Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Disease-Modifying Treatments for Multiple Sclerosis Affect Measures of Cellular Immune Responses to EBNA-1 Peptides.

BACKGROUND AND OBJECTIVES: Epstein-Barr virus (EBV) has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Despite this, there are no routinely used tests to measure cellular response to EBV. In this study, we analyzed the cellular response to EBV nuclear antigen-1 (EBNA-1) in people with MS (pwMS) using a whole blood assay. METHODS: This cross-sectional study took place in a dedicated MS clinic in a university hospital. We recruited healthy controls, people with epilepsy (PWE), and pwMS taking a range of disease-modifying treatments (DMTs) including natalizumab, anti-CD20 monoclonal antibodies (mAbs), dimethyl fumarate (DMF), and also treatment naïve. Whole blood samples were stimulated with commercially available PepTivator EBNA1 peptides and a control virus-cytomegalovirus (CMV) peptide. We recorded the cellular response to stimulation with both interferon gamma (IFN-γ) and interleukin-2 (IL-2). We also compared the cellular responses to EBNA1 with IgG responses to EBNA1, viral capsid antigen (VCA), and EBV viral load. RESULTS: We recruited 86 pwMS, with relapsing remitting MS, in this group, and we observed a higher level of cellular response recorded with IFN-γ (0.79 IU/mL ± 1.36) vs healthy controls (0.29 IU/mL ± 0.90, p = 0.0048) and PWE (0.17 IU/mL ± 0.33, p = 0.0088). Treatment with either anti-CD20 mAbs (0.28 IU/mL ± 0.57) or DMF (0.07 IU/mL ± 0.15) resulted in a cellular response equivalent to control levels or in PWE (p = 0.26). The results of recording IL-2 response were concordant with IFN-γ: with suppression also seen with anti-CD20 mAbs and DMF. By contrast, we did not record any differential effect of DMTs on the levels of IgG to either EBNA-1 or VCA. Nor did we observe differences in cellular response to cytomegalovirus between groups. DISCUSSION: This study demonstrates how testing and recording the cellular response to EBNA-1 in pwMS may be beneficial. EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE. In addition, we show a differential effect of currently available DMTs on this response. The functional assay deployed uses whole blood samples with minimal preprocessing suggesting that employment as a treatment response measure in clinical trials targeting EBV may be possible.

Evaluation of Inflammation in the Peripheral Multiple Sclerosis Retina Using Ultra-Widefield Optical Coherence Tomography: A Pilot Study.

BACKGROUND AND OBJECTIVE: Reports of fundus fluorescein angiography (FFA) in active multiple sclerosis (MS) have shown peripheral perivenous sheathing. We sought to assess the feasibility of ultra-widefield (UWF) FFA and optical coherence tomography (OCT) in assessing the peripheral retina in MS. MATERIALS AND METHODS: Participants with MS and healthy controls underwent bilateral UWF fundus photography and FFA. Swept-source OCTs were captured centrally, peripherally, and to delineate any abnormalities visualized. RESULTS: We recruited five people with relapsing remitting MS, with a mean age of 36.9 (± 9.9), mean disease duration of 11 years (± 6.3), and a median expanded disability status score of 0.75 (0 to 2.5). In all MS participants, the disease was not active clinically or radiologically. Using UWF-FFA and OCT, we did not detect clear evidence of peripheral retinal abnormalities, which is consistent with the participants having inactive MS. CONCLUSION: A pilot study using UWF-FFA and peripheral OCT to examine the retina in MS suggests that it may be useful to perform a larger prospective longitudinal study to establish its potential as a monitor of disease activity. [Ophthalmic Surg Lasers Imaging Retina 2023;54:586-588.].

Everolimus precision therapy for the GATOR1-related epilepsies: A case series.

BACKGROUND: Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. METHODS: We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. RESULTS: Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3%-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. CONCLUSIONS: Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.

Concurrent diagnoses of Tuberous sclerosis and multiple sclerosis.

Tuberous sclerosis (TS) is a monogenic disorder which causes disabling neurological symptoms. Similarly, multiple sclerosis (MS) may result in disability, but in contrast, is diagnosed without genetic testing. Clinicians are advised to exercise caution in diagnosing MS in the presence of a pre-existing genetic disorder, as it may be a potential 'red flag'. A dual diagnosis of MS and TS has not previously been reported in the literature. We provide two cases of known cases of TS who presented with new neurological symptoms and associated physical signs compatible with a dual diagnosis of TS/MS.

Word finding, prosody and social cognition in multiple sclerosis.

BACKGROUND: Impairments in speech and social cognition have been reported in people with multiple sclerosis (pwMS), although their relationships with neuropsychological outcomes and their clinical utility in MS are unclear. OBJECTIVES: To evaluate word finding, prosody and social cognition in pwMS relative to healthy controls (HC). METHODS: We recruited people with relapsing MS (RMS, n = 21), progressive MS (PMS, n = 24) and HC (n = 25) from an outpatient MS clinic. Participants completed a battery of word-finding, social cognitive, neuropsychological and clinical assessments and performed a speech task for prosodic analysis. RESULTS: Of 45 pwMS, mean (SD) age was 49.4 (9.4) years, and median (range) Expanded Disability Severity Scale score was 3.5 (1.0-6.5). Compared with HC, pwMS were older and had slower information processing speed (measured with the Symbol Digit Modalities Test, SDMT) and higher depression scores. Most speech and social cognitive measures were associated with information processing speed but not with depression. Unlike speech, social cognition consistently correlated with intelligence and memory. Visual naming test mean response time (VNT-MRT) demonstrated worse outcomes in MS versus HC (p = .034, Nagelkerke's R2  = 65.0%), and in PMS versus RMS (p = .009, Nagelkerke's R2  = 50.2%). Rapid automatised object naming demonstrated worse outcomes in MS versus HC (p = .014, Nagelkerke's R2  = 49.1%). These word-finding measures showed larger effect sizes than that of the SDMT (MS vs. HC, p = .010, Nagelkerke's R2  = 40.6%; PMS vs. RMS, p = .023, Nagelkerke's R2  = 43.5%). Prosody and social cognition did not differ between MS and HC. CONCLUSIONS: Word finding, prosody and social cognition in MS are associated with information processing speed and largely independent of mood. Impairment in visual object meaning perception is potentially a unique MS disease-related deficit that could be further explored and cautiously considered as an adjunct disability metric for MS.

Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

BACKGROUND: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. OBJECTIVE: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. METHODS: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). RESULTS: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability (r = -0.40/-0.62, p < 0.05, corrected). CONCLUSIONS: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

Vaccine hesitancy among people with multiple sclerosis.

BACKGROUND: The current severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has raised awareness of vaccine hesitancy. Specific reasons for vaccine hesitancy among people with multiple sclerosis (pwMS) have not been fully described. Notably, pwMS may experience higher morbidity from vaccine-preventable diseases such as influenza, pneumococcal disease, and human papillomavirus (HPV)-associated warts and malignancies. Furthermore, screening for immunity against measles, mumps and rubella (MMR) is not standard practice, despite a resurgence of measles and mumps outbreaks in Europe and worldwide. We aimed to evaluate general vaccination status among pwMS to better inform vaccine practices in this cohort. METHODS: This was a prospective audit of pwMS attending an Irish tertiary referral MS centre. We designed a questionnaire that explored awareness, uptake, and hesitancy for the influenza, pneumococcal, SARS-CoV-2, HPV, and MMR vaccines. The clinician administered the questionnaire during the outpatient MS clinic. RESULTS: One-hundred-and-five pwMS participated in the audit, mean (SD) age 47.3 (12.8) years, mean MS disease duration 14.1 (9.5) years, median Expanded Disability Severity Scale (EDSS) score 2.0 (IQR 1.0-6.0), forty-nine (46.7%) were taking either maintenance immunosuppressive or immune reconstitution therapies. SARS-CoV-2 vaccine willingness among pwMS was higher (90.5 vs 60-80%) than that reported in other Western countries, and higher than that for the influenza and pneumococcal vaccines (∼80%) for which perceived unnecessity and unfamiliarity respectively were the main limiting factors. The primary reason for SARS-CoV-2 vaccine hesitancy was safety concern. PwMS who were explicitly advised by a healthcare professional to obtain the influenza vaccine were more likely to do so than those who were not (odds ratio, 8.1, 95% CI 2.8 - 23.4, p<0.001). Of pwMS currently receiving B-cell therapy (ocrelizumab/rituximab, n=12), all but one (n=11, 91.7%) have never received the pneumococcal vaccine, and a quarter (n=3) were uncertain whether to obtain this in the future. Patient-reported uptake of HPV (1.0%) and MMR (51.4%) vaccines were suboptimal. Prevalence of vaccine promotion among healthcare professionals was low (influenza vaccine, 4.8 - 32.4%; pneumococcal vaccine, 0 - 18.1%). CONCLUSIONS: Vaccine hesitancy is common (10-20%) in pwMS, consequent to insufficient knowledge and misconceptions about vaccination among pwMS and suboptimal vaccine promotion by healthcare professionals who manage pwMS. Conscientious and context-specific vaccination counselling is necessary to tackle vaccine hesitancy among pwMS, including (i) avoiding infection-associated disability accrual during MS relapses, (ii) reducing the potentially higher risk of life-threatening/treatment-refractory complications that may be observed in those who develop vaccine-preventable infections while receiving certain DMTs, and (iii) avoiding attenuated vaccine responses or delayed/interrupted DMT with early pre-treatment vaccine delivery where possible.

Modeling seizures in the Human Phenotype Ontology according to contemporary ILAE concepts makes big phenotypic data tractable.

OBJECTIVE: The clinical features of epilepsy determine how it is defined, which in turn guides management. Therefore, consideration of the fundamental clinical entities that comprise an epilepsy is essential in the study of causes, trajectories, and treatment responses. The Human Phenotype Ontology (HPO) is used widely in clinical and research genetics for concise communication and modeling of clinical features, allowing extracted data to be harmonized using logical inference. We sought to redesign the HPO seizure subontology to improve its consistency with current epileptological concepts, supporting the use of large clinical data sets in high-throughput clinical and research genomics. METHODS: We created a new HPO seizure subontology based on the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types, and integrated concepts of status epilepticus, febrile, reflex, and neonatal seizures at different levels of detail. We compared the HPO seizure subontology prior to, and following, our revision, according to the information that could be inferred about the seizures of 791 individuals from three independent cohorts: 2 previously published and 150 newly recruited individuals. Each cohort's data were provided in a different format and harmonized using the two versions of the HPO. RESULTS: The new seizure subontology increased the number of descriptive concepts for seizures 5-fold. The number of seizure descriptors that could be annotated to the cohort increased by 40% and the total amount of information about individuals' seizures increased by 38%. The most important qualitative difference was the relationship of focal to bilateral tonic-clonic seizure to generalized-onset and focal-onset seizures. SIGNIFICANCE: We have generated a detailed contemporary conceptual map for harmonization of clinical seizure data, implemented in the official 2020-12-07 HPO release and freely available at hpo.jax.org. This will help to overcome the phenotypic bottleneck in genomics, facilitate reuse of valuable data, and ultimately improve diagnostics and precision treatment of the epilepsies.

Postural stability is a valid and meaningful disability metric in progressive MS with potential for use in neuroprotective therapy trials.

BACKGROUND: Balance impairment is observed in up to 70% of people with MS (pwMS) and worsens with disease progression. Posturography using a force platform is the current gold standard in the measurement of balance. However, posturography has not been adequately studied or widely accepted for use as a disability outcome measure for pwMS. Importantly, the recent emergence of both successful and failed neuroprotective therapy trials in progressive MS has emphasised the need for new disability outcome measures for people with progressive MS. The main objectives of this study were to evaluate the clinical validity, reliability and feasibility of posturography as a disability metric in progressive MS. METHODS: This was a prospective cross-sectional study. We recruited 73 people with progressive MS (age 18-65 years, EDSS 3.5-6.0). Participants stood in the centre of a force platform, feet comfortably apart, under various conditions: (i) eyes open (EO), (ii) eyes closed (EC) - a single task, each lasting ninety seconds; and simultaneous EO with a cognitive test: (iii) N-Back, a three-minute test whereby participants were instructed to click the mouse when two identical letters were displayed consecutively on a screen, (iv) Sustained Attention Response Task, a five-minute test whereby participants were instructed to click the mouse for every number "1″ to "9″ except "3″ - i.e., dual-tasks. Additionally, we performed a battery of validated physical and cognitive outcome measures. Posturographic data was processed using Matlab. Statistical analysis was performed using SPSS version 26. We used multiple linear regression modelling to determine whether significant univariate correlations between posturography and clinical metrics were independent of covariates that may influence the associations seen. A two-tailed significance level of 0.05 was used. RESULTS: Of 73 participants, mean age 52.4 (8.5) years, mean MS disease duration 13.8 (10.3) years, median EDSS 5.0 (IQR 4.0-6.0), 44 (60.4%) were female. EO-Path-Length independently predicted upper extremity function (9-Hole-Peg-Test) with a larger effect size (adjusted R2=20.0%, p = 0.001) than that for walking measures (Timed 25-Foot Walk, adjusted R2=1.6%, p = 0.01; Two-Minute Walk Test, adjusted R2=7.2%, p = 0.002), while controlling for age, disease duration, height, weight, and sex. The addition of EO-Mediolateral-Displacement to the MS Functional Composite (MSFC) created a four-component z-score that increased the variance explained for quality of life (QOL) by 62.1%. Postural stability was significantly lower with mediolateral vs anteroposterior direction of sway, removal of vision, increased body weight, male sex, and fampridine use. Postural stability improved during dual-tasks compared to EO single task. Posturography detected significant worsening of balance over a single prolonged stance. CONCLUSION: Postural stability independently predicted a wide range of clinical metrics including upper extremity function, walking ability, cognition and QOL, therefore establishing construct and concurrent validity as a disability outcome measure for people with progressive MS. Additionally, posturography is a quantitative, non-invasive, quick-and-easy-to-administer, and highly sensitive device, demonstrating its high feasibility for use as a time- and resource-efficient disability metric in neuroprotective therapy trials for progressive MS.

Association of Gray Matter Atrophy Patterns With Clinical Phenotype and Progression in Multiple Sclerosis.

OBJECTIVES: Gay matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes. METHODS: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 patients with MS (34 with clinically isolated syndrome [CIS], 226 with relapsing-remitting MS [RRMS], 95 with secondary progressive MS [SPMS], and 43 with primary progressive MS [PPMS]). Fifty-seven HCs and 144 with MS underwent 1-year follow-up. Baseline GM loss, atrophy progression, and correlations with disability and 1-year clinical worsening were assessed. RESULTS: SBM identified 26 cerebellar, subcortical, sensory, motor, and cognitive GM components. GM atrophy was found in patients with MS vs HCs in almost all components (p range <0.001-0.04). Compared to HCs, patients with CIS showed circumscribed subcortical, cerebellar, temporal, and salience GM atrophy, while patients with RRMS exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience, and frontoparietal GM atrophy was found in patients with PPMS vs HCs and in patients with SPMS vs those with RRMS. At 1 year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated (R 2 = 0.65) with baseline lower normalized brain volume (ß = -0.13, p = 0.001), greater sensorimotor GM atrophy (ß = -0.12, p = 0.002), and longer disease duration (ß = 0.09, p = 0.04). Baseline normalized GM volume (odds ratio 0.98, p = 0.008) and cerebellar GM atrophy (odds ratio 0.40, p = 0.01) independently predicted clinical worsening (area under the curve 0.83). CONCLUSION: GM atrophy differed across disease phenotypes and progressed at 1 year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening.

Coproducing health and well-being in partnership with patients, families, and healthcare providers: A qualitative study exploring the role of an epilepsy patient portal.

BACKGROUND: Coproduced epilepsy care sees people with epilepsy (PwE), their care-proxies, and healthcare providers (HCPs), working together as partners to build strong relationships, improve communication, trust, and share decision-making. Coproduction underpins good quality patient- and family-centered care (PFCC) that is responsive to individual patient needs, preferences, and values. By facilitating information sharing and exchange between partners, electronic patient portals (ePortal) can enable coproduction. This paper explores what HCPs, PwE, and their care-proxies value from their user experience of PiSCES, the Irish epilepsy ePortal. METHODS: A purposeful sample of actors involved in the receipt and delivery of epilepsy care and services were recruited via adult epilepsy centers at St James's and Beaumont Hospitals in Dublin. Interactive codesign sessions, surveys, and focus groups were used to elicit perspectives from PwE, care-proxies, and HCPs to understand their perception of how PiSCES could enhance or inhibit the epilepsy care process. RESULTS: Results illustrate that participants welcome the role PiSCES can play in: empowering PwE/care-proxies, strengthening confidence in the healthcare system; aiding memory; advancing health literacy, motivating PwE to understand their condition better; acting as a passport of care between different clinical settings; and creating a foundation for stronger coproduction partnerships. PiSCES was generally embraced; however, some HCPs expressed plausible concerns about how clinical implementation might impact their work practices. CONCLUSION: "Nothing about me without me" is a core value of the PiSCES initiative, recognizing that people need to be included in the planning of their own treatment and care. Our data show that PwE, their care-proxies, and HCPs value PiSCES potential, particularly in bolstering healthcare partnerships that foster inclusion, confidence, and trust.

The Human Phenotype Ontology in 2021.

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

An evaluation of optimal tutorial methodologies for neurology teaching at undergraduate level : Optimal tutorial methods for neurology.

AIM: We aim to determine the efficacy of an intensive week of large group tutorials in the teaching of neurology to medical students. We also look to compare teaching methods within our centre. METHODS: Students were asked to complete a questionnaire before and after large group tutorials ranking their confidence in neurology. Students from two consecutive years were studied, each using a different tutorial method. An 'intensive week' approach was then compared to a 'once a week' approach. RESULTS: Responses from pre and post the tutorial week were compared. Students reported an improvement in all domains following either method of delivering tutorials. There was no statistically significant difference between the two approaches. CONCLUSION: Large group tutorials are an effective way of delivering neurology teaching to undergraduate medical students.

A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability.

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.

Clinically relevant cranio-caudal patterns of cervical cord atrophy evolution in MS.

OBJECTIVE: To characterize the distribution and regional evolution of cervical cord atrophy in patients with multiple sclerosis (MS) in a multicenter dataset. METHODS: MRI and clinical evaluations were acquired from 179 controls and 435 patients (35 clinically isolated syndromes [CIS], 259 relapsing-remitting multiple sclerosis [RRMS], 99 secondary progressive multiple sclerosis [SPMS], and 42 primary progressive multiple sclerosis [PPMS]). Sixty-nine controls and 178 patients underwent a 1-year MRI and clinical follow-up. Patients were classified as clinically stable/worsened according to their disability change. Longitudinal changes of cord atrophy were investigated with linear mixed-effect models. Sample size calculations were performed using age-, sex- and site-adjusted annualized percentage normalized cord cross-sectional area (CSAn) changes. RESULTS: Baseline CSAn was lower in patients with MS vs controls (p < 0.001), but not different between controls and patients with CIS or between patients with early RRMS (disease duration ≤5 years) and patients with CIS. Patients with late RRMS (disease duration >5 years) showed significant cord atrophy vs patients with early RRMS (p = 0.02). Patients with progressive MS had decreased CSAn (p < 0.001) vs patients with RRMS. Atrophy was located between C1/C2 and C5 in patients with RRMS vs patients with CIS, and widespread along the cord in patients with progressive MS vs patients with RRMS, with an additional C5/C6 involvement in patients with SPMS vs patients with PPMS. At follow-up, CSAn decreased in all phenotypes (p < 0.001), except CIS. Cord atrophy rates were highest in patients with early RRMS and clinically worsened patients, who had a more widespread cord involvement than stable patients. The sample size per arm required to detect a 50% treatment effect was 118 for patients with early RRMS. CONCLUSIONS: Cord atrophy increased in MS during 1 year, except for CIS. Faster atrophy contributed to explain clinical worsening.