Blood-brain barrier water exchange measurements using contrast-enhanced ASL.

A technique for quantifying regional blood-brain barrier (BBB) water exchange rates using contrast-enhanced arterial spin labelling (CE-ASL) is presented and evaluated in simulations and in vivo. The two-compartment ASL model describes the water exchange rate from blood to tissue, k b , but to estimate k b in practice it is necessary to separate the intra- and extravascular signals. This is challenging in standard ASL data owing to the small difference in T 1 values. Here, a gadolinium-based contrast agent is used to increase this T 1 difference and enable the signal components to be disentangled. The optimal post-contrast blood T 1 ( T 1 , b post ) at 3 T was determined in a sensitivity analysis, and the accuracy and precision of the method quantified using Monte Carlo simulations. Proof-of-concept data were acquired in six healthy volunteers (five female, age range 24-46 years). The sensitivity analysis identified the optimal T 1 , b post at 3 T as 0.8 s. Simulations showed that k b could be estimated in individual cortical regions with a relative error ϵ < 1 % and coefficient of variation CoV = 30 %; however, a high dependence on blood T 1 was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit time t A = 1 . 15 ± 0 . 49 s, cerebral blood flow f = 58 . 0 ± 14 . 3 mL blood/min/100 mL tissue and water exchange rate k b = 2 . 32 ± 2 . 49 s-1 . CE-ASL can provide regional BBB water exchange rate estimates; however, the clinical utility of the technique is dependent on the achievable accuracy of measured T 1 values.

Myeloperoxidase-positive ANCA-associated vasculitis presenting as myalgia, proximal weakness and a normal CK.

We describe an unusual presentation of myeloperoxidase positive antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis managed by a multidisciplinary approach. A 75-year-old man gave a 3-week history of proximal lower limb weakness and exertional myalgia. His serum creatine kinase was normal and many of his non-specific symptoms suggested small vessel vasculitis. His investigations for common causes of muscle weakness were normal, and renal biopsy was normal despite haemoproteinuria. CT scan of the chest identified a pulmonary nodule of uncertain significance, not amenable to biopsy. MR scan of the thighs showed muscle oedema, and muscle biopsy confirmed typical features of vasculitis. Following high-dose corticosteroids his exertional myalgia quickly resolved and his normal mobility returned. Early immunosuppression is essential to improving clinical outcomes in ANCA-associated vasculitis, but diagnostic investigations often lack sensitivity.

Numbers and types of neurological emergencies in England and the influence of socioeconomic deprivation: a retrospective analysis of hospital episode statistics data.

OBJECTIVES: In this first large-scale analysis of neurological emergency admissions in England, we determine the number and types of emergency admissions with neurological emergency diagnostic codes, how many are under the care of a neurologist or neurosurgeon and how such admissions vary by levels of deprivation. DESIGN: Retrospective empirical research employing a derived list of neurological emergency diagnostic codes SETTING: This study used the Hospital Episode Statistics data set for the financial year 2019/2020 based on 17 million in-year inpatient admissions in England including 6.5 million (100%) emergency admissions with any diagnosis codes. RESULTS: There were 1.4 million (21.2%) emergency inpatient admissions with a mention of any neurological code, approx. 248 455 (3.8%) with mention of a specific neurological emergency code from the derived list, and 72 485 (1.1%) included such a code as the primary reason for admission. The highest number of in-year admissions for adults was for epilepsy (145 995), with epilepsy as the primary diagnostic code in 15 945 (10.9%). Acute nerve root/spinal cord syndrome (41 215), head injury (29 235) and subarachnoid haemorrhage (18 505) accounted for the next three highest number of admissions. 3230 (1.4%) in-year emergency hospital admissions with mention of a neurological emergency code were under the care of a neurologist or neurosurgeon, with only 1315 (0.9%) admissions with mention of an epilepsy code under a neurologist. There was significant variation for epilepsy and functional neurological disorders (FNDs) in particular by Index of Multiple Deprivation decile. The association between deprivation and epilepsy and FND was significant with p-values of 2.5e-6 and 1.5e-8, respectively. CONCLUSIONS: This study has identified important findings in relation to the burden of neurological emergency admissions but further work is needed, with greater clinical engagement in diagnostic coding, to better understand the implications for workforce and changes to service delivery needing to be implemented.

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review.

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.

The Dual GLP-1/GIP Receptor Agonist DA4-JC Shows Superior Protective Properties Compared to the GLP-1 Analogue Liraglutide in the APP/PS1 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder for which there is no cure. Here, we test a dual GLP-1/GIP receptor agonist (DA4-JC) that has a cell penetrating sequence added to enhance blood-brain barrier penetration. We show in a receptor activity study that DA4-JC has balanced activity on both GLP-1 and GIP receptors but not on GLP-2 or Glucagon receptors. A dose-response study in the APP/PS1 mouse model of AD showed both a dose-dependent drug effect on the inflammation response and the reduction of amyloid plaques in the brain. When comparing DA4-JC with the GLP-1 analogue liraglutide at equal doses of 10nmol/kg bw ip. once-daily for 8 weeks, DA4-JC was more effective in reversing memory loss, enhancing synaptic plasticity (LTP) in the hippocampus, reducing amyloid plaques and lowering pro-inflammatory cytokine levels in the brain. The results suggest that DA4-JC may be a novel treatment for AD.

Neurosarcoidosis associated with intracerebral haemorrhage: a challenge in diagnosis and management.

Sarcoidosis is an idiopathic multisystem granulomatous disorder of unknown cause. Nervous system involvement (central and/or peripheral) is uncommon, developing in 5%-10%. The presenting symptoms are variable, reflecting the level of involvement, and frequently fluctuate and progress. Diagnosing neurosarcoidosis in people with previously confirmed systemic disease may be relatively straightforward, but diagnosing primary neurosarcoidosis is challenging. Managing neurosarcoidosis is primarily consensus based; corticosteroid is its mainstay, alongside corticosteroid-sparing agents and emerging novel therapies. We describe a 39-year-old woman who presented with cranial neuropathy. Serial imaging, cerebrospinal fluid sampling and tissue biopsy gave a diagnosis of probable neurosarcoidosis. Her clinical course was complicated by intracerebral haemorrhage following intravenous corticosteroids for neurological relapse. This is a very rare complication of neurosarcoidosis; we discuss its possible causes and suggest ways to reduce its risk.

The Utility of FDG-PET/CT in Clinically Suspected Paraneoplastic Neurological Syndrome: A Literature Review and Retrospective Case Series.

Paraneoplastic neurological syndrome (PNS) describes a spectrum of rare, heterogeneous neurological conditions associated with an underlying malignancy. Diagnosis of PNS is inherently difficult, with frequent misdiagnosis and delay. The literature suggests an underlying immune-mediated pathophysiology, and patients are usually tested for the presence of onconeural antibodies. With direct tumor therapy being the most effective method of stabilizing patients, there is a strong emphasis on detecting underlying tumors. The sensitivity of conventional CT imaging is often inadequate in such patients. While FDG-PET imaging has already been shown to be effective at detecting these tumors, FDG-PET/CT, combining both structural and functional imaging in a single study, is a more recent technique. To study the utility of FDG-PET/CT, we conducted a systematic literature review and a retrospective study. We identified 41 patients who underwent imaging for clinically suspected PNS at the regional PET-CT and neurosciences center based at the Royal Preston Hospital between 2007 and 2014 and compared the results to conventional investigations. Five patients had FDG-PET/CT tracer avidity suspicious of malignant disease, and four of these were subsequently diagnosed with cancer. Sensitivity and specificity were calculated to be 100 and 97.3%, respectively, with positive predictive value 80% and negative predictive value 100%. This compares to a sensitivity and specificity of 50 and 100%, respectively, for CT and 50 and 89%, respectively, for onconeural antibodies. These findings are in line with previous studies and support the diagnostic accuracy of FDG-PET/CT for the detection of underlying malignancy.

Morvan Syndrome: A Case Report With Patient Narrative and Video.

A 74-year-old gentleman was admitted to the regional neurosciences center with encephalopathy, myokymia, and dysautonomia. Chest imaging had previously identified an incidental mass in the anterior mediastinum, consistent with a primary thymic tumor. Antivoltage-gated potassium channel (anti-VGKC) antibodies were positive (titer 1273 pmol/L) and he was hypokalemic. Electromyogram and nerve conduction studies were in keeping with peripheral nerve hyperexcitability syndrome, and an electroencephalogram was consistent with encephalopathy. A diagnosis of Morvan syndrome was made, for which he was initially treated with high-dose steroids, followed by a 5-day course of intravenous immunoglobulin (IVIG) therapy. He also underwent thymectomy, followed by a postexcision flare of his symptoms requiring intensive care management. Further steroids, plasmapheresis, and IVIG achieved stabilization of his clinical condition, enabling transfer for inpatient neurorehabilitation. He was commenced on azathioprine and a prolonged oral steroid taper. A subsequent presumed incipient relapse responded well to further IVIG treatment. This case report documents a thymoma-associated presentation of anti-VGKC-positive Morvan syndrome supplemented by patient and carer narrative and video, both of which provide valuable further insights into this rare disorder. There are a limited number of publications surrounding this rare condition available in the English literature. This, combined with the heterogenous presentation, association with underlying malignancy, response to treatment, and prognosis, provides a diagnostic challenge. However, the association with anti-VGKC antibody-associated complexes and 2 recent case series have provided some scope for both accurate diagnosis and management.