Scottish Intercollegiate Guidelines Network Guidance on Dementia: The Investigation of Suspected Dementia (SIGN 168) with Focus on Biomarkers-Executive Summary.

This is an executive summary of the recent guidance produced by the Scottish Intercollegiate Guidelines Network (SIGN) dementia guideline group with regards to the investigation of suspected dementia. This is a sub-section of the broader SIGN 168 guideline released in November 2023. The guideline group included clinicians with expertise in Old Age Psychiatry, Neurology, Radiology, and Nuclear Medicine supported by colleagues from the SIGN and Healthcare Improvement Scotland teams. There was representation from carers and support organizations with experience of dementia, to ensure the recommendations were appropriate from the perspective of the people being assessed for possible dementia and their carers. As the 2018 National Institute for Health and Clinical Excellence (NICE) dementia review included a review of the evidenced investigation of dementia, the SIGN guideline development group decided to focus on a review on the up-to-date evidence regarding the role of imaging and fluid biomarkers in the diagnosis of dementia. To give context to the consideration of more advanced diagnostic biomarker investigations, the guideline and this summary include the NICE guidance on the use of standard investigations as well as more specialist investigations. The evidence review supports consideration of the use of structural imaging, nuclear medicine imaging, and established Alzheimer's cerebrospinal fluid biomarkers (amyloid and tau) in the diagnosis of dementia. Although routine use of amyloid positron emission tomography imaging was not recommended, its potential use, under specialist direction, in patients with atypical or young-onset presentations of suspected Alzheimer's dementia was included as a clinical good practice point.

Robotic-assisted surgery for left-sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study.

INTRODUCTION: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. METHODS: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. RESULTS: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p < 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p < 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p < 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). CONCLUSIONS: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile.

National audit of pathways in epileptic seizure referrals (NAPIER): A national, multicentre audit of first seizure clinics throughout the UK and Ireland.

BACKGROUND: Current guidelines set clinical standards for the management of suspected first seizures and epilepsy. We aimed to assess if these standards are being met across first seizure clinics nationally, to describe variations in care and identify opportunities for service delivery improvement. METHODS: Multicentre audit assessing the care of adults (≥16 years) referred to first seizure clinics from 31st December 2019 going backwards (30 consecutive patients per centre). Patients with pre-existing diagnosis of epilepsy were excluded. Anonymised referral, clinic, and follow-up data are reported with descriptive statistics. RESULTS: Data provided for 727 patients from 25 hospitals in the UK and Ireland (median age 41 years [IQR 26-59], 52% males). Median time to review was 48 days (IQR 26-86), with 13.8% (IQR 3.3%-24.0%) of patients assessed within 2 weeks. Seizure recurrence was seen in 12.7% (IQR 6.6%-17.4%) of patients awaiting first appointment. Documentation for witness accounts and driving advice was evident in 85.0% (IQR 74.0%-100%) and 79.7% (IQR 71.2%-96.4%) of first seizure/epilepsy patients, respectively. At first appointment, discussion of sudden unexpected death in epilepsy was documented in 30.1% (IQR 0%-42.5%) of patients diagnosed with epilepsy. In epilepsy patients, median time to MRI neuroimaging was 37 days [IQR 22-56] and EEG was 30 days [IQR 19-47]. 30.4% ([IQR 0%-59.5%]) of epilepsy patients were referred to epilepsy nurse specialists. CONCLUSIONS: There is variability nationally in the documented care of patients referred to first seizure clinics. Many patients are facing delays to assessment with epilepsy specialists with likely subsequent impact on further management.

Valproate pregnancy prevention scheme: what are the barriers to enrolling patients and how do we meet them?

Background: The UK Medicines Health products Regulation Agency instructs that valproate prescriptions should be restricted in women of childbearing age to those consenting to the Pregnancy Prevention Programme (PPP). We assessed the compliance and barriers to the valproate PPP. Methods: We retrospectively audited NHS Grampian's compliance with PPP guidelines among women of childbearing potential prescribed valproate between October 2017 and March 2018. Additionally, we prospectively reviewed new valproate prescriptions from February 2019 to March 2022 and compared this with our retrospective data to assess the effectiveness of our identification process using descriptive statistics. Results: We identified 351 women retrospectively and 80 women prospectively. Epilepsy, migraine and psychiatry were the main indications. There was a decline in valproate use over the years, particularly for epilepsy. Initially, only 132 (37.6%) met the PPP requirement, and eventually, 81 (23%) stopped the medication. Despite efforts, 38 (10.8%) had contact with secondary care but still did not meet PPP and 100 (28.5%) had no documentation or referral to secondary care. Patients not meeting PPP lacked capacity, most commonly with severe learning difficulties. Women treated for psychiatric purposes were less likely to meet PPP than other indications. Conclusions: A significant proportion of women continue valproate treatment without meeting the PPP requirement. This is linked to their indication for prescription and their comorbidities. Collaborative input from relevant specialities and primary care is required to fully achieve PPP if a national valproate database is to be established.

The effect of substance P and its common in vivo-formed metabolites on MRGPRX2 and human mast cell activation.

The tachykinin neuropeptide substance P (SP) is the canonical agonist peptide for the neurokinin 1 receptor (NK1 R). More recently, it has also been shown to activate the Mas-related G protein-coupled receptor X2 (MRGPRX2) receptor on mast cells (MCs), triggering degranulation and release of inflammatory mediators. SP undergoes rapid C-terminal truncation in vivo by a number of proteases to generate the metabolites SP(1-9)-COOH and in particular SP(1-7)-COOH. While the C terminus of SP is critical for NK1 R activation, studies have shown that the peptide polycationic N terminus is key for MRGPRX2 and mast cell activation. The study thus aimed to determine if the C-terminally truncated metabolites of SP, SP(1-9)-COOH, and SP(1-7)-COOH retained stimulatory activity at MRGPRX2. SP, SP(1-9)-COOH, and SP(1-7)-COOH were synthesized and tested on HEK293 cells expressing NK1 R or MRGPRX2, and LAD2 human mast cells, to determine the activity of SP and its metabolites in Ca2+ mobilization, degranulation, and cytokine assays. As expected from prior studies, both C-terminally truncated SP metabolites had essentially no activity at NK1 R, even at very high concentrations. In contrast, the in vivo metabolite of SP, SP(1-9)-COOH retained ability to activate MRGPRX2 across all parameters tested, albeit with reduced potency compared to intact SP. SP(1-7)-COOH did not produce any significant MRGRPX2 activation. Our results suggest that the SP metabolite, SP(1-9)-COOH, may play a regulatory role through the activation of MRGPRX2. However, given the relatively low potency of both SP and SP(1-9)-COOH at MRGPRX2, additional work is needed to better understand the biological importance of this expanded SP/MRGPRX2 pathway.

Evaluation of telemedicine for new outpatient neurological consultations.

Objective: The COVID-19 pandemic has broadened the use of teleneurology, how this compares with face-to-face (F2F) clinics is unclear. This study compared virtual with F2F new neurological consultations. Methods: We retrospectively evaluated new outpatient consultations in neurology clinics in Aberdeen Royal Infirmary. We compared sociodemographic data, time to consultation, time to diagnosis, the need for reassessment and re-investigation between traditional F2F and virtual clinics using the web-based Attend Anywhere platform or telephone into patients' own homes (or chosen location) without a trained assistant. We calculated the relative risk (RR) of the need for reassessment and re-investigation over 6-month periods by the suspected neurological diagnosis. Results: 73% of consultations were virtual (Attend Anywhere or telephone) between June and October 2020, this was almost non-existent (<0.1%) in June-October 2019. We analysed 352 F2F (June-July 2019) and 225 virtual consultations (June-July 2020). Compared with F2F clinics, virtual clinics had a longer time to diagnosis (p=0.019), were more likely to be reassessed (RR: 2.2, 95% CI: 1.5 to 3.2; p<0.0001) and re-investigated (RR: 1.50, 95% CI: 0.88 to 2.54; p=0.133), this was likelier in those aged ≥60 years. Patients with headaches and suspected seizures were less likely to need reassessment or re-investigation following virtual clinics than multiple sclerosis and neuroinflammatory disorders, spinal cord disorders and functional neurological disorders. Conclusion: This study demonstrates that virtual clinics have higher rates of reassessment and re-investigation than F2F clinics. As virtual clinics become a potential consultation alternative, this study should instruct the selection of patients for either consultation type.

The first reptilian allergen and major allergen for fish-allergic patients: Crocodile ß-parvalbumin.

BACKGROUND: Clinical cross-reactivity between bony fish, cartilaginous fish, frog, and chicken muscle has previously been demonstrated in fish-allergic patients. In indicative studies, two reports of anaphylaxis following the consumption of crocodile meat and IgE-cross-binding were linked to the major fish allergen parvalbumin (PV). This study investigates IgE-binding proteins in crocodile meat with a focus on PV and their clinical relevance. METHODS: Proteins were extracted from muscle tissue of crocodile, three bony fish, and two cartilaginous fish. A cohort of fish-allergic pediatric patients (n = 77) underwent allergen skin prick testing (SPT) to three fish preparations (n = 77) and crocodile (n = 12). IgE-binding proteins were identified and quantified by SDS-PAGE, mass spectrometric analyses, and immunoblotting using commercial and in-house antibodies, as well as individual and pooled patients' serum. PV isoforms were purified or recombinantly expressed before immunological analyses, including human mast cell degranulation assay. RESULTS: Of the tissues analyzed, PV was most abundant in heated crocodile preparation, triggering an SPT of ≥3 mm in 8 of 12 (67%) fish-allergic patients. Seventy percent (31 of 44) of fish PV-sensitized patients demonstrated IgE-binding to crocodile PV. Crocodile ß-PV was the major IgE-binding protein but 20-fold less abundant than α-PV. Cellular reactivity was demonstrated for ß-PV and epitopes predicted, explaining frequent IgE-cross-binding of ß-PVs. Both PV isoforms are now registered as the first reptile allergens with the WHO/IUIS (ß-PV as Cro p 1 and α-PV as Cro p 2). CONCLUSION: Fish-allergic individuals may be at risk of an allergy to crocodile and should seek specialist advice before consuming crocodilian meat.

Antibody or Anybody? Considering the Role of MRGPRX2 in Acute Drug-Induced Anaphylaxis and as a Therapeutic Target.

Acute anaphylaxis to small molecule drugs is largely considered to be antibody-mediated with immunogloblin E (IgE) and mast cell activation being key. More recently, a role for drug-reactive immunoglobulin G (IgG) with neutrophil activation has also been suggested, at least in reactions to neuromuscular blocking agents (NMBAs). However, the mast cell receptor MRGPRX2 has also been highlighted as a possible triggering mechanism in acute anaphylaxis to many clinically used drugs. Significantly, MRGPRX2 activation is not dependent upon the presence of drug-recognising antibody. Given the reasonable assumption that MRGPRX2 is expressed in all individuals, the corollary of this is that in theory, anybody could respond detrimentally to triggering drugs (recently suggested to be around 20% of a drug-like compound library). But this clearly is not the case, as the incidence of acute drug-induced anaphylaxis is very low. In this mini-review we consider antibody-dependent and -independent mechanisms of mast cell activation by small molecule drugs with a focus on the MRGPRX2 pathway. Moreover, as a juxtaposition to these adverse drug actions, we consider how increased understanding of the role of MRGPRX2 in anaphylaxis is important for future drug development and can complement exploration of this receptor as a drug target in broader clinical settings.

Fc Binding by FcγRIIa Is Essential for Cellular Activation by the Anti-FcγRIIa mAbs 8.26 and 8.2.

FcγR activity underpins the role of antibodies in both protective immunity and auto-immunity and importantly, the therapeutic activity of many monoclonal antibody therapies. Some monoclonal anti-FcγR antibodies activate their receptors, but the properties required for cell activation are not well defined. Here we examined activation of the most widely expressed human FcγR; FcγRIIa, by two non-blocking, mAbs, 8.26 and 8.2. Crosslinking of FcγRIIa by the mAb F(ab')2 regions alone was insufficient for activation, indicating activation also required receptor engagement by the Fc region. Similarly, when mutant receptors were inactivated in the Fc binding site, so that intact mAb was only able to engage receptors via its two Fab regions, again activation did not occur. Mutation of FcγRIIa in the epitope recognized by the agonist mAbs, completely abrogated the activity of mAb 8.26, but mAb 8.2 activity was only partially inhibited indicating differences in receptor recognition by these mAbs. FcγRIIa inactivated in the Fc binding site was next co-expressed with the FcγRIIa mutated in the epitope recognized by the Fab so that each mAb 8.26 molecule can contribute only three interactions, each with separate receptors, one via the Fc and two via the Fab regions. When the Fab and Fc binding were thus segregated onto different receptor molecules receptor activation by intact mAb did not occur. Thus, receptor activation requires mAb 8.26 Fab and Fc interaction simultaneously with the same receptor molecules. Establishing the molecular nature of FcγR engagement required for cell activation may inform the optimal design of therapeutic mAbs.

MRGPRX2 activation in mast cells by neuromuscular blocking agents and other agonists: Modulation by sugammadex.

BACKGROUND: Neuromuscular-blocking agents (NMBAs) can cause both IgE-dependent and IgE-independent anaphylactic reactions, with activation of the mast cell receptor MRGPRX2 being important to the latter. Sugammadex, a reversal agent for certain aminosteroid NMBAs, has been proposed as an antidote for these anaphylactic events with conflicting outcomes. OBJECTIVE: We further characterize the involvement of MRGPRX2 in NMBA-induced mast cell activation and determine how this is influenced by sugammadex. We then apply these in vitro results to infer the possible utility of sugammadex in the acute management of non-IgE-dependent anaphylaxis. METHODS: The LAD2 human mast cell line and a MRGPRX2 knock-down derivative were used to validate the involvement of MRGPRX2 and to test the effect of sugammadex on mast cell activation by NMBAs and other MRGPRX2 agonists. RESULTS: All MRGPRX2 agonists tested were shown to induce MRGPRX2-dependent LAD2 mast cell calcium mobilization and cytokine release and all, apart from rocuronium, induced degranulation. Co-treatment of mast cells with sugammadex and some MRGPRX2 agonists significantly reduced cell activation, but if sugammadex was administered a few minutes following stimulation, degranulation was not attenuated. However, addition of sugammadex up to 180 min following LAD2 MRGPRX2 stimulation, significantly reduced CCL2 mRNA and protein induction. CONCLUSIONS AND CLINICAL RELEVANCE: We show that sugammadex, known to reverse muscle blockade by certain NMBAs, is also able to reduce MRGPRX2 activation by NMBAs and other, but not all, MRGPRX2 agonists. As sugammadex was ineffective in attenuating mast cell degranulation when added rapidly post MRGPRX2 activation, this suggests against the agent having efficacy in controlling acute symptoms of anaphylaxis to NMBAs caused by MRGPRX2 activation. Interestingly, however, sugammadex did impair MRGPRX2-induced CCL2 release, suggesting that it may have some benefit in perhaps dampening less well-defined adverse effects of MRGPRX2-dependent anaphylaxis associated with the more slowly elaborated mast cell mediators.

Autoimmune encephalitis.

Autoimmune encephalitis is emerging as an important and relatively common cause of encephalitis in the developed world. Crucially, early recognition and prompt initiation of a range of immunotherapies is likely to improve the outcomes of patients with autoimmune encephalitis, particularly for those with identifiable antibodies against neuronal cell surface proteins. There are a rapidly growing number of specific autoantibodies and associated syndromes, but many of these remain very rare. The majority of cases comprise anti-N-methyl-D-aspartate (NMDA) receptor encephalitis or anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis with the remaining cases a mixture of over 10 other specific antibodies or being seronegative. The core anti-NMDA encephalitis phenotype is a distinct symptom complex involving psychiatric and neurological features and anti-LGI1 encephalitis presents with cognitive changes and distinct seizure types. Diagnosis can be delayed owing to limited access to specialised laboratory testing or in cases with atypical or limited features.

Possible dose dependent effect of perioperative dexamethasone and laparoscopic surgery on the postoperative systemic inflammatory response and complications following surgery for colon cancer.

BACKGROUND: Perioperative dexamethasone is associated with attenuation of the postoperative systemic inflammatory response and fewer postoperative complications following elective surgery for colorectal cancer. This study examined the impact of different doses of dexamethasone, given to reduce postoperative nausea and vomiting (PONV) after elective colonic resection for cancer, on the postoperative Glasgow Prognostic Score (poGPS) and morbidity. METHODS: Patients from a single centre were included if they underwent potentially curative resection of colonic cancer from 2008 to 2017 (n = 480). Patients received no dexamethasone (209, 44%), or either 4 mg (166, 35%), or 8 mg (105, 21%), intravenously during anaesthesia, at the discretion of the anaesthetist. The postoperative Glasgow Prognostic Score (poGPS) on day 3 and 4, and complication rate at discharge were recorded. RESULTS: When patients were grouped by surgical approach (open or laparoscopic) and dexamethasone dose (0 mg, 4 mg or 8 mg), there was a statistically significant linear trend toward a lower postoperative systemic inflammatory response (day 3 poGPS) with the use of minimally invasive surgery and higher doses of dexamethasone (p < 0.001). Furthermore, this combination of laparoscopic surgery and higher doses of dexamethasone was significantly associated with a lower proportion of postoperative complications (p < 0.001). At multivariate Cox regression, dexamethasone was not significantly associated with either improved or poorer cancer specific or overall survival. CONCLUSIONS: Higher doses of perioperative dexamethasone are associated with greater reduction in postoperative systemic inflammation and complications following surgery for colonic cancer without negative impact on survival.

Cancer and motor neuron disease-causal or coincidental? Two contrasting cases.

INTRODUCTION: Motor neuron disease (MND) can occur in patients with cancer, but there is minimal evidence that this is more than by chance. We contrast two cases of motor neuronopathies occurring in the context of systemic malignancy and argue that in one case the cause was most likely paraneoplastic, while in the other it was not. CASE 1: A 61-year-old woman developed progressive walking difficulties over 9 months with weakness and stiffness in her legs. EMG showed fibrillations and positive sharp waves in multiple lower limb muscles bilaterally, with neurogenic units and a reduced recruitment pattern. An invasive ductal carcinoma of the breast was identified and she continued to deteriorate neurologically with worsening mobility, upper limb spasticity and fasciculations. She died approximately 26 months after symptom onset. CASE 2: A 57-year-old woman developed weight loss and weakness of her right arm without any sensory symptoms. At presentation, she had wasting and fasciculations in her right upper limb muscles, with normal reflexes, normal left upper limb and lower limb examination. Over the following week, she developed left upper limb weakness and fasciculations, brisk knee reflexes, and flexor plantar responses. Her EMG showed upper and lower limb denervation. She was found to have anti-Hu and anti-CV2 antibodies present in serum. A PET-CT showed active uptake in lymph nodes in the right hilum. Biopsy confirmed a small cell lung cancer. She had chemoradiation therapy and the tumour went into remission. She has remained well on follow-up 24 months later, regaining weight and strength after her chemotherapy. She continues to be monitored for cancer recurrence, but thus far appears to be in remission. CONCLUSION: In cases with rapidly progressive MND, particularly of upper limb onset, consideration should be given to testing anti-neuronal antibodies and searching for an occult tumour.