Unselected brain imaging in suspected meningitis delays lumbar puncture, can prolong hospitalisation and may increase antibiotic costs - a pilot study

Background: Antibiotics reduce mortality in bacterial meningitis; a lumbar puncture (LP) will demonstrate that many patients with suspected meningitis do not need them; but delays reduce chances of culture, particularly if N8 h. Guidelines advise a LP without brain imaging unless specific features are present. Objective: We assessed the duration of hospitalisation and inpatient costs incurred with delays in LP in a Northwest of England teaching hospital. Methods: We screened the cerebrospinal fluid (CSF) database to identify patients with suspected meningitis over 3 months (07–09/ 2010). Data were recorded from clinical case notes; costs were calculated with established datasets and the British national formulary. Results: 142 patients were screened; 35 had a suspected CNS infection; 10 had a CNS infection proven: 3 bacterial meningitis; 4 aseptic meningitis and 3 viral encephalitis. Brain imaging delayed the LP for 19 (54%), (11.08 vs 5.29 hrs, p= 0.10); ten (53%) did not need imaging. 11 (42%) of those given antibiotics before the LP were delayed N8 h. For patients with aseptic meningitis and those who had a CNS infection excluded, without prior antibiotics, the delay in LP increased duration of hospitalisation (r=0.94, p=0.02 and r=0.96, p=0.01 respectively). Overall there was no trend with LP delays and antibiotic cost. However, 4 patients had antibiotics continued despite negative cultures; 2 of whom had the LP delayed N8 h, with an antibiotic cost of £215.96. Conclusion: Inappropriate brain imaging often delayed the LP; in patients who did not need antibiotics this led to longer hospitalisation

Dosimetric verification of brain and head and neck intensity-modulated radiation therapy treatment using EDR2 films and 2D ion chamber array matrix

Background: The evaluation of the agreement between measured and calculated dose plays an essential role in the quality assurance (QA) procedures of intensity-modulated radiation therapy (IMRT). Aim: The purpose of this study is to compare performances of the two dosimetric systems (EDR2 and I\u2032matriXX) in the verification of the dose distributions calculated by the TPS for brain and head and neck dynamic IMRT cases. Materials and Methods: The comparison of cumulative fluence by using Kodak extended dose rate (EDR2) and I\u2032matriXX detectors has been done for the evaluation of 10 brain, 10 head and neck IMRT cases treated with 6 MV beams. The parameter used to assess the quality of dose calculation is the gamma-index (g -index) method. The acceptance limits for g calculation we have used are 3% and 3 mm respectively for dose agreement and distance to agreement parameters. Statistical analyses were performed by using the paired, two-tailed Student t-test, and P< 0.01 is kept as a threshold for the significance level. Results: The qualitative dose distribution comparison was performed using composite dose distribution in the measurement plane and profiles along various axes for TPS vs. EDR2 film and TPS Vs I\u2032matriXX. The quantitative analysis between the calculated and measured dose distribution was evaluated using DTA and g-index. The percentage of pixels matching with the set DTA and g values are comparable for both with EDR2 film and I\u2032matriXX array detectors. Statistically there was no significant variation observed between EDR2 film and I\u2032matriXX in terms of the mean percentage of pixel passing g for brain cases (98.77 \ub1 1.03 vs 97.62 \ub1 1.66, P = 0.0218) and for head and neck cases (97.39 \ub1 2.13 vs 97.17 \ub1 1.52%, P = 0.7404). Conclusion: Due to simplicity and fast evaluation process of array detectors, it can be routinely used in busy departments without compromising the measurement accuracy

Physical activity monitoring to assess disability progression in multiple sclerosis

Background: Clinical outcome measurement in multiple sclerosis (MS) usually requires a physical visit. Remote activity monitoring (RAM) using wearable technology provides a rational alternative, especially desirable when distance is involved or in a pandemic setting. Objective: To validate RAM in progressive MS using (1) traditional psychometric methods (2) brain atrophy. Methods: 56 people with progressive MS participated in a longitudinal study over 2.5 years. An arm-worn RAM device measured activity over six days, every six months, and incorporated triaxial accelerometry and transcutaneous physiological variable measurement. Five RAM variables were assessed: physical activity duration, step count, active energy expenditure, metabolic equivalents and a composite RAM score incorporating all four variables. Other assessments every six months included EDSS, MSFC, MSIS-29, Chalder Fatigue Scale and Beck’s Depression Inventory. Annualized brain atrophy was measured using SIENA. Results: RAM was tolerated well by people with MS; the device was worn 99.4% of the time. RAM had good convergent and divergent validity and was responsive, especially with respect to step count. Measurement of physical activity over one day was as responsive as six days. The composite RAM score positively correlated with brain volume loss. Conclusion: Remote activity monitoring is a valid and acceptable outcome measure in MS

UK-Wide Surveillance of Neurological and Neuropsychiatric Complications of COVID-19: The First 153 Patients

Background: Increasingly neurological complications of COVID-19 are identified, mostly in small series. Larger studies have been limited by both geography and specialty. Consequently, the breadth of complications is not represented. Comprehensive characterization of clinical syndromes is critical to rationally select and evaluate potential therapies. / Methods: During the exponential pandemic phase, we developed coordinated online portals for rapid notification across the spectrum of major UK neuroscience bodies, representing neurology, stroke, psychiatry, and intensive care. Evidence of infection and clinical case definitions were applied prospectively. Cases were compared to overall Government Public Health COVID-19 reporting. / Findings: Within three weeks, 153 cases were notified, both geographically and temporally representative of overall COVID-19 Public Health reports. Median (range) age was 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes, nine (12%) intracerebral hemorrhages, and one CNS vasculitis. The second most common group were 39 (31%) who had altered mental status, including 16 (41%) with encephalopathy of whom seven (44%) had encephalitis. The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses; including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4 (17%) an affective disorder. Cerebrovascular events predominated in older patients. Conversely, altered mental status, whilst present in all ages, had disproportionate representation in the young. / Interpretation: This is the first nationwide, cross-specialty surveillance study of acute complications of COVID-19 in the nervous system. Alteration in mental status was common, reflecting encephalopathy/encephalitis and primary psychiatric diagnoses, often in young patients. These data provide valuable and timely information urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy throughout the areas of neurology and neuropsychiatry

UK-Wide Surveillance of Neurological and Neuropsychiatric Complications of COVID-19: The First 153 Patients

Background: Increasingly neurological complications of COVID-19 are identified, mostly in small series. Larger studies have been limited by both geography and specialty.Consequently, the breadth of complications is not represented. Comprehensive characterization of clinical syndromes is critical to rationally select and evaluate potential therapies.Methods: During the exponential pandemic phase, we developed coordinated online portals for rapid notification across the spectrum of major UK neuroscience bodies, representing neurology, stroke, psychiatry, and intensive care. Evidence of infection and clinical case definitions were applied prospectively. Cases were compared to overall Government Public Health COVID-19 reporting.Findings: Within three weeks, 153 cases were notified, both geographically and temporally representative of overall COVID-19 Public Health reports. Median (range) age was 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes, nine (12%) intracerebral hemorrhages, and one CNS vasculitis.The second most common group were 39 (31%) who had altered mental status, including 16 (41%) with encephalopathy of whom seven (44%) had encephalitis. The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses; including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4 (17%) an affective disorder. Cerebrovascular events predominated in older patients. Conversely, altered mental status, whilst present in all ages, had disproportionate representation in the young.Interpretation: This is the first nationwide, cross-specialty surveillance study of acute complications of COVID-19 in the nervous system. Alteration in mental status was common, reflecting encephalopathy/encephalitis and primary psychiatric diagnoses, often in young patients.These data provide valuable and timely information urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy throughout the areas of neurology and neuropsychiatry

Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients 60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials

Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study.

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients 60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials

Complement in the pathogenesis of Alzheimer's disease

The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer’s disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer’s disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain

The restorative role of annexin A1 at the blood–brain barrier

Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS vasculature, and its potential for repairing blood–brain barrier damage in disease and aging

Association of peripheral interleukin-6 with global cognitive decline in non-demented adults: a meta-analysis of prospective studies

Background: Elevated biomarkers of systemic inflammation have been reported in individuals with cognitive decline, however, most of the literature concerns cross-sectional analyses that have produced mixed results. This study investigates the aetiology of this association by performing meta-analyses on prospective studies investigating the relationship between baseline interleukin-6 (IL-6), an established marker of peripheral inflammation, with cognitive decline risk in non-demented adults at follow-up. Methods: We reviewed studies reporting peripheral IL-6 with future cognitive decline, up to February 2017 by searching the PubMed, Science Direct, Scopus and Google Scholar databases. Studies which contained odds ratios (ORs) for the association between circulating baseline IL-6 and longitudinal cognitive performance in non-demented community dwelling older adults were pooled in random-effects models. Results: The literature search retrieved 5,642 potential articles, of which 7 articles containing 8 independent ageing cohorts were eligible for review. Collectively, these studies included 15,828 participants at baseline. Those with high circulating IL-6 were 1.42 times more likely to experience global cognitive decline at follow-up, over a 2 – 7-year period, compared to those with low IL-6 (OR 1.42, 95% CI 1.18 – 1.70; p < 0.001). Subgroup and sensitivity analyses suggests that this association is independent of the study sample size, duration of follow-up and cognitive assessments used. Conclusions: These results add further evidence for the association between high peripheral inflammation, as measured by blood IL-6, and global cognitive decline. Measuring circulating IL-6 may be a useful indication for future cognitive health