Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis.

BackgroundNeurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome.MethodsWe conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models.ResultsWe included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region.InterpretationNeurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission

Improving the effectiveness of secondary prevention in patients with minor stroke and transient ischaemic attack

Stroke is the second leading cause of death worldwide, accounting for about 9% of all deaths. It is the leading cause of neurological disability and in developed countries accounts for more than 4% of direct health care expenditure. The burden of stroke is predicted to increase during the next 20 years because of the ageing population. Whilst effective primary prevention is essential about 30% of strokes occur in individuals with a previous transient ischaemic attack: (TIA) or stroke. Recent prospective studies have shown high early risk of recurrent stroke in the days after TIA or minor stroke. Accurate identification and early treatment of these high risk patients is likely to have substantial benefits for stroke prevention. In this thesis, I aimed to study risk of recurrent stroke after TIA in the hyper-acute phase and the role of current clinical scoring systems for use in the hyperacute phase after TIA, in minor stroke, in posterior circulation TIAs and also for predicting the severity of recurrent events. I have also studied patient behaviour immediately after TIA and minor stroke to determine factors associated with delays to calling for medical attention. I have used data from a large population based study; the Oxford Vascular Study (OXVASC). OXVASC is a prospective, population-based incidence study of vascular disease in all territories in Oxfordshire, UK, which started in 2002 and is ongoing. The study population comprises all 91,106 individuals registered with nine general practices and uses multiple overlapping methods of "hot" and ' cold" pursuit to identify all patients with acute vascular events. The research described in this thesis has resulted in several clinically useful findings. Firstly, I have shown that about half of all recurrent strokes during the seven days after a TIA occur in the first 24 hours, with 6-h, 12-h and 24-h stroke risks of 1.2%, 2.1 % and 5.1 % respectively, and that the 24 hour risk was strongly related to the ABC02 score highlighting this as a reliable risk prediction tool in the hyperacute phase. Second ly, I showed that the ABC02 score was highly predictive of major recurrent stroke and inversely related to risk of recurrent TIA. These findings have implications for policies on hospital admission in patients with high scores and for the advice given to patients with low scores. Thirdly, I demonstrated that the predictive power of the ABC02 score is relatively modest in patients with minor stroke, and neither the Essen Stroke Risk Score (ESRS) nor the Stroke Prognostic Indicator II (SPI-II) predict 9O-day recurrence. Fourthly, I was able to show that the risk of stroke was as high after posterior circulation TIA as carotid TIA and that the ABC02 score was predictive in those patients presenting with posterior circulation TIA. Fifthly, I contributed to a study that showed that in patients presenting with TIA or minor stroke irrespective of age, early initiation of existing treatments in those referred to a daily clinic was associated with an 80% reduction in early recurrent strokes. Finally, I highlighted that about 70% of patients do not correctly recognise their TIA or minor stroke and about 30% delay seeking medical attention for over 24 hours. Higher risk patients lend to contact health services most quickly, but 30% of early recurrent strokes still occur prior to any attempt to do so. iiEThOS - Electronic Theses Online ServiceGBUnited Kingdo

Acute Stroke Treatment in an Anticoagulated Patient: When Is Thrombolysis an Option?

Purpose of Review: Direct oral anticoagulants (DOACs: the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran) are the mainstay of stroke prevention in patients with non-valvular atrial fibrillation (AF). Nevertheless, there is a residual stroke risk of 1–2% per year despite DOAC therapy. Intravenous thrombolysis (IVT) reduces morbidity in patients with ischemic stroke and improves functional outcome. Prior DOAC therapy is a (relative) contraindication for IVT but emerging evidence supports its use in selected patients. // Recent Findings: Recent observational studies highlighted that IVT in patients on prior DOAC therapy seems feasible and did not yield major safety issues. Different selection criteria and approaches have been studied including selection by DOAC plasma levels, non-specific coagulation assays, time since last intake, and prior reversal agent use. The optimal selection process is however not clear and most studies comprised few patients. // Summary: IVT in patients taking DOAC is a clinically challenging scenario. Several approaches have been proposed without major safety issues but current evidence is weak. A patient-oriented approach balancing potential benefits of IVT (i.e., amount of salvageable penumbra) against expected bleeding risk including appropriate monitoring of anticoagulant activity seem justified

Cerebral amyloid angiopathy-related inflammation: a rare but important cause of acute confusion on the general medical take

Cerebral amyloid angiopathy is a common small vessel disease caused by abnormal protein deposition within cerebral blood vessels. In the last 20 years, improved diagnostics have implicated cerebral amyloid angiopathy in the pathophysiology of intracerebral haemorrhage. Cerebral amyloid angiopathy is relevant to general medical doctors, as it can cause transient focal neurological episodes (‘amyloid spells’) which mimic seizures and transient ischaemic attacks; it also has a significant bearing on anticoagulation decisions. With the ageing population, general medics are more likely to encounter patients with cerebral amyloid angiopathy. This case highlights an important cause of confusion related to cerebral amyloid angiopathy in an older adult presenting on the general medical take

Lactate and glucose as energy substrates during, and after, oxygen deprivation in rat hippocampal acute and cultured slices

The effects of raised brain lactate levels on neuronal survival following hypoxia or ischemia is still a source of controversy among basic and clinical scientists. We have sought to address this controversy by studying the effects of glucose and lactate on neuronal survival in acute and cultured hippocampal slices. Following a 1-h hypoxic episode, neuronal survival in cultured hippocampal slices was significantly higher if glucose was present in the medium compared with lactate. However, when the energy substrate during the hypoxic period was glucose and then switched to lactate during the normoxic recovery period, the level of cell damage in the CA1 region of organotypic cultures was significantly improved from 64.3 +/- 2.1 to 74.6 +/- 2.1% compared with cultures receiving glucose during and after hypoxia. Extracellular field potentials recorded from the CA1 region of acute slices were abolished during oxygen deprivation for 20 min, but recovered almost fully to baseline levels with either glucose (82.6 +/- 10.0%) or lactate present in the reperfusion medium (108.1 +/- 8.3%). These results suggest that lactate alone cannot support neuronal survival during oxygen deprivation, but a combination of glucose followed by lactate provides for better neuroprotection than either substrate alone

Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study

Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG. Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2. Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management. Funding: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study

BackgroundA new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes.MethodsFor this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3–6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis.FindingsBetween April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients (two, 2–3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022).InterpretationCerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate