ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK.

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries.

Bone marrow necrosis and fat embolism syndrome in sickle cell disease during COVID-19 infection treated successfully with sequential red cell and plasma exchange.

Fat embolism syndrome (FES) is a rare life-threatening condition that is particularly seen in milder forms of sickle cell disease (SCD). Widespread systemic fat emboli are generated in the context of extensive bone marrow necrosis. Multi-organ failure with a high morbidity and mortality may quickly develop. Infection with Parvovirus B19 is a common precipitant. Here, the authors report the case of a 35-year-old Afro-Caribbean man with HbSC disease who presented with FES having tested positive for SARS-COV-2. He rapidly became critically ill and required admission to the intensive care unit for organ support. He was treated with red cell exchange and plasma exchange and made a good recovery to leave hospital at week 7.

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

BACKGROUND: A 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. METHODS: For 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. FINDINGS: Between 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). INTERPRETATION: Cerebral 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. FUNDING: None.

Idiopathic intracranial hypertension: consensus guidelines on management.

The aim was to capture interdisciplinary expertise from a large group of clinicians, reflecting practice from across the UK and further, to inform subsequent development of a national consensus guidance for optimal management of idiopathic intracranial hypertension (IIH). METHODS: Between September 2015 and October 2017, a specialist interest group including neurology, neurosurgery, neuroradiology, ophthalmology, nursing, primary care doctors and patient representatives met. An initial UK survey of attitudes and practice in IIH was sent to a wide group of physicians and surgeons who investigate and manage IIH regularly. A comprehensive systematic literature review was performed to assemble the foundations of the statements. An international panel along with four national professional bodies, namely the Association of British Neurologists, British Association for the Study of Headache, the Society of British Neurological Surgeons and the Royal College of Ophthalmologists critically reviewed the statements. RESULTS: Over 20 questions were constructed: one based on the diagnostic principles for optimal investigation of papilloedema and 21 for the management of IIH. Three main principles were identified: (1) to treat the underlying disease; (2) to protect the vision; and (3) to minimise the headache morbidity. Statements presented provide insight to uncertainties in IIH where research opportunities exist. CONCLUSIONS: In collaboration with many different specialists, professions and patient representatives, we have developed guidance statements for the investigation and management of adult IIH.

Cerebrospinal fluid immunoglobulin light chain ratios predict disease progression in multiple sclerosis.

OBJECTIVE: To determine whether the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda light chains at time of multiple sclerosis (MS) diagnosis predicts disease progression and whether this was intrinsic to CSF plasmablasts. METHODS: CSF and peripheral blood were obtained from patients undergoing elective diagnostic lumbar puncture and included clinically isolated syndrome (CIS) (n=43), relapsing remitting MS (RRMS; n=50), primary progressive MS (PPMS; n=20) and other neurological disease controls, both inflammatory (ONID; n=23) and non-inflammatory (OND; n=114). CSF samples were assayed for free and immunoglobulin-associated light chains and on B cells and plasmablasts. Clinical follow-up data were collected during a 5-year follow-up period where available. RESULTS: There was an increased median CSF κ:λ free light chain (FLC) in all MS groups (CIS: 18.2, 95% CI 6.8 to 30.3; RRMS: 4.4, 95% CI 2.7 to 11.4; PPMS: 12.0, 95% CI 3.6 to 37.1) but not controls (OND: 1.61, 95% CI 1.4 to 1.9; ONID: 1.7, 95% CI 1.3 to 2.2; p<0.001). This ratio predicted Expanded Disability Status Scores (EDSS) progression at 5 years, with a lower median EDSS in the group with high (>10) CSF κ:λ FLC (0.0, 95% CI 0 to 2.5 vs 2.5, 95% CI 0 to 4, high vs low; p=0.049). CSF κ:λ FLC correlated with CSF IgG1 κ:λ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026). CONCLUSIONS: These data demonstrate that CSF immunoglobulin κ:λ ratios, determined at the time of diagnostic lumbar puncture, predict MS disease progression and may therefore be useful prognostic markers for early therapeutic stratification.

Idiopathic intracranial hypertension, hormones, and 11ß-hydroxysteroid dehydrogenases.

Idiopathic intracranial hypertension (IIH) results in raised intracranial pressure (ICP) leading to papilledema, visual dysfunction, and headaches. Obese females of reproductive age are predominantly affected, but the underlying pathological mechanisms behind IIH remain unknown. This review provides an overview of pathogenic factors that could result in IIH with particular focus on hormones and the impact of obesity, including its role in neuroendocrine signaling and driving inflammation. Despite occurring almost exclusively in obese women, there have been a few studies evaluating the mechanisms by which hormones and adipokines exert their effects on ICP regulation in IIH. Research involving 11ß-hydroxysteroid dehydrogenase type 1, a modulator of glucocorticoids, suggests a potential role in IIH. Improved understanding of the complex interplay between adipose signaling factors such as adipokines, steroid hormones, and ICP regulation may be key to the understanding and future management of IIH.

Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management.

Idiopathic intracranial hypertension (IIH) is a rare but important disease associated with significant morbidity. There is an expected rise in prevalence in line with the escalating global burden of obesity. Modern revisions in the terminology and diagnostic criteria for IIH help guide clinicians in investigations and researchers in standardising recruitment criteria for clinical trials. The pathophysiology of IIH is incompletely characterised; suggested underpinning mechanisms include the role of cerebrospinal fluid regulation as well as metabolic and endocrinological perspectives. Recent treatment trials are providing insights into the management but debate still surrounds key areas in treatment. This review will provide an up-to-date discussion on the potential pathogenic mechanisms and management of IIH.

The role of metabolomics in neurological disease.

Metabolomic analysis has the potential to generate disease-specific metabolite signatures unique to individuals. Autoimmune illnesses, such as inflammatory uveitis, have highlighted the discriminative power of metabolomics by allowing disease sub-classification. Elucidating surrogate markers for neurological disease is particularly important, given the constraints in accessing central nervous system tissue in vivo. Metabolomic analysis, using either (1)H NMR spectroscopy or mass spectroscopy can be performed using biofluids such as urine, blood or cerebrospinal fluid and may permit the identification of disease specific metabolite signatures which may be useful as disease biomarkers. This is particularly relevant to complex diseases such as multiple sclerosis where promising preliminary work has been carried out. Future work in this field may well generate metabolite profiles to monitor disease evolution, prognosticate and guide therapeutic decisions.

Management and prognosis of multiple sclerosis.

Multiple sclerosis is a common disease of the CNS. The first of these articles (Hassan-Smith and Douglas, 2011) examined its epidemiology and diagnosis. This article explores the management and prognosis of multiple sclerosis, including the rapidly evolving field of disease-modifying therapeutics. However, equally important is the management of problems related to chronic multiple sclerosis and knowledge of which symptomatic treatments may be helpful. Finally, the prognosis is discussed; vital when counselling newly diagnosed patients.

Epidemiology and diagnosis of multiple sclerosis.

Multiple sclerosis is an inflammatory disease of the CNS. The disease is predominantly diagnosed in young adults, with long-term implications for both their personal and professional lives. The economic impact of the condition is particularly significant as the majority of patients are of working age, costing the UK economy approximately £1.4 billion (McCrone et al, 2008).

Motor and sensory conduction failure in overlap of Guillain-Barré and Miller Fisher syndrome: two simultaneous cases.

We report 2 patients diagnosed simultaneously with an overlap of Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS), who had anti-GT1a, anti-GQ1b, anti-GD1a and anti-GD1b antibodies. There was no identifiable specific preceding infection. Both patients presented with upper and lower limb paresthesias and severe weakness, bulbar and facial weakness, ophthalmoparesis and areflexia. In one, electrophysiology demonstrated multifocal conduction blocks (CBs) and mild motor conduction velocity slowing in intermediate segments and absent sensory nerve action potentials (SNAPs). The patient improved rapidly and fully recovered within 18 days from onset. CBs resolved, distal compound muscle action potential (CMAP) amplitudes increased and SNAPs normalized on subsequent testing. In the other patient, initial studies showed low/normal CMAPs, with absent SNAPs, without demyelinating features. This patient fully recovered within 21 days from onset. CMAPs markedly increased, SNAPs improved marginally. These 2 patients exhibited features indicative of the pathophysiological mechanism of conduction failure in motor and sensory fibers. This phenomenon relates to rapidly resolving CBs possibly induced by the transitory and limited attack of antiganglioside antibodies at the axolemma of the nodes of Ranvier not progressing to axonal degeneration. These cases widen the range of GBS subtypes in which reversible conduction failure has been described, to include overlap syndromes with MFS. The factors determining the electrophysiology, as well as the rate, degree and quality of recovery in GBS subtypes remain uncertain at the present time.