Cohort profile: a longitudinal study of HIV infection in the central nervous system with focus on cerebrospinal fluid - the Gothenburg HIV CSF Study Cohort.

PURPOSE: In order to enable long-term follow-up of the natural course of HIV infection in the central nervous system, a longitudinal cohort study with repeated cerebrospinal fluid (CSF) analyses at intervals over time was initiated in 1985. When antiretrovirals against HIV were introduced in the late 1980s, short-term and long-term effects of various antiretroviral treatment (ART) regimens were added to the study. PARTICIPANTS: All adult people living with HIV (PLWH) who were diagnosed at or referred to the Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden were asked to participate in the Gothenburg HIV CSF Study Cohort. PLWH with neurological symptoms or other clinical symptoms of HIV, as well as those with no symptoms of HIV infection, were included. Most participants were asymptomatic, which distinguishes this cohort from most other international HIV CSF studies. In addition, HIV-negative controls were recruited. These included people on HIV pre-exposure prophylaxis who served as lifestyle-matched controls to HIV-infected men who have sex with men. Since lumbar puncture (LP) is an invasive procedure, some PLHW only consented to participate in one examination. Furthermore, at the beginning of the study, several participants were lost to follow-up having died from AIDS. Of 662 PLWH where an initial LP was done, 415 agreed to continue with follow-up. Among the 415, 56 only gave permission to be followed with LP for less than 1 year, mainly to analyse the short-term effect of ART. The remaining 359 PLWH were followed up with repeated LP for periods ranging from >1 to 30 years. This group was defined as the 'longitudinal cohort'. So far, on 7 April 2022, 2650 LP and samplings of paired CSF/blood had been performed, providing a unique biobank. FINDINGS TO DATE: A general finding during the 37-year study period was that HIV infection in the central nervous system, as mirrored by CSF findings, appears early in the infectious course of the disease and progresses slowly in the vast majority of untreated PLWH. Combination ART has been highly effective in reducing CSF viral counts, inflammation and markers of neural damage. Minor CSF signs of long-term sequels or residual inflammatory activity and CSF escape (viral CSF blips) have been observed during follow-up. The future course of these changes and their clinical impact require further studies. FUTURE PLANS: PLWH today have a life expectancy close to that of non-infected people. Therefore, our cohort provides a unique opportunity to study the long-term effects of HIV infection in the central nervous system and the impact of ART and is an ongoing study.

Bruton tyrosine kinase inhibitors for multiple sclerosis.

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.

SARS-Cov-2 infection and neuropathological findings: a report of 18 cases and review of the literature.

INTRODUCTION: COVID-19-infected patients harbour neurological symptoms such as stroke and anosmia, leading to the hypothesis that there is direct invasion of the central nervous system (CNS) by SARS-CoV-2. Several studies have reported the neuropathological examination of brain samples from patients who died from COVID-19. However, there is still sparse evidence of virus replication in the human brain, suggesting that neurologic symptoms could be related to mechanisms other than CNS infection by the virus. Our objective was to provide an extensive review of the literature on the neuropathological findings of postmortem brain samples from patients who died from COVID-19 and to report our own experience with 18 postmortem brain samples. MATERIAL AND METHODS: We used microscopic examination, immunohistochemistry (using two different antibodies) and PCR-based techniques to describe the neuropathological findings and the presence of SARS-CoV-2 virus in postmortem brain samples. For comparison, similar techniques (IHC and PCR) were applied to the lung tissue samples for each patient from our cohort. The systematic literature review was conducted from the beginning of the pandemic in 2019 until June 1st, 2022. RESULTS: In our cohort, the most common neuropathological findings were perivascular haemosiderin-laden macrophages and hypoxic-ischaemic changes in neurons, which were found in all cases (n = 18). Only one brain tissue sample harboured SARS-CoV-2 viral spike and nucleocapsid protein expression, while all brain cases harboured SARS-CoV-2 RNA positivity by PCR. A colocalization immunohistochemistry study revealed that SARS-CoV-2 antigens could be located in brain perivascular macrophages. The literature review highlighted that the most frequent neuropathological findings were ischaemic and haemorrhagic lesions, including hypoxic/ischaemic alterations. However, few studies have confirmed the presence of SARS-CoV-2 antigens in brain tissue samples. CONCLUSION: This study highlighted the lack of specific neuropathological alterations in COVID-19-infected patients. There is still no evidence of neurotropism for SARS-CoV-2 in our cohort or in the literature.

Central nervous system reactivation of herpesviridae family in patients with COVID-19.

The objective of this study is to describe our COVID-19 patients with herpesviridae reactivation in the central nervous system (CNS). Four patients were described including two with acute encephalitis and two with acute encephalomyelitis. Three of four patients had abnormal findings on neuroimaging studies. One of four patients died, one survived with major neurological sequelae, and two others fully recovered. Herpesviridae reactivation in the CNS in patients with COVID-19 is a rare but serious coincidence. The optimal therapeutic management has not been investigated and until more information is available, it is prudent to treat these patients with appropriate antivirals with or without anti-inflammatory agents.

The Potential Role of Microorganisms on Enteric Nervous System Development and Disease.

The enteric nervous system (ENS), the inherent nervous system of the gastrointestinal (GI) tract is a vast nervous system that controls key GI functions, including motility. It functions at a critical interface between the gut luminal contents, including the diverse population of microorganisms deemed the microbiota, as well as the autonomic and central nervous systems. Critical development of this axis of interaction, a key determinant of human health and disease, appears to occur most significantly during early life and childhood, from the pre-natal through to the post-natal period. These factors that enable the ENS to function as a master regulator also make it vulnerable to damage and, in turn, a number of GI motility disorders. Increasing attention is now being paid to the potential of disruption of the microbiota and pathogenic microorganisms in the potential aetiopathogeneis of GI motility disorders in children. This article explores the evidence regarding the relationship between the development and integrity of the ENS and the potential for such factors, notably dysbiosis and pathogenic bacteria, viruses and parasites, to impact upon them in early life.

SARS-CoV-2 neurotropism and other possible causes of olfactory disorders in COVID-19.

Coronavirus disease 2019 (COVID-19) is an acute infectious respiratory disease (AIRD) caused by infection with the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first cases were diagnosed and reported in Wuhan, central China, in November 2019. The disease initially occurred locally. However, the number of infected individuals increased dynamically and spread worldwide. The most common symptoms of the SARS-CoV-2 infection include malaise, fever, dry cough and dyspnoea. Over time, reports of new COVID-19 symptoms included taste and smell disorders. A potential cause of these disorders is related to neurotropism, i.e. the affinity of SARS-CoV-2 to the nervous system. Angiotensin-converting enzyme 2 receptor is essential in the pathogenesis of SARS-CoV-2 infection. The receptor is found in many tissues and organs, including the olfactory epithelium, neurons and neuroglial cells. Another potential cause is neuroinvasiveness, i.e. the ability of the virus to invade the central nervous system, and thereby damage its structures. As a result, olfactory disorders may occur. Other concepts, such as the inflammatory response of the body and the concept of stroke or damage to olfactory supporting cells, are also considered.

Nervous system manifestations related to COVID-19 and their possible mechanisms.

In December 2019, the novel coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection broke. With the gradual deepening understanding of SARS-CoV-2 and COVID-19, researchers and clinicians noticed that this disease is closely related to the nervous system and has complex effects on the central nervous system (CNS) and peripheral nervous system (PNS). In this review, we summarize the effects and mechanisms of SARS-CoV-2 on the nervous system, including the pathways of invasion, direct and indirect effects, and associated neuropsychiatric diseases, to deepen our knowledge and understanding of the relationship between COVID-19 and the nervous system.

Diagnosis of Pediatric Stroke in Resource Limited Settings.

Global awareness of stroke as a significant cause of neurologic sequelae and death in children has increased over the years as more data in this field becomes available. However, most published literature on pediatric stroke have limited geographic representation. Data on childhood stroke from developing countries remains limited. Thus, this paper reviewed geographic/ethnic differences in pediatric stroke risk factors highlighting those reported in low- and middle-income countries, and proposes a childhood arterial ischemic stroke diagnostic algorithm for resource limited settings. Stroke risk factors include cardiac disorders, infectious diseases, cerebral arteriopathies, hematologic disorders, inflammatory diseases, thrombophilia and genetic conditions. Infection of the central nervous system particularly tuberculous meningitis, is a leading cause of pediatric arterial ischemic stroke in developing countries. Stroke should be considered in children with acute focal neurologic deficit especially in the presence of aforementioned risk factors. Cranial magnetic resonance imaging with angiography is the neuroimaging modality of choice but if unavailable, cranial computed tomography with angiography may be performed as an alternative. If both are not available, transcranial doppler together with neurologic exam may be used to screen children for arterial ischemic stroke. Etiological diagnosis follows with the aid of appropriate laboratory tests that are available in each level of care. International collaborative research on stroke risk factors that are prevalent in low and middle income countries will provide information for drafting of stroke care guidelines that are universal yet inclusive taking into consideration regional differences in available resources with the goal of reducing global stroke burden.

Modeling infectious diseases of the central nervous system with human brain organoids.

Bacteria, fungi, viruses, and protozoa are known to infect and induce diseases in the human central nervous system (CNS). Modeling the mechanisms of interaction between pathogens and the CNS microenvironment is essential to understand their pathophysiology and develop new treatments. Recent advancements in stem cell technologies have allowed for the creation of human brain organoids, which more closely resembles the human CNS microenvironment when compared to classical 2-dimensional (2D) cultures. Now researchers can utilize these systems to investigate and reinvestigate questions related to CNS infection in a human-derived brain organoid system. Here in this review, we highlight several infectious diseases which have been tested in human brain organoids and compare similarities in response to these pathogens across different investigations. We also provide a brief overview of some recent advancements which can further enrich this model to develop new and better therapies to treat brain infections.

Infection and inflammation: radiological insights into patterns of pediatric immune-mediated CNS injury.

The central nervous system (CNS) undergoes constant immune surveillance enabled via regionally specialized mechanisms. These include selectively permissive barriers and modifications to interlinked innate and adaptive immune systems that detect and remove an inciting trigger. The end-points of brain injury and edema from these triggers are varied but often follow recognizable patterns due to shared underlying immune drivers. Imaging provides insights to understanding these patterns that often arise from unique interplays of infection, inflammation and genetics. We review the current updates in our understanding of these intersections and through examples of cases from our practice, highlight that infection and inflammation follow diverse yet convergent mechanisms that can challenge the CNS in children.

COVID-19-induced neurological symptoms: focus on the role of metal ions.

Neurological symptoms are prevalent in both the acute and post-acute phases of coronavirus disease 2019 (COVID-19), and they are becoming a major concern for the prognosis of COVID-19 patients. Accumulation evidence has suggested that metal ion disorders occur in the central nervous system (CNS) of COVID-19 patients. Metal ions participate in the development, metabolism, redox and neurotransmitter transmission in the CNS and are tightly regulated by metal ion channels. COVID-19 infection causes neurological metal disorders and metal ion channels abnormal switching, subsequently resulting in neuroinflammation, oxidative stress, excitotoxicity, neuronal cell death, and eventually eliciting a series of COVID-19-induced neurological symptoms. Therefore, metal homeostasis-related signaling pathways are emerging as promising therapeutic targets for mitigating COVID-19-induced neurological symptoms. This review provides a summary for the latest advances in research related to the physiological and pathophysiological functions of metal ions and metal ion channels, as well as their role in COVID-19-induced neurological symptoms. In addition, currently available modulators of metal ions and their channels are also discussed. Collectively, the current work offers a few recommendations according to published reports and in-depth reflections to ameliorate COVID-19-induced neurological symptoms. Further studies need to focus on the crosstalk and interactions between different metal ions and their channels. Simultaneous pharmacological intervention of two or more metal signaling pathway disorders may provide clinical advantages in treating COVID-19-induced neurological symptoms.

Varicella zoster virus cerebellitis without skin manifestations in an immunocompetent adult.

The varicella zoster virus (VZV) is a ubiquitous, neurotropic pathogen capable of reactivation from sensory ganglion cells to cause dermatomal herpes zoster infection, alongside a range of pathologies within the central nervous system. The presence of VZV cerebellitis without skin manifestations, however, is exceedingly rare in immunocompetent adults.We report a case of VZV cerebellitis in an immunocompetent woman in her 70s, in the absence of a rash. The patient presented with a 2-week history of progressive gait ataxia, headache and mild confusion. Serological tests and neuroimaging were unremarkable. Diagnosis was confirmed through cerebrospinal fluid (CSF) analysis which revealed lymphocytosis and the presence of VZV DNA on PCR analysis. The patient showed symptomatic improvement following empirical acyclovir treatment, corroborated by favourable CSF analysis 10 days post-treatment initiation.Infective aetiology, including VZV, should be considered in patients presenting with acute cerebellar ataxia, even in immunocompetent adults with an absence of dermatological signs.

Acute central nervous system inflammation following COVID-19 vaccination: An observational cohort study.

BACKGROUND: Reports suggest a potential association between coronavirus disease 2019 (COVID-19) vaccines and acute central nervous system (CNS) inflammation. OBJECTIVE: The main objective of this study is to describe features of acute CNS inflammation following COVID-19 vaccination. METHODS: A retrospective observational cohort study was performed at the BARLO MS Centre in Toronto, Canada. Clinicians reported acute CNS inflammatory events within 60 days after a COVID-19 vaccine from March 2021 to August 2022. Clinical characteristics were evaluated. RESULTS: Thirty-eight patients (median age 39 (range: 20-82) years; 60.5% female) presented within 0-55 (median 15) days of a receiving a COVID-19 vaccine and were diagnosed with relapsing remitting multiple sclerosis (MS) (n = 16), post-vaccine transverse myelitis (n = 7), clinically isolated syndrome (n = 5), MS relapse (n = 4), tumefactive demyelination (n = 2), myelin oligodendrocyte glycoprotein antibody disease (n = 1), neuromyelitis optica spectrum disorder (n = 1), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (n = 1) and primary autoimmune cerebellar ataxia (n = 1). Twenty-two received acute treatment and 21 started disease-modifying therapy. Sixteen received subsequent COVID-19 vaccination, of which 87.5% had no new or worsening neurological symptoms. CONCLUSION: To our knowledge, this is the largest study describing acute CNS inflammation after COVID-19 vaccination. We could not determine whether the number of inflammatory events was higher than expected.

[Toxoplasmosis in the practice of a neurologist]. / Toksoplazmoz v praktike nevrologa.

Toxoplasmosis is a zoonotic protozoal disease characterized by a chronic course, polymorphism of clinical manifestations, predominant damage to the central nervous system, organs of vision, liver and lungs. The causative agent of the disease is the obligate intracellular parasite Toxoplasma gondii, which circulates widely in the external environment and has a large circle of intermediate hosts. Toxoplasmosis is classified by the method of infection (congenital or acquired), by pathogenesis (acute or chronic), by manifestation (latent or with the manifestation of symptoms). According to the state of the human immune system, the disease can occur without immunodeficiency, while the patient has a chronic lifelong carrier, and with immunodeficiency. People with HIV most commonly present with cerebral toxoplasmosis. The article presents a case of the development of toxoplasmosis in a patient in the absence of a burdened history.

The potential impact of Covid-19 on CNS and psychiatric sequels.

Due to its high prevalence and fatality, the current Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) virus, which first emerged in China in 2019, quickly spread around the world and immediately became a serious global health concern. Although respiratory issues were initially the most prominent symptom of coronavirus disease 2019 (COVID-19), it became obvious rapidly that COVID-19, like many other coronavirus family members, could affect the central nervous system (CNS). During the pandemic, CNS involvement expressed itself in a variety of forms, including insomnia, anosmia, headaches, encephalopathies, encephalitis, cerebrovascular accidents, cognitive and memory impairment, and increased psychiatric disorders. Almost everyone who has been infected has at least one of these neurological symptoms, demonstrating that the virus has a high ability to impact the CNS. As the coronavirus pandemic passes its second year, the manifestations it can cause in the long run, such as its psychological sequels, have not yet been thoroughly studied. Given the high importance of this issue in today's society and due to the lack of reliable knowledge about the COVID-19 landscape on psychiatric disorders, we intend to investigate coronavirus's possible effect on mental illnesses based on available literature. Because the majority of the psychological effects of the coronavirus can continue for a long period after the pandemic ends, our research can give insight into potential psychiatric sequels associated with COVID-19.

Human brain organoids to explore SARS-CoV-2-induced effects on the central nervous system.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In less than three years, an estimated 600 million infections with SARS-CoV-2 occurred worldwide, resulting in a pandemic with tremendous impact especially on economic and health sectors. Initially considered a respiratory disease, COVID-19, along with its long-term sequelae (long-COVID) rather is a systemic disease. Neurological symptoms like dementia or encephalopathy were reported early during the pandemic as concomitants of the acute phase and as characteristics of long-COVID. An excessive inflammatory immune response is hypothesized to play a major role in this context. However, direct infection of neural cells may also contribute to the neurological aspects of (long)-COVID-19. To mainly explore such direct effects of SARS-CoV-2 on the central nervous system, human brain organoids provide a useful platform. Infecting these three-dimensional tissue cultures allows the study of viral neurotropism as well as of virus-induced effects on single cells or even the complex cellular network within the organoid. In this review, we summarize the experimental studies that used SARS-CoV-2-infected human brain organoids to unravel the complex nature of (long)-COVID-19-related neurological manifestations.

Deconstructing the functional neuroanatomy of the choroid plexus: an ontogenetic perspective for studying neurodevelopmental and neuropsychiatric disorders.

The choroid plexus (CP) is a delicate and highly vascularized structure in the brain comprised of a dense network of fenestrated capillary loops that help in the synthesis, secretion and circulation of cerebrospinal fluid (CSF). This unique neuroanatomical structure is comprised of arachnoid villi stemming from frond-like surface projections-that protrude into the lumen of the four cerebral ventricles-providing a key source of nutrients to the brain parenchyma in addition to serving as a 'sink' for central nervous system metabolic waste. In fact, the functions of the CP are often described as being analogous to those of the liver and kidney. Beyond forming a barrier/interface between the blood and CSF compartments, the CP has been identified as a modulator of leukocyte trafficking, inflammation, cognition, circadian rhythm and the gut brain-axis. In recent years, advances in molecular biology techniques and neuroimaging along with the use of sophisticated animal models have played an integral role in shaping our understanding of how the CP-CSF system changes in relation to the maturation of neural circuits during critical periods of brain development. In this article we provide an ontogenetic perspective of the CP and review the experimental evidence implicating this structure in the pathophysiology of neurodevelopmental and neuropsychiatric disorders.

Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity and Interferon Pressure.

The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients' brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.

Do SARS-CoV-2 Variants Differ in Their Neuropathogenicity?

Neurological complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a huge societal problem. Although the neuropathogenicity of SARS-CoV-2 is not yet fully understood, there is evidence that SARS-CoV-2 can invade and infect cells of the central nervous system. Kong et al. (https://doi.org/10.1128/mbio.02308-22) shows that the mechanism of virus entry into astrocytes in brain organoids and primary astrocytes differs from entry into respiratory epithelial cells. However, how SARS-CoV-2 enters susceptible CNS cells and whether there are differences among SARS-CoV-2 variants is still unclear. In vivo and in vitro models are useful to study these important questions and may reveal important differences among SARS-CoV-2 variants in their neuroinvasive, neurotropic, and neurovirulent potential. In this commentary we address how this study contributes to the understanding of the neuropathology of SARS-CoV-2 and its variants.