Publications by authors named "Rhys H Thomas"

83 Publications

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

Epilepsia 2021 May 5. Epub 2021 May 5.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1111/epi.16908DOI Listing
May 2021

Trait impulsivity in Juvenile Myoclonic Epilepsy.

Ann Clin Transl Neurol 2021 01 2;8(1):138-152. Epub 2020 Dec 2.

Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs).

Methods: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects.

Results: The mean BIS-brief score in JME was 18.1 ± 4.4 compared with 16.2 ± 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse effects.

Interpretation: Trait impulsivity is elevated in JME and comparable to scores in personality and neurotic disorders. Increased seizure frequency and absence of circadian seizure pattern moderate BIS score, suggesting disruption of both cortico-striatal and thalamocortical networks as a shared mechanism between seizures and impulsivity in JME. These findings warrant consideration of impulsivity as a distinct target of intervention, and as a stratifying factor for AED treatment in JME, and perhaps other types of epilepsy. The role of impulsivity in treatment adherence and psychosocial outcome requires further investigation.
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http://dx.doi.org/10.1002/acn3.51255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818143PMC
January 2021

COVID-19 and psychosis risk: Real or delusional concern?

Neurosci Lett 2021 01 18;741:135491. Epub 2020 Nov 18.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Historical epidemiological perspectives from past pandemics and recent neurobiological evidence link infections and psychoses, leading to concerns that COVID-19 will present a significant risk for the development of psychosis. But are these concerns justified, or mere sensationalism? In this article we review the historical associations between viral infection and the immune system more broadly in the development of psychosis, before critically evaluating the current evidence pertaining to SARS-CoV-2 and risk of psychosis as an acute or post-infectious manifestation of COVID-19. We review the 42 cases of psychosis reported in infected patients to date, and discuss the potential implications of in utero infection on subsequent neurodevelopment and psychiatric risk. Finally, in the context of the wider neurological and psychiatric manifestations of COVID-19 and our current understanding of the aetiology of psychotic disorders, we evaluate possible neurobiological and psychosocial mechanisms as well as the numerous challenges in ascribing a causal pathogenic role to the infection.
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http://dx.doi.org/10.1016/j.neulet.2020.135491DOI Listing
January 2021

Paediatric sudden unexpected death in epilepsy: A parental report cohort.

Acta Neurol Scand 2021 May 8;143(5):509-513. Epub 2020 Dec 8.

Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.

Background: Sudden unexpected death in epilepsy (SUDEP) accounts for a large percentage of deaths in children with epilepsy. Contributing factors to paediatric SUDEP are incompletely understood.

Aims Of Study: The Epilepsy Deaths Register (EDR) is an anonymized register that compiles information on deaths related to epilepsy, across all ages and epilepsy classifications. Using the EDR, we sought to identify key risk factors for SUDEP in children to assist the development of preventive measures.

Methods: All registrations between the ages of 1 and 16 years were reviewed to identify definite or probable SUDEP. These cases were analysed to identify common demographics, comorbidities, monitoring, treatments and circumstances near to the deaths.

Results: We identified forty-six cases (27 males) of definite or probable SUDEP. Paediatric SUDEP is more common in a 12- to 16-year age group and in those with neuro-disability. Most paediatric SUDEP occurs during apparent sleep. There were four cases with a vagus nerve stimulator. SUDEP can occur early after the onset of seizures.

Conclusions: This is the largest single cohort of SUDEP reported in children. Reports from caregivers can augment population data. Surveillance in sleep is a priority area of development.
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http://dx.doi.org/10.1111/ane.13378DOI Listing
May 2021

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Sci Adv 2020 Nov 18;6(47). Epub 2020 Nov 18.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.
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http://dx.doi.org/10.1126/sciadv.abc6457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673818PMC
November 2020

Characterising neuropsychiatric disorders in patients with COVID-19 - Authors' reply.

Lancet Psychiatry 2020 11;7(11):934-935

The National Institute for Health Research Health Protection Research Unit for Emerging and Zoonotic Infections, Liverpool, UK; Department of Clinical Infection Microbiology and Immunology, Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(20)30420-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561324PMC
November 2020

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Department of Paediatric Neurology, University Hospital of Wales, Cardiff, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Epilepsy, an orphan disorder within the neurodevelopmental family.

J Neurol Neurosurg Psychiatry 2020 12 14;91(12):1245-1247. Epub 2020 Sep 14.

Department of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1136/jnnp-2020-324660DOI Listing
December 2020

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.

Am J Hum Genet 2020 10 26;107(4):683-697. Epub 2020 Aug 26.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536581PMC
October 2020

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

Brain 2020 08;143(8):2454-2473

Department of Neurology, Medical University of South Carolina, Charleston 29425 SC, USA.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.
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http://dx.doi.org/10.1093/brain/awaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567169PMC
August 2020

The prevalence of genetically diagnosable epilepsies in young adulthood: How many should we be looking for?

Epilepsia 2020 09 12;61(9):2053-2054. Epub 2020 Aug 12.

Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals National Health Service Foundation Trust, Newcastle Upon Tyne, UK.

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http://dx.doi.org/10.1111/epi.16640DOI Listing
September 2020

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study.

Lancet Psychiatry 2020 10 25;7(10):875-882. Epub 2020 Jun 25.

The National Institute for Health Research Health Protection Research Unit for Emerging and Zoonotic Infections, Liverpool, UK; Department of Clinical Infection Microbiology and Immunology, Institute of Infection, Veterinary, and Ecological Sciences, University of Liverpool, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK. Electronic address:

Background: Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterisation of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain.

Methods: During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies.

Findings: The ABN portal was launched on April 2, 2020, the BASP portal on April 3, 2020, and the RCPsych portal on April 21, 2020. Data lock for this report was on April 26, 2020. During this period, the platforms received notification of 153 unique cases that met the clinical case definitions by clinicians in the UK, with an exponential growth in reported cases that was similar to overall COVID-19 data from UK Government public health bodies. Median patient age was 71 years (range 23-94; IQR 58-79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years.

Interpretation: To our knowledge, this is the first nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients. This study provides valuable and timely data that are urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy.

Funding: None.
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http://dx.doi.org/10.1016/S2215-0366(20)30287-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316461PMC
October 2020

The ENIGMA-Epilepsy working group: Mapping disease from large data sets.

Hum Brain Mapp 2020 May 29. Epub 2020 May 29.

Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.
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http://dx.doi.org/10.1002/hbm.25037DOI Listing
May 2020

Clinical Reasoning: A 25-year-old woman with recurrent episodes of collapse and loss of consciousness.

Neurology 2020 06 1;94(22):994-999. Epub 2020 May 1.

From the Departments of Neurology (J.W., M.R.B., R.H.T.), Clinical Neurophysiology (M.R.B.), and Infectious Disease (D.A.P.), Royal Victoria Infirmary; Institute of Neuroscience (M.R.B., R.H.T.), Newcastle-Upon-Tyne, UK; Institute of Neurosciences Kolkata (S.T., H.K.), India; Division of Evolution and Genomic Sciences (G.I.R.), School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre; Centre for Genomic and Experimental Medicine (Y.C.), MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK; and Laboratory of Neurogenetics and Neuroinflammation (Y.C.), Institut Imagine, Paris Descartes University, France.

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http://dx.doi.org/10.1212/WNL.0000000000009533DOI Listing
June 2020

Expert opinion: use of valproate in girls and women of childbearing potential with epilepsy: recommendations and alternatives based on a review of the literature and clinical experience-a European perspective.

J Neurol 2020 Apr 1. Epub 2020 Apr 1.

Department of Neurology, Vivantes Humboldt-Klinikum Berlin, Berlin, Germany.

Valproate is a broad-spectrum antiepileptic drug (AED) of particular interest in pediatric epilepsy syndromes and idiopathic generalized epilepsy, as it is relatively more effective in these syndromes than other AEDs. In 2018, the European Medicines Agency introduced new restrictions on the use of valproate in girls and women of childbearing potential to avoid exposure during pregnancy. The strengthening of existing restrictions sparked controversy and debate among patients and the medical community. The high prevalence of epilepsy syndromes amenable to valproate treatment in women of childbearing age and the little information available on the teratogenic potential of alternative treatments have created uncertainty on how to manage these patients. In this consensus statement, based on a review of the literature and the clinical experience of a panel of European epilepsy experts, we present general recommendations for the optimal clinical management of AED treatment in girls, women of childbearing potential, and pregnant women across the different epilepsy syndromes.
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http://dx.doi.org/10.1007/s00415-020-09809-0DOI Listing
April 2020

Self-driving cars: a qualitative study into the opportunities, challenges and perceived acceptability for people with epilepsy.

J Neurol Neurosurg Psychiatry 2020 07 26;91(7):781-782. Epub 2020 Mar 26.

Department of Neuroscience, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK

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http://dx.doi.org/10.1136/jnnp-2019-322610DOI Listing
July 2020

Early-onset genetic epilepsies reaching adult clinics.

Brain 2020 03;143(3):e19

Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.

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http://dx.doi.org/10.1093/brain/awaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089663PMC
March 2020

Response to letter to editor: "Knowing when and how to use epilepsy screening questionnaires".

Epilepsia 2020 04 2;61(4):826-827. Epub 2020 Mar 2.

Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.

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http://dx.doi.org/10.1111/epi.16463DOI Listing
April 2020

The mitochondrial epilepsies.

Eur J Paediatr Neurol 2020 Jan 7;24:47-52. Epub 2020 Jan 7.

Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom; Department of Neurology, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle-Upon-Tyne, NE1 4LP, United Kingdom; Institute of Neuroscience, Henry Wellcome Building, Framlington Place, Newcastle University, Newcastle-Upon-Tyne, NE2 4HH, United Kingdom. Electronic address:

Mitochondria are vital organelles within cells that undertake many important metabolic roles, the most significant of which is to generate energy to support organ function. Dysfunction of the mitochondrion can lead to a wide range of clinical features, predominantly affecting organs with a high metabolic demand such as the brain. One of the main neurological manifestations of mitochondrial disease is metabolic epilepsies. These epileptic seizures are more frequently of posterior quadrant and occipital lobe onset, more likely to present with non-convulsive status epilepticus which may last months and be more resistant to treatment from the onset. The onset of can be of any age. Childhood onset epilepsy is a major phenotypic feature in mitochondrial disorders such as Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies, and Leigh syndrome. Meanwhile, adults with classical mitochondrial disease syndrome such as MELAS, MERFF or POLG-related disorders could present with either focal or generalised seizures. There are no specific curative treatments for mitochondrial epilepsy. Generally, the epileptic seizures should be managed by specialist neurologist with appropriate use of anticonvulsants. As a general rule, especially in disorders associated with mutation in POLG, sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal.
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http://dx.doi.org/10.1016/j.ejpn.2019.12.021DOI Listing
January 2020

The view of the clinician and the scientist on the family experience of sudden epilepsy deaths.

Epilepsy Behav 2020 02 9;103(Pt B):106679. Epub 2019 Dec 9.

University of Glasgow, United Kingdom. Electronic address:

A sudden epilepsy-associated death is a tragedy for the bereaved, a failure for the clinician and a challenge for a research scientist. Sudden death in epilepsy cannot be truly anticipated or prepared for by the bereaved, or the clinical team. Communications and provision of pastoral care following sudden unexpected death in epilepsy (SUDEP) is an important part of an epilepsy service where interaction with the family and specialist services for the bereaved can be rewarding. Sudden death and SUDEP are valid targets for research attention, but families may be less aware of opportunities to assist in life science research or conversely feel coerced at a vulnerable time. We have a responsibility to ensure that the SUDEP risk is minimized and that we maximize the learning potential from each death. Out of such tragedies some good must come, but this will take combined efforts from doctors, families, and the voluntary sector acting in league with scientific and academic funders. In this review, we set out to consider the dual viewpoints of the clinician and the scientist and how they consider the family experience of sudden deaths to provide advice for all parties. "This paper is for the Special Issue: Prevent 21: SUDEP Summit - Time to Listen".
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http://dx.doi.org/10.1016/j.yebeh.2019.106679DOI Listing
February 2020

Clinicians embracing social media: Potential and pitfalls.

Epilepsy Behav 2021 02 12;115:106462. Epub 2019 Nov 12.

Institute of Neuroscience, Newcastle University, United Kingdom of Great Britain and Northern Ireland; Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom of Great Britain and Northern Ireland. Electronic address:

The bedrock of clinical medicine is effective communication. A generation ago, this was primarily the clinical consultation, the letter to the general practitioner, and the occasional scientific paper. In 2019, the avenues and opportunities for communication have exploded and include a pantheon of new and social media. We review the current state of how doctors use social media, and what can be gained by doing so. We provide strategies about how best to utilize these tools, depending on what you wish to gain. We discuss why every clinician needs a 'social media strategy' even if this is one of increasing your privacy levels and removing incorrect information from the web. We discuss the risks and harms of these newer forms of communication and how best to avoid embarrassment or censure. Social media fills an information vacuum, and in many ways, patients have embraced the opportunities with greater enthusiasm than have clinicians. To 'speak their language', we need to know how best to engage in social media.
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http://dx.doi.org/10.1016/j.yebeh.2019.106462DOI Listing
February 2021

A tiered strategy for investigating status epilepticus.

Seizure 2020 Feb 22;75:165-173. Epub 2019 Oct 22.

Royal Victoria Infirmary, Newcastle-upon-Tyne, UK; Institute of Neuroscience, Newcastle University, UK. Electronic address:

In status epilepticus the imperative to start anti-seizure therapy, initially subjugates the need to investigate the cause. Once treatment is initiated this balance shifts in favour of identifying: the causes and consequences of the seizure; the factors that predetermined the occurrence of status epilepticus; and finally the prognosis of this acute episode. Just as there are multiple causes of seizures and epilepsy, there are a vast number of causes of status epilepticus. We discuss the more common and the more important to identify as they may dictate a change in therapy or a certain prognosis. Acknowledging that the burden of epilepsy and status epilepticus is preferentially felt in lower and middle income countries, we have tried to rationalise the investigation of status epilepticus. Basic laboratory studies are necessary in all patients with status epilepticus as systemic complications can occur early and can involve every organ system. Aetiology is important, however the morbidity from treatment does not discriminate when treatment resistant status epilepticus is due to dissociative seizures. Seven percent of epilepsy hospitalisations are for status epilepticus and epilepsy is a prior diagnosis half the time; awareness of prior history is invaluable. EEG is critical for diagnosis in the anaesthetised patient or those in non-convulsive status epilepticus. There is poor correlation of EEG with aetiology except in rare circumstances. Currently quantitative EEG methods should best be viewed as screening tool to reduce EEG reviewing time. MRI is clearly superior for identifying cytotoxic change and the networks that are or were involved in the episode of status epilepticus. Sequential imaging changes may give an estimate of recovery but there is insufficient detail to use MRI as a prognostication tool. We suggest the following model: 1) immediate investigations; 2) investigations targeted by the clinical scenario; 3) investigations targeted following results from bloods, imaging or EEG; 4) investigations targeted for rarer causes and super-refractory status epilepticus.
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http://dx.doi.org/10.1016/j.seizure.2019.10.004DOI Listing
February 2020

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.

Genet Med 2020 03 3;22(3):524-537. Epub 2019 Oct 3.

CHU de Rennes, service de génétique clinique, Rennes, France.

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.

Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.

Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.

Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
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http://dx.doi.org/10.1038/s41436-019-0657-0DOI Listing
March 2020

Learnings from deaths - the Epilepsy Deaths Register.

Epilepsy Behav 2020 02 17;103(Pt B):106454. Epub 2019 Aug 17.

SUDEP Action, 18 Newbury Street, Wantage OX12 8DA, United Kingdom.

The Epilepsy Deaths Register (EDR) differs from typical registries which concentrate primarily on clinical information. It is completed by bereaved relatives and focuses on the circumstances immediately before, and the support following, a death. It can be augmented by copies of death certificates from the families of the deceased, and all epilepsy associated deaths can be entered. The EDR is underpinned by the research and experience of the SUDEP Action team and the clinical advisors who helped design the methodology and the web-based platform. The EDR has been open since 2013 and currently has over 750 entries from over 20 different countries, the majority from the United Kingdom and the Republic of Ireland. The bereaved have shown that they place their trust in the register as a vehicle to be involved in research, even under the most difficult of circumstances. As the EDR matures, we hope to identify the common and rarer patterns of epilepsy-associated death; maintaining our dual ambitions to remain committed to listen, and to make every death count. This paper is for the Special Issue: Prevent 21: SUDEP Summit - Time to Listen.
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http://dx.doi.org/10.1016/j.yebeh.2019.106454DOI Listing
February 2020

Niemann-Pick type C: contemporary diagnosis and treatment of a classical disorder.

Pract Neurol 2019 Oct 26;19(5):420-423. Epub 2019 Jun 26.

Department of Clinical Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne, UK

Niemann-Pick type C is an uncommon neurodegenerative lysosomal storage disorder that can cause a progressive neuropsychiatric syndrome associated with supranuclear vertical gaze palsy and a movement disorder. There have been recent developments in testing that make diagnosis easier and new therapies that aim to stabilise the disease process. A new biochemical test to measure serum cholesterol metabolites supersedes the skin biopsy and is practical and robust. It is treatable with miglustat, a drug that inhibits glycosphingolipid synthesis. We describe a patient, aged 22 years, with juvenile-onset Niemann-Pick type C who presented with seizures and a label of 'cerebral palsy'. We describe the approach to this syndrome in general, and highlight the classical features and red flags that should alert a neurologist to this treatable condition.
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http://dx.doi.org/10.1136/practneurol-2019-002236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839726PMC
October 2019

Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders.

Epilepsia 2019 05 11;60(5):818-829. Epub 2019 Apr 11.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK.

Objective: The true prevalence of epileptic seizures and epilepsy in 22q11.2 deletion syndrome (22q11.2DS) is unknown, because previous studies have relied on historical medical record review. Associations of epilepsy with other neurodevelopmental manifestations (eg, specific psychiatric diagnoses) remain unexplored.

Methods: The primary caregivers of 108 deletion carriers (mean age 13.6 years) and 60 control siblings (mean age 13.1 years) completed a validated epilepsy screening questionnaire. A subsample (n = 44) underwent a second assessment with interview, prolonged electroencephalography (EEG), and medical record and epileptologist review. Intelligence quotient (IQ), psychopathology, and other neurodevelopmental problems were examined using neurocognitive assessment and questionnaire/interview.

Results: Eleven percent (12/108) of deletion carriers had an epilepsy diagnosis (controls 0%, P = 0.004). Fifty-seven of the remaining 96 deletion carriers (59.4%) had seizures or seizurelike symptoms (controls 13.3%, 8/60, P < 0.001). A febrile seizure was reported for 24.1% (26/107) of cases (controls 0%, P < 0.001). One deletion carrier with a clinical history of epilepsy was diagnosed with an additional type of unprovoked seizure during the second assessment. One deletion carrier was newly diagnosed with epilepsy, and two more with possible nonmotor absence seizures. A positive screen on the epilepsy questionnaire was more likely in deletion carriers with lower performance IQ (odds ratio [OR] 0.96, P = 0.018), attention-deficit/hyperactivity disorder (ADHD) (OR 3.28, P = 0.021), autism symptoms (OR 3.86, P = 0.004), and indicative motor coordination disorder (OR 4.56, P = 0.021).

Significance: Even when accounting for deletion carriers diagnosed with epilepsy, reports of seizures and seizurelike symptoms are common. These may be "true" epileptic seizures in some cases, which are not recognized during routine clinical care. Febrile seizures were far more common in deletion carriers compared to known population risk. A propensity for seizures in 22q11.2DS was associated with cognitive impairment, psychopathology, and motor coordination problems. Future research is required to determine whether this reflects common neurobiologic risk pathways or is a consequence of recurrent seizures.
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http://dx.doi.org/10.1111/epi.14722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519005PMC
May 2019

Genetic chameleons: remember the relapsing disorders.

Pract Neurol 2019 08 4;19(4):282-283. Epub 2019 Apr 4.

Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1136/practneurol-2018-002181DOI Listing
August 2019

Clinical spectrum of -related epileptic disorders.

Neurology 2019 03 8;92(11):e1238-e1249. Epub 2019 Feb 8.

From the University of Tübingen (S. Wolking, J.M., Y.G.W., H.L., J.S.), Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany; Luxembourg Centre for Systems Biomedicine (P.M.), University of Luxembourg, Esch-sur-Alzette; Pediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G., C.M.), Children's Hospital Anna Meyer, University of Florence, Italy; Danish Epilepsy Centre (R.S.M.), Dianalund; Institute for Regional Health Services (R.S.M.), University of Southern Denmark, Odense; Department of Clinical and Experimental Epilepsy (S.B.), UCL Institute of Neurology and Epilepsy Society, UK, London; Division of Neurology (K.L.H., I.H.), Children's Hospital of Philadelphia, PA; Department of Pediatric Neurology (C.D.A.), Centre de Compétences Maladies Rares, CHU Besançon; Service de Génétique (N.C.), Hospices Civils des Lyon, Bron; GENDEV Team (N.C.), Neurosciences Research Center of Lyon, Bron, France; Neuropediatric Clinic and Clinic for Neurorehabilitation (K.S.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; Beaumont Hospital (P.W.-W.), Dublin, Ireland; Department of Pediatrics, Division of Medical Genetics, Institute of Human Genetics (B.A.M.), Departments of Neurology and Pediatrics (A.N.), and Departments of Neurology and Pediatrics, and Institute of Human Genetics (M.R.C.), University of California, San Francisco; Department of Neurology (W.V.P.), University Hospitals Leuven, Belgium; Department of Pediatrics (L.L.S.), Hvidovre Hospital, Denmark; King's College Hospital (S.O., E.H., S.G., D.K.P.), London; Evelina London Children's Hospital (S.O., E.H., S.G.), London, UK; Section of Genetics (K.B., M.S.S.), Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora; Clinique Bernoise Montana (T.D.), Crans-Montana, Switzerland; Department of Neuropediatrics (H.M.), University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany; National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics (A.T.P., S.J.L.K., J.C.T.) and Department of Oncology (D.V.V.), University of Oxford, UK; Epilepsy Center (M.P.C.), Health Sciences Department, San Paolo Hospital, University of Milan; Child Neuropsychiatry (F.D.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Italy; Departments of Neurology and Clinical Genomics (R.H.G.) and Health Sciences Research and Clinical Genomics (E.W.K., C.K.), Mayo Clinic, Rochester, MN; Ambry Genetics (Z.P.), Aliso Viejo, CA; Department of Clinical Neuroscience (S.T.), King's College London; New Medicines (M.A., D.M.), UCB Pharma, Slough, UK; Neuropediatric Clinic and Clinic for Neurorehabilitation (G.J.K.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; Research Institute for Rehabilitation, Transition and Palliation (G.J.K.), PMU Salzburg, Austria; Department of Neurology (D.H.L.), University of California, San Francisco; Neurogenetics Group (S. Weckhuysen), Center for Molecular Neurology, VIB, Antwerp; Laboratory of Neurogenetics (S. Weckhuysen), Institute Born-Bunge, University of Antwerp; Department of Neurology (S. Weckhuysen), Antwerp University Hospital, Antwerp, Belgium; Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience (D.K.P.), MRC Centre for Neurodevelopmental Disorders (D.K.P.), King's College London, UK; Evelina London Children's Hospital (D.K.P.), London, UK; Department of Neuropediatrics (I.H.), University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany; Institute of Neuroscience (R.H.T.), Henry Wellcome Building, Newcastle University; Neurology Research Group (M.I.R.), Institute of Life Science, Swansea University Medical School, Swansea, UK; Service de Génétique (G.L.), Hospices Civils des Lyon, Bron; GENDEV Team (G.L.), Neurosciences Research Center of Lyon, Bron, France; NIHR University College London Hospitals Biomedical Research Centre (S.M.S.), UCL Institute of Neurology, London, UK; Cologne Center for Genomics (D.L.), University of Cologne, Germany; Stanley Center for Psychiatric Research (D.L.) and Program in Medical and Population Genetics (D.L.), Broad Institute of MIT and Harvard, Cambridge; Psychiatric and Neurodevelopmental Genetics Unit (D.L.), Massachusetts General Hospital and Harvard Medical School, Boston.

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to , encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants.

Methods: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools.

Results: We describe 17 new variants in , which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes.

Conclusion: These data expand the genetic and phenotypic spectrum of -related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in are protean and contribute to many different epilepsy phenotypes, similar to , the most important gene associated with fever-associated epilepsies.
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http://dx.doi.org/10.1212/WNL.0000000000007089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511102PMC
March 2019

Neurologic phenotypes associated with / mutations: Expanding the spectrum of disease.

Neurology 2018 11 9;91(22):e2078-e2088. Epub 2018 Nov 9.

From the Department of Clinical and Experimental Epilepsy (S.Z., Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.) and Division of Neuropathology (Z.M., M.T.), UCL Institute of Neurology, London, UK; Clinic of Neurology (S.Z.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy; Department of Pediatric Neurology and Neurological Rehabilitation (C.S., T.H., P.W., G.J.K.) and Neurosurgery Clinic and Clinic for Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth; Department of Pediatrics (C.S., M.S.), Children's Hospital Augsburg, Germany; UCL Great Ormond Street Institute of Child Health (J.R.N., K.V., S.M.V., J.H.C.), London, UK; Paediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G.), A. Meyer Children's Hospital, University of Florence, Italy; Chalfont Centre for Epilepsy (Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.), Chalfont-St-Peter, Buckinghamshire, UK; CeGaT-Center for Genomics and Transcriptomics (A.P., S. Biskup), Tübingen, Germany; Neurogenetics Unit (M.L.), Department of Medical Genetics, Hospital de São João, Porto, Portugal; Department of Pediatrics and Adolescent Medicine (J.G.), University Medical Center Göttingen; Hospital for Children and Adolescents (A.M.), University Clinic Leipzig, Germany; Freiburg Medical Laboratory (M.J.), Dubai; The Danish Epilepsy Centre (R.S.M., E.G.), Dianalund; Institute for Regional Health Services (R.S.M., E.G.), University of Southern Denmark, Odense; Department of Clinical Genetics (B.S.K.), Odense University Hospital; Hans Christian Andersen Children's Hospital (L.K.H.), Odense, Denmark; Pediatric Neurology and Muscular Diseases Unit (M.S.V., P.S.), Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa "G. Gaslini" Institute, Italy; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Department of Neurology (S.D., C.L.S.-H.), Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD; Center for Genomic Medicine (N.H.-F.), Tohoku University; Department of Pediatrics (N.H.-F.), Tohoku University School of Medicine, Sendai, Japan; Department of Pediatrics (T.T., R.L.) and Institute of Clinical Medicine (K.O.), University of Tartu; Children's Clinic (T.T., R.L.), Department of Radiology (P.I.), and Department of Clinical Genetics, United Laboratories (K.O.), Tartu University Hospital, Estonia; Ludwig-Maximilians-University Munich (I.K.); Department of Pediatric Neurology (A.H.), Clinic Traunstein; Children's Hospital (M.K.), Dr. Horst Schmidt Klinik, Wiesbaden; Altona Children's Hospital (J.H.), Hamburg; Department of Pediatrics (C. Makowski), Technische Universität München, Germany; Department of Clinical Genetics (S.G.), Royal North Shore Hospital, St Leonards; John Hunter Children's Hospital (G.M.S.), New Lambton Heights, New South Wales, Australia; Department of Neurology (R.T.), University Hospital of Wales; Institute of Psychological Medicine and Clinical Neurosciences (R.H.T.), Cardiff University; Division of Neuroradiology (C. Micallef), National Hospital for Neurology and Neurosurgery, London; Department of Brain Repair & Rehabilitation (D.J.W.), Stroke Research Centre, UCL Institute of Neurology, London, UK; Paracelsus Medical University (G.J.K.), Salzburg, Austria; and IRCCS Stella Maris Foundation (R.G.), Pisa, Italy.

Objective: To characterize the neurologic phenotypes associated with mutations and to seek genotype-phenotype correlation.

Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with mutations.

Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across and a clear genotype-phenotype correlation did not emerge.

Conclusion: mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.
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http://dx.doi.org/10.1212/WNL.0000000000006567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239PMC
November 2018

Cannabis and epilepsy.

Pract Neurol 2018 Dec 18;18(6):465-471. Epub 2018 Oct 18.

School of Medicine, Discipline of Physiology, University of Dublin Trinity College, Dublin, Ireland.

Click here to listen to the Podcast The one-third of people who do not gain seizure control through current treatment options need a revolution in epilepsy therapeutics. The general population appears to be showing a fundamental and rapid shift in its opinion regarding cannabis and cannabis-related drugs. It is quite possible that cannabidiol, licensed in the USA for treating rare genetic epilepsies, may open the door for the widespread legalisation of recreational cannabis. It is important that neurologists understand the difference between artisanal cannabidiol products available legally on the high street and the cannabidiol medications that have strong trial evidence. In the UK in 2018 there are multiple high-profile reports of the response of children taking cannabis-derived medication, meaning that neurologists are commonly asked questions about these treatments in clinic. We address what an adult neurologist needs to know now, ahead of the likely licensing of Epidiolex in the UK in 2019.
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http://dx.doi.org/10.1136/practneurol-2018-002058DOI Listing
December 2018