Immune-Mediated Neuropathies: Pathophysiology and Management.

Dysfunction of the immune system can result in damage of the peripheral nervous system. The immunological mechanisms, which include macrophage infiltration, inflammation and proliferation of Schwann cells, result in variable degrees of demyelination and axonal degeneration. Aetiology is diverse and, in some cases, may be precipitated by infection. Various animal models have contributed and helped to elucidate the pathophysiological mechanisms in acute and chronic inflammatory polyradiculoneuropathies (Guillain-Barre Syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, respectively). The presence of specific anti-glycoconjugate antibodies indicates an underlying process of molecular mimicry and sometimes assists in the classification of these disorders, which often merely supports the clinical diagnosis. Now, the electrophysiological presence of conduction blocks is another important factor in characterizing another subgroup of treatable motor neuropathies (multifocal motor neuropathy with conduction block), which is distinct from Lewis-Sumner syndrome (multifocal acquired demyelinating sensory and motor neuropathy) in its response to treatment modalities as well as electrophysiological features. Furthermore, paraneoplastic neuropathies are also immune-mediated and are the result of an immune reaction to tumour cells that express onconeural antigens and mimic molecules expressed on the surface of neurons. The detection of specific paraneoplastic antibodies often assists the clinician in the investigation of an underlying, sometimes specific, malignancy. This review aims to discuss the immunological and pathophysiological mechanisms that are thought to be crucial in the aetiology of dysimmune neuropathies as well as their individual electrophysiological characteristics, their laboratory features and existing treatment options. Here, we aim to present a balance of discussion from these diverse angles that may be helpful in categorizing disease and establishing prognosis.

Barriers to the management of sexual dysfunction among people with psychosis: analysis of qualitative data from the REMEDY trial.

BACKGROUND: More than half of people who use antipsychotic medication for psychosis report having sexual dysfunction. The REMEDY trial aimed to find out if switching antipsychotic medication provides an effective way to reduce sexual dysfunction among people with psychosis. We set out to recruit 216 participants over a two-year period, but recruitment was stopped after an extended 12-month pilot phase, during which we recruited only 10 participants. As part of a nested process evaluation, we conducted qualitative interviews with front-line clinicians to examine barriers to recruitment to the trial. METHODS: We developed a semi-structured interview schedule to explore staff views on factors that influenced whether they referred potential participants to the study. We interviewed a purposive sample of 51 staff from four National Health Service (NHS) Trusts in England, ensuring a range of different backgrounds, seniority, and levels of involvement in the trial. Audio recordings of interviews were transcribed for verbatim, and data were analysed using an inductive approach to thematic analysis. RESULTS: Nine interconnected themes were generated. Six themes concerned barriers to recruitment; including; prioritising patients' mental stability, mutual discomfort and embarrassment about discussing a "taboo" subject, and concerns about unintended consequences of asking people with psychosis about their sexual functioning. Three themes, including the quality of treatment relationships and strategies for opening dialogue suggested ways to improve recognition of these "hidden" side effects. CONCLUSION: The identification and management of sexual dysfunction among people with psychosis are not priorities for mental health services in England at this time. Many staff working in front-line services feel unprepared and uncomfortable asking people with psychosis about these problems. While greater use of screening tools may improve the identification of sexual dysfunction among people with psychosis, the evaluation and implementation of interventions to manage them will continue to be challenging unless NHS leaders and senior clinicians demonstrate greater commitment to changing current clinical practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12307891.

Complement System in Alzheimer's Disease.

Alzheimer's disease is a type of dementia characterized by problems with short-term memory, cognition, and difficulties with activities of daily living. It is a progressive, neurodegenerative disorder. The complement system is an ancient part of the innate immune system and comprises of more than thirty serum and membrane-bound proteins. This system has three different activating pathways and culminates into the formation of a membrane attack complex that ultimately causes target cell lysis (usually pathogens) The complement system is involved in several important functions in the central nervous system (CNS) that include neurogenesis, synaptic pruning, apoptosis, and neuronal plasticity. Here, we discuss how the complement system is involved in the effective functioning of CNS, while also contributing to chronic neuroinflammation leading to neurodegenerative disorders such as Alzheimer's disease. We also discuss potential targets in the complement system for stopping its harmful effects via neuroinflammation and provide perspective for the direction of future research in this field.

Host-pathogen interaction in COVID-19: Pathogenesis, potential therapeutics and vaccination strategies.

The current coronavirus pandemic, COVID-19, is the third outbreak of disease caused by the coronavirus family, after Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome. It is an acute infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This severe disease is characterised by acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Currently, no drugs or vaccines exist against the disease and the only course of treatment is symptom management involving mechanical ventilation, immune suppressants, and repurposed drugs. The severe form of the disease has a relatively high mortality rate. The last six months have seen an explosion of information related to the host receptors, virus transmission, virus structure-function relationships, pathophysiology, co-morbidities, immune response, treatment and the most promising vaccines. This review takes a critically comprehensive look at various aspects of the host-pathogen interaction in COVID-19. We examine the genomic aspects of SARS-CoV-2, modulation of innate and adaptive immunity, complement-triggered microangiopathy, and host transmission modalities. We also examine its pathophysiological impact during pregnancy, in addition to emphasizing various gaps in our knowledge. The lessons learnt from various clinical trials involving repurposed drugs have been summarised. We also highlight the rationale and likely success of the most promising vaccine candidates.

Prevalence, management, and outcomes of SARS-CoV-2 infections in older people and those with dementia in mental health wards in London, UK: a retrospective observational study.

BACKGROUND: People living in group situations or with dementia are more vulnerable to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older people and those with multimorbidity have higher mortality if they become infected than the general population. However, no systematic study exists of COVID-19-related outcomes in older inpatients in psychiatric units, who comprise people from these high-risk groups. We aimed to describe the period prevalence, demographics, symptoms (and asymptomatic cases), management, and survival outcomes of COVID-19 in the older inpatient psychiatric population and people with young-onset dementia in five National Health Service Trusts in London, UK, from March 1 to April 30, 2020. METHODS: In this retrospective observational study, we collected demographic data, mental health diagnoses, clinical diagnosis of COVID-19, symptoms, management, and COVID-19-related outcome data of inpatients aged 65 years or older or with dementia who were already inpatients or admitted as inpatients to five London mental health Trusts between March 1 and April 30, 2020, and information about available COVID-19-related resources (ie, testing and personal protective equipment). Patients were determined to have COVID-19 if they had a positive SARS-CoV-2 PCR test, or had relevant symptoms indicative of COVID-19, as determined by their treating physician. We calculated period prevalence of COVID-19 and analysed patients' characteristics, treatments, and outcomes. FINDINGS: Of 344 inpatients, 131 (38%) were diagnosed with COVID-19 during the study period (period prevalence 38% [95% CI 33-43]). The mean age of patients who had COVID-19 was 75·3 years (SD 8·2); 68 (52%) were women and 47 (36%) from ethnic minority groups. 16 (12%) of 131 patients were asymptomatic and 121 (92%) had one or more disease-related comorbidity. 108 (82%) patients were compulsorily detained. 74 (56%) patients had dementia, of whom 13 (18%) had young-onset dementia. On average, sites received COVID-19 testing kits 4·5 days after the first clinical COVID-19 presentation. 19 (15%) patients diagnosed with COVID-19 died during the study period, and their deaths were determined to be COVID-19 related. INTERPRETATION: Patients in psychiatric inpatient settings who were admitted without known SARS-CoV-2 infection had a high risk of infection with SARS-CoV-2 compared with those in the community and had a higher proportion of deaths from COVID-19 than in the community. Implementation of the long-standing policy of parity of esteem for mental health and planning for future COVID-19 waves in psychiatric hospitals is urgent. FUNDING: None.

Molecular Heterogeneity and Immunosuppressive Microenvironment in Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis, despite surgical resection combined with radio- and chemotherapy. The major clinical obstacles contributing to poor GBM prognosis are late diagnosis, diffuse infiltration, pseudo-palisading necrosis, microvascular proliferation, and resistance to conventional therapy. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and the dynamic plasticity of GBM cells. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. An immunosuppressive tumor microenvironment of GBM provides multiple pathways for tumor immune evasion. Infiltrating immune cells, mostly tumor-associated macrophages, comprise much of the non-neoplastic population in GBM. Further understanding of the immune microenvironment of GBM is essential to make advances in the development of immunotherapeutics. Recently, whole-genome sequencing, epigenomics and transcriptional profiling have significantly helped improve the prognostic and therapeutic outcomes of GBM patients. Here, we discuss recent genomic advances, the role of innate and adaptive immune mechanisms, and the presence of an established immunosuppressive GBM microenvironment that suppresses and/or prevents the anti-tumor host response.

Secretion of functionally active complement factor H related protein 5 (FHR5) by primary tumour cells derived from Glioblastoma Multiforme patients.

The complement system is an important humoral immune surveillance mechanism against tumours. However, many malignant tumours are resistant to complement mediated lysis. Here, we report secretion of complement factor H related protein 5 (FHR5) by primary tumour cells derived from Glioblastoma multiforme (GBM) patients. We investigated whether the secreted FHR5 exhibited functional activity similar to factor H, including inhibition of complement mediated lysis, acting as a co-factor for factor I mediated cleavage of C3b, and decay acceleration of C3 convertase. Immunoblotting analysis of primary GBM cells (B30, B31 and B33) supernatant showed the active secretion of FHR5, but not of Factor H. ELISA revealed that the secretion of soluble GBM-FHR5 by cultured GBM cells increased in a time-dependent manner. Primary GBM-FHR5 inhibited complement mediated lysis, possessed co-factor activity for factor I mediated cleavage and displayed decay acceleration of C3 convertase. In summary, we detected the secretion of FHR5 by primary GBM cells B30, B31 and B33. The results demonstrated that GBM-FHR5 shares biological function with FH as a mechanism primary GBM cells potentially use to resist complement mediated lysis.

Recognition and treatment of depression in older adults admitted to acute hospitals in England.

Levels of awareness and treatment of depression in older adults admitted to acute hospitals are unclear. This study aims to examine the proportion of older adults diagnosed with depression in acute hospitals, treatment, referral, and communication between secondary and primary healthcare services following discharge. Retrospective examination of records of 766 older adults admitted to 27 acute hospitals in England was carried out. Ninety-eight (12.7%, 95% confidence interval (CI) = 10.6-15.3) records included a diagnosis of depression of which eight (1.0%, 95% CI = 0.5-2.0) had a new diagnosis made during their hospital admission. All newly diagnosed and 76 (84.4%, 95% CI = 75.5-90.5) of those with an existing diagnosis of depression were prescribed antidepressant medication. Six (75.0%, 95% CI = 40.9-92.8) of those with a new diagnosis, and 21 (23.3%, 95% CI = 15.8-33.0) with an existing diagnosis of depression were referred to liaison psychiatry. References to mental health were made in 50 (51.0%, 95% CI = 41.2-60.6) discharge letters sent to primary care. Very few older adults admitted to acute hospitals in this study were diagnosed with depression during their inpatient stay. Opportunities for improving the mental and physical health of such patients appear to be being missed.

Women with epilepsy: clinically relevant issues.

Women with epilepsy (WWE) face specific challenges throughout their lifespan due to the effects of seizures and antiepileptic drugs on hormonal function, potentially affecting both sexual and reproductive health. This review article addresses the most common issues of practical relevance to clinicians treating WWE: epidemiology and clinical presentations (including catamenial epilepsy), contraception, reproductive and sexual dysfunction, pregnancy, lactation, menopause-related issues (including bone health), and mental health aspects. Awareness of these gender-specific issues and implementation/adaptation of effective interventions for WWE results in significantly improved health-related quality of life in this patient population.

Obstructive sleep apnoea and dementia: is there a link?

OBJECTIVE: Obstructive sleep apnoea is a common sleep disturbance in people of all ages, while dementia is an increasing entity among the ageing population of the world. Recent studies have established a link between sleep apnoea and cognitive decline. This literature review explores this relationship and examines the mechanisms, neurobiology and treatment modalities. DESIGN: The study was conducted with the use of narrative literature overview. RESULTS AND CONCLUSIONS: While there are numerous studies that establish a clear relationship between obstructive sleep apnoea, cognitive decline and dementia, more work is needed in understanding the mechanism and processes involved. A detailed understanding of pathophysiology of sleep and the relationship with cognitive decline will be vital in addressing the possibility of averting a likely reversible cause of dementia or cognitive decline.

Emerging and Novel Functions of Complement Protein C1q.

Complement protein C1q, the recognition molecule of the classical pathway, performs a diverse range of complement and non-complement functions. It can bind various ligands derived from self, non-self, and altered self and modulate the functions of immune and non-immune cells including dendritic cells and microglia. C1q involvement in the clearance of apoptotic cells and subsequent B cell tolerance is more established now. Recent evidence appears to suggest that C1q plays an important role in pregnancy where its deficiency and dysregulation can have adverse effects, leading to preeclampsia, missed abortion, miscarriage or spontaneous loss, and various infections. C1q is also produced locally in the central nervous system, and has a protective role against pathogens and possible inflammatory functions while interacting with aggregated proteins leading to neurodegenerative diseases. C1q role in synaptic pruning, and thus CNS development, its anti-cancer effects as an immune surveillance molecule, and possibly in aging are currently areas of extensive research.

Innate immunity and neuroinflammation.

Inflammation of central nervous system (CNS) is usually associated with trauma and infection. Neuroinflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuroinflammation is considered to have beneficial effects whereas chronic neuroinflammation can be harmful. Innate immune system consisting of pattern-recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuroinflammation and neurodegeneration.