Defining causality in COVID-19 and neurological disorders.

When faced with acute neurological presentations in a patient with COVID-19, how confident can one be that SARS-CoV2 is causal

COVID-19 Encephalitis with SARS-CoV-2 Detected in Cerebrospinal Fluid Presenting as a Stroke Mimic

We report the case of a 35-year-old male with COVID-19 encephalitis presenting as a stroke mimic with sudden-onset expressive and receptive dysphasia, mild confusion and right arm incoordination. The patient received thrombolysis for a suspected ischaemic stroke, but later became febrile and SARS-CoV-2 was detected in cerebrospinal fluid. Electroencephalography demonstrated excess in slow waves, but neuroimaging was reported as normal. Respiratory symptoms were absent throughout and nasopharyngeal swab was negative for SARS-CoV-2. At the most recent follow-up, the patient had made a full neurological recovery. Clinicians should therefore consider testing for SARS-CoV-2 in CSF in patients who present with acute focal neurology, confusion and fever during the pandemic, even when there is no evidence of respiratory infection

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

The blood-brain barrier in systemic inflammation

The blood-brain barrier (BBB) plays a key role in maintaining the specialized microenvironment of the central nervous system (CNS), and enabling communication with the systemic compartment. BBB changes occur in several CNS pathologies. Here, we review disruptive and non-disruptive BBB changes in systemic infections and other forms of systemic inflammation, and how this may affect CNS function in health and disease. We first describe the structure and function of the BBB, and outline the techniques used to study the BBB in vitro, and in animal and human settings. We then summarise the evidence from a range of models linking BBB changes with systemic inflammation, and the underlying mechanisms. The clinical relevance of these BBB changes during systemic inflammation are discussed in the context of clinically-apparent syndromes such as sickness behaviour, delirium, and septic encephalopathy, as well as neurological conditions such as Alzheimer’s disease and multiple sclerosis. We review emerging evidence for two novel concepts: (1) a heightened sensitivity of the diseased, versus healthy, BBB to systemic inflammation, and (2) the contribution of BBB changes induced by systemic inflammation to progression of the primary disease process

Encephalitis in the clinical spectrum of dengue infection

Dengue viral infections are common worldwide. Clinical manifestations form a broad spectrum, and include uncomplicated dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Encephalopathy has been well reported and has classically been thought to result from the multisystem derangement that occurs in severe dengue infection; with liver failure, shock, and coagulopathy causing cerebral insult. However, there is increasing evidence for dengue viral neurotropism, suggesting that, in a proportion of cases, there may be an element of direct viral encephalitis. Understanding the pathophysiology of dengue encephalopathy is crucial toward developing a more effective management strategy. This review provides an overview of the clinical spectrum of dengue infection, and examines evidence supporting the existence of dengue encephalitis

Systemic infections in Multiple Sclerosis

Infections outside the brain can affect the brain. These ‘systemic infections’ are very common and occur much more frequently than infections inside the brain itself. Despite the existence of a blood-brain barrier (BBB), the systemic immune system does communicate with the brain. In people with a neurological disease, such as multiple sclerosis (MS), the effect of systemic infections on the brain can be magnified, and harmful. In the SIMS study (Systemic Infections in MS), 53 people with progressive MS were followed up for an average of two and a half years. In that time, over half of the group experienced progression in their level of disability. Systemic inflammatory episodes were common, occurring on average more than 3 times per year, most commonly infections. People with a high systemic inflammatory response, measured by urinary neopterin, experienced significantly faster brain atrophy than those people with a low response, and had nearly 10 times the chance of developing significant brain atrophy. This effect was particularly marked in those people with a high level of disability to start with.People with MS have a leaky BBB. It may be that the BBB is disrupted during an inflammatory episode, and that this leads to disease progression. If this is the mechanism, then repairing or protecting the BBB may be a therapeutic target in MS. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to study the BBB in humans and test this hypothesis. In a series of experiments, a protocol for DCE-MRI was devised, refined, and tested. It was found that the marker of BBB permeability derived from DCE-MRI, Ki, behaves as expected, and that measurement variability could be significantly improved with a series of optimisations.In the SIBIMS study (Systemic Infections and the BBB in MS), BBB permeability was measured using DCE-MRI in 12 individuals during a urinary tract infection (UTI) and again once fully recovered. There was strong evidence for an effect of UTI on the brain, with significant increases in symptoms. There was also modest evidence for BBB disruption during UTI, with a 53% increase in Ki during infection.This thesis demonstrates two main points. Firstly, that DCE-MRI can be used to study the human BBB in health and disease. Secondly, that systemic infections can have both short- and long-term effects on the brain. BBB disruption may be one possible mechanism linking systemic events with the brain, and warrants further study

LPS in vivo dataset

Comprehensive literature review of studies examining disruptive BBB change in animals after LPS challenge in vivo.</span

Long Term Neurological condtions urgent care dataset

&quot;Assigned DOI: https://doi.org/10.5258/SOTON/D1832 will be registered once the dataset is finalised&quot;. Dataset supports article &#39;Systemic infection is an important driver of urgent care needs in adults with long-term neurological conditions&#39; in Journal of Neurology, Neurosurgery and Psychiatry. </span

Systemic infection drives urgent care needs and outcome in adults with long-term neurological conditions

It is estimated that 1 in 6 people are living with a long-term neurological condition (LTNC). Although it is likely that systemic infections are a common trigger for urgent tertiary care needs in LTNCs, there is a lack of data. Yet this is important since systemic infections are a modifiable risk factor, and hence the motivation for a formal evaluation. We undertook case note review of 155 consecutive unselected adult patients with LTNC receiving urgent care at a tertiary hospital between November and December 2019. Data were collected on presenting symptoms, diagnosis, length of stay, complications, and change in social needs. The most common LTNCs were neurocognitive disorders (n = 68, 44%), cerebrovascular disorders (n = 65, 42%), and epilepsy (n = 19, 12%). Respiratory infections were most common (n = 40, 62.5%), followed by urinary (n = 16, 25%), skin (n = 4, 6%), gastrointestinal (n = 3, 5%) and bone (n = 1, 1.5%). Systemic infection was the trigger for urgent care in 41.3% of patients and in multivariable regression was associated with an increased likelihood of admission (p &lt; 10 -5, OR = 7.8, Nagelkerke R 2 = 0.37), longer length of stay (p = 0.03, β = 5.91, R 2 = 0.06), and death (p = 0.045, OR = 4.3, Nagelkerke R 2 = 0.22). Altered mental status was the presenting symptom most frequently associated with infection (p &lt; 10 -8, χ 2 test). In conclusion, systemic infections are a major trigger of acute tertiary care needs in adults with LTNCs, and play a role in determining clinical outcome. Since systemic infections are preventable or can be treated if identified early, they may represent a modifiable target to improve quality of life, clinical outcomes and health service efficiency. </p