{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:14:16Z","timestamp":1789809256113,"version":"4.0.1"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Centre for Mitochondrial Research","award":["203105"],"award-info":[{"award-number":["203105"]}]},{"name":"Biotechnology and Biological Sciences Research Council and Medical Research Council","award":["L016354"],"award-info":[{"award-number":["L016354"]}]},{"name":"UK National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust"},{"DOI":"10.13039\/501100022186","name":"Lily Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022186","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UK Medical Research Council and Brains for Dementia Research, a joint venture between Alzheimer\u2019s Society and Alzheimer\u2019s Research UK"},{"name":"Department of Health\u2019s National Institute for Health Research Biomedical Research Centres funding scheme"},{"name":"NIHR Clinical Lectureship in Neurology","award":["CL-2016-01-003"],"award-info":[{"award-number":["CL-2016-01-003"]}]},{"name":"Medical Research Council Centre of Neuromuscular Diseases for his PhD study","award":["MR\/K000608\/1"],"award-info":[{"award-number":["MR\/K000608\/1"]}]},{"name":"Alzheimer\u2019s Research UK Fellowship","award":["ARUK-RF2018C-005"],"award-info":[{"award-number":["ARUK-RF2018C-005"]}]},{"name":"Medical Research Council Clinician Scientist Fellowship","award":["MR\/S002065\/1"],"award-info":[{"award-number":["MR\/S002065\/1"]}]},{"name":"Medical Research Council strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases","award":["MR\/S005021\/1"],"award-info":[{"award-number":["MR\/S005021\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors.<\/jats:p>\n                  <jats:p>Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk.<\/jats:p>\n                  <jats:p>The most common genetic cause of stroke-like episodes was the m.3243A&amp;gt;G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode \u226540 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A&amp;gt;G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A&amp;gt;G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A&amp;gt;G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82\u20130.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P &amp;lt; 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005].<\/jats:p>\n                  <jats:p>Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A&amp;gt;G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.<\/jats:p>","DOI":"10.1093\/brain\/awab353","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T11:19:54Z","timestamp":1633000794000},"page":"542-554","source":"Crossref","is-referenced-by-count":70,"title":["Forecasting stroke-like episodes and outcomes in mitochondrial disease"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7591-2034","authenticated-orcid":false,"given":"Yi Shiau","family":"Ng","sequence":"first","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nichola Z","family":"Lax","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair P","family":"Blain","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1752-5343","authenticated-orcid":false,"given":"Daniel","family":"Erskine","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R","family":"Baker","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Campus for Ageing and Vitality, Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Newcastle upon Tyne NE4 5PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomo","family":"Polvikoski","sequence":"additional","affiliation":[{"name":"Campus for Ageing and Vitality, Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Newcastle upon Tyne NE4 5PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhys H","family":"Thomas","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M","family":"Morris","sequence":"additional","affiliation":[{"name":"Campus for Ageing and Vitality, Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Newcastle upon Tyne NE4 5PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Lai","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger G","family":"Whittaker","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair","family":"Gebbels","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Winder","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Hall","sequence":"additional","affiliation":[{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Feeney","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Farrugia","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Hirst","sequence":"additional","affiliation":[{"name":"Trust Headquarters, One Talbot Gateway, Baglan Energy Park, Baglan, Port Talbot SA12 7BR, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Roberts","sequence":"additional","affiliation":[{"name":"Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford M6 8HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Lawthom","sequence":"additional","affiliation":[{"name":"Aneurin Bevan Epilepsy Specialist Team, Aneurin Bevan University Health Board, Newport, NP20 2UB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexia","family":"Chrysostomou","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sligo University Hospital, Sligo F91 H684, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Baird","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Maddison","sequence":"additional","affiliation":[{"name":"Department of Neurology, Queen\u2019s Medical Centre, Nottingham NG7 2UH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callum","family":"Duncan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen AB25 2ZN, 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L","family":"Blakely","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug M","family":"Turnbull","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"McFarland","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e1inne S","family":"Gorman","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Directorate of Neurosciences, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"},{"name":"Department of Neurosciences, NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne NE2 4HH, 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