Abstract
Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from ...patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) 14 800 pg/ml (400, 32 400), compared to those with encephalopathy 1410 pg/ml (756, 1446), peripheral syndromes (Guillain–Barré syndrome) 740 pg/ml (507, 881) and controls 872 pg/ml (654, 1200). Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.
Paterson, Benjamin et al. report elevation of CSF neurofilament light (NfL), reflecting CNS damage, in some but not all SARS-CoV-2 associated neurological syndromes. Increased NfL concentration was a common finding in hospitalized patients with COVID-19, likely predominantly reflecting peripheral neuronal damage. Non-hospitalized individuals did not have elevated NfL.
Graphical Abstract
Graphical Abstract
Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are ...typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range IQR, 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 IQR, 4-18 versus 6 IQR, 3-14), P=0.03; (odds ratio, 1.69 95% CI, 1.08-2.65 for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 IQR, 2-6 versus 2 IQR, 1-4, P<0.001) and death (odds ratio, 4.3 95% CI, 2.22-8.30) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.
Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is ...undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-intensity direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation.
The Rivaroxaban for Stroke patients with APS trial seeks to determine whether high-intensity rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations.
This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, with target international normalized ratio range of 3.0 to 4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-intensity rivaroxaban pharmacokinetic modeling.
Should Rivaroxaban for Stroke patients with APS trial demonstrate noninferior efficacy and safety of high-intensity rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.
Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and ...inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.
Background Fast medical assessment is essential after TIA and stroke. Several countries have had out public education campaigns to increase symptom recognition and reduce delays in seeking medical ...attention. However, since campaigns tend to focus on symptoms and signs of major stroke, individuals with TIA or minor stroke might be falsely reassured. Methods We determined patient perception and behaviour after TIA, minor stroke (NIHSS≤5) and major stroke in the community from 2002 to 2012 in a population based study (Oxford Vascular Study) before and after the 2009 FAST (Face-Arm-Speech-Time) media campaign. Results Among 2251 consecutive patients (817 TIA, 968 minor stroke, 466 major stroke), those with major stroke were slightly more likely to correctly diagnose their symptoms after the FAST campaign (52.4% vs. 43.0%, OR 1.5 0.7–3.0, p=0.30) and to present directly to emergency services (OR 2.6 1.6–4.2, p<0.001), with an improvement in time to calling help in the early hours following symptom onset (log-rank test, p=0.02). Amongst patients with TIA or minor stroke, those who correctly diagnosed their symptoms sought medical attention more quickly (median delay IQR in hours–2.5 0.5–18.3 vs. 7.0 1.0–41.0, p<0.001), but correct self-diagnosis declined after the FAST campaign from 38.4% to 29.6% (OR 0.67, 0.53–0.85, p=0.001), although delay in seeking medical attention was unchanged (log-rank test, p=0.82). Correct self-diagnosis was still lowest for TIA and stroke with non-FAST symptoms, particularly isolated visual symptoms (11.4%) and isolated vertigo (15.6%). Conclusion The U.K. FAST campaign appears to have improved recognition and behaviour after major stroke, but symptom recognition remains poor in TIA and minor stroke and may have been adversely affected. Public education campaigns should consider potential unintended consequences of focussing only on FAST-test symptoms and on major stroke.
FEVER AND CONFUSION IN A RETURNING SOLDIER Chandratheva, Arvind; Singh, Anil Ramlackhan; Sturman, Steve ...
Journal of neurology, neurosurgery and psychiatry,
11/2013, Letnik:
84, Številka:
11
Journal Article
Recenzirano
A 36–year–old army engineer returned from a 6–week deployment in Afghanistan. He had complained of upper respiratory tract infection even before his travel. On return he was found to be increasingly ...sleepy and later developed unsteadiness, slurred speech and confusion. His initial blood tests were normal, with CSF and MRI suggesting signs of encephalitis. He continued to deteriorate, requiring intubation and ventilation. Several bacterial, viral, protozoal and fungal tests were negative. He developed pancytopenia requiring frequent packed red cell and platelet transfusions. Spleen was found to be marginally enlarged. A bone marrow examination showed hyperplastic left shift pattern with marked granulocyte, red cell and megakaryocyte precursor activity. At this stage his EBV DNA was found to be strongly positive, with over a million copies identified in the blood. EBV was also isolated from the CSF. His pancytopenia continued to worsen, with worsening neuroinflammation on MR imaging. The ferritin level was very high at 14000 mcg/L, with low fibrinogen and raised soluble CD25. A diagnosis of haemophagocytic lymphohistiocystosis (HLH) was made as per established criteria. He was treated with multiple chemotherapeutic agents including Etoposide, Cyclosporine, Rituximab and Dexamethasone initially. After an initial good response, the HLH relapsed, and second line therapy including Alemtuzumab (Campath) and intrathecal methotrexate was added with a view of definitive treatment, which is allogenic bone marrow transplantation. Haemophagocytic lymphohistiocytosis is a rare and life–threatening immune dysregulation syndrome predominantly affecting infants and children. HLH typically presents with prolonged febrile illness, pancytopenia, organomegaly and neurological symptoms. Perforin–dependent lymphocytic cytotoxic function seems to be impaired in the majority of patients, although perforin levels and other genetic susceptibility markers (Eg: XLP1, XLP2, ITK) were normal in this patient, suggesting an immune trigger. Secondary HLH occurs in response to infections, malignancy or autoimmune diseases. The common infectious agents known to cause HLH includes EBV, CMV, HHV8, HIV, Mycobacteria, mycoplasma, leishmania, plasmodium and Cryptococcus. Neoplastic triggers include leukemias and lymphomas, particularly T–cell lymphoma. Exact pathophysiology of secondary HLH is less well understood than in the genetic subtypes. Neurological symptoms including altered consciousness, seizures, meningism and ataxia may be seen in approximately 30% of patients and carries a poorer prognosis. Laboratory findings supporting the diagnosis in addition to the pancytopenia are very high ferritin levels (more than 10000 mcg/L), hypofibrinogenemia, hypertriglyceridemia, elevated liver enzymes, low albumin, elevated soluble CD25 levels and reduced NK cell cytotoxicity. Treatment is aimed at suppressing the hyperinflammatory component of the condition, using steroids, cyclosporine, etoposide, intrathecal methotrexate and alemtuzumab. EBV–triggered HLH often require concomitant Rituximab therapy. Once remission is achieved, haematopoietic stem cell transplantation is recommended. Despite the advances in therapy unfortunately HLH is fatal in 40–60% of patients. Neurologists should be aware of rare, but potentially treatable haematological conditions which can manifest with pure neurological symptoms. HLH is almost invariably a fatal disease if not diagnosed and treated early.
Abstract The risk of thrombolysis in patients taking novel anticoagulants remains unclear. We describe a patient with a large acute ischaemic stroke, who had a low calibrated anti-factor Xa level, ...who safely received thrombolysis 15–17 hours after standard dose rivaroxaban without subsequent intracerebral haemorrhage.
Background and Purpose— The ABCD 2 score predicts the early risk of stroke after transient ischemic attack (TIA). However, data on the severity of recurrent events would also be useful. Do patients ...with high scores also have more severe early recurrent strokes, perhaps further justifying hospital admission? Do patients with low scores have a low early risk of recurrent TIA as well as recurrent stroke? Methods— We completed a prospective, population-based study in Oxfordshire, England, of 500 consecutive patients presenting with TIA from April 1, 2002, by using multiple methods of case ascertainment (Oxford Vascular Study). Recurrent TIA, minor stroke, and major stroke (National Institutes of Health Stroke Scale score >3 at the time of first assessment) were identified by face-to-face follow-up. Predictive value was expressed as the area under the receiver operating characteristic curve. Results— Of 500 patients with TIA, 55 had a recurrent TIA (11.0%; 95% CI, 8.3% to 13.7%) and 50 had a recurrent stroke (10.0%; 95% CI, 7.5% to 12.0%) within 7 days. The ABCD 2 score was highly predictive of major recurrent stroke (area under the receiver operating characteristic curve=0.80; 95% CI, 0.72 to 0.87, P <0.0001), weakly predictive of minor stroke (area under the receiver operating characteristic curve=0.57; 95% CI, 0.43 to 0.71, P =0.26), and inversely related to risk of recurrent TIA (area under the receiver operating characteristic curve=0.37; 95% CI, 0.29 to 0.44, P =0.001) (overall heterogeneity, P <0.0001). The score predicted stroke-related disability, length of stay for recurrent stroke, and hence, overall acute hospital care costs. Conclusions— The ABCD 2 score predicts severity of recurrent events after TIA, high scores being associated with major recurrent stroke and low scores with high rates of recurrent TIA. These findings have implications for cost-benefit analyses of policies on hospital admission for patients with high scores and for the advice given to patients with low scores.
The ABCD(2) score predicts the early risk of stroke after transient ischemic attack (TIA). However, data on the severity of recurrent events would also be useful. Do patients with high scores also ...have more severe early recurrent strokes, perhaps further justifying hospital admission? Do patients with low scores have a low early risk of recurrent TIA as well as recurrent stroke?
We completed a prospective, population-based study in Oxfordshire, England, of 500 consecutive patients presenting with TIA from April 1, 2002, by using multiple methods of case ascertainment (Oxford Vascular Study). Recurrent TIA, minor stroke, and major stroke (National Institutes of Health Stroke Scale score >3 at the time of first assessment) were identified by face-to-face follow-up. Predictive value was expressed as the area under the receiver operating characteristic curve.
Of 500 patients with TIA, 55 had a recurrent TIA (11.0%; 95% CI, 8.3% to 13.7%) and 50 had a recurrent stroke (10.0%; 95% CI, 7.5% to 12.0%) within 7 days. The ABCD(2) score was highly predictive of major recurrent stroke (area under the receiver operating characteristic curve=0.80; 95% CI, 0.72 to 0.87, P<0.0001), weakly predictive of minor stroke (area under the receiver operating characteristic curve=0.57; 95% CI, 0.43 to 0.71, P=0.26), and inversely related to risk of recurrent TIA (area under the receiver operating characteristic curve=0.37; 95% CI, 0.29 to 0.44, P=0.001) (overall heterogeneity, P<0.0001). The score predicted stroke-related disability, length of stay for recurrent stroke, and hence, overall acute hospital care costs.
The ABCD(2) score predicts severity of recurrent events after TIA, high scores being associated with major recurrent stroke and low scores with high rates of recurrent TIA. These findings have implications for cost-benefit analyses of policies on hospital admission for patients with high scores and for the advice given to patients with low scores.
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