The small conductance Ca2+-activated K+ channel activator GW542573X impairs hippocampal memory in C57BL/6J mice.

Small conductance Ca2+-activated K+ (SK) channels, expressed throughout the CNS, are comprised of SK1, SK2 and SK3 subunits, assembled as homotetrameric or heterotetrameric proteins. SK channels expressed somatically modulate the excitability of neurons by mediating the medium component of the afterhyperpolarization. Synaptic SK channels shape excitatory postsynaptic potentials and synaptic plasticity. Such SK-mediated effects on neuronal excitability and activity-dependent synaptic strength likely underlie the modulatory influence of SK channels on memory encoding. Converging evidence indicates that several forms of long-term memory are facilitated by administration of the SK channel blocker, apamin, and impaired by administration of the pan-SK channel activator, 1-EBIO, or by overexpression of the SK2 subunit. The selective knockdown of dendritic SK2 subunits facilitates memory to a similar extent as that observed after systemic apamin. SK1 subunits co-assemble with SK2; yet the functional significance of SK1 has not been clearly defined. Here, we examined the effects of GW542573X, a drug that activates SK1 containing SK channels, as well as SK2/3, on several forms of long-term memory in male C57BL/6J mice. Our results indicate that pre-training, but not post-training, systemic GW542573X impaired object memory and fear memory in mice tested 24 h after training. Pre-training direct bilateral infusion of GW542573X into the CA1 of hippocampus impaired object memory encoding. These data suggest that systemic GW542573X impairs long-term memory. These results add to growing evidence that SK2 subunit-, and SK1 subunit-, containing SK channels can regulate behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory.

Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

The Bone Marrow Microenvironment in Immune-Mediated Inflammatory Diseases: Implications for Mesenchymal Stromal Cell-Based Therapies.

Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) are promising candidates for cell-based therapy for several immune-mediated inflammatory diseases (IMIDs) due to their multiplicity of immunomodulatory and reparative properties and favorable safety profile. However, although preclinical data were encouraging, the clinical benefit demonstrated in clinical trials of autologous MSC transplantation in a number of conditions has been less robust. This may be explained by the growing body of evidence pointing to abnormalities of the bone marrow microenvironment in IMIDs, including impaired MSC function. However, it is not currently known whether these abnormalities arise as a cause or consequence of disease, the role they play in disease initiation and/or progression, or whether they themselves are targets for disease modification. Here, we review current knowledge about the function of the BM microenvironment in IMIDs including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type I diabetes, focusing on MSCs in particular. We predict that an improved understanding of disease-related changes in the bone marrow microenvironment including the role of MSCs in vivo, will yield new insights into pathophysiology and aid identification of new drug targets and optimization of cell-based therapy in IMIDs.

European Stroke Organisation (ESO) guidelines on Primary Angiitis of the Central Nervous System (PACNS).

The European Stroke Organisation (ESO) guideline on Primary Angiitis of the Central Nervous System (PACNS), developed according to ESO standard operating procedures (SOP) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology, was elaborated to assist clinicians in the diagnostic and treatment pathway of patients with PACNS in their decision making. A working group involving vascular neurologists, neuroradiologists, rheumatologists, a neuropathologist and a methodologist identified 17 relevant clinical questions; these were addressed according to the patient/population, intervention, comparison and outcomes (PICO) framework and systematic literature reviews were performed. Notably, each PICO was addressed with respect to large vessel (LV)-PACNS and small vessel (SV)-PACNS. Data to answer many questions were scarce or lacking and the quality of evidence was very low overall, so, for some PICOs, the recommendations reflect the ongoing uncertainty. When the absence of sufficient evidence precluded recommendations, Expert Consensus Statements were formulated. In some cases, this applied to interventions in the diagnosis and treatment of PACNS which are embedded widely in clinical practice, for example patterns of cerebrospinal fluid (CSF) and Magnetic Resonance Imaging (MRI) abnormalities. CSF analysis for hyperproteinorrachia and pleocytosis does not have evidence supporting their use as diagnostic tools. The working group recommended that caution is employed in the interpretation of non-invasive vascular imaging due to lack of validation and the different sensitivities in comparison with digital subtraction angiography (DSA) and histopathological analyses. Moreover, there is not a neuroimaging pattern specific for PACNS and neurovascular issues are largely underreported in PACNS patients. The group's recommendations on induction and maintenance of treatment and for primary or secondary prevention of vascular events also reflect uncertainty due to lack of evidence. Being uncertain the role and practical usefulness of current diagnostic criteria and being not comparable the main treatment strategies, it is suggested to have a multidisciplinary team approach in an expert center during both work up and management of patients with suspected PACNS. Highlighting the limitations of the currently accepted diagnostic criteria, we hope to facilitate the design of multicenter, prospective clinical studies and trials. A standardization of neuroimaging techniques and reporting to improve the level of evidence underpinning interventions employed in the diagnosis and management of PACNS. We anticipate that this guideline, the first comprehensive European guideline on PACNS management using GRADE methodology, will assist clinicians to choose the most effective management strategy for PACNS.

Evaluation of the feasibility and acceptability of an integrative group psychological intervention for people with Multiple Sclerosis: A study protocol.

Multiple Sclerosis (MS) is characterised by significant symptom diversity and complexity. The unpredictability of the symptoms and the emotional and cognitive facets of the disease have a significant impact on the patients' quality of life, relationships and other significant areas of living. Psychological interventions have been found to have moderate effects on quality of life, depression, stress reduction, improvement of wellbeing, anxiety, fatigue, sleep disturbances and emotion regulation. Most interventions so far are based on generic models of therapy which cannot always cover the complexity and unpredictability of MS. The present research project follows from an exploratory mixed method study on the experience of psychological interventions and the impact on the management of MS. The results of that study generated themes that led to the development of an integrative group psychological intervention named MyMS-Ally. The current study aims to explore the feasibility and acceptability of MyMS-Ally intervention and obtain preliminary data on the effects on quality of life, emotion regulation, depression and anxiety through the application of a convergent mixed methods design. People with MS will be recruited at the Bristol and Avon Multiple Sclerosis centre, North Bristol NHS Trust. They will participate in MyMS-Ally group intervention for 8 weeks. Individual semi-structured interviews drawing on Interpretative Phenomenological methodology will be conducted before and after the intervention and at three months follow up. Participants will complete quantitative measures on quality of life, emotion regulation, depression and anxiety before and after the intervention and at one and three months follow up. The aim is to explore the relevance, sustainability and adherence to the intervention and study processes (feasibility) as well as the appropriateness of the intervention based on the emotional and cognitive responses, satisfaction and perceived effectiveness (acceptability). It is aspired that this patient-centred psychological intervention will address needs and preferences of people with MS. The results of the present study will provide data for further development of the intervention and will lead to a big scale evaluation study.

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia.

Friedreich's ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cell (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G-CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.

Repeat infusion of autologous bone marrow cells in progressive multiple sclerosis - A phase I extension study (SIAMMS II).

BACKGROUND: During the safety and feasibility 'Study of Intravenous Autologous Marrow in Multiple Sclerosis (SIAMMS)', intravenous infusion of autologous marrow was well tolerated. The efficacy of the approach is being explored in a placebo-controlled randomised controlled trial (ACTiMuS, NCT01815632) but it is not known whether repeated infusions will be required to optimise benefit. The objective of the current study was to explore the safety and feasibility of repeat treatment with intravenous autologous bone marrow for patients with progressive multiple sclerosis (MS). METHODS: 'SIAMMS II' was a prospective, single centre phase I extension study in which participants in the SIAMMS study were offered repeat bone marrow harvest and infusion of autologous, unfractionated bone marrow as a day-case procedure. The primary outcome measure was number of adverse events and secondary outcome measures included change in clinical rating scales of disability, global evoked potential and cranial magnetic resonance imaging (MRI). RESULTS: In total, 4 of the 6 participants in the SIAMMS study had repeat bone marrow harvest and infusion of filtered autologous marrow as a day case procedure which was well tolerated. There were no serious adverse effects. Additional outcome measures including clinical scales, global evoked potentials and cranial MRI were stable. CONCLUSION: SIAMMS II demonstrates the safety and feasibility of repeated, non-myeloablative autologous bone marrow-derived cell therapy in progressive MS.

Assessment and Treatment of Nocturia in Neurological Disease in a Primary Care Setting: Systematic Review and Nominal Group Technique Consensus.

CONTEXT: Neurological disease can affect the rate of urine production and bladder storage function, increasing nocturia severity, with additional risks if mobility or cognition is impaired. OBJECTIVE: To conduct a systematic review (SR) of nocturia in neurological diseases and achieve expert consensus for management in clinics without neurologist input. EVIDENCE ACQUISITION: Four databases were searched from January 2000 to April 2020. A total of 6262 titles and abstracts were screened and 43 studies were included for full-text screening. Eleven of these met the inclusion criteria and two studies were identified through other sources. The nominal group technique (NGT) was used to develop consensus in panel comprising experts and public representation. EVIDENCE SYNTHESIS: Thirteen studies (seven in Parkinson's disease, five in multiple sclerosis) were included, all undertaken in secondary care. Neurological disease severity was incompletely described, and nocturia severity was generally measured subjectively. NGT consensus supported basic neurological assessment, and the use of bladder diaries where neurological impairment permits. Treatments include pelvic-floor muscle training, review of medications, risk mitigation, improving bowel function, therapy for overactive bladder syndrome (if urgency is reported in association with nocturia episodes), treatment of postvoid residual and desmopressin according to licence. Measures to improve mobility and mitigate risk when using the toilet overnight should be considered. Multifactorial issues such as obstructive sleep apnoea and hypoventilation must be considered. CONCLUSIONS: Nocturia in neurological disease is complex and lacks a robust evidence base, with very little research done in the primary care context. Guidance should be pragmatic, with reduction of risk a key requirement, until a multidisciplinary evidence base can be developed. PATIENT SUMMARY: People with a neurological disease can suffer severe sleep disturbance because of the need to pass urine several times overnight (called nocturia). We looked at published research and found very little information to help general practitioners in managing this condition. We assembled a group of experts to develop practical approaches for assessing and treating nocturia in neurological disease.

Reduced expression of mitochondrial fumarate hydratase in progressive multiple sclerosis contributes to impaired in vitro mesenchymal stromal cell-mediated neuroprotection.

BACKGROUND: Cell-based therapies for multiple sclerosis (MS), including those employing autologous bone marrow-derived mesenchymal stromal cells (MSC) are being examined in clinical trials. However, recent studies have identified abnormalities in the MS bone marrow microenvironment. OBJECTIVE: We aimed to compare the secretome of MSC isolated from control subjects (C-MSC) and people with MS (MS-MSC) and explore the functional relevance of findings. METHODS: We employed high throughput proteomic analysis, enzyme-linked immunosorbent assays and immunoblotting, as well as in vitro assays of enzyme activity and neuroprotection. RESULTS: We demonstrated that, in progressive MS, the MSC secretome has lower levels of mitochondrial fumarate hydratase (mFH). Exogenous mFH restores the in vitro neuroprotective potential of MS-MSC. Furthermore, MS-MSC expresses reduced levels of fumarate hydratase (FH) with downstream reduction in expression of master regulators of oxidative stress. CONCLUSIONS: Our findings are further evidence of dysregulation of the bone marrow microenvironment in progressive MS with respect to anti-oxidative capacity and immunoregulatory potential. Given the clinical utility of the fumaric acid ester dimethyl fumarate in relapsing-remitting MS, our findings have potential implication for understanding MS pathophysiology and personalised therapeutic intervention.

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. Relative to those >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.

CNS demyelination associated with immune dysregulation and a novel CTLA-4 variant.

BACKGROUND: The cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway acts as a negative immune regulator of T-cell activation and promotes self-tolerance. CASE: We report the first case of biopsy-proven central nervous system inflammatory demyelination in the context of primary immunodeficiency and a novel CTLA-4 variant. CONCLUSION: This case has significant implications for the development of novel treatments for autoimmune conditions including multiple sclerosis and further emphasises the need for caution with clinical use of CTLA-4 immune checkpoint inhibitors in those with a history of inflammatory demyelination.

Takotsubo stress cardiomyopathy following explantation of sEEG electrodes.

Objective: Takotsubo stress cardiomyopathy is characterized by dysfunction of the left ventricle of the heart including apical ballooning and focal wall-motion abnormalities. Although reported in association with seizures and intracerebral hemorrhage, there are no studies reporting its occurrence in patients having stereoelectroencephalography (sEEG). Methods: A 38-year-old lady with no prior history of cardiac disease experienced sudden onset chest pain and acute left ventricular failure 4 hours following explantation of stereoelectroencephalogram electrodes. Results: A small parenchymal hematoma related to the right posterior temporal electrode had been noted postelectrode insertion but was asymptomatic. Focal-onset seizures from nondominant mesial temporal structures were recorded during sEEG. Following the presentation with LVF, new-onset anterolateral T-wave inversion with reciprocal changes in leads II, III, and aVF was noted on electrocardiogram (ECG) and the chest X-ray findings were consistent with pulmonary edema. Echocardiography demonstrated hypokinesis of the cardiac apex and septum consistent with Takotsubo stress cardiomyopathy. Significance: Awareness of the possible complication of Takotsubo stress cardiomyopathy is required in an epilepsy surgery program.