putative synaptic plasticity – the mismatch negativity – in a roving auditory oddball paradigm. Using recent advances in Bayesian modelling of group effects in dynamic causal modelling, we fit biophysically plausible network models of the auditory processing hierarchy to whole-scalp evoked response potential recordings. This allowed us to identify the regionally specific effects of ketamine in a distributed network of interacting cortical sources. Under placebo, our analysis replicated previous findings regarding the effects of stimulus repetition and deviance on connectivity within the auditory hierarchy. Crucially, we show that the effect of ketamine is best explained as a selective change in intrinsic inhibition, with a pronounced ketamine-induced reduction of inhibitory interneuron connectivity in frontal sources. These results are consistent with findings from invasive recordings in animal models exposed to NMDAR blockers, and provide evidence that inhibitory-interneuron specific NMDAR dysfunction may be sufficient to explain electrophysiological abnormalities of sensory learning induced by ketamine in human subjects. Significance Statement Dysfunction of N-methyl-D-aspartate receptors (NMDARs) has been implicated in a range of psychopathologies, yet mechanisms translating receptor-level abnormalities to whole-brain pathology remain unclear. We use computational modelling to infer microcircuit mechanisms by which ketamine, an NMDAR-blocker, alters brain responses to changing sequences of sounds that rely on sensory learning. This dynamic causal modelling (DCM) approach shows that ketamine-effects can be explained with brain region specific changes in inhibitory interneuron coupling alone, with a striking reduction in inhibition in the prefrontal cortex. This suggests that NMDAR-effects on excitation-inhibition balance differ between brain regions, and provides evidence from healthy human subjects that NMDAR blockade may cause prefrontal cortex disinhibition, one of the mechanisms hypothesised to underlie psychopathology in schizophrenia.

Network dynamics in the healthy and epileptic developing brain

Electroencephalography (EEG) allows recording of cortical activity at high temporal resolution. EEG recordings can be summarized along different dimensions using network-level quantitative measures, such as channel-to-channel correlation, or band power distributions across channels. These reveal network patterns that unfold over a range of different timescales and can be tracked dynamically. Here we describe the dynamics of network state transitions in EEG recordings of spontaneous brain activity in normally developing infants and infants with severe early infantile epileptic encephalopathies (n = 8, age: 1–8 months). We describe differences in measures of EEG dynamics derived from band power, and correlation-based summaries of network-wide brain activity. We further show that EEGs from different patient groups and controls may be distinguishable on a small set of the novel quantitative measures introduced here, which describe dynamic network state switching. Quantitative measures related to the sharpness of switching from one correlation pattern to another show the largest differences between groups. These findings reveal that the early epileptic encephalopathies are associated with characteristic dynamic features at the network level. Quantitative network-based analyses like the one presented here may in the future inform the clinical use of quantitative EEG for diagnosis.

Dynamic Causal Modelling of Dynamic Dysfunction in NMDA-Receptor Antibody Encephalitis

Using electroencephalography (EEG) dynamic brain function can be measured and its abnormalities identified and described. However, inferring pathological mechanisms from EEG recordings is an ill-posed, inverse problem. Here we illustrate the use of neural mass model based dynamic causal modelling to address this inverse problem. Using Bayesian model inversion and model comparison, DCM allows evaluation of different hypotheses regarding pathomechanisms leading to dynamic brain dysfunction in NMDA receptor encephalitis.

Narcolepsy Following Yellow Fever Vaccination: A Case Report.

Narcolepsy with cataplexy is a rare, but important differential diagnosis for daytime sleepiness and atonic paroxysms in an adolescent. A recent increase in incidence in the pediatric age group probably linked to the use of the Pandemrix influenza vaccine in 2009, has increased awareness that different environmental factors can “trigger” narcolepsy with cataplexy in a genetically susceptible population. Here, we describe the case of a 13-year-old boy with narcolepsy following yellow fever vaccination. He carries the HLA DQB1*0602 haplotype strongly associated with narcolepsy and cataplexy. Polysomnography showed rapid sleep onset with rapid eye movement (REM) latency of 47 min, significant sleep fragmentation and a mean sleep latency of 1.6 min with sleep onset REM in four out of four nap periods. Together with the clinical history, these findings are diagnostic of narcolepsy type 1. The envelope protein E of the yellow fever vaccine strain 17D has significant amino acid sequence overlap with both hypocretin and the hypocretin receptor 2 receptors in protein regions that are predicted to act as epitopes for antibody production. These findings raise the question whether the yellow fever vaccine strain may, through a potential molecular mimicry mechanism, be another infectious trigger for this neuro-immunological disorder.

Incorporating epilepsy genetics into clinical practice: A 360°evaluation

We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team. We held an educational workshop for paediatricians and nurses. We sent questionnaires to referring paediatricians and families. We analysed investigation costs for 16 neonatal epilepsy patients. Of 96 patients, a genetic diagnosis was made in 34% of patients with seizure onset < 2 years, and 4% > 2 years, with turnaround time of 21 days. Pathogenic variants were seen in SCN8A, SCN2A, SCN1A, KCNQ2, HNRNPU, GRIN2A, SYNGAP1, STXBP1, STX1B, CDKL5, CHRNA4, PCDH19 and PIGT. Clinician prediction was poor. Clinicians and families rated the service highly. In neonates, the cost of investigations could be reduced from £9362 to £2838 by performing gene panel earlier and the median diagnostic delay of 3.43 years reduced to 21 days. Panel testing for epilepsy has a high yield among children with onset < 2 years, and an appreciable clinical and financial impact. Parallel gene testing supersedes single gene testing in most early onset cases that do not show a clear genotype-phenotype correlation. Clinical interpretation of laboratory results, and in-depth discussion of implications for patients and their families, necessitate multidisciplinary input and skilled genetic counseling.Genetic screening: actionable information for epilepsy patients and cliniciansScreening for epilepsy-related gene variants can lead to effective, personalized treatment plans while reducing costs. UK and Danish scientists, led by Deb Pal, King’s College London, evaluated a new service within the UK that searches for genetic variants in patients that cause epilepsy. The authors assessed the impact of next-generation gene panel tests, as well as the necessary resources to make such a service effective. Genetic testing was most effective in patients with seizure onset under 2 years old (21% diagnosed) and yield even higher in neonatal-onset epilepsy (63% diagnosed). For many patients with pathogenic variants, the diagnoses allowed for recommendations on treatment or enrolment in clinical trials. The researchers found that diagnostic delay and financial burden in neonatal epilepsy could be drastically reduced with gene panel testing. The scheme was highly rated by users and patients alike.