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OBJECTIVES: Cerebral microemboli can be detected by transcranial Doppler monitoring (TCDM) and may elucidate stroke etiology, the effect of preventive therapy, and the risk of stroke recurrence. Microemboli detection is usually performed for up to 60 minutes, but due to temporal variability, microembolization may be missed if the monitoring time is too short. We aimed to assess the time course of microembolization in acute ischemic stroke and explore the utility of prolonged and repeated microemboli detection. MATERIALS AND METHODS: Patients with suspected ischemic stroke and symptom onset within 24 hours were examined with bilateral, stationary TCDM for one hour followed by unilateral, ambulatory TCDM for two hours. Unilateral TCDM was repeated for the following two days and after three months. RESULTS: We included 47 patients, of which 41 had ischemic stroke, five had transient ischemic attack, and one had amaurosis fugax. Microemboli were detected in 60 % of patients. The occurrence was highest within 24 hours after onset and significantly lower at three months. Prolonged and repeated microemboli detection yielded only one additional microemboli-positive patient. Hence, patients who initially were microemboli negative tended to remain negative. We could not demonstrate an association between microemboli occurrence and clinical outcome or stroke recurrence. CONCLUSIONS: Microembolic signals are frequent within 24 hours after ischemic stroke onset, but prolonged and repeated microemboli detection did not increase the yield of MES positive patients. CLINICAL TRIAL REGISTRATION-URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT03543319.
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Embolia Intracraniana , AVC Isquêmico , Valor Preditivo dos Testes , Ultrassonografia Doppler Transcraniana , Humanos , Masculino , Feminino , Idoso , AVC Isquêmico/etiologia , AVC Isquêmico/terapia , AVC Isquêmico/diagnóstico , AVC Isquêmico/diagnóstico por imagem , Fatores de Tempo , Pessoa de Meia-Idade , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/etiologia , Embolia Intracraniana/diagnóstico , Idoso de 80 Anos ou mais , Noruega/epidemiologia , Estudos Prospectivos , Fatores de Risco , Recidiva , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/terapiaRESUMO
Mature neurons in the human central nervous system (CNS) fail to regenerate after injuries. This is a common denominator across different aetiologies, including multiple sclerosis, spinal cord injury and ischemic stroke. The lack of regeneration leads to permanent functional deficits with a substantial impact on patient quality of life, representing a significant socioeconomic burden worldwide. Great efforts have been made to decipher the responsible mechanisms and we now know that potent intra- and extracellular barriers prevent axonal repair. This knowledge has resulted in numerous clinical trials, aiming to promote neuroregeneration through different approaches. Here, we summarize the current understanding of the causes to the poor regeneration within the human CNS. We also review the results of the treatment attempts that have been translated into clinical trials so far.
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In multiple sclerosis (MS), there is a great need for treatment with the ability to suppress compartmentalized inflammation within the central nervous system (CNS) and to promote remyelination and regeneration. Mesenchymal stem cells (MSCs) represent a promising therapeutic option, as they have been shown to migrate to the site of CNS injury and exert neuroprotective properties, including immunomodulation, neurotrophic factor secretion, and endogenous neural stem cell stimulation. This review summarizes the current understanding of the underlying neuroprotective mechanisms and discusses the translation of MSC transplantation and their derivatives from pre-clinical demyelinating models to clinical trials with MS patients.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Esclerose Múltipla , Células-Tronco Neurais , Humanos , Esclerose Múltipla/terapia , Sistema Nervoso CentralRESUMO
BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate long-term outcomes of HSCT in MS. METHODS: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). RESULTS: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. CONCLUSION: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs.
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Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla Recidivante-Remitente , Transplante Autólogo , Humanos , Adulto , Feminino , Masculino , Noruega , Seguimentos , Estudos Retrospectivos , Esclerose Múltipla Recidivante-Remitente/terapia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto Jovem , Progressão da Doença , Resultado do TratamentoRESUMO
INTRODUCTION: Multiple sclerosis (MS) is characterized by chronic inflammation, demyelination, and axonal degeneration within the central nervous system (CNS), for which there is no current treatment available with the ability to promote neuroprotection or remyelination. Some aspects of the progressive form of MS are displayed in the murine cuprizone model, where demyelination is induced by the innate immune system without major involvement of the adaptive immune system. Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory and neuroprotective potential. In this study, we aimed to assess the neuroprotective potential of MSCs from bone marrow (BM-MSCs) and stem cells from human exfoliated deciduous teeth (SHED) in the cuprizone model. METHODS: Human BM-MSCs and SHED were isolated and characterized. Nine-week-old female C57BL/6 mice were randomized to receive either human BM-MSCs, human SHED or saline intraperitoneally. Treatments were administered on day -1, 14 and 21. Outcomes included levels of local demyelination and inflammation, and were assessed with immunohistochemistry and histology. RESULTS: BM-MSCs were associated with increased myelin content and reduced microglial activation whereas mice treated with SHED showed reduced microglial and astroglial activation. There were no differences between treatment groups in numbers of mature oligodendrocytes or axonal injury. MSCs were identified in the demyelinated corpus callosum in 40% of the cuprizone mice in both the BM-MSC and SHED group. CONCLUSION: Our results suggest a neuroprotective effect of MSCs in a toxic MS model, with demyelination mediated by the innate immune system.
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Células-Tronco Mesenquimais , Esclerose Múltipla , Humanos , Feminino , Animais , Camundongos , Cuprizona , Medula Óssea/patologia , Neuroproteção , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Oligodendroglia/patologia , Inflamação/patologia , Dente Decíduo , Corpo Caloso/patologiaRESUMO
BACKGROUND: Several studies have shown that stroke mimics occur more often among young patients. Our aims were to identify the common mimics in young patients under the age of 60 years who received thrombolysis, to analyze the risk of hemorrhage after treatment with thrombolysis, and to identify risk factors and clinical parameters that might identify mimics in this group. METHODS: Norwegian Tenecteplase Stroke Trial was a phase-3 trial investigating safety and efficacy of tenecteplase vs. alteplase in patients with acute ischemic stroke. Patients diagnosed with either acute cerebral ischemia or transient ischemic attack were categorized as stroke group, and patients with any diagnosis other than ischemic stroke or transient ischemic attack as mimics group. Patients were grouped post-hoc into young (< 60 years) and old (≥ 60 years). Logistic regression analyses were performed with mimics vs. stroke as dependent variable to identify predictors of mimics. RESULTS: Of the 1091 patients included in the trial, 211 patients (19.3%) were under the age of 60 years. Out of the 1091 patients, 434 (39.8%) were female, median age 77 years (18-99 years), and median NIHSS was 4. Sixty-nine patients (32.7%) out of the 211 patients under the age of 60 were diagnosed as mimic. Mimics were significantly more frequent among the young (OR = 3.3, 32.7% vs. 12.8%, p = < 0.001). The most frequent mimics diagnoses among patients under 60 years of age were migraine (11.8%), no definite diagnosis (11.4%) and peripheral vertigo (3.3%). Mimics were independently associated with age < 50 years (OR = 4.97, p = < 0.001), not currently working/studying (OR = 3.38, p = 0.002) and not having aphasia on admission (OR = 2.95, p = 0.025). None of the mimics under the age of 60 years had symptomatic or asymptomatic intracerebral hemorrhage as a complication to thrombolysis. CONCLUSION: We found significantly more mimics in the young, of which migraine was the most predominant diagnosis. Thrombolysis with alteplase or tenecteplase did not cause ICH in any mimics under 60 years.
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Isquemia Encefálica , Ataque Isquêmico Transitório , AVC Isquêmico , Transtornos de Enxaqueca , Acidente Vascular Cerebral , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Masculino , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Fibrinolíticos/efeitos adversos , Ataque Isquêmico Transitório/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/tratamento farmacológico , Noruega/epidemiologia , Transtornos de Enxaqueca/tratamento farmacológico , Resultado do TratamentoRESUMO
Background The optimal dose of tenecteplase in acute ischemic stroke remains to be defined. We present a pooled analysis of the 2 NOR-TESTs (Norwegian Tenecteplase Stroke Trials) exploring the efficacy and safety of tenecteplase, 0.4 mg/kg. Methods and Results We retrospectively reviewed 2 PROBE (Prospective Randomized Open, Blinded End-point) trials, NOR-TEST and NOR-TEST 2A. Patients were randomized to either tenecteplase, 0.4 mg/kg, or alteplase, 0.9 mg/kg. The primary end point was favorable functional outcome at 3 months (modified Rankin Scale score, 0-1) or return to baseline if prestroke modified Rankin Scale score was 2. Secondary end points included favorable functional and clinical outcome and safety data. The pooled analysis includes patients with National Institutes of Health Stroke Scale score ≥6 from both trials and an additional post hoc analysis of patients with National Institutes of Health Stroke Scale score ≤5 from NOR-TEST. The per-protocol analysis contains 483 patients, of whom 235 were assigned to tenecteplase and 248 were assigned to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cutoff modified Rankin Scale score of 2 (odds ratio [OR], 0.52 [95% CI, 0.33-0.80]; P=0.003) and expressed by ordinal shift analysis (OR, 1.64 [95% CI, 1.17-2.28]; P=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR, 2.48 [95% CI, 1.20-5.10]; P=0.01). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. Conclusions Tenecteplase, 0.4 mg/kg, is unsafe in moderate and severe stroke, and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01949948, NCT03854500.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Tenecteplase/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Fibrinolíticos/efeitos adversos , AVC Isquêmico/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Hemorragias Intracranianas/induzido quimicamente , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Mesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS). Methods: A systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model. Findings: Of 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively. Interpretation: MSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.
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BACKGROUND: Tenecteplase is a modified tissue plasminogen activator with pharmacological and practical advantages over alteplase-which is currently the only approved thrombolytic drug for ischaemic stroke. The NOR-TEST trial showed that 0·4 mg/kg tenecteplase had an efficacy and safety profile similar to that of a standard dose (0·9 mg/kg) of alteplase, albeit in a patient population with a high prevalence of minor stroke. The aim of NOR-TEST 2 was to establish the non-inferiority of tenecteplase 0·4 mg/kg to alteplase 0·9 mg/kg for patients with moderate or severe ischaemic stroke. METHODS: This phase 3, randomised, open-label, blinded endpoint, non-inferiority trial was performed at 11 hospitals with stroke units in Norway. Patients with suspected acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or more who were eligible for thrombolysis and admitted within 4·5 h of symptom onset were consecutively included. Random assignment, done by a computer with a block size of 4 and with allocations placed into opaque envelopes to be opened consecutively, was 1:1 between intravenous tenecteplase (0·4 mg/kg) or standard dose alteplase (0·9 mg/kg). Doctors and nurses providing acute care were not masked to treatment, but primary outcome assessment at 3 months was masked. The primary outcome was favourable functional outcome defined as a modified Rankin Scale score of 0-1 at 3 months, assessed in the modified intention-to-treat analysis (excluding patients who did not qualify for thrombolysis after randomisation or who withdrew informed consent). The non-inferiority margin was 3%. This trial (NOR-TEST 2) is registered with EudraCT (number 2018-003090-95) and ClinicalTrials.gov (NCT03854500). The trial was stopped early for safety reasons and is designated part A for analysis. Part B is ongoing with a lower dose of tenecteplase (0·25 mg/kg). FINDINGS: Between Oct 28, 2019, and Sept 26, 2021, 216 patients were enrolled. Patient enrolment was stopped after a per-protocol safety review showed an imbalance in the rates of symptomatic intracranial haemorrhage between the treatment groups, which surpassed the prespecified criteria for stopping the trial. Of 204 patients entering the modified intention-to-treat analysis, 100 were randomly allocated tenecteplase and 104 were allocated alteplase. All patients were followed up within 14 days of the end of the 3-months' follow-up period. A favourable functional outcome was reported less frequently in patients receiving tenecteplase (31 [32%] of 96 patients) compared with alteplase (52 [51%] of 101 patients; unadjusted OR 0·45 [95% CI 0·25-0·80]; p=0·0064). Any intracranial haemorrhage was significantly more frequent with tenecteplase (21 [21%] of 100 patients) than with alteplase (seven [7%] of 104 patients; unadjusted OR 3·68 [95% CI 1·49-9·11]; p=0·0031). Mortality at 3 months was also significantly higher with tenecteplase (15 [16%] of 96 patients) than with alteplase (five [5%] of 101 patients; unadjusted OR 3·56 [95% CI 1·24-10·21]; p=0·013). Numerically more cases of symptomatic intracranial haemorrhage were reported with tenecteplase (six [6%] of 100 patients) than with alteplase (one [1%] of 104 patients; unadjusted OR 6·57 [95% CI 0·78-55·62]; p=0·061). INTERPRETATION: In this prematurely terminated study (terminated to fulfil the prespecified safety criteria), tenecteplase at a dose of 0·4 mg/kg yielded worse safety and functional outcomes compared with alteplase. Our study consequently could not show that 0·4 mg/kg tenecteplase is non-inferior to alteplase in moderate and severe ischaemic stroke. Future stroke trials should assess a lower dose of tenecteplase versus alteplase in patients with moderate or severe stroke. FUNDING: The Norwegian National Programme for Clinical Therapy Research.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos , Humanos , Hemorragias Intracranianas/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Sex differences in acute ischemic stroke is of increasing interest in the era of precision medicine. We aimed to explore sex disparities in baseline characteristics, management and outcomes in patients treated with intravenous thrombolysis included in the Norwegian Tenecteplase trial (NOR-TEST). METHODS: NOR-TEST was an open-label, randomized, blinded endpoint trial, performed from 2012 to 2016, comparing treatment with tenecteplase to treatment with alteplase within 4.5 h after acute ischemic stroke symptom onset. Sex differences at baseline, treatment and outcomes were compared using multivariable logistic regression models. Heterogeneity in treatment was evaluated by including an interaction term in the model. RESULTS: Of 1100 patients enrolled, 40% were women, and in patients aged >80 years, the proportion of women was greater than men (19% vs. 14%; p = 0.02). Women had a lower burden of cardiovascular risk factors, such as diabetes mellitus (11% vs. 15%; p = 0.05) and a higher mean high-density lipoprotein cholesterol level (1.7 ± 0.6 mmol/L vs. 1.3 ± 0.4 mmol/L; p < 0.001), and a higher proportion of women had never smoked (45% vs. 33%; p < 0.001) compared with men. While there was no sex difference in time from onset of symptoms to admission, door to needle time or in-hospital workup, women were admitted with more severe stroke (National Institutes of Health Stroke Scale [NIHSS] score 6.2 ± 5.6 vs. 5.3 ± 5.1; p = 0.01). Stroke mimic diagnosis was more common in women (21% vs. 15%; p = 0.01). There were no significant sex differences in clinical outcome, measured by the NIHSS, the modified Rankin Scale, intracranial hemorrhage and mortality. CONCLUSION: Women were underrepresented in number in NOR-TEST. The included women had a lower cardiovascular risk factor burden and more severe strokes.
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AVC Isquêmico , Tenecteplase , Idoso de 80 Anos ou mais , Feminino , Fibrinolíticos/efeitos adversos , Humanos , AVC Isquêmico/epidemiologia , Masculino , Distribuição por Sexo , Tenecteplase/efeitos adversos , Ativador de Plasminogênio Tecidual , Resultado do TratamentoRESUMO
Background: Carotid artery atherosclerosis is a major risk factor for ischemic stroke. This risk is related to plaque vulnerability and is characterized by plaque morphology, intraplaque neovascularization, and cerebral microembolization. Advanced neurosonology can identify vulnerable plaques and aid in preventing subsequent stroke. We aimed to assess the time course of cerebral microembolization and intraplaque neovascularization during 6 months of follow-up and to explore the utility of advanced neurosonology in patients with acute cerebral ischemia. Methods: Fifteen patients with acute cerebral ischemia and carotid artery plaques underwent comprehensive extra- and intracranial ultrasound examinations, including microemboli detection and contrast-enhanced ultrasound. The examinations were repeated after 3 and 6 months. Results: We examined 28 plaques in 15 patients. The ultrasonographic features of plaque vulnerability were frequent in symptomatic and asymptomatic plaques. There were no significant differences in stenosis degree, plaque composition, plaque surface, neovascularization, or cerebral microembolization between symptomatic and asymptomatic plaques, but symptomatic plaques had a higher number of vulnerable features. None of the patients had recurrent clinical stroke or transient ischemic attack during the follow-up period. We observed a decrease in cerebral microembolization at 6 months, but no significant change in intraplaque neovascularization. Conclusions: In patients with acute cerebral ischemia and carotid artery plaques, cerebral microembolization decreased during 6 months of follow-up, indicating plaque stabilization. Clinical Trial Registration:ClinicalTrial.gov, identifier NCT02759653.
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BACKGROUND AND PURPOSE: Microembolic signals (MES) are detectable by transcranial Doppler monitoring and associated with increased risk of first or recurrent ischemic stroke. MES detection can also illuminate stroke etiology and the effect of prophylactic treatment. MES detection cannot accurately distinguish between stroke-related microemboli and ultrasound contrast agents. These agents contain microbubbles and are frequently used in neuro- and cardiovascular diagnostics. We aimed to assess how long after contrast infusion microbubbles are detectable by transcranial Doppler monitoring. METHODS: Ten healthy volunteers received an intravenous infusion of stabilized sulfur hexafluoride microbubbles (SonoVue®) for 30 minutes. The infusion was followed by continuous unilateral Doppler monitoring (TCD-X, Atys Medical, Soucieu-en-Jarrest, France) for 3.5 hours. RESULTS: MES persisted for 12 to 77 minutes (median 40.5 minutes), and the frequency tended to decrease gradually until cessation. CONCLUSIONS: None of the subjects had detectable MES for more than 77 minutes after ultrasound contrast infusion. MES detection with the intent to detect stroke-related microemboli should wait for at least this long after completed infusion.
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Circulação Cerebrovascular/efeitos dos fármacos , Embolia Intracraniana/diagnóstico por imagem , Microbolhas , Fosfolipídeos/administração & dosagem , Hexafluoreto de Enxofre/administração & dosagem , Ultrassonografia Doppler Transcraniana , Adulto , Idoso , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Ultrassonografia DopplerRESUMO
Background and Purpose- Tenecteplase represents a promising alternative to alteplase as thrombolytic treatment in acute ischemic stroke. There are limited data on tenecteplase 0.4 mg/kg in patients with increased stroke severity. We aimed to assess safety and efficacy of tenecteplase 0.4 mg/kg in patients with moderate and severe ischemic stroke. Methods- NOR-TEST (Norwegian Tenecteplase Stroke Trial) was a phase III trial designed to investigate the safety and efficacy of tenecteplase 0.4 mg/kg versus alteplase 0.9 mg/kg in ischemic stroke. In this post hoc analysis, moderate stroke was defined as admission National Institutes of Health Stroke Scale; 6 to 14 and severe stroke as National Institutes of Health Stroke Scale; ≥15. Rates of favorable outcome at 90 days, symptomatic intracerebral hemorrhage (sICH), and mortality after 7 and 90 days were assessed. Results- In patients with moderate stroke (n=261), there were no differences in rates of favorable outcome, sICH, or mortality between tenecteplase and alteplase. In patients with severe stroke (n=87), there were no differences in outcome, frequency of sICH, or mortality at 7 days, but all-cause mortality at 90 days was increased in patients treated with tenecteplase (10 [26.3%] versus 4 [9.1%]; P=0.045). One patient died of sICH in the tenecteplase group, and 2 patients died of sICH in the alteplase group. Conclusions- Rates of favorable outcome and sICH were similar between treatment groups in patients with moderate and severe stroke. Mortality after 90 days was increased in patients with severe stroke receiving tenecteplase. Future studies assessing tenecteplase 0.4 mg/kg should monitor safety parameters closely in patients with severe stroke. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.
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Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Índice de Gravidade de Doença , Acidente Vascular Cerebral/tratamento farmacológico , Tenecteplase/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Método Simples-Cego , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: Stroke mimics are frequently treated with thrombolysis in clinical practice and thrombolytic trials. Although alteplase in stroke mimics has proven to be safe, safety of tenecteplase in stroke mimics has not been assessed in an ischemic stroke study setting. We aimed to assess clinical characteristics and safety of stroke mimics treated with thrombolysis in the Norwegian Tenecteplase Stroke Trial. We also aimed to identify possible predictors of stroke mimics as compared to patients with acute cerebral ischemia. METHODS: Norwegian Tenecteplase Stroke Trial was a phase-3 trial investigating safety and efficacy of tenecteplase vs. alteplase in patients with suspected acute cerebral ischemia. Two groups were defined based on diagnose at discharge: patients with a different diagnose than ischemic stroke or transient ischemic attack (stroke mimics group) and patients diagnosed with ischemic stroke or transient ischemic attack (acute cerebral ischemia group). Logistic regression analyses were performed with stroke mimics vs. acute cerebral ischemia as dependent variable to identify predictors of stroke mimics. RESULTS: Of 1091 randomized patients, 181 (16.6%) were stroke mimics. Migraine (22.2%) and peripheral vertigo (11.4%) were the two most frequent stroke mimic-diagnoses. There was no symptomatic intracerebral hemorrhage in the stroke mimics group. Stroke mimics were independently associated with age ≤60 years (OR 2.75, p < 0.001), female sex (OR 1.48, p = 0.026), no history of myocardial infarction (OR 2.03, p = 0.045), systolic BP ≤ 150 mmHg (OR 2.33, p < 0.001), NIHSS ≤ 6 points (OR 1.83, p = 0.011), sensory loss (OR 1.55, p = 0.015), and no facial paresis (OR 2.41, p < 0.001) on admission. CONCLUSION: Thrombolysis with tenecteplase seems to be as safe as with alteplase in stroke mimics. Predictors were identified for stroke mimics which may contribute to differentiate stroke mimics from acute cerebral ischemia in future stroke trials.
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Erros de Diagnóstico/efeitos adversos , Erros de Diagnóstico/estatística & dados numéricos , Acidente Vascular Cerebral/diagnóstico , Tenecteplase/efeitos adversos , Fatores Etários , Idoso , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/tratamento farmacológico , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
Introduction: It has been difficult to state specific guidelines for IV-tPA use in cancer patients. Many of the randomized tPA-trials included too few patients with cancer or excluded patients with cancer entirely. In this report, we aimed to study the use of IV-tPA in patients with active cancer and acute ischemic stroke. We also investigated if the cancer patients who received IV-tPA experienced adverse events. Methods: All patients with ischemic stroke admitted to the Stroke Unit at Haukeland University Hospital were prospectively registered in the NORSTROKE database and every patient's medical record was searched for cancer diagnoses. Results: Of 1,646 patients admitted with ischemic stroke, 82 (5.0%) patients had active cancer. The total number of patients treated with IV-tPA was 16.2%. Five patients with stroke and active cancer were treated with IV-tPA (6.1%) and none suffered adverse events. Of the patients with no history of cancer, 261 (16.7%) were treated with IV-tPA and 3.8% experienced tPA-related adverse events. Conclusions: Few patients with active cancer receive thrombolysis for acute ischemic stroke. We report five cancer patients (three known and two occult) treated with IV-tPA for ischemic stroke without tPA-related adverse events.
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BACKGROUND AND PURPOSE: Ischemic stroke can be the first manifestation of cancer and it is therefore important to ascertain which stroke patients should be considered for cancer-diagnostic investigations. We aimed to determine the frequency of active cancer in patients with acute ischemic stroke and to compare clinical findings in stroke patients with active cancer to ischemic stroke patients with no history of cancer. Finally, we aimed to develop a predictive and feasible score for clinical use to uncover underlying malignancy. METHODS: All ischemic stroke patients admitted to the stroke unit in the Department of Neurology, Haukeland University Hospital were consecutively included in the Norwegian Stroke Research Registry (NORSTROKE). Stroke etiology was determined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Data on cancer diagnoses was obtained from patients' medical records and the Cancer Registry of Norway. Active cancer was defined as cancer diagnosis, metastasis of known cancer, recurrent cancer or receiving cancer treatment, all within 12 months before or after the index stroke. Based on variables independently associated with active cancer, a predictive score was developed using the area under the receiver operating characteristic (AUC-ROC) curves. Bayes' theorem was used to calculate post-test probabilities of active cancer. RESULTS: Of the 1,646 ischemic stroke patients included, 82 (5.0%) had active cancer. Increased D-dimer (OR = 1.1, 95% CI: 1.1-1.2, p = <0.001), lower Hb (OR = 0.6, 95% CI: 0.5-0.7, p = <0.001), smoking (OR = 2.2, 95% CI: 1.2-4.3, p = 0.02) and suffering a stroke of undetermined etiology (OR = 1.9, 95% CI: 1.1-3.3, p = 0.03) were factors independently associated with active cancer. These were included in the final predictive score which gave an AUC of 0.73 (95% CI: 0.65-0.81) in patients younger than 75 years of age. Assuming the prevalence of cancer to be 5%, the score shows that if a patient fulfills all 3 score points, the probability of active cancer is 53%. CONCLUSIONS: Active cancer was found in 5% of our ischemic stroke patients. We found that a clinical score comprising elevated D-dimer ≥3 mg/L, lower Hb ≤12.0 g/dL and previous or current smoking is feasible for predicting active cancer in ischemic stroke patients.
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Isquemia Encefálica/diagnóstico , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Neoplasias/diagnóstico , Acidente Vascular Cerebral/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Isquemia Encefálica/epidemiologia , Estudos de Viabilidade , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/epidemiologia , Noruega/epidemiologia , Valor Preditivo dos Testes , Prevalência , Prognóstico , Sistema de Registros , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: A hypertensive response after ischemic stroke is frequent, yet its pathophysiology is unknown. Mechanisms related to local ischemic damage, major vascular occlusion, and psychological stress due to acute illness have been proposed. We assessed the natural course of blood pressure (BP) within the first 24 h in groups of ischemic stroke patients with different characteristics. We hypothesized that a consistent BP reduction, regardless of stroke location, time window from debut to admission and presence of persistent vascular occlusion, would favor a stress-related mechanism as an important cause of the hypertensive response after ischemic stroke. METHODS: Ischemic stroke patients (n=1067) were prospectively registered, and BP was measured on admission and <3 h, 3-6 h, 6-12 h and 12-24 h after admission. Patients were categorized according to the location of diffusion-weighted imaging (DWI) lesions (cortical, large subcortical, mixed cortico-subcortical, lacunar, cerebellar, brain stem or multiple), time window (admitted within or after 6 h of symptom onset) and presence of persistent proximal middle cerebral artery (MCA) occlusion versus normal findings on magnetic resonance angiography (MRA) at 24 h. RESULTS: A reduction in systolic BP and diastolic BP from baseline to 12-24 h was found across all DWI locations except for diastolic BP in cerebellar (P=0.072) lesions. Apart from diastolic BP in patients with normal MRA findings at 24 h (P=0.060), a significant fall in systolic BP and diastolic BP at 12-24 h was registered, irrespective of whether patients were admitted within 6 h or after 6 h of stroke onset or had persistent MCA occlusion versus normal MRA findings. CONCLUSION: We found a relatively consistent decline in BP within 24 h after admission across different stroke locations in patients admitted within or after 6 h of stroke onset and in patients with persistent MCA occlusion. Our findings suggest that a systemic factor such as psychological stress may be an important contributor to the frequently elevated BP on admission in patients with ischemic stroke.
Assuntos
Pressão Sanguínea , Isquemia Encefálica/complicações , Hipertensão/etiologia , Estresse Psicológico/complicações , Acidente Vascular Cerebral/complicações , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Estresse Psicológico/diagnóstico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Positive family history (FH+) of cardiovascular disease (CVD) is a risk factor for own CVD. We aimed to analyze the effect of different types of FH (stroke, coronary heart disease (CHD), peripheral artery disease (PAD) on carotid intima-media thickness (cIMT) in young and middle-aged ischemic stroke patients. METHODS: First-degree FH of CVD was assessed in ischemic stroke patients ≤ 60y using a standardized interview. Carotid ultrasound was performed and far wall cIMT in three carotid artery segments was registered, representing the common carotid (CCA-IMT), carotid bifurcation (BIF-IMT) and the internal carotid artery (ICA-IMT). Measurements were compared between FH+ and FH negative groups and stepwise backward regression analyses were performed to identify factors associated with increased cIMT. RESULTS: During the study period 382 patients were enrolled, of which 262 (68%) were males and 233 (61%) reported FH of CVD. Regression analyses adjusting for risk factors revealed age as the most important predictor of cIMT in all segments. The association between FH+ and cIMT was modified by age (p = 0.014) and was significant only regarding ICA-IMT. FH+ was associated with increased ICA-IMT in patients aged < 45y (p = 0.001), but not in patients ≥ 45y (p = 0.083). The association with ICA-IMT was present for a FH of stroke (p = 0.034), but not a FH+ of CHD or PAD. CONCLUSIONS: FH of stroke is associated with higher ICA-IMT in young ischemic stroke patients. Subtyping of cardiovascular FH is important to investigate heredity in young ischemic stroke patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01597453.