年终盘点：2020年神经病学领域25项临床研究突破（附解读链接）
1. N Engl J Med—最新临床证据不支持地塞米松用于治疗慢性硬膜下血肿
Abstract
Background: Chronic subdural hematoma is acommon neurologic disorder that is especially prevalent among older people. Theeffect of dexamethasone on outcomes in patients with chronic subdural hematomahas not been well studied.
Methods: We conducted a multicenter,randomized trial in the United Kingdom that enrolled adult patients with symptomaticchronic subdural hematoma. The patients were assigned in a 1:1 ratio toreceive a 2-week tapering course of oral dexamethasone, starting at 8 mgtwice daily, or placebo. The decision to surgically evacuate the hematomawas made by the treating clinician. The primary outcome was a score of 0 to3, representing a favorable outcome, on the modified Rankin scale at 6 monthsafter randomization; scores range from 0 (no symptoms) to 6 (death).
Results: From August 2015 through November2019, a total of 748 patients were included in the trial after randomization -375 were assigned to the dexamethasone group and 373 to the placebo group. Themean age of the patients was 74 years, and 94% underwent surgery to evacuatetheir hematomas during the index admission; 60% in both groups had a score of 1to 3 on the modified Rankin scale at admission. In a modifiedintention-to-treat analysis that excluded the patients who withdrew consent forparticipation in the trial or who were lost to follow-up, leaving a total of680 patients, a favorable outcome was reported in 286 of 341 patients(83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in theplacebo group (difference, -6.4 percentage points [95% confidence interval,-11.4 to -1.4] in favor of the placebo group; P = 0.01). Among the patientswith available data, repeat surgery for recurrence of the hematoma wasperformed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of350 patients (7.1%) in the placebo group. More adverse events occurred in thedexamethasone group than in the placebo group.
Conclusions: Among adults with symptomaticchronic subdural hematoma, most of whom had undergone surgery to removetheir hematomas during the index admission, treatment with dexamethasoneresulted in fewer favorable outcomes and more adverse events than placebo at 6months, but fewer repeat operations were performed in the dexamethasone group.(Funded by the National Institute for Health Research Health TechnologyAssessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.).
参考文献：Trial of Dexamethasone for Chronic SubduralHematoma. N Engl J Med. 2020 Dec 16.
2. Nature genetics—GWAS研究揭示颅内动脉瘤的遗传风险位点：11个新遗传位点 与吸烟/高血压遗传风险重叠
Abstract
Rupture of an intracranial aneurysm leads tosubarachnoid hemorrhage, a severe type of stroke. To discover new risk loci andthe genetic architecture of intracranial aneurysms, we performed across-ancestry, genome-wide association study in 10,754 cases and 306,882controls of European and East Asian ancestry. We discovered 17 risk loci, 11 ofwhich are new. We reveal a polygenic architecture and explain over half of thedisease heritability. We show a high genetic correlation between ruptured andunruptured intracranial aneurysms. We also find a suggestive role forendothelial cells by using gene mapping and heritability enrichment.Drug-target enrichment shows pleiotropy between intracranial aneurysms andantiepileptic and sex hormone drugs, providing insights into intracranialaneurysm pathophysiology. Finally, genetic risks for smoking and high bloodpressure, the two main clinical risk factors, play important roles inintracranial aneurysm risk, and drive most of the genetic correlation betweenintracranial aneurysms and other cerebrovascular traits.
参考文献：Genome-wide association study of intracranialaneurysms identifies 17 risk loci and genetic overlap with clinical riskfactors. Nat Genet. 2020 Dec;52(12):1303-1313.
3. Lancet—荟萃分析：起病时间未知的卒中患者实施基于影像学mismatch证据的静脉阿替普酶溶栓可显著改善其神经功能预后
Abstract
Background: Patients who have had a strokewith unknown time of onset have been previously excluded from thrombolysis. Weaimed to establish whether intravenous alteplase is safe and effective in suchpatients when salvageable tissue has been identified with imaging biomarkers.
Methods: We did a systematic review andmeta-analysis of individual patient data for trials published before Sept 21,2020. Randomised trials of intravenous alteplase versus standard of care orplacebo in adults with stroke with unknown time of onset withperfusion-diffusion MRI, perfusion CT, or MRI with diffusion weightedimaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible.The primary outcome was favourable functional outcome (score of 0-1 on themodified Rankin Scale [mRS]) at 90 days indicating no disability using anunconditional mixed-effect logistic-regression model fitted to estimate thetreatment effect. Secondary outcomes were mRS shift towards a better functionaloutcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes includeddeath, severe disability or death (mRS score 4-6), and symptomatic intracranialhaemorrhage. This study is registered with PROSPERO, CRD42020166903.
Findings: Of 249 identified abstracts, fourtrials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, andECASS-4. The four trials provided individual patient data for 843 individuals,of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo orstandard care. A favourable outcome occurred in 199 (47%) of 420 patients withalteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio[OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies(I2=27%). Alteplase was associated with a significant shift towards betterfunctional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and ahigher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). Inthe alteplase group, 90 (21%) patients were severely disabled or died (mRSscore 4-6), compared with 102 (25%) patients in the control group (adjusted OR0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14(3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). Theprevalence of symptomatic intracranial haemorrhage was higher in the alteplasegroup than among controls (11 [3%] vs two [<1%], adjusted OR 5·58[1·22-25·50]; p=0·024).
Interpretation: In patients who have had astroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch,intravenous alteplase resulted in better functional outcome at 90 days thanplacebo or standard care. A net benefit was observed for all functionaloutcomes despite an increased risk of symptomatic intracranial haemorrhage.Although there were more deaths with alteplase than placebo, there were fewercases of severe disability or death.
参考文献：Intravenous alteplase for stroke with unknowntime of onset guided by advanced imaging: systematic review and meta-analysisof individual patient data. Lancet. 2020 Nov 14;396(10262):1574-1584.
4. Nature genetics—重磅！！科学家发现8个可能引起脑瘫的风险基因：神经突生成异常是关键！！
Abstract
In addition to commonly associatedenvironmental factors, genomic factors may cause cerebral palsy. We performedwhole-exome sequencing of 250 parent-offspring trios, and observed enrichmentof damaging de novo mutations in cerebral palsy cases. Eight genes had multipledamaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-widesignificance. We identified two novel monogenic etiologies, FBXO31 and RHOB,and showed that the RHOB mutation enhances active-state Rho effector bindingwhile the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsyrisk genes overlapped with neurodevelopmental disorder genes. Network analyses identifiedenrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeletonpathways. Cerebral palsy risk genes in enriched pathways were shown to regulateneuromotor function in a Drosophila reverse genetics screen. We estimate that14% of cases could be attributed to an excess of damaging de novo or recessivevariants. These findings provide evidence for genetically mediateddysregulation of early neuronal connectivity in cerebral palsy.
参考文献：Mutations disrupting neuritogenesis genesconfer risk for cerebral palsy. Nat Genet. 2020 Oct;52(10):1046-1056.
5. NEJM—渐冻症再突破！！苯丁酸钠-Taurursodiol可改善渐冻症患者的功能评分
Abstract
Background: Sodium phenylbutyrate andtaurursodiol have been found to reduce neuronal death in experimental models.The efficacy and safety of a combination of the two compounds in persons withamyotrophic lateral sclerosis (ALS) are not known.
Methods: In this multicenter, randomized,double-blind trial, we enrolled participants with definite ALS who had had anonset of symptoms within the previous 18 months. Participants were randomlyassigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g ofsodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3weeks and then twice a day) or placebo. The primary outcome was the rate ofdecline in the total score on the Amyotrophic Lateral Sclerosis FunctionalRating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicatingbetter function) through 24 weeks. Secondary outcomes were the rates of declinein isometric muscle strength, plasma phosphorylated axonal neurofilament Hsubunit levels, and the slow vital capacity; the time to death, tracheostomy,or permanent ventilation; and the time to death, tracheostomy, permanentventilation, or hospitalization.
Results: A total of 177 persons with ALS werescreened for eligibility, and 137 were randomly assigned to receive sodiumphenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). Ina modified intention-to-treat analysis, the mean rate of change in the ALSFRS-Rscore was -1.24 points per month with the active drug and -1.66 points permonth with placebo (difference, 0.42 points per month; 95% confidence interval,0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantlybetween the two groups. Adverse events with the active drug were mainlygastrointestinal.
Conclusions: Sodium phenylbutyrate-taurursodiolresulted in slower functional decline than placebo as measured by the ALSFRS-Rscore over a period of 24 weeks. Secondary outcomes were not significantlydifferent between the two groups. Longer and larger trials are necessary to evaluatethe efficacy and safety of sodium phenylbutyrate-taurursodiol in persons withALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.govnumber, NCT03127514.).
参考文献：Trial of Sodium Phenylbutyrate-Taurursodiolfor Amyotrophic Lateral Sclerosis. N Engl J Med. 2020 Sep 3;383(10):919-930.
6. N Engl J Med—对于急性缺血性卒中，血管内血栓切除术治疗并不差于血管内血栓切除术联合阿替普酶治疗
Abstract
Background: In acute ischemic stroke, there isuncertainty regarding the benefit and risk of administering intravenousalteplase before endovascular thrombectomy.
Methods: We conducted a trial at 41 academictertiary care centers in China to evaluate endovascular thrombectomy with orwithout intravenous alteplase in patients with acute ischemic stroke. Patientswith acute ischemic stroke from large-vessel occlusion in the anteriorcirculation were randomly assigned in a 1:1 ratio to undergo endovascularthrombectomy alone (thrombectomy-alone group) or endovascular thrombectomypreceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of bodyweight, administered within 4.5 hours after symptom onset (combination-therapygroup). The primary analysis for noninferiority assessed the between-groupdifference in the distribution of the modified Rankin scale scores (range, 0[no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the95% confidence interval of the adjusted common odds ratio equal to or larger than0.8. We assessed various secondary outcomes, including death and reperfusion ofthe ischemic area.
Results: Of 1586 patients screened, 656 wereenrolled, with 327 patients assigned to the thrombectomy-alone group and 329assigned to the combination-therapy group. Endovascular thrombectomy alone wasnoninferior to combined intravenous alteplase and endovascular thrombectomywith regard to the primary outcome (adjusted common odds ratio, 1.07; 95%confidence interval, 0.81 to 1.40; P = 0.04 for noninferiority) but wasassociated with lower percentages of patients with successful reperfusionbefore thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4%vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and18.8% in the combination-therapy group.
Conclusions: In Chinese patients with acuteischemic stroke from large-vessel occlusion, endovascular thrombectomy alonewas noninferior with regard to functional outcome, within a 20% margin ofconfidence, to endovascular thrombectomy preceded by intravenous alteplaseadministered within 4.5 hours after symptom onset. (Funded by the StrokePrevention Project of the National Health Commission of the People's Republicof China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.govnumber, NCT03469206.).
参考文献：Endovascular Thrombectomy with or withoutIntravenous Alteplase in Acute Stroke. N Engl J Med. 2020 May21;382(21):1981-1993.
7. NEJM—帕金森病治疗新突破！！个性化iPSC来源的多巴胺祖细胞移植治疗帕金森病初见成效
Abstract
We report the implantation of patient-derivedmidbrain dopaminergic progenitor cells, differentiated in vitro from autologousinduced pluripotent stem cells (iPSCs), in a patient with idiopathicParkinson's disease. The patient-specific progenitor cells were produced underGood Manufacturing Practice conditions and characterized as having thephenotypic properties of substantia nigra pars compacta neurons; testing in ahumanized mouse model (involving peripheral-blood mononuclear cells) indicated anabsence of immunogenicity to these cells. The cells were implanted into theputamen (left hemisphere followed by right hemisphere, 6 months apart) of apatient with Parkinson's disease, without the need for immunosuppression.Positron-emission tomography with the use offluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinicalmeasures of symptoms of Parkinson's disease after surgery stabilized orimproved at 18 to 24 months after implantation. (Funded by the NationalInstitutes of Health and others.).
参考文献：Personalized iPSC-Derived Dopamine ProgenitorCells for Parkinson's Disease. N Engl J Med. 2020 May 14;382(20):1926-1932.
8. Lancet—左乙拉西坦、磷苯妥英和丙戊酸钠均可作为苯二氮卓类药物难治性癫痫持续状态的首选治疗
Abstract
Background: Benzodiazepine-refractory, orestablished, status epilepticus is thought to be of similar pathophysiology inchildren and adults, but differences in underlying aetiology andpharmacodynamics might differentially affect response to therapy. In theEstablished Status Epilepticus Treatment Trial (ESETT) we compared the efficacyand safety of levetiracetam, fosphenytoin, and valproate in established statusepilepticus, and here we describe our results after extending enrolment inchildren to compare outcomes in three age groups.
Methods: In this multicentre, double-blind,response-adaptive, randomised controlled trial, we recruited patients from 58hospital emergency departments across the USA. Patients were eligible forinclusion if they were aged 2 years or older, had been treated for ageneralised convulsive seizure of longer than 5 min duration with adequate dosesof benzodiazepines, and continued to have persistent or recurrent convulsionsin the emergency department for at least 5 min and no more than 30 min afterthe last dose of benzodiazepine. Patients were randomly assigned in aresponse-adaptive manner, using Bayesian methods and stratified by age group(<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin,or valproate. All patients, investigators, study staff, and pharmacists weremasked to treatment allocation. The primary outcome was absence of clinicallyapparent seizures with improved consciousness and without additionalantiseizure medication at 1 h from start of drug infusion. The primary safetyoutcome was life-threatening hypotension or cardiac arrhythmia. The efficacyand safety outcomes were analysed by intention to treat. This study isregistered in ClinicalTrials.gov, NCT01960075.
Findings: Between Nov 3, 2015, and Dec 29,2018, we enrolled 478 patients and 462 unique patients were included: 225children (aged <18 years), 186 adults (18-65 years), and 51 older adults(>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142(31%) to fosphenyltoin, and 145 (31%) were to valproate. Baselinecharacteristics were balanced across treatments within age groups. The primaryefficacy outcome was met in those treated with levetiracetam for 52% (95%credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) ofolder adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) ofadults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) ofchildren, 46% (34-58) of adults, and 47% (25-70) of older adults. Nodifferences were detected in efficacy or primary safety outcome by drug withineach age group. With the exception of endotracheal intubation in children,secondary safety outcomes did not significantly differ by drug within each agegroup.
Interpretation: Children, adults, and olderadults with established status epilepticus respond similarly to levetiracetam,fosphenytoin, and valproate, with treatment success in approximately half ofpatients. Any of the three drugs can be considered as a potential first-choice,second-line drug for benzodiazepine-refractory status epilepticus.
参考文献：Efficacy of levetiracetam, fosphenytoin, andvalproate for established status epilepticus by age group (ESETT): adouble-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020Apr 11;395(10231):1217-1224.
9. N Engl J Med—相比于特立氟胺，抗CD20抗体Ofatumumab可显著降低多发性硬化患者的复发率
Abstract
Background: Ofatumumab, a subcutaneousanti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, anoral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation.The relative effects of these two drugs in patients with multiple sclerosis arenot known.
Methods: In two double-blind, double-dummy,phase 3 trials, we randomly assigned patients with relapsing multiple sclerosisto receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loadingdoses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30months. The primary end point was the annualized relapse rate. Secondary endpoints included disability worsening confirmed at 3 months or 6 months,disability improvement confirmed at 6 months, the number ofgadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI)scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serumneurofilament light chain levels at month 3, and change in brain volume.
Results: Overall, 946 patients were assignedto receive ofatumumab and 936 to receive teriflunomide; the median follow-upwas 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomidegroups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95%confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 intrial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooledtrials, the percentage of patients with disability worsening confirmed at 3months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio,0.66; P = 0.002); the percentage with disability worsening confirmed at 6months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and thepercentage with disability improvement confirmed at 6 months was 11.0% and 8.1%(hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions perT1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, andserum neurofilament light chain levels, but not the change in brain volume,were in the same direction as the primary end point. Injection-relatedreactions occurred in 20.2% in the ofatumumab group and in 15.0% in theteriflunomide group (placebo injections). Serious infections occurred in 2.5%and 1.8% of the patients in the respective groups.
Conclusions: Among patients with multiplesclerosis, ofatumumab was associated with lower annualized relapse rates thanteriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.govnumbers, NCT02792218 and NCT02792231.).
参考文献：Ofatumumab versus Teriflunomide in MultipleSclerosis. N Engl J Med. 2020 Aug 6;383(6):546-557.
10. NEJM—这是药物的叠加效应！！替格瑞洛和阿司匹林联合治疗预防卒中再发优于阿司匹林单药治疗
Abstract
Background: Trials have evaluated the use ofclopidogrel and aspirin to prevent stroke after an ischemic stroke or transientischemic attack (TIA). In a previous trial, ticagrelor was not better thanaspirin in preventing vascular events or death after stroke or TIA. The effectof the combination of ticagrelor and aspirin on prevention of stroke has not beenwell studied.
Methods: We conducted a randomized,placebo-controlled, double-blind trial involving patients who had had amild-to-moderate acute noncardioembolic ischemic stroke, with a NationalInstitutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42,with higher scores indicating more severe stroke), or TIA and who were notundergoing thrombolysis or thrombectomy. The patients were assigned within 24hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of eitherticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin(300 to 325 mg on the first day followed by 75 to 100 mg daily) or matchingplacebo plus aspirin. The primary outcome was a composite of stroke or deathwithin 30 days. Secondary outcomes were first subsequent ischemic stroke andthe incidence of disability within 30 days. The primary safety outcome wassevere bleeding.
Results: A total of 11,016 patients underwentrandomization (5523 in the ticagrelor-aspirin group and 5493 in the aspiringroup). A primary-outcome event occurred in 303 patients (5.5%) in theticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group(hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02).Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin groupand in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI,0.68 to 0.93; P = 0.004). The incidence of disability did not differsignificantly between the two groups. Severe bleeding occurred in 28 patients(0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspiringroup (P = 0.001).
Conclusions: Among patients with amild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIAwho were not undergoing intravenous or endovascular thrombolysis, the risk ofthe composite of stroke or death within 30 days was lower with ticagrelor-aspirinthan with aspirin alone, but the incidence of disability did not differsignificantly between the two groups. Severe bleeding was more frequent withticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number,NCT03354429.).
参考文献：Ticagrelor and Aspirin or Aspirin Alone inAcute Ischemic Stroke or TIA. N Engl J Med. 2020 Jul 16;383(3):207-217.
11. N Engl J Med—人工智能凭借眼底照片可精确识别视乳头水肿和其他视盘异常
Abstract
Background: Nonophthalmologist physicians donot confidently perform direct ophthalmoscopy. The use of artificialintelligence to detect papilledema and other optic-disk abnormalities fromfundus photographs has not been well studied.
Methods: We trained, validated, and externallytested a deep-learning system to classify optic disks as being normal or havingpapilledema or other abnormalities from 15,846 retrospectively collected ocularfundus photographs that had been obtained with pharmacologic pupillary dilationand various digital cameras in persons from multiple ethnic populations. Ofthese photographs, 14,341 from 19 sites in 11 countries were used for trainingand validation, and 1505 photographs from 5 other sites were used for externaltesting. Performance at classifying the optic-disk appearance was evaluated bycalculating the area under the receiver-operating-characteristic curve (AUC),sensitivity, and specificity, as compared with a reference standard of clinicaldiagnoses by neuro-ophthalmologists.
Results: The training and validation data setsfrom 6779 patients included 14,341 photographs: 9156 of normal disks, 2148 ofdisks with papilledema, and 3037 of disks with other abnormalities. Thepercentage classified as being normal ranged across sites from 9.8 to 100%; thepercentage classified as having papilledema ranged across sites from zero to59.5%. In the validation set, the system discriminated disks with papilledemafrom normal disks and disks with nonpapilledema abnormalities with an AUC of0.99 (95% confidence interval [CI], 0.98 to 0.99) and normal from abnormaldisks with an AUC of 0.99 (95% CI, 0.99 to 0.99). In the external-testing dataset of 1505 photographs, the system had an AUC for the detection of papilledemaof 0.96 (95% CI, 0.95 to 0.97), a sensitivity of 96.4% (95% CI, 93.9 to 98.3),and a specificity of 84.7% (95% CI, 82.3 to 87.1).
Conclusions: A deep-learning system usingfundus photographs with pharmacologically dilated pupils differentiated amongoptic disks with papilledema, normal disks, and disks with nonpapilledemaabnormalities. (Funded by the Singapore National Medical Research Council andthe SingHealth Duke-NUS Ophthalmology and Visual Sciences Academic ClinicalProgram.).
参考文献：Artificial Intelligence to Detect Papilledemafrom Ocular Fundus Photographs. N Engl J Med. 2020 Apr 30;382(18):1687-1695.
12. Nature genetics—重磅突破！！SORD突变是引起隐性遗传性周围神经病的最常见遗传变异
Abstract
Here we report biallelic mutations in thesorbitol dehydrogenase gene (SORD) as the most frequent recessive form ofhereditary neuropathy. We identified 45 individuals from 38 families acrossmultiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27)variant in SORD, in either a homozygous or compound heterozygous state. SORD isan enzyme that converts sorbitol into fructose in the two-step polyol pathwaypreviously implicated in diabetic neuropathy. In patient-derived fibroblasts,we found a complete loss of SORD protein and increased intracellular sorbitol.Furthermore, the serum fasting sorbitol levels in patients were dramaticallyincreased. In Drosophila, loss of SORD orthologs caused synaptic degenerationand progressive motor impairment. Reducing the polyol influx by treatment withaldose reductase inhibitors normalized intracellular sorbitol levels inpatient-derived fibroblasts and in Drosophila, and also dramaticallyameliorated motor and eye phenotypes. Together, these findings establish anovel and potentially treatable cause of neuropathy and may contribute to abetter understanding of the pathophysiology of diabetes.
参考文献：Biallelic mutations in SORD cause a common andpotentially treatable hereditary neuropathy with implications for diabetes. NatGenet. 2020 May;52(5):473-481.
13. Lancet Neurol—最新临床试验证据！！强的松可以用于丛集性头痛的短期预防
Abstract
Background: Prednisone is commonly used forinitial short-term therapy of episodic cluster headaches before preventivemedication such as verapamil becomes effective, but this strategy has not beentested in large randomised trials. We aimed to access the safety and efficacyof this treatment approach.
Methods: This study was a multicentre,randomised, double-blind, placebo-controlled trial done in ten specialisedheadache centres in Germany. Patients with episodic cluster headaches who wereaged between 18 and 65 years and within a current pain episode for not morethan 30 days, received 100 mg oral prednisone for 5 days followed by taperingof 20 mg every 3 days, or matching placebo (17 days total exposure). Allpatients received oral verapamil for long-term prevention, starting with 40 mgthree times daily and increasing to 120 mg three times daily by day 19;patients then continued with verapamil 120 mg throughout the study.Randomisation was computer-generated at a 1:1 ratio by use of an interactiveweb-response system, with stratification according to age, sex, andparticipating site. Participants, investigators, and those assessing outcomeswere unaware of treatment allocation. The primary endpoint was the mean numberof attacks within the first week of treatment with prednisone compared withplacebo. An attack was defined as a unilateral headache with moderate-to-severeintensity of at least five on a numerical rating scale. All efficacy and safetyanalyses were done in the modified intention-to-treat (mITT) population, whichconsisted of all patients who had been randomly assigned to a trial group andreceived at least one dose of prednisone or placebo. The study was stoppedearly due to slow recruitment and expired funding. The study was registeredwith EudraCT (2011-006204-13) and with the German Clinical Trials Register(DRKS00004716).
Findings: Between April 5, 2013, and Jan 11,2018, 118 patients were enrolled in the study. Two patients dropped outimmediately and 116 patients were randomly assigned (57 patients to prednisoneand 59 patients to placebo); 109 patients were included in the mITT analysis(53 patients assigned to prednisone and 56 patients assigned to placebo).Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks withinthe first week compared with 9·5 (6·0) attacks in the placebo group (difference-2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse eventsoccurred, both in the placebo group (inguinal hernia and severe deteriorationof cluster headache). A total of 270 adverse events were observed: in theprednisone group, 37 (71%) of 52 patients reported 135 adverse events (mostcommon were headache, palpitations, dizziness, and nausea) and in the placebogroup, 39 (71%) of 55 patients had 135 adverse events (most common were nausea,dizziness, and headache).
Interpretation: Oral prednisone was aneffective short-term preventive therapy in our population of patients withepisodic cluster headache. Our findings support the use of prednisone as afirst-line treatment in parallel to the up-titration of verapamil, although theefficacy of prednisone alongside other long-term prevention requires additionalinvestigation.
参考文献：Safety and efficacy of prednisone versusplacebo in short-term prevention of episodic cluster headache: a multicentre,double-blind, randomised controlled trial. Lancet Neurol. 2021 Jan;20(1):29-37.
14. Lancet Neurol—科学家使用全外显子测序技术揭示肌张力障碍患者存在单基因遗传变异
Abstract
Background: Dystonia is a clinically andgenetically heterogeneous condition that occurs in isolation (isolateddystonia), in combination with other movement disorders (combined dystonia), orin the context of multisymptomatic phenotypes (isolated or combined dystoniawith other neurological involvement). However, our understanding of itsaetiology is still incomplete. We aimed to elucidate the monogenic causes forthe major clinical categories of dystonia.
Methods: For this exome-wide sequencing study,study participants were identified at 33 movement-disorder and neuropaediatricspecialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia,and Switzerland. Each individual with dystonia was diagnosed in accordance withthe dystonia consensus definition. Index cases were eligible for this study ifthey had no previous genetic diagnosis and no indication of an acquired causeof their illness. The second criterion was not applied to a subset ofparticipants with a working clinical diagnosis of dystonic cerebral palsy.Genomic DNA was extracted from blood of participants and whole-exome sequenced.To find causative variants in known disorder-associated genes, all variantswere filtered, and unreported variants were classified according to AmericanCollege of Medical Genetics and Genomics guidelines. All considered variantswere reviewed in expert round-table sessions to validate their clinicalsignificance. Variants that survived filtering and interpretation procedureswere defined as diagnostic variants. In the cases that went undiagnosed,candidate dystonia-causing genes were prioritised in a stepwise workflow.
Findings: We sequenced the exomes of 764individuals with dystonia and 346 healthy parents who were recruited betweenJune 1, 2015, and July 31, 2019. We identified causative or probable causativevariants in 135 (19%) of 728 families, involving 78 distinct monogenicdisorders. We observed a larger proportion of individuals with diagnosticvariants in those with dystonia (either isolated or combined) with coexistingnon-movement disorder-related neurological symptoms (100 [45%] of 222;excepting cases with evidence of perinatal brain injury) than in those withcombined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across allcategories of dystonia, 104 (65%) of the 160 detected variants affected geneswhich are associated with neurodevelopmental disorders. We found diagnosticvariants in 11 genes not previously linked to dystonia, and propose apredictive clinical score that could guide the implementation of exomesequencing in routine diagnostics. In cases without perinatal sentinel events,genomic alterations contributed substantively to the diagnosis of dystoniccerebral palsy. In 15 families, we delineated 12 candidate genes. These includeIMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidenceexisted for its involvement in a neurodevelopmental disorder with dystonia. Weidentified six variants in IMPDH2, collected from four independent cohorts,that were predicted to be deleterious de-novo variants and expected to resultin deregulation of purine metabolism.
Interpretation: In this study, we have determinedthe role of monogenic variants across the range of dystonic disorders,providing guidance for the introduction of personalised care strategies andfostering follow-up pathophysiological explorations.
参考文献：Monogenic variants in dystonia: an exome-widesequencing study. Lancet Neurol. 2020 Nov;19(11):908-918.
15. Nature medicine—散发性先天性脑积水的致病基因找到了：神经-胶质细胞发育相关基因异常是重要致病基础（附语音解读）
Abstract
Congenital hydrocephalus (CH), characterizedby enlarged brain ventricles, is considered a disease of excessivecerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgicalCSF diversion with high morbidity and failure rates. The poorneurodevelopmental outcomes and persistence of ventriculomegaly in somepost-surgical patients highlight our limited knowledge of disease mechanisms.Through whole-exome sequencing of 381 patients (232 trios) with sporadic,neurosurgically treated CH, we found that damaging de novo mutations account for>17% of cases, with five different genes exhibiting a significant de novomutation burden. In all, rare, damaging mutations with large effect contributedto ~22% of sporadic CH cases. Multiple CH genes are key regulators of neuralstem cell biology and converge in human transcriptional networks and cell typespertinent for fetal neuro-gliogenesis. These data implicate genetic disruptionof early brain development, not impaired CSF dynamics, as the primarypathomechanism of a significant number of patients with sporadic CH.
参考文献：Exome sequencing implicates genetic disruptionof prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nat Med.2020 Nov;26(11):1754-1765.
16. Lancet Neurol—科学家使用全基因组关联分析揭示散发性克雅氏病的致病性遗传位点
Abstract
Background: Human prion diseases are rare andusually rapidly fatal neurodegenerative disorders, the most common beingsporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene thatencodes prion protein are strong risk factors for sCJD but, although thecondition has similar heritability to other neurodegenerative disorders, noother genetic risk loci have been confirmed. We aimed to discover new geneticrisk factors for sCJD, and their causal mechanisms.
Methods: We did a genome-wide associationstudy of sCJD in European ancestry populations (patients diagnosed withprobable or definite sCJD identified at national CJD referral centres) with atwo-stage study design using genotyping arrays and exome sequencing.Conditional, transcriptional, and histological analyses of implicated genes andproteins in brain tissues, and tests of the effects of risk variants onclinical phenotypes, were done using deep longitudinal clinical cohort data.Control data from healthy individuals were obtained from publicly availabledatasets matched for country.
Findings: Samples from 5208 cases wereobtained between 1990 and 2014. We found 41 genome-wide significant singlenucleotide polymorphisms (SNPs) and independently replicated findings at threeloci associated with sCJD risk; within PRNP (rs1799990; additive model oddsratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 ×10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1(rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showedthat associations at PRNP and GAL3ST1 are likely to be caused by commonvariants that alter the protein sequence, whereas risk variants in STX6 areassociated with increased expression of the major transcripts indisease-relevant brain regions.
Interpretation: We present, to our knowledge,the first evidence of statistically robust genetic associations in sporadichuman prion disease that implicate intracellular trafficking and sphingolipidmetabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared withprogressive supranuclear palsy, a neurodegenerative disease associated withmisfolding of protein tau, indicating that sCJD might share the same causalmechanisms as prion-like disorders.
参考文献：Identification of novel risk loci and causalinsights for sporadic Creutzfeldt-Jakob disease: a genome-wide associationstudy. Lancet Neurol. 2020 Oct;19(10):840-848.
17. Lancet neurol—帕金森病免疫治疗进展！！α-synuclein主动免疫药物PD01A的耐受性和安全性良好
Abstract
Background: Robust evidence supports the roleof α-synuclein pathology as a driver of neuronal dysfunction in Parkinson'sdisease. PD01A is a specific active immunotherapy with a short peptideformulation targeted against oligomeric α-synuclein. This phase 1 studyassessed the safety and tolerability of the PD01A immunotherapeutic in patientswith Parkinson's disease.
Methods: We did a first-in-human, randomised,phase 1 study of immunisations with PD01A, followed by three consecutive studyextensions. Patients aged 45-65 years with a clinical diagnosis of Parkinson'sdisease (≤4 years since diagnosis and Hoehn and Yahr Stage 1 to 2), imagingresults (dopamine transporter single photon emission CT and MRI) consistentwith their Parkinson's disease diagnosis, and on stable doses of Parkinson'sdisease medications for at least 3 months were recruited at a single privateclinic in Vienna, Austria. Patients were randomly assigned (1:1), using acomputer-generated sequence with varying block size, to receive foursubcutaneous immunisations with either 15 μg or 75 μg PD01A injected into theupper arms and followed up initially for 52 weeks, followed by a further 39weeks' follow-up. Patients were then randomly assigned (1:1) again to receivethe first booster immunisation at 15 μg or 75 μg and were followed up for 24weeks. All patients received a second booster immunisation of 75 μg and werefollowed up for an additional 52 weeks. Patients were masked to doseallocation. Primary (safety) analyses included all treated patients. These fourstudies were registered with EU Clinical Trials Register, EudraCT numbers2011-002650-31, 2013-001774-20, 2014-002489-54, and 2015-004854-16.
Findings: 32 patients were recruited betweenFeb 14, 2012, and Feb 6, 2013, and 24 were deemed eligible and randomlyassigned to receive four PD01A priming immunisations. One patient had adiagnosis change to multiple system atrophy and was withdrawn and two patientswithdrew consent during the studies. 21 (87%) of 24 patients received all siximmunisations and completed 221-259 weeks in-study (two patients in the 15 μgdose group and one patient in the 75 μg dose group discontinued). All patientsexperienced at least one adverse event, but most of them were consideredunrelated to study treatment (except for transient local injection sitereactions, which affected all but one patient). Serial MRI assessments alsoruled out inflammatory processes. Systemic treatment-related adverse eventswere fatigue (n=4), headache (n=3), myalgia (n=3), muscle rigidity (n=2), andtremor (n=2). The geometric group mean titre of antibodies against theimmunising peptide PD01 increased from 1:46 at baseline to 1:3580 at week 12 inthe 15 μg dose group, and from 1:76 to 1:2462 at week 12 in the 75 μg dosegroup. Antibody titres returned to baseline over 2 years, but could be rapidlyreactivated after booster immunisation from week 116 onwards, reachinggeometric group mean titres up to 1:20218.
Interpretation: Repeated administrations ofPD01A were safe and well tolerated over an extended period. Specific activeimmunotherapy resulted in a substantial humoral immune response with targetengagement. Phase 2 studies are needed to further assess the safety andefficacy of PD01A for the treatment of Parkinson's disease.
参考文献：Safety and immunogenicity of the α-synucleinactive immunotherapeutic PD01A in patients with Parkinson's disease: arandomised, single-blinded, phase 1 trial. Lancet Neurol. 2020 Jul;19(7):591-600.
18. Lancet Neurol—抗CD20抗体利妥昔单抗可显著预防AQP4阳性NMOSD患者的复发
Abstract
Background: Pharmacological prevention againstrelapses in patients with neuromyelitis optica spectrum disorder (NMOSD) isdeveloping rapidly. We aimed to investigate the safety and efficacy ofrituximab, an anti-CD20 monoclonal antibody, against relapses in patients withNMOSD.
Methods: We did a multicentre, randomised,double-blind, placebo-controlled clinical trial at eight hospitals in Japan.Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4(AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an ExpandedDisability Status Scale (EDSS) score of 7·0 or less were eligible for thestudy. Individuals taking any other immunosuppressants were excluded.Participants were randomly allocated (1:1) either rituximab or placebo by acomputer-aided dynamic random allocation system. The doses of concomitantsteroid (converted to equivalent doses of prednisolone) and relapses inprevious 2 years were set as stratification factors. Participants and thoseassessing outcomes were unaware of group assignments. Rituximab (375 mg/m2) wasadministered intravenously every week for 4 weeks, then 6-month interval dosingwas done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation).A matching placebo was administered intravenously. Concomitant oralprednisolone was gradually reduced to 2-5 mg/day, according to the protocol.The primary outcome was time to first relapse within 72 weeks. Relapses weredefined as patient-reported symptoms or any new signs consistent with CNSlesions and attributable objective changes in MRI or visual evoked potential.The primary analysis was done in the full analysis set (all randomly assignedpatients) and safety analyses were done in the safety analysis set (allpatients who received at least one infusion of assigned treatment). The primaryanalysis was by intention-to-treat principles. This trial is registered withthe UMIN clinical trial registry, UMIN000013453.
Findings: Between May 10, 2014, and Aug 15,2017, 38 participants were recruited and randomly allocated either rituximab(n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinuedthe study and were analysed as censored cases. Seven (37%) relapses occurred inpatients allocated placebo and none were recorded in patients assignedrituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). Eightserious adverse events were recorded, four events in three (16%) patientsassigned rituximab (lumbar compression fracture and infection around nail ofright foot [n=1], diplopia [n=1], and uterine cancer [n=1]) and four events intwo (11%) people allocated to placebo (exacerbation of glaucoma and bleeding inthe right eye chamber after surgery [n=1], and visual impairment andasymptomatic white matter brain lesion on MRI [n=1]); all patients recovered.No deaths were reported.
Interpretation: Rituximab prevented relapsesfor 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This studyis limited by its small sample size and inclusion of participants with milddisease activity. However, our results suggest that rituximab could be usefulmaintenance therapy for individuals with NMOSD who are AQP4 antibody-positive.
参考文献：Safety and efficacy of rituximab inneuromyelitis optica spectrum disorders (RIN-1 study): a multicentre,randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020Apr;19(4):298-306.
19. Lancet Neurol—Nusinersen治疗5q脊肌萎缩症初见成效
Abstract
Background: Nusinersen is approved for thetreatment of 5q spinal muscular atrophy of all types and stages in patients ofall ages. Although clinical trials have shown improvements in motor function ininfants and children treated with the drug, data for adults are scarce. Weaimed to assess the safety and efficacy of nusinersen in adults with 5q spinalmuscular atrophy.
Methods: We did an observational cohort studyat ten academic clinical sites in Germany. Patients with genetically confirmed5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion ofexons 7, 8, or both, or with compound heterozygous mutations were eligible forinclusion and received nusinersen treatment in accordance with the label for aminimum treatment time of 6 months to a follow-up of up to 14 months. Theprimary outcome was the change in the total Hammersmith Functional Motor ScaleExpanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-postcomparisons. This study is registered with the German Clinical Trials Register(number DRKS00015702).
Findings: Between July 13, 2017, and May 1,2019, 173 patients were screened, of whom 139 (80%) were eligible for dataanalysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%)in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients withmissing baseline HFMSE scores were excluded from these analyses. Mean HFMSEscores were significantly increased compared with baseline at 6 months (meandifference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39],p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinicallymeaningful improvements (≥3 points increase) in HFMSE scores were seen in 35(28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of57 at 14 months. To 14-month follow-up, the most frequent adverse effects among173 patients were headache (61 [35%] patients), back pain (38 [22%]), andnausea (19 [11%]). No serious adverse events were reported.
Interpretation: Despite the limitations of theobservational study design and a slow functional decline throughout the naturaldisease course, our data provide evidence for the safety and efficacy ofnusinersen in the treatment of adults with 5q spinal muscular atrophy, withclinically meaningful improvements in motor function in a real-world cohort.
参考文献：Nusinersen in adults with 5q spinal muscularatrophy: a non-interventional, multicentre, observational cohort study. LancetNeurol. 2020 Apr;19(4):317-325.
20. Lancet Neurol—相比于咪唑硫嘌呤，抗人白细胞介素-6受体抗体Tocilizumab可显著降低NMOSD患者的复发风险
Abstract
Background: Azathioprine is used as afirst-line treatment to prevent relapses of neuromyelitis optica spectrumdisorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activityin retrospective case reports. We aimed to compare the safety and efficacy oftocilizumab and azathioprine in patients with highly relapsing NMOSD.
Methods: We did an open-label, multicentre,randomised, phase 2 trial at six hospitals in China. We recruited adultpatients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who hadan Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had ahistory of at least two clinical relapses during the previous 12 months orthree relapses during the previous 24 months with at least one relapse withinthe previous 12 months. Patients were randomly assigned (1:1) to intravenoustocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2-3 mg/kg per day) byan independent statistician using computer-generated randomisation softwarewith permuted blocks of four. The central review committee, EDSS raters,laboratory personnel, and radiologists were masked to the treatment assignment,but investigators and patients were aware of treatment allocation. The minimumplanned duration of treatment was 60 weeks following randomisation. The primaryoutcome was time to first relapse in the full analysis set, which included allrandomly assigned patients who received at least one dose of study drug, andthe per-protocol population, which included all patients who used azathioprineor tocilizumab as monotherapy. For the analyses of the primary outcome, thepatients were prespecified into two subgroups according to concomitantautoimmune disease status. Safety was assessed in the full analysis set. Thisstudy is registered with ClinicalTrials.gov, NCT03350633.
Findings: Between Nov 1, 2017, and Aug 3,2018, we enrolled 118 patients, of whom 59 were randomly assigned totocilizumab and 59 were randomly assigned to azathioprine. All 118 patientsreceived one dose of study drug and were included in the full analysis set. 108participants were included in the per-protocol analysis (56 in the tocilizumabgroup and 52 in the azathioprine group). In the full analysis set, median timeto the first relapse was longer in the tocilizumab group than the azathioprinegroup (78·9 weeks [IQR 58·3-90·6] vs 56·7 [32·9-81·7] weeks; p=0·0026). Eight (14%)of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in theazathioprine group had a relapse at the end of the study (hazard ratio [HR]0·236 [95% CI 0·107-0·518]; p<0·0001). In the per-protocol analysis, 50(89%) of 56 patients in the tocilizumab group were relapse-free compared with29 (56%) of 52 patients in the azathioprine group at the end of the study (HR0·188 [95% CI 0·076-0·463]; p<0·0001); the median time to first relapse wasalso longer in the tocilizumab group than the azathioprine group (67·2 weeks[IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p<0·0001). In the prespecified subgroupanalysis of the full analysis set stratified by concomitant autoimmunediseases, among patients without concomitant autoimmune diseases, three (9%) of34 patients in the tocilizumab group and 13 (35%) of 37 patients in theazathioprine group had relapsed by the end of the study. Among patients withconcomitant autoimmune diseases, a lower proportion of patients in thetocilizumab group had a relapse than in the azathioprine group (five [20%] of25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070-0·531];p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59patients in the azathioprine group had adverse events. Treatment-associatedadverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49(83%) of 59 azathioprine-treated patients. One death (2%) occurred in thetocilizumab group and one (2%) in the azathioprine group, but neither of thedeaths were treatment-related.
Interpretation: Tocilizumab significantlyreduced the risk of a subsequent NMOSD relapse compared with azathioprine.Tocilizumab might therefore be another safe and effective treatment to preventrelapses in patients with NMOSD.
参考文献：Safety and efficacy of tocilizumab versusazathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO):an open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020May;19(5):391-401.
21. Lancet Neurol—抗人白细胞介素-6受体抗体Satralizumab单药治疗可显著降低NMOSD患者的复发风险
Abstract
Background: Satralizumab, a humanisedmonoclonal antibody targeting the interleukin-6 receptor, reduced the risk ofrelapse in patients with neuromyelitis optica spectrum disorder (NMOSD) whenadded to immunosuppressant therapy. This study assessed the safety and efficacyof satralizumab monotherapy in patients with the disorder.
Methods: In this phase 3, double-blind,placebo-controlled, parallel-group trial, we enrolled adults aged 18-74 yearswith aquaporin-4 antibody seropositive or seronegative NMOSD at 44investigational sites in 13 countries. Eligible participants had experienced atleast one documented NMOSD attack or relapse in the past 12 months and had ascore of 6·5 or less on the Expanded Disability Status Scale. Exclusioncriteria included clinical relapse 30 days or fewer before baseline. Participantswere randomly assigned (2:1) to receive satralizumab 120 mg or visually matchedplacebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Takingimmunosuppressants concomitantly was prohibited. The primary endpoint was timeto the first protocol-defined relapse, based on the intention-to-treatpopulation and analysed with stratification for two randomisation factors(previous therapy for prevention of attacks and nature of the most recentattack). Safety was assessed in all participants who received at least one doseof satralizumab or placebo. The double-blind phase was due to last until 44protocol-defined relapses occurred or 1·5 years after random assignment of thelast patient enrolled, whichever occurred first; participants could enter anopen-label phase after the occurrence of a protocol-defined relapse or at theend of the double-blind phase. The study is registered with ClinicalTrials.gov,NCT02073279.
Findings: 95 (57%) of 168 screenedparticipants were randomly assigned to treatment (63 to satralizumab; 32 toplacebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapsesoccurred in 19 (30%) patients receiving satralizumab and 16 (50%) receivingplacebo (hazard ratio 0·45, 95% CI 0·23-0·89; p=0·018). 473·9 adverse eventsper 100 patient-years occurred in the satralizumab group, as did 495·2 per 100patient-years in the placebo group; the incidence of serious adverse events andadverse events leading to withdrawal was similar between groups.
Interpretation: Satralizumab monotherapyreduced the rate of NMOSD relapse compared with placebo in the overall trialpopulation, with a favourable safety profile. The patient population included aratio of aquaporin-4 antibody seropositive and seronegative patients that wasreflective of clinical practice. Satralizumab has the potential to become avaluable treatment option for patients with NMOSD.
参考文献：Safety and efficacy of satralizumabmonotherapy in neuromyelitis optica spectrum disorder: a randomised,double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol.2020 May;19(5):402-412.
22. Lancet Neurol—最新临床证据支持CGRP抑制剂Galcanezumab用于偏头痛的预防治疗
Abstract
Background: Many patients who require migrainepreventive treatment have not been able to tolerate or have not responded tomultiple previous preventive medications. We aimed to assess the safety andefficacy of galcanezumab, an antibody to calcitonin gene-related peptide, inpatients with migraine who had not benefited from preventive medications fromtwo to four categories.
Methods: CONQUER was a multicentre,randomised, double-blind, placebo-controlled, phase 3b trial done at 64 sites(hospitals, clinics, or research centres) in 12 countries (Belgium, Canada,Czech Republic, France, Germany, Hungary, Japan, the Netherlands, South Korea,Spain, the UK, and the USA). Patients were 18-75 years of age, with episodic orchronic migraine, with migraine onset before the age of 50 years, who had adocumented failure of preventive medications from two to four drug categoriesin the past 10 years owing to lack of efficacy or tolerability, or both.Patients were randomised 1:1 to receive subcutaneous placebo or galcanezumab120 mg per month (with a 240 mg loading dose administered as two 120 mginjections) for 3 months. For masking purposes, patients receiving placebo alsoreceived two injections during the first dosing visit. Randomisation was doneby a computer-generated random sequence by means of an interactive web-responsesystem stratified by country and migraine frequency (low frequency episodicmigraine, four to fewer than eight migraine headache days per month; highfrequency episodic migraine, eight to 14 migraine headache days per month andfewer than 15 headache days per month; chronic migraine, at least eightmigraine headache days per month and at least 15 headache days per month). Theprimary endpoint was the overall mean change from baseline in number of monthlymigraine headache days during the 3-month treatment period in all patients whowere randomly assigned and received at least one dose of study drug. This trialis registered with ClinicalTrials.gov, NCT03559257, and is now completed.
Findings: Between Sept 10, 2018, and March 21,2019, 462 participants with episodic (269 [58%]) or chronic (193 [42%])migraine were randomly assigned and received at least one injection withplacebo (n=230) or galcanezumab (n=232). Galcanezumab-treated patients hadsignificantly greater reduction in migraine headache days versus placebo acrossmonths 1-3. The galcanezumab group had on average 4·1 fewer monthly migraine headachedays compared with baseline (13·4), while the placebo group had on average 1·0fewer than at baseline (13·0; between-group difference -3·1 [95% CI -3·9 to-2·3]; p<0·0001; effect size=0·72). Types and number of treatment-emergentadverse events were similar between galcanezumab and placebo.Treatment-emergent adverse events were reported in 122 (53%) of 230 patients inthe placebo group and 119 (51%) of 232 patients in the galcanezumab group.There were four serious adverse events during the study, two (1%) reported inthe placebo group and two (1%) reported in the galcanezumab group.
Interpretation: Galcanezumab was superior toplacebo in the preventive treatment of migraine and was safe and well toleratedin patients for whom multiple previous standard-of-care preventive treatmentshad failed. Galcanezumab might represent an important treatment option forpatients who have not benefited from or tolerated previous standard-of-caretreatments.
参考文献：Safety and efficacy of galcanezumab inpatients for whom previous migraine preventive medication from two to fourcategories had failed (CONQUER): a multicentre, randomised, double-blind,placebo-controlled, phase 3b trial. Lancet Neurol. 2020 Oct;19(10):814-825.
23. Lancet neurol—好事，降压药可以预防痴呆？最新荟萃分析表明高血压患者服用降压药可以降低罹患痴呆和AD的风险
Abstract
Background: Dementia is a major health concernfor which prevention and treatment strategies remain elusive. Lowering highblood pressure with specific antihypertensive medications (AHMs) could reducethe burden of disease. We investigated whether specific AHM classes reduced therisk for dementia.
Methods: We did a meta-analysis of individualparticipant data from eligible observational studies published between Jan 1,1980, and Jan 1, 2019. Cohorts were eligible for inclusion if theyprospectively recruited community-dwelling adults; included more than 2000participants; collected data for dementia events over at least 5 years; hadmeasured blood pressure and verified use of AHMs; included in-person exams,supplemented with additional data, to capture dementia events; and had followedup cases for mortality. We assessed the association of incident dementia andclinical Alzheimer's disease with use of five AHM classes, within strata ofbaseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic bloodpressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg)blood pressure. We used a propensity score to control for confounding factorsrelated to the probability of receiving AHM. Study-specific effect estimateswere pooled using random-effects meta-analyses.
Results: Six prospective community-basedstudies (n=31 090 well phenotyped dementia-free adults older than 55 years)with median follow-ups across cohorts of 7-22 years were eligible for analysis.There were 3728 incident cases of dementia and 1741 incident Alzheimer'sdisease diagnoses. In the high blood pressure stratum (n=15 537), those usingany AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95%CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021)compared with those not using AHM. We did not find any significant differencesbetween one drug class versus all others on risk of dementia. In the normalblood pressure stratum (n=15 553), there was no association between AHM use andincident dementia or Alzheimer's disease.
Interpretation: Over a long period ofobservation, no evidence was found that a specific AHM drug class was more effectivethan others in lowering risk of dementia. Among people with hypertensive levelsof blood pressure, use of any AHM with efficacy to lower blood pressure mightreduce the risk for dementia. These findings suggest future clinical guidelinesfor hypertension management should also consider the beneficial effect of AHMon the risk for dementia.
参考文献：Antihypertensive medications and risk forincident dementia and Alzheimer's disease: a meta-analysis of individualparticipant data from prospective cohort studies. Lancet Neurol. 2020Jan;19(1):61-70.
24. JAMA—全球首个口服CGRP偏头痛药物Ubrogepant可显著降低偏头痛患者的头痛症状和其他烦人症状
Abstract
Importance: Ubrogepant is an oral calcitoningene-related peptide receptor antagonist under investigation for acutetreatment of migraine.
Objective: To evaluate the efficacy andtolerability of ubrogepant compared with placebo for acute treatment of asingle migraine attack.
Design, setting, and participants: Phase 3,multicenter, randomized, double-blind, placebo-controlled, single-attack,clinical trial (ACHIEVE II) conducted in the United States (99 primary care andresearch clinics; August 26, 2016-February 26, 2018). Participants were adultswith migraine with or without aura experiencing 2 to 8 migraine attacks permonth.
Interventions: Ubrogepant 50 mg (n = 562),ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack ofmoderate or severe pain intensity.
Main outcomes and measures: Co-primaryefficacy outcomes were pain freedom and absence of the participant-designatedmost bothersome migraine-associated symptom (among photophobia, phonophobia,and nausea) at 2 hours after taking the medication.
Results: Among 1686 randomized participants,1465 received study treatment (safety population; mean age, 41.5 years; 90%female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mggroup, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) inthe placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI,2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03).Absence of the most bothersome associated symptom at 2 hours was reported by180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434(34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebogroup (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P =.01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most commonadverse events within 48 hours of any dose were nausea (50 mg, 10 of 488[2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness(50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]).
Conclusions and relevance: Among adults withmigraine, acute treatment with ubrogepant compared with placebo led tosignificantly greater rates of pain freedom at 2 hours with 50-mg and 25-mgdoses, and absence of the most bothersome migraine-associated symptom at 2hours only with the 50-mg dose. Further research is needed to assess theeffectiveness of ubrogepant against other acute treatments for migraine and toevaluate the long-term safety of ubrogepant among unselected patientpopulations.
参考文献：Effect of Ubrogepant vs Placebo on Pain andthe Most Bothersome Associated Symptom in the Acute Treatment of Migraine: TheACHIEVE II Randomized Clinical Trial. JAMA. 2019 Nov 19;322(19):1887-1898.
25. Lancet Neurol—对于椎基底动脉动脉阻塞，血管内治疗并不优于常规医学治疗
Abstract
Background: Previous randomised trials haveshown an overwhelming benefit of mechanical thrombectomy for treating patientswith stroke caused by large vessel occlusion of the anterior circulation.Whether endovascular treatment is beneficial for vertebrobasilar arteryocclusion remains unknown. In this study, we aimed to investigate the safetyand efficacy of endovascular treatment of acute strokes due to vertebrobasilarartery occlusion.
Methods: We did a multicentre, randomised,open-label trial, with blinded outcome assessment of thrombectomy in patientspresenting within 8 h of vertebrobasilar occlusion at 28 centres in China.Patients were randomly assigned (1:1) to endovascular therapy plus standardmedical therapy (intervention group) or standard medical therapy alone (controlgroup). The randomisation sequence was computer-generated and stratified byparticipating centres. Allocation concealment was implemented by use of sealedenvelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 orlower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treatbasis. The primary safety outcome was mortality at 90 days. Secondary safetyendpoints included the rates of symptomatic intracranial haemorrhage,device-related complications, and other severe adverse events. The BEST trialis registered with ClinicalTrials.gov, NCT02441556.
Findings: Between April 27, 2015, and Sept 27,2017, we assessed 288 patients for eligibility. The trial was terminated earlyafter 131 patients had been randomly assigned (66 patients to the interventiongroup and 65 to the control group) because of high crossover rate and poorrecruitment. In the intention-to-treat analysis, there was no evidence of adifference in the proportion of participants with mRS 0-3 at 90 days accordingto treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81-3·74).Secondary prespecified analyses of the primary outcome, done to assess theeffect of crossovers, showed higher rates of mRS 0-3 at 90 days in patients whoactually received the intervention compared with those who received standardmedical therapy alone in both per-protocol (28 [44%] of 63 patients withintervention vs 13 [25%] of 51 with standard therapy; adjusted OR 2·90, 95% CI1·20-7·03) and as-treated (36 [47%] of 77 patients with intervention vs 13[24%] of 54 with standard therapy; 3·02, 1·31-7·00) populations. The 90-daymortality was similar between groups (22 [33%] of 66 patients in theintervention vs 25 [38%] of 65 in the control group; p=0·54) despite anumerically higher prevalence of symptomatic intracranial haemorrhage in theintervention group.
Interpretation: There was no evidence of adifference in favourable outcomes of patients receiving endovascular therapycompared with those receiving standard medical therapy alone. Results mighthave been confounded by loss of equipoise over the course of the trial,resulting in poor adherence to the assigned study treatment and a reducedsample size due to the early termination of the study.
参考文献：Endovascular treatment versus standard medicaltreatment for vertebrobasilar artery occlusion (BEST): an open-label,randomised controlled trial. Lancet Neurol. 2020 Feb;19(2):115-122.
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