Pub Date : 2024-12-18DOI: 10.1016/s1474-4422(24)00479-4
Michael Benatar, Janice Robertson, Peter Munch Andersen
Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.
{"title":"Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention","authors":"Michael Benatar, Janice Robertson, Peter Munch Andersen","doi":"10.1016/s1474-4422(24)00479-4","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00479-4","url":null,"abstract":"Pathogenic variants in the superoxide dismutase 1 (<em>SOD1</em>) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of <em>SOD1</em> ALS. The understanding that <em>SOD1</em> ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of <em>SOD1</em> ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest <em>SOD1</em> ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of <em>SOD1</em> ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"260 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1016/s1474-4422(24)00495-2
Sheth KN, Albers GW, Saver JL, et al. Intravenous glibenclamide for cerebral oedema after large hemispheric stroke (CHARM): a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Neurol 2024; 23: 1205–13 —In this Article, the CHARM Trial investigators and the appendix have been updated. This correction has been made as of Dec 18, 2024.
{"title":"Correction to Lancet Neurol 2024; 23: 1205–13","authors":"","doi":"10.1016/s1474-4422(24)00495-2","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00495-2","url":null,"abstract":"<em>Sheth KN, Albers GW, Saver JL, et al. Intravenous glibenclamide for cerebral oedema after large hemispheric stroke (CHARM): a phase 3, double-blind, placebo-controlled, randomised trial.</em> Lancet Neurol <em>2024; <strong>23:</strong> 1205–13</em> —In this Article, the CHARM Trial investigators and the appendix have been updated. This correction has been made as of Dec 18, 2024.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1016/s1474-4422(24)00490-3
No Abstract
{"title":"Bridging the diagnostic gap in Alzheimer's disease","authors":"","doi":"10.1016/s1474-4422(24)00490-3","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00490-3","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1016/s1474-4422(24)00485-x
Patricia Pozo-Rosich
No Abstract
{"title":"Headache research in 2024: new data on migraine prevention","authors":"Patricia Pozo-Rosich","doi":"10.1016/s1474-4422(24)00485-x","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00485-x","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1016/s1474-4422(24)00430-7
Jennifer V Gettings, Fatemeh Mohammad Alizadeh Chafjiri, Archana A Patel, Simon Shorvon, Howard P Goodkin, Tobias Loddenkemper
Status epilepticus is a common neurological emergency that is characterised by prolonged or recurrent seizures without recovery between episodes and associated with substantial morbidity and mortality. Prompt recognition and targeted therapy can reduce the risk of complications and death associated with status epilepticus, thereby improving outcomes. The most recent International League Against Epilepsy definition considers two important timepoints in status epilepticus: first, when the seizure does not self-terminate; and second, when the seizure can have long-term consequences, including neuronal injury. Recent advances in our understanding of the pathophysiology of status epilepticus indicate that changes in neurotransmission as status epilepticus progresses can increase excitatory seizure-facilitating and decrease inhibitory seizure-terminating mechanisms at a cellular level. Effective clinical management requires rapid initiation of supportive measures, assessment of the cause of the seizure, and first-line treatment with benzodiazepines. If status epilepticus continues, management should entail second-line and third-line treatment agents, supportive EEG monitoring, and admission to an intensive care unit. Future research to study early seizure detection, rescue protocols and medications, rapid treatment escalation, and integration of fundamental scientific and clinical evidence into clinical practice could shorten seizure duration and reduce associated complications. Furthermore, improved recognition, education, and treatment in patients who are at risk might help to prevent status epilepticus, particularly for patients living in low-income and middle-income countries.
{"title":"Diagnosis and management of status epilepticus: improving the status quo","authors":"Jennifer V Gettings, Fatemeh Mohammad Alizadeh Chafjiri, Archana A Patel, Simon Shorvon, Howard P Goodkin, Tobias Loddenkemper","doi":"10.1016/s1474-4422(24)00430-7","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00430-7","url":null,"abstract":"Status epilepticus is a common neurological emergency that is characterised by prolonged or recurrent seizures without recovery between episodes and associated with substantial morbidity and mortality. Prompt recognition and targeted therapy can reduce the risk of complications and death associated with status epilepticus, thereby improving outcomes. The most recent International League Against Epilepsy definition considers two important timepoints in status epilepticus: first, when the seizure does not self-terminate; and second, when the seizure can have long-term consequences, including neuronal injury. Recent advances in our understanding of the pathophysiology of status epilepticus indicate that changes in neurotransmission as status epilepticus progresses can increase excitatory seizure-facilitating and decrease inhibitory seizure-terminating mechanisms at a cellular level. Effective clinical management requires rapid initiation of supportive measures, assessment of the cause of the seizure, and first-line treatment with benzodiazepines. If status epilepticus continues, management should entail second-line and third-line treatment agents, supportive EEG monitoring, and admission to an intensive care unit. Future research to study early seizure detection, rescue protocols and medications, rapid treatment escalation, and integration of fundamental scientific and clinical evidence into clinical practice could shorten seizure duration and reduce associated complications. Furthermore, improved recognition, education, and treatment in patients who are at risk might help to prevent status epilepticus, particularly for patients living in low-income and middle-income countries.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<h3>Background</h3>Intra-arterial prourokinase has been shown to be a promising thrombolytic agent in patients with acute ischaemic stroke. Given the global shortage of thrombolytics, we aimed to assess the non-inferiority of intravenous recombinant human prourokinase compared with alteplase in patients with acute ischaemic stroke who were ineligible for or who refused endovascular thrombectomy.<h3>Methods</h3>PROST-2 was a phase 3, open-label, non-inferiority, randomised controlled trial conducted at 61 hospitals in China. Patients older than 18 years with acute ischaemic stroke, who were ineligible for or who refused endovascular thrombectomy, were randomly assigned in a 1:1 ratio within 4·5 h of stroke onset to receive intravenous recombinant human prourokinase (15 mg bolus followed by 20 mg infusion within 30 min) or intravenous alteplase (0·9 mg per kg, maximum dose 90 mg; 10% bolus followed by remainder as infusion over 60 min). The primary efficacy outcome was the proportion of patients with a modified Rankin Scale score of 0 or 1 at 90 days, assessed via masked review in the intention-to-treat population, with a non-inferiority margin for the risk ratio of 0·93. The primary safety outcome was the incidence of symptomatic intracranial haemorrhage within 36 h. This trial is registered with <span><span>ClinicalTrials.gov</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span> (<span><span>NCT05700591</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>) and is now completed.<h3>Findings</h3>Between Jan 29, 2023, and March 14, 2024, 1552 patients were randomly assigned: 775 received recombinant human prourokinase and 777 received alteplase. The primary outcome of a modified Rankin Scale score of 0 or 1 at 90 days was reached by 558 (72·0%) of 775 patients in the recombinant human prourokinase group versus 534 (68·7%) of 777 in the alteplase group (risk ratio 1·04 [95% CI 0·98 to 1·10]; p<0·0001 for non-inferiority). The frequency of symptomatic intracranial haemorrhage within 36 h was lower in the recombinant human prourokinase group than in the alteplase group (two [0·3%] of 770 patients <em>vs</em> ten [1·3%] of 775, risk difference –1·0 percentage points [95% CI –2·1 to –0·1]; p=0·021), as was the incidence of major bleeding at 7 days (four [0·5%] vs 16 [2·1%]; –1·5 percentage points (–2·8 to –0·4); p=0·0072). All-cause mortality within 7 days did not differ between groups (five [0·6%] deaths in the recombinant human prourokinase group <em>vs</em> 13 [1·7%] in the alteplase group; risk difference –1·0 percentage points; 95% CI –2·3 to 0·1]; p=0·060).<h3>Interpretation</h3>In our trial, recombinant human prourokinase was shown t
{"title":"Safety and efficacy of intravenous recombinant human prourokinase for acute ischaemic stroke within 4·5 h after stroke onset (PROST-2): a phase 3, open-label, non-inferiority, randomised controlled trial","authors":"Shuya Li, Hong-Qiu Gu, Baoyu Feng, Hao Li, Xuechun Wang, Qiang Dong, Dongsheng Fan, Yun Xu, Suiqiang Zhu, Hongguo Dai, Yan Wei, Ziran Wang, Guozhi Lu, Yutong Ma, Zixiao Li, Yilong Wang, Xia Meng, Xingquan Zhao, Liping Liu, Yongjun Wang","doi":"10.1016/s1474-4422(24)00436-8","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00436-8","url":null,"abstract":"<h3>Background</h3>Intra-arterial prourokinase has been shown to be a promising thrombolytic agent in patients with acute ischaemic stroke. Given the global shortage of thrombolytics, we aimed to assess the non-inferiority of intravenous recombinant human prourokinase compared with alteplase in patients with acute ischaemic stroke who were ineligible for or who refused endovascular thrombectomy.<h3>Methods</h3>PROST-2 was a phase 3, open-label, non-inferiority, randomised controlled trial conducted at 61 hospitals in China. Patients older than 18 years with acute ischaemic stroke, who were ineligible for or who refused endovascular thrombectomy, were randomly assigned in a 1:1 ratio within 4·5 h of stroke onset to receive intravenous recombinant human prourokinase (15 mg bolus followed by 20 mg infusion within 30 min) or intravenous alteplase (0·9 mg per kg, maximum dose 90 mg; 10% bolus followed by remainder as infusion over 60 min). The primary efficacy outcome was the proportion of patients with a modified Rankin Scale score of 0 or 1 at 90 days, assessed via masked review in the intention-to-treat population, with a non-inferiority margin for the risk ratio of 0·93. The primary safety outcome was the incidence of symptomatic intracranial haemorrhage within 36 h. This trial is registered with <span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> (<span><span>NCT05700591</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>) and is now completed.<h3>Findings</h3>Between Jan 29, 2023, and March 14, 2024, 1552 patients were randomly assigned: 775 received recombinant human prourokinase and 777 received alteplase. The primary outcome of a modified Rankin Scale score of 0 or 1 at 90 days was reached by 558 (72·0%) of 775 patients in the recombinant human prourokinase group versus 534 (68·7%) of 777 in the alteplase group (risk ratio 1·04 [95% CI 0·98 to 1·10]; p<0·0001 for non-inferiority). The frequency of symptomatic intracranial haemorrhage within 36 h was lower in the recombinant human prourokinase group than in the alteplase group (two [0·3%] of 770 patients <em>vs</em> ten [1·3%] of 775, risk difference –1·0 percentage points [95% CI –2·1 to –0·1]; p=0·021), as was the incidence of major bleeding at 7 days (four [0·5%] vs 16 [2·1%]; –1·5 percentage points (–2·8 to –0·4); p=0·0072). All-cause mortality within 7 days did not differ between groups (five [0·6%] deaths in the recombinant human prourokinase group <em>vs</em> 13 [1·7%] in the alteplase group; risk difference –1·0 percentage points; 95% CI –2·3 to 0·1]; p=0·060).<h3>Interpretation</h3>In our trial, recombinant human prourokinase was shown t","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"196 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1016/s1474-4422(24)00438-1
Nyika D Kruyt, Paul J Nederkoorn, Else Charlotte Sandset, Patrick Lyden, Lili Song, Craig S Anderson
No Abstract
无摘要
{"title":"A cautionary view on blood pressure lowering in patients with acute ischaemic stroke receiving reperfusion therapy","authors":"Nyika D Kruyt, Paul J Nederkoorn, Else Charlotte Sandset, Patrick Lyden, Lili Song, Craig S Anderson","doi":"10.1016/s1474-4422(24)00438-1","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00438-1","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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